Zidovudine, abacavir and lamivudine increase the radiosensitivity of human esophageal squamous cancer cell lines.

PubMed

Chen, Xuan; Wang, Cong; Guan, Shanghui; Liu, Yuan; Han, Lihui; Cheng, Yufeng

2016-07-01

Telomerase is a type of reverse transcriptase that is overexpressed in almost all human tumor cells, but not in normal tissues, which provides an opportunity for radiosensitization targeting telomerase. Zidovudine, abacavir and lamivudine are reverse transcriptase inhibitors that have been applied in clinical practice for several years. We sought to explore the radiosensitization effect of these three drugs on human esophageal cancer cell lines. Eca109 and Eca9706 cells were treated with zidovudine, abacavir and lamivudine for 48 h before irradiation was administered. Samples were collected 1 h after irradiation. Clonal efficiency assay was used to evaluate the effect of the combination of these drugs with radiation doses of 2, 4, 6 and 8 Gy. DNA damage was measured by comet assay. Telomerase activity (TA) and relative telomere length (TL) were detected and evaluated by real-time PCR. Apoptosis rates were assessed by flow cytometric analysis. The results showed that all the drugs tested sensitized the esophageal squamous cell carcinoma (ESCC) cell lines to radiation through an increase in radiation-induced DNA damage and cell apoptosis, deregulation of TA and decreasing the shortened TL caused by radiation. Each of the drugs investigated (zidovudine, abacavir and lamivudine) could be used for sensitizing human esophageal cancer cell lines to radiation. Consequently, the present study supports the potential of these three drugs as therapeutic agents for the radiosensitization of esophageal squamous cell cancer.

Calorimetric and spectroscopic studies of the interaction between zidovudine and human serum albumin

NASA Astrophysics Data System (ADS)

Pîrnău, Adrian; Mic, Mihaela; Neamţu, Silvia; Floare, Călin G.; Bogdan, Mircea

2018-02-01

A quantitative analysis of the interaction between zidovudine (AZT) and human serum albumin (HSA) was achieved using Isothermal titration calorimetry (ITC) in combination with fluorescence and 1H NMR spectroscopy. ITC directly measure the heat during a biomolecular binding event and gave us thermodynamic parameters and the characteristic association constant. By fluorescence quenching, the binding parameters of AZT-HSA interaction was determined and location to binding site I of HSA was confirmed. Via T1 NMR selective relaxation time measurements the drug-protein binding extent was evaluated as dissociation constants Kd and the involvement of azido moiety of zidovudine in molecular complex formation was put in evidence. All three methods indicated a very weak binding interaction. The association constant determined by ITC (3.58 × 102 M- 1) is supported by fluorescence quenching data (2.74 × 102 M- 1). The thermodynamic signature indicates that at least hydrophobic and electrostatic type interactions played a main role in the binding process.

A cost analysis of approved antiretroviral strategies in persons with advanced human immunodeficiency virus disease and zidovudine intolerance.

PubMed

Bozzette, S A; Parker, R; Hay, J

1994-04-01

Treatment with zidovudine has been standard therapy for patients with advanced HIV infection, but intolerance is common. Previously, management of intolerance has consisted of symptomatic therapy, dose interruption/discontinuation, and, when appropriate, transfusion. The availability of new antiretroviral agents such as didanosine as well as adjunctive recombinant hematopoietic growth factors makes additional strategies possible for the zidovudine-intolerant patient. Because all of these agents are costly, we evaluated the cost implications of these various strategies for the management of zidovudine-intolerant individuals within a population of persons with advanced HIV disease. We performed a decision analysis using iterative algorithmic models of 1 year of antiretroviral care under various strategies. The real costs providing antiretroviral therapy were estimated by deflating medical center charges by specific Medi-Cal (Medicaid) charge-to-payment ratios. Clinical data were extracted from the medical literature, product package inserts, investigator updates, and personal communications. Sensitivity analysis was used to test the effect of error in the estimation of parameters. The models predict that a strategy of dose interruption and transfusion for zidovudine intolerance will provide an average of 46 weeks of therapy per year to the average patient at a cost of $5,555/year of therapy provided (1991 U.S. dollars). The models predict that a strategy of adding hematopoietic growth factors to the regimen of appropriate patients would increase the average amount of therapy provided to the average patient by 3 weeks (6%) and the costs attributable to therapy by 77% to $9,805/year of therapy provided.(ABSTRACT TRUNCATED AT 250 WORDS)

Different degree of immune recovery using antiretroviral regimens with Vonavir or Zidovudine/Lamivudine and Efavirenz in Patients receiving first line treatment in Iran.

PubMed

Sadeghi, Leila; Moallemi, Samaneh; Tabatabai, Reza Adl; Esmaeilzadeh, Ali; Ahsani-Nasab, Sara; Ahmadi, Niloofar Eghbal; Bayanolhagh, Saeed; Lolaie, Mahin; Narouei, Arsalan; Alinaghi, Ahmad; Mohraz, Minoo

2018-01-07

The initial ART regimens used by most national treatment guidelines in resource-limited settings include 2 nucleoside reverse-transcriptase inhibitors (NRTIs) and 1 non-nucleoside reverse-transcriptase inhibitor (NNRTI). The NRTIshave consistedof Zidovudine (AZT) or Stavudine (d4T) with Lamivudine (3TC); the NNRTI component hasbeen Nevirapine (NVP) or Efavirenz (EFV). There exists few data indicating if Vonavir is more effective in increasing CD4+ T cell counts or other first-line drugs of ART.Immunological outcomes of 134 individuals who just started antiretroviral therapy with Vonavir or Zidovudine/Lamivudine and Efavirenzanalyzed. Immunological response was then assessed during 28 weeks and indicated significant CD4+ T cell increase in both groups. The increase in CD4+ T cell counts was greater in Zidovudine/Lamivudine and Efavirenz treated group. A rapid CD4+ T cell increase occurred after the first 12 weeks of therapy in Vonavir treated group with initial CD4+ T cell counts ≤100 despite the individuals with higher CD4+ T cell counts. As previous studies, we observed the noticeable increase rate of CD4+ Tcells is in the first three months of therapy. A rapid CD4+ Tcell increase occurred shortly after beginning anti retroviraltherapy using either Vonaviror Zidovudine/Lamivudine and Efavirenz. Late increases in CD4+ T cell counts are more pronounced in therapy using Zidovudine/Lamivudine and Efavirenz. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Foetal loss and enhanced fertility observed in mice treated with Zidovudine or Nevirapine.

PubMed

Onwuamah, Chika K; Ezechi, Oliver C; Herbertson, Ebiere C; Audu, Rosemary A; Ujah, Innocent A O; Odeigah, Peter G C

2014-01-01

Health concerns for HIV-infected persons on antiretroviral therapy (ART) have moved from morbidity to the challenges of long-term ART. We investigated the effect of Zidovudine or Nevirapine on reproductive capacity across two mouse generations. A prospective mouse study with drugs administered through one spermatogenic cycle. Mouse groups (16 males and 10 females) were given Zidovudine or Nevirapine for 56 days. Males were mated to untreated virgin females to determine dominant lethal effects. Twenty females (10 treated and 10 untreated) mated with the treated males per dose and gave birth to the F1 generation. Parental mice were withdrawn from drugs for one spermatogenic cycle and mated to the same dams to ascertain if effects are reversible. The F1 generation were exposed for another 56 days and mated to produce the F2 generation. Foetal loss was indicated in the dominant lethal assay as early as four weeks into drug administration to the males. At the first mating of the parental generation to produce the F1 generation, births from 10 dams/dose when the 'father-only' was exposed to Zidovudine (10, 100 and 250 mg/kg) was 3, 2 and 1 while it was 7, 1 and 4 respectively when 'both-parents' were exposed. Similarly births from the parental generation first mating when the 'father-only' was exposed to Nevirapine (5, 50 and 150 mg/kg) was 2, 2 and 0 while it was 6, 5 and 9 respectively when 'both-parents' were exposed. However, fertility was not significantly different neither by dose nor by the parental exposure. The F1 mice mated to produce the F2 generation recorded only one birth. The dominant lethal analysis showed foetal loss occurred when the "fathers-only" were treated while fertility was enhanced when "both-parents" were on therapy at the time of mating.

Abacavir, zidovudine, or stavudine as paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial.

PubMed

Mulenga, Veronica; Musiime, Victor; Kekitiinwa, Adeodata; Cook, Adrian D; Abongomera, George; Kenny, Julia; Chabala, Chisala; Mirembe, Grace; Asiimwe, Alice; Owen-Powell, Ellen; Burger, David; McIlleron, Helen; Klein, Nigel; Chintu, Chifumbe; Thomason, Margaret J; Kityo, Cissy; Walker, A Sarah; Gibb, Diana M

2016-02-01

WHO 2013 guidelines recommend universal treatment for HIV-infected children younger than 5 years. No paediatric trials have compared nucleoside reverse-transcriptase inhibitors (NRTIs) in first-line antiretroviral therapy (ART) in Africa, where most HIV-infected children live. We aimed to compare stavudine, zidovudine, or abacavir as dual or triple fixed-dose-combination paediatric tablets with lamivudine and nevirapine or efavirenz. In this open-label, parallel-group, randomised trial (CHAPAS-3), we enrolled children from one centre in Zambia and three in Uganda who were previously untreated (ART naive) or on stavudine for more than 2 years with viral load less than 50 copies per mL (ART experienced). Computer-generated randomisation tables were incorporated securely within the database. The primary endpoint was grade 2-4 clinical or grade 3/4 laboratory adverse events. Analysis was intention to treat. This trial is registered with the ISRCTN Registry number, 69078957. Between Nov 8, 2010, and Dec 28, 2011, 480 children were randomised: 156 to stavudine, 159 to zidovudine, and 165 to abacavir. After two were excluded due to randomisation error, 156 children were analysed in the stavudine group, 158 in the zidovudine group, and 164 in the abacavir group, and followed for median 2·3 years (5% lost to follow-up). 365 (76%) were ART naive (median age 2·6 years vs 6·2 years in ART experienced). 917 grade 2-4 clinical or grade 3/4 laboratory adverse events (835 clinical [634 grade 2]; 40 laboratory) occurred in 104 (67%) children on stavudine, 103 (65%) on zidovudine, and 105 (64%), on abacavir (p=0·63; zidovudine vs stavudine: hazard ratio [HR] 0·99 [95% CI 0·75-1·29]; abacavir vs stavudine: HR 0·88 [0·67-1·15]). At 48 weeks, 98 (85%), 81 (80%) and 95 (81%) ART-naive children in the stavudine, zidovudine, and abacavir groups, respectively, had viral load less than 400 copies per mL (p=0·58); most ART-experienced children maintained suppression (p=1·00). All

Abacavir, zidovudine, or stavudine as paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial

PubMed Central

Mulenga, Veronica; Musiime, Victor; Kekitiinwa, Adeodata; Cook, Adrian D; Abongomera, George; Kenny, Julia; Chabala, Chisala; Mirembe, Grace; Asiimwe, Alice; Owen-Powell, Ellen; Burger, David; McIlleron, Helen; Klein, Nigel; Chintu, Chifumbe; Thomason, Margaret J; Kityo, Cissy; Walker, A Sarah; Gibb, Diana M

2016-01-01

Summary Background WHO 2013 guidelines recommend universal treatment for HIV-infected children younger than 5 years. No paediatric trials have compared nucleoside reverse-transcriptase inhibitors (NRTIs) in first-line antiretroviral therapy (ART) in Africa, where most HIV-infected children live. We aimed to compare stavudine, zidovudine, or abacavir as dual or triple fixed-dose-combination paediatric tablets with lamivudine and nevirapine or efavirenz. Methods In this open-label, parallel-group, randomised trial (CHAPAS-3), we enrolled children from one centre in Zambia and three in Uganda who were previously untreated (ART naive) or on stavudine for more than 2 years with viral load less than 50 copies per mL (ART experienced). Computer-generated randomisation tables were incorporated securely within the database. The primary endpoint was grade 2–4 clinical or grade 3/4 laboratory adverse events. Analysis was intention to treat. This trial is registered with the ISRCTN Registry number, 69078957. Findings Between Nov 8, 2010, and Dec 28, 2011, 480 children were randomised: 156 to stavudine, 159 to zidovudine, and 165 to abacavir. After two were excluded due to randomisation error, 156 children were analysed in the stavudine group, 158 in the zidovudine group, and 164 in the abacavir group, and followed for median 2·3 years (5% lost to follow-up). 365 (76%) were ART naive (median age 2·6 years vs 6·2 years in ART experienced). 917 grade 2–4 clinical or grade 3/4 laboratory adverse events (835 clinical [634 grade 2]; 40 laboratory) occurred in 104 (67%) children on stavudine, 103 (65%) on zidovudine, and 105 (64%), on abacavir (p=0·63; zidovudine vs stavudine: hazard ratio [HR] 0·99 [95% CI 0·75–1·29]; abacavir vs stavudine: HR 0·88 [0·67–1·15]). At 48 weeks, 98 (85%), 81 (80%) and 95 (81%) ART-naive children in the stavudine, zidovudine, and abacavir groups, respectively, had viral load less than 400 copies per mL (p=0·58); most ART

Quasispecies dynamics and the emergence of drug resistance during zidovudine therapy of HIV infection.

PubMed

Frost, S D; McLean, A R

1994-03-01

To investigate the roles of mutation, competition and population dynamics in the emergence of drug resistant mutants during zidovudine therapy. A mathematical model of the population dynamics of the viral quasispecies during zidovudine therapy was investigated. The model was used to simulate changes in the numbers of uninfected and infected cells and the composition of the viral quasispecies in the years following initiation of therapy. Resulting scenarios in asymptomatic and AIDS patients were compared. The model was also used to investigate the efficacy of a treatment regimen involving alternating zidovudine and dideoxyinosine therapy. The behaviour of the model can be divided into three stages. Before therapy, mutation maintains a small pool of resistant mutants, outcompeted to very low levels by sensitive strains. When therapy begins there is a dramatic fall in the total viral load and resistant strains suddenly have the competitive advantage. Thus, it is resistant strains that infect the rising number of uninfected CD4+ cells. During this second stage the rapid effects of population dynamics swamp any effects of mutation between strains. When the populations of infected and uninfected cells approach their treatment equilibrium levels, mutation again becomes important in the slow generation of highly resistant strains. The short-term reduction in viral replication at the initiation of therapy generates a pool of uninfected cells which cause the eventual increase in viral burden. This increase is associated with (but not caused by) a rise in frequency of resistant strains which are at a competitive advantage in the presence of the drug. When therapy is ceased, reversion of resistance is slow as resistant strains are nearly as fit as sensitive strains in the absence of drug.

Maternal anaemia and duration of zidovudine in antiretroviral regimens for preventing mother-to-child transmission: a randomized trial in three African countries.

PubMed

Sartorius, Benn K D; Chersich, Matthew F; Mwaura, Mary; Meda, Nicolas; Temmerman, Marleen; Newell, Marie Louise; Farley, Timothy M M; Luchters, Stanley

2013-11-06

Although substantiated by little evidence, concerns about zidovudine-related anaemia in pregnancy have influenced antiretroviral (ARV) regimen choice for preventing mother-to-child transmission of HIV-1, especially in settings where anaemia is common. Eligible HIV-infected pregnant women in Burkina Faso, Kenya and South Africa were followed from 28 weeks of pregnancy until 12-24 months after delivery (n = 1070). Women with a CD4 count of 200-500 cells/mm(3) and gestational age 28-36 weeks were randomly assigned to zidovudine-containing triple-ARV prophylaxis continued during breastfeeding up to 6-months, or to zidovudine during pregnancy plus single-dose nevirapine (sd-NVP) at labour. Additionally, two cohorts were established, women with CD4 counts: <200 cells/mm(3) initiated antiretroviral therapy, and >500 cells/mm(3) received zidovudine during pregnancy plus sd-NVP at labour. Mild (haemoglobin 8.0-10.9 g/dl) and severe anaemia (haemoglobin < 8.0 g/dl) occurrence were assessed across study arms, using Kaplan-Meier and multivariable Cox proportional hazards models. At enrolment (corresponded to a median 32 weeks gestation), median haemoglobin was 10.3 g/dl (IQR = 9.2-11.1). Severe anaemia occurred subsequently in 194 (18.1%) women, mostly in those with low baseline haemoglobin, lowest socio-economic category, advanced HIV disease, prolonged breastfeeding (≥ 6 months) and shorter ARV exposure. Severe anaemia incidence was similar in the randomized arms (equivalence P-value = 0.32). After 1-2 months of ARV's, severe anaemia was significantly reduced in all groups, though remained highest in the low CD4 cohort. Severe anaemia occurs at a similar rate in women receiving longer triple zidovudine-containing regimens or shorter prophylaxis. Pregnant women with pre-existing anaemia and advanced HIV disease require close monitoring. ISRCTN71468401.

Maternal anaemia and duration of zidovudine in antiretroviral regimens for preventing mother-to-child transmission: a randomized trial in three African countries

PubMed Central

2013-01-01

Background Although substantiated by little evidence, concerns about zidovudine-related anaemia in pregnancy have influenced antiretroviral (ARV) regimen choice for preventing mother-to-child transmission of HIV-1, especially in settings where anaemia is common. Methods Eligible HIV-infected pregnant women in Burkina Faso, Kenya and South Africa were followed from 28 weeks of pregnancy until 12–24 months after delivery (n = 1070). Women with a CD4 count of 200-500cells/mm3 and gestational age 28–36 weeks were randomly assigned to zidovudine-containing triple-ARV prophylaxis continued during breastfeeding up to 6-months, or to zidovudine during pregnancy plus single-dose nevirapine (sd-NVP) at labour. Additionally, two cohorts were established, women with CD4 counts: <200 cells/mm3 initiated antiretroviral therapy, and >500 cells/mm3 received zidovudine during pregnancy plus sd-NVP at labour. Mild (haemoglobin 8.0-10.9 g/dl) and severe anaemia (haemoglobin < 8.0 g/dl) occurrence were assessed across study arms, using Kaplan-Meier and multivariable Cox proportional hazards models. Results At enrolment (corresponded to a median 32 weeks gestation), median haemoglobin was 10.3 g/dl (IQR = 9.2-11.1). Severe anaemia occurred subsequently in 194 (18.1%) women, mostly in those with low baseline haemoglobin, lowest socio-economic category, advanced HIV disease, prolonged breastfeeding (≥6 months) and shorter ARV exposure. Severe anaemia incidence was similar in the randomized arms (equivalence P-value = 0.32). After 1–2 months of ARV’s, severe anaemia was significantly reduced in all groups, though remained highest in the low CD4 cohort. Conclusions Severe anaemia occurs at a similar rate in women receiving longer triple zidovudine-containing regimens or shorter prophylaxis. Pregnant women with pre-existing anaemia and advanced HIV disease require close monitoring. Trial registration number ISRCTN71468401 PMID:24192332

Zidovudine (AZT) versus AZT plus didanosine (ddI) versus AZT plus zalcitabine (ddC) in HIV infected adults.

PubMed

Darbyshire, J; Foulkes, M; Peto, R; Duncan, W; Babiker, A; Collins, R; Hughes, M; Peto, T; Walker, A

2000-01-01

Zidovudine (AZT) monotherapy was the first antiretroviral drug to be tested widely. The next two drugs to be developed were didanosine (ddI) and zalcitabine (ddC). To assess the effects of zidovudine (AZT), zidovudine plus didanosine (ddI) and zidovudine plus zalcitabine (ddC) on HIV disease progression and survival. Investigators and pharmaceutical companies were contacted, and MEDLINE searches were supplemented by searching conference abstracts. Randomised controlled trials comparing any two of AZT plus ddI, AZT plus ddC or AZT alone in participants with or without AIDS which collected information on deaths and new AIDS events. Individual patient data with, wherever possible, follow-up obtained beyond that previously published were obtained and checked for internal consistency and consistency with any published reports; any apparent discrepancies were resolved with the trialists. Time to death and to disease progression (defined as a new AIDS-defining event or prior death) were analysed on an intention to treat basis, stratified to avoid direct comparisons between participants in different trials. Six trials were included in the meta-analysis. During a median follow-up of 29 months, 2904 individuals progressed, of whom 1850 died. The addition of ddI to AZT delayed both progression (RR 0.74; 95% CI 0.67 to 0.82, P<0.0001) and death (RR 0.72; 95% CI 0.64 to 0.82, P<0.0001). Likewise, the addition of ddC to AZT also delayed progression (RR 0. 86; 95% CI 0.78 to 0.94, P=0.001) and death (RR 0.87; 95% CI 0.77 to 0.98, P=0.02). After 3 years the estimated percentages alive and without a new AIDS event were 53% for AZT+ddI, 49% for AZT+ddC and 44% for AZT alone; the percentages alive were 68%, 63% and 59% respectively. Five of the six trials involved randomised comparisons of AZT+ddI versus AZT+ddC: in these, the AZT+ddI regimen had greater effects on disease progression (P=0.004) and death (P=0.009). The use of ddI and, to a lesser extent, ddC delayed both HIV disease

Comparative pharmacokinetics of two prodrugs of zidovudine in rabbits: enhanced levels of zidovudine in brain tissue.

PubMed

Lupia, R H; Ferencz, N; Lertora, J J; Aggarwal, S K; George, W J; Agrawal, K C

1993-04-01

The pharmacokinetics of two prodrugs of zidovudine (AZT), 1,4-dihydro-1-methyl-3-[(pyridylcarbonyl)oxy] ester and isoleucinyl ester (DPAZT and IAZT, respectively), were investigated in a rabbit model to determine their potential utility as drugs against human immunodeficiency virus. Drugs were administered by intravenous infusion over 5 min at doses equal to 10 mg of AZT per kg of body weight. The levels of the prodrugs and of released AZT in plasma, cerebrospinal fluid (CSF), and brain were determined by high-performance liquid chromatography analysis. DPAZT disappeared rapidly from plasma, whereas IAZT maintained a sustained level in plasma for up to 4 h. The levels in plasma of AZT released from DPAZT were consistently lower than the levels of AZT released from IAZT or AZT itself. At 75 min after infusion of AZT, DPAZT, and IAZT, the CSF plasma AZT ratios were 0.23, 0.30, and 0.25, while the brain/CSF AZT ratios were 0.32, 0.63, and 0.64, respectively. These results indicate that the administration of each of the prodrugs produced a higher concentration of AZT in the brain than did the direct administration of AZT. Both prodrugs therefore may be superior to AZT itself with respect to achieving anti-human immunodeficiency virus concentrations within the central nervous system.

Comparative pharmacokinetics of two prodrugs of zidovudine in rabbits: enhanced levels of zidovudine in brain tissue.

PubMed Central

Lupia, R H; Ferencz, N; Lertora, J J; Aggarwal, S K; George, W J; Agrawal, K C

1993-01-01

The pharmacokinetics of two prodrugs of zidovudine (AZT), 1,4-dihydro-1-methyl-3-[(pyridylcarbonyl)oxy] ester and isoleucinyl ester (DPAZT and IAZT, respectively), were investigated in a rabbit model to determine their potential utility as drugs against human immunodeficiency virus. Drugs were administered by intravenous infusion over 5 min at doses equal to 10 mg of AZT per kg of body weight. The levels of the prodrugs and of released AZT in plasma, cerebrospinal fluid (CSF), and brain were determined by high-performance liquid chromatography analysis. DPAZT disappeared rapidly from plasma, whereas IAZT maintained a sustained level in plasma for up to 4 h. The levels in plasma of AZT released from DPAZT were consistently lower than the levels of AZT released from IAZT or AZT itself. At 75 min after infusion of AZT, DPAZT, and IAZT, the CSF plasma AZT ratios were 0.23, 0.30, and 0.25, while the brain/CSF AZT ratios were 0.32, 0.63, and 0.64, respectively. These results indicate that the administration of each of the prodrugs produced a higher concentration of AZT in the brain than did the direct administration of AZT. Both prodrugs therefore may be superior to AZT itself with respect to achieving anti-human immunodeficiency virus concentrations within the central nervous system. PMID:8494380

Rapid accumulation of HIV-1 thymidine analogue mutations and phenotypic impact following prolonged viral failure on zidovudine-based first-line ART in sub-Saharan Africa.

PubMed

Goodall, Ruth L; Dunn, David T; Nkurunziza, Peter; Mugarura, Lincoln; Pattery, Theresa; Munderi, Paula; Kityo, Cissy; Gilks, Charles; Kaleebu, Pontiano; Pillay, Deenan; Gupta, Ravindra K

2017-05-01

Lack of viral load monitoring of ART is known to be associated with slower switch from a failing regimen and thereby higher prevalence of MDR HIV-1. Many countries have continued to use thymidine analogue drugs despite recommendations to use tenofovir in combination with a cytosine analogue and NNRTI as first-line ART. The effect of accumulated thymidine analogue mutations (TAMs) on phenotypic resistance over time has been poorly characterized in the African setting. A retrospective analysis of individuals with ongoing viral failure between weeks 48 and 96 in the NORA (Nevirapine OR Abacavir) study was conducted. We analysed 36 genotype pairs from weeks 48 and 96 of first-line ART (14 treated with zidovudine/lamivudine/nevirapine and 22 treated with zidovudine/lamivudine/abacavir). Phenotypic drug resistance was assessed using the Antivirogram assay (v. 2.5.01, Janssen Diagnostics). At 96 weeks, extensive TAMs (≥3 mutations) were present in 50% and 73% of nevirapine- and abacavir-treated patients, respectively. The mean (SE) number of TAMs accumulating between week 48 and week 96 was 1.50 (0.37) in nevirapine-treated participants and 1.82 (0.26) in abacavir-treated participants. Overall, zidovudine susceptibility of viruses was reduced between week 48 [geometric mean fold change (FC) 1.3] and week 96 (3.4, P  =   0.01). There was a small reduction in tenofovir susceptibility (FC 0.7 and 1.0, respectively, P  =   0.18). Ongoing viral failure with zidovudine-containing first-line ART is associated with rapidly increasing drug resistance that could be mitigated with effective viral load monitoring. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

Toward global standards for comparator pharmaceutical products: case studies of amoxicillin, metronidazole, and zidovudine in the Americas.

PubMed

Löbenberg, Raimar; Chacra, Nadia B; Stippler, Erika S; Shah, Vinod P; DeStefano, Anthony J; Hauck, Walter W; Williams, Roger L

2012-09-01

This study compared in vitro dissolution characteristics and other quality measures of different amoxicillin, metronidazole, and zidovudine products purchased in the Americas to a comparator pharmaceutical product (CPP). These three drugs are classified as Biopharmaceutics Classification System Class I drugs with the possibility that dissolution findings might be used to document bioequivalence. All investigated zidovudine products were found to be in vitro equivalent to the CPP. Only 3 of 12 tested amoxicillin products were found to be in vitro equivalent to the CPP. None of the tested metronidazole products were in vitro equivalent to the CPP. These findings suggest but do not confirm bioinequivalence where in vitro comparisons failed, given that an in vivo blood level study might have confirmed bioequivalence. At times, identifying a CPP in one of the selected markets proved difficult. The study demonstrates that products sold across national markets may not be bioequivalent. When coupled with the challenge of identifying a CPP in different countries, the results of this study suggest the value of an international CPP as well as increased use of BCS approaches as means of either documenting bioequivalence or signaling the need for further in vivo studies. Because of increased movement of medicines across national borders, practitioners and patients would benefit from these approaches.

Human immunodeficiency virus types 1 and 2 exhibit comparable sensitivities to Zidovudine and other nucleoside analog inhibitors in vitro.

PubMed

Smith, Robert A; Gottlieb, Geoffrey S; Anderson, Donovan J; Pyrak, Crystal L; Preston, Bradley D

2008-01-01

Using an indicator cell assay that directly quantifies viral replication, we show that human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2, respectively) exhibit similar sensitivities to 3'-azido-3'-deoxythymidine (zidovudine) as well as other nucleoside analog inhibitors of reverse transcriptase. These data support the use of nucleoside analogs for antiviral therapy of HIV-2 infection.

Safety and efficacy of ritonavir and saquinavir in combination with zidovudine and lamivudine.

PubMed

Michelet, C; Bellissant, E; Ruffault, A; Arvieux, C; Delfraissy, J F; Raffi, F; Bazin, C; Renard, I; Sébille, V; Chauvin, J P; Dohin, E; Cartier, F

1999-06-01

Ritonavir is a potent inhibitor of cytochrome P4503A4 that strongly increases saquinavir bioavailability. In this study we assessed the safety and antiretroviral efficacy of the combination of these two compounds in patients pretreated and receiving continued treatment with zidovudine and lamivudine who were protease inhibitor naive and who had a CD4 cell counts below 200/mm3. In this 48-week pilot study, all patients received 600 mg ritonavir and 400 mg saquinavir twice daily. Administration of zidovudine and lamivudine was continued without a change in previous doses. Viral load, CD4 cell count, and the emergence of resistance to the two protease inhibitors were evaluated repeatedly up to week 48. Sixteen patients were included in the study. Previous nucleoside analog treatment duration was 48+/-22 months (mean +/- SD). Two patients quit taking both protease inhibitors within 2 weeks. The ritonavir dose had to be reduced in 10 other patients because of side effects. Between inclusion and week 48, plasma viremia varied from 4.87+/-0.43 to 3.00+/-1.29 log10 copies/mL and CD4 cell counts ranged from 98+/-61 to 250+/-139/mm3. Ten patients (63%) had viral loads below 200 copies/mL and 7 (44%) had viral loads below 50 copies/mL. A single key mutation that conferred ritonavir resistance I84V and V82A/V developed in two patients. A mutation at codon 54 developed in another patient. These mutations were associated with repeated cessations of antiretroviral treatment. No lipodystrophy was observed. Ritonavir and saquinavir in combination are quite well tolerated and induce a high and sustained antiretroviral efficacy. A four-drug combination that includes these two protease inhibitors should be considered as a first line of treatment in patients with low CD4 cell counts.

Spectra resolution for simultaneous spectrophotometric determination of lamivudine and zidovudine components in pharmaceutical formulation of human immunodeficiency virus drug based on using continuous wavelet transform and derivative transform techniques.

PubMed

Sohrabi, Mahmoud Reza; Tayefeh Zarkesh, Mahshid

2014-05-01

In the present paper, two spectrophotometric methods based on signal processing are proposed for the simultaneous determination of two components of an anti-HIV drug called lamivudine (LMV) and zidovudine (ZDV). The proposed methods are applied to synthetic binary mixtures and commercial pharmaceutical tablets without the need for any chemical separation procedures. The developed methods are based on the application of Continuous Wavelet Transform (CWT) and Derivative Spectrophotometry (DS) combined with the zero cross point technique. The Daubechies (db5) wavelet family (242 nm) and Dmey wavelet family (236 nm) were found to give the best results under optimum conditions for simultaneous analysis of lamivudine and zidovudine, respectively. In addition, the first derivative absorption spectra were selected for the determination of lamivudine and zidovudine at 266 nm and 248 nm, respectively. Assaying various synthetic mixtures of the components validated the presented methods. Mean recovery values were found to be between 100.31% and 100.2% for CWT and 99.42% and 97.37% for DS, respectively for determination of LMV and ZDV. The results obtained from analyzing the real samples by the proposed methods were compared to the HPLC reference method. One-way ANOVA test at 95% confidence level was applied to the results. The statistical data from comparing the proposed methods with the reference method showed no significant differences. Copyright © 2014 Elsevier B.V. All rights reserved.

Common occurrence of anaemia at the end of pregnancy following exposure to zidovudine-free regimens.

PubMed

Pinnetti, Carmela; Baroncelli, Silvia; Molinari, Atim; Nardini, Giulia; Genovese, Orazio; Ricerca, Bianca Maria; Cavaliere, Anna Franca; Guaraldi, Giovanni; Antoni, Anna Degli; Tamburrini, Enrica; Floridia, Marco

2011-08-01

Although zidovudine-free regimens are increasingly used in pregnancy, their haematological effects in mothers and newborns are incompletely defined. The haematological profiles of 119 HIV-infected women and their neonates with highly active antiretroviral regimens (HAART) in pregnancy including or not zidovudine (ZDV) were investigated. Three groups were compared: 1) women who started ZDV-lamivudine (3TC)-based HAART during pregnancy (ZDVs, n = 60); 2) women on ZDV-3TC-based HAART from conception (ZDVc, n = 18); 3) women on ZDV-free HAART from conception (ZDVf, n = 41). At the beginning of pregnancy, haemoglobin levels were similar in the three groups. By week 36 compared to baseline, haemoglobin levels had a significantly greater decrease in ZDVf women compared to ZDVs women (ZDVf: -2.03 g/dl; ZDVs: -1.36 g/dl, p = 0.036). A similar trend was observed for occurrence of maternal anaemia at 36 weeks. Newborns with no prenatal ZDV exposure had significantly higher haemoglobin levels at birth (ZDVf: 16.1 ± 1.4 g/dl, ZDVs: 14.3 ± 2.0 g/dl; ZDVc: 14.6 ± 2.4 g/dl, p = 0.044 and 0.003, respectively). Half of ZDV-unexposed mothers had anaemia at the end of pregnancy, but their neonates had normal haemoglobin levels. ZDV initiation was associated with a lower occurrence of maternal anaemia during the third trimester and decreased haemoglobin levels in the newborns. We hypothesize that foetal iron requirements could represent a major determinant of maternal anaemia at the end of pregnancy. Copyright © 2011 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Compact quadruple therapy with the lamivudine/zidovudine combination tablet plus abacavir and efavirenz, followed by the lamivudine/zidovudine/abacavir triple nucleoside tablet plus efavirenz in treatment-naïve HIV-infected adults.

PubMed

Ruane, Peter J; Parenti, David M; Margolis, David M; Shepp, David H; Babinchak, Timothy J; Van Kempen, Amy S; Kauf, Teresa L; Danehower, Susan A; Yau, Linda; Hessenthaler, Siegrid M; Goodwin, Diane; Hernandez, Jaime E

2003-01-01

To assess efficacy, safety, and adherence with compact quadruple therapy comprising one lamivudine 150-mg/zidovudine 300-mg tablet (COM) twice daily + one abacavir (ABC) 300-mg tablet twice daily + three efavirenz (EFV) 200-mg capsules at bedtime for 24 weeks, followed by one lamivudine 150-mg/zidovudine 300-mg/ABC 300-mg triple nucleoside tablet (TZV) twice daily + three EFV 200-mg capsules at bedtime for 24 weeks. A pilot 48-week, prospective, open-label trial in which 38 antiretroviral-naïve HIV-infected adults (baseline median HIV-1 RNA 5.1 log(10) copies/mL, CD4+ cell count 285/microL) received the above treatment and were monitored regularly with respect to plasma HIV-1 RNA levels, CD4+ cell counts, T-cell receptor excision circles (TRECs), adherence, and adverse events. At Week 48, intent-to-treat, switch-included analysis showed plasma HIV-1 RNA levels <400 copies/mL in 100% (29/29) of patients and <50 copies/mL in 93% (27/29); 59% of patients who achieved <50 copies/mL had <3 copies/mL (16/27). Similar virologic suppression was observed in patients with baseline HIV-1 RNA above or below 100000 copies/mL. HIV-1 RNA and CD4+ cell counts changed from baseline by a median of -3.4 log(10) copies/mL and +172 cells/microL, respectively. One virologic failure occurred at Week 16. Median TRECs/100000 peripheral blood lymphocytes increased 6-fold between baseline and Week 48. Median adherence rates were consistently 100% by self-report and 94% by pill count. Grade 2-4 treatment-related adverse events included dreams (16%), nausea (13%), decreased white cells (8%), dizziness (8%), sleep disorders (8%), and malaise and fatigue (8%). A suspected ABC hypersensitivity reaction occurred in 8% (3/38) of patients. COM/ABC/EFV or TZV/EFV produced potent, durable virologic suppression and immunologic benefits, was associated with high adherence rates, and was generally well tolerated.

[Prevalence of transmission of zidovudine-resistant viruses in Switzerland. l'Etude suisse de cohorte VIH].

PubMed

Yerly, S; Rakik, A; Kinloch-de-Loes, S; Erb, P; Vernazza, P; Hirschel, B; Perrin, L

1996-10-26

Zidovudine (ZDV) was the most widely used anti-HIV drug between 1987 and 1995, and, as already reported, transmission of ZDV-resistant viruses occurs. Several mutations of the reverse transcriptase gene have been identified; one of them affects the 215 codon and is associated with a high degree of resistance. We have determined, using selective PCR, the prevalence of transmission of 215 mutant isolates in 134 patients with primary HIV infection (PHI) and have identified 8 patients with 215 mutant virus between 1989 and 1995 in Switzerland. Mutant resistant viruses have been isolated from patients treated with most antiviral drugs. A systematic search for mutant viruses may provide useful information for the adaptation of treatment strategies.

Investigating the dissolution profiles of amoxicillin, metronidazole, and zidovudine formulations used in Trinidad and Tobago, West Indies.

PubMed

Stuart, Arlene Villarroel; Zuo, Jieyu; Löbenberg, Raimar

2014-10-01

Trinidad and Tobago is a twin-island Republic in the Caribbean and like many developing countries, it has included generic drugs on the national drug formulary to decrease the financial burden of pharmaceutical medications. However, to ensure that medications received by patients are beneficial, generic drugs need to be interchangeable with the innovator which has demonstrated safety, efficacy, and quality. The objective of the study was to compare the dissolution profiles and weight variations for different formulations of amoxicillin, metronidazole, and zidovudine that are on the national drug formulary and marketed in Trinidad and Tobago. All the products investigated are categorized as class 1 drugs according to the Biopharmaceutics Classification System (BCS) and the dissolution profiles were assessed according to the World Health Organization (WHO) criteria for interchangeability between products. The similarity factor, f 2, was used to determine sameness between the products. No generic formulation was found to be similar to Amoxil® 500-mg capsules. The two generic products for metronidazole 200-mg tablets demonstrated more than 85% drug release within 15 min in all three of the buffers; however, their 400-mg counterparts did not fulfill this requirement. The zidovudine 300-mg tablet complied with the requirements in buffer pH 4.5 and simulated gastric fluid (SGF) but not for simulated intestinal fluid (SIF). Some Class 1 pharmaceutical formulations may possess the same active ingredient and amount of drug but may show significant differences to in vitro equivalence requirements. Nevertheless, the dissolution process is suitable to detect these variations.

Phase I study of 2'-3'-dideoxyinosine administered orally twice daily to patients with AIDS or AIDS-related complex and hematologic intolerance to zidovudine.

PubMed

Connolly, K J; Allan, J D; Fitch, H; Jackson-Pope, L; McLaren, C; Canetta, R; Groopman, J E

1991-11-01

To evaluate the safety and hematologic tolerance of 2'-3'-dideoxyinosine (didanosine, ddI) in subjects with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex and prior hematologic intolerance to zidovudine. A Phase I trial with two dose groups at a single-center, university-affiliated hospital ambulatory care center. Of 30 subjects enrolled, 21 had AIDS and nine had AIDS-related complex. All had CD4 lymphocyte counts less than 0.2 x 10(9)/L at entry. Didanosine was administered orally twice daily at a total daily dose of 750 mg or 1,500 mg for 12 weeks. Subjects who completed the 12-week study continued to receive ddI at the lower dose. All subjects were monitored for toxicity. Virologic and immunologic response markers were also measured. For the group as a whole, there was no significant decrease in mean hemoglobin level or leukocyte or platelet counts. The dose-limiting toxicity was peripheral neuropathy. Other significant toxicities included pancreatitis and hypocalcemia. Uric acid elevations were common but were without clinical consequence. A sustained decrease in serum p24 antigen of at least 50% was noted in 42% of subjects who were p24 antigen-positive at entry. The mean CD4 lymphocyte count showed an initial increase that was not sustained over the 12-week study. All subjects remained anergic to skin testing. Didanosine is well tolerated hematologically in some patients with prior significant hematologic intolerance to zidovudine. The toxicity profile for ddI differs from that of zidovudine and includes peripheral neuropathy and pancreatitis. Changes in CD4 lymphocyte number and HIV p24 antigen levels in some patients suggest antiviral activity of ddI in this population.

Fourier transform infrared spectra and normal mode analysis of drug molecules: Zidovudine

NASA Astrophysics Data System (ADS)

Jain, Nivedita; Prabhakar, Santosh; Singh, R. A.

2013-03-01

The FTIR spectra of zidovudine molecule have been recorded in the range 4000-400 cm-1. The title compound is used as a drug against AIDS or HIV. The molecular structure, fundamental vibrational frequencies and intensities of vibrational bands are evaluated using density functional theory (DFT) using BLYP, B3LYP, B3PW91 and MPW1PW91 methods with 6-31+G(d,p) standard basis set. Comparison of simulated spectra with the experimental spectrum provides important informations and the ability of the computational method to describe the vibrational modes. These calculations have allowed finding most stable conformational structure of AZT. Calculated results of the title compound indicate that the drug molecule has syn orientation. The glycosidic bond in AZT and a minimum-energy structure in which the glycosy torsion angle χ and torsion angle γ values are consistent with those in the conformation of AZT in the AZT5-triphosphate bound to HIV RT is determined.

Switching to lopinavir/ritonavir with or without abacavir/lamivudine in lipoatrophic patients treated with zidovudine/abacavir/lamivudine.

PubMed

Bernardino, J I; Pulido, F; Martinez, E; Arrizabalaga, J; Domingo, P; Portilla, J; Ocampo, A; Muñoz, J; Torres, R; Arribas, J R

2013-06-01

Discontinuation of thymidine nucleoside reverse transcriptase inhibitors (tNRTIs) is the only proven strategy for improving lipoatrophy. It is unclear whether switching to NRTI-sparing or to non-thymidine NRTI-containing therapy has differential effects on body fat recovery. This was a 96 week, open-label, randomized study in suppressed patients with moderate/severe lipoatrophy and no prior virological failure while receiving a protease inhibitor and who had their triple NRTI regimen (zidovudine/lamivudine/abacavir) switched to lopinavir/ritonavir plus abacavir/lamivudine for a 1 month run-in period and then randomized to lopinavir/ritonavir plus abacavir/lamivudine versus lopinavir/ritonavir monotherapy. The KRETA trial is registered with ClinicalTrials.gov (number NCT00865007). Of 95 patients included, 88 were randomized to lopinavir/ritonavir plus abacavir/lamivudine (n = 44) or lopinavir/ritonavir monotherapy (n = 44). Median (IQR) baseline limb fat was 2.5 (1.6-3.7) kg in the lopinavir/ritonavir plus abacavir/lamivudine group and 2.5 (2.0-5.4) kg in the lopinavir/ritonavir monotherapy group. Six patients in the triple therapy group and 13 in the monotherapy group had discontinued study drugs by week 96. Although there were limb fat gains in each group at weeks 48/96 (+324/+358 g in lopinavir/ritonavir plus abacavir/lamivudine, P = 0.09/0.07, versus +215/+416 g in the lopinavir/ritonavir monotherapy group, P = 0.28/0.16), differences between groups were not significant [difference +109 g (95% CI -442, +660)/-57 g (95% CI -740, +625)]. In lipoatrophic patients treated with zidovudine/lamivudine/abacavir, switching to lopinavir/ritonavir monotherapy had no additional benefit in limb fat recovery relative to switching to lopinavir/ritonavir with abacavir/lamivudine. These data suggest that non-thymidine nucleosides such as abacavir/lamivudine are not an obstacle to limb fat recovery.

Formulation and optimization of coated PLGA – Zidovudine nanoparticles using factorial design and in vitro in vivo evaluations to determine brain targeting efficiency

PubMed Central

Peter Christoper, G.V.; Vijaya Raghavan, C.; Siddharth, K.; Siva Selva Kumar, M.; Hari Prasad, R.

2013-01-01

In the current study zidovudine loaded PLGA nanoparticles were prepared, coated and further investigated for its effectiveness in brain targeting. IR and DSC studies were performed to determine the interaction between excipients used and to find out the nature of drug in the formulation. Formulations were prepared by adopting 23 factorial designs to evaluate the effects of process and formulation variables. The prepared formulations were subjected for in vitro and in vivo evaluations. In vitro evaluations showed particle size below 100 nm, entrapment efficiency of formulations ranges of 28–57%, process yield of 60–76% was achieved and drug release for the formulations were in the range of 50–85%. The drug release from the formulations was found to follow Higuchi release pattern, n–value obtained after Korsemeyer plot was in the range of 0.56–0.78. In vivo evaluations were performed in mice after intraperitoneal administration of zidovudine drug solution, uncoated and coated formulation. Formulation when coated with Tween 80 achieved a higher concentration in the brain than that of the drug in solution and of the uncoated formulation. Stability studies indicated that there was no degradation of the drug in the formulation after 90 days of preparation when stored in refrigerated condition. PMID:24648825

Investigation of the Role of Breast Cancer Resistance Protein (Bcrp/Abcg2) on Pharmacokinetics and Central Nervous System Penetration of Abacavir and Zidovudine in the Mouse

PubMed Central

Giri, Nagdeep; Shaik, Naveed; Pan, Guoyu; Terasaki, Tetsuya; Mukai, Chisato; Kitagaki, Shinji; Miyakoshi, Naoki; Elmquist, William F.

2016-01-01

Many anti-human immunodeficiency virus 1 nucleoside reverse-transcriptase inhibitors have low central nervous system (CNS) distribution due in part to active efflux transport at the blood-brain barrier. We have previously shown that zidovudine (AZT) and abacavir (ABC) are in vitro substrates for the efflux transport protein breast cancer resistance protein (Bcrp) 1. We evaluated the influence of Bcrp1 on plasma pharmacokinetics and brain penetration of zidovudine and abacavir in wild-type and Bcrp1-deficient (Bcrp1−/−) FVB mice. There was no difference in either area under the concentration-time profiles for plasma (AUCplasma) or brain (AUCbrain) for zidovudine between the wild-type and Bcrp1−/− mice. The AUCplasma of abacavir was 20% lower in the Bcrp1−/− mice, whereas the AUCbrain was 20% greater. This difference resulted in a 1.5-fold increase in abacavir brain exposure in the Bcrp1−/− mice. The effect of selective and nonselective transport inhibitors on the ABC brain/plasma ratio at a single time point was evaluated. 3-(6-Isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indol-3-yl)-propionicacid tert-butyl ester (Ko143), N[4[2-(6, 7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]-5-methoxy-9-oxo-10H-acridine-4-carboxamide (GF120918), probenecid, and Pluronic P85 increased abacavir plasma concentrations in the wild-type mice. Abacavir plasma concentrations in Bcrp1−/− mice were increased by (R)-4-((1aR,6R,10bS)-1,2-difluoro-1,1a,6,10b-tetrahydrodibenzo(a,e)cyclopropa(c)cycloheptan-6-yl)-α-((5-quinoloyloxy)methyl)-1-piperazineethanol trihydrochloride (LY335979), GF120918, and probenecid, but not by Ko143. Brain/plasma concentration ratios in both the wild-type and Bcrp1−/− mice were increased by the P-glycoprotein inhibitors LY335979 and GF120918, but not by BCRP-selective inhibitors. These data indicate that deletion of Bcrp1 has little influence on the pharmacokinetics or brain

Evaluation of Microemulsion and Lamellar Liquid Crystalline Systems for Transdermal Zidovudine Delivery.

PubMed

Carvalho, André Luis Menezes; Silva, José Alexsandro da; Lira, Ana Amélia Moreira; Conceição, Tamara Matos Freire; Nunes, Rogéria de Souza; de Albuquerque Junior, Ricardo Luiz Cavalcanti; Sarmento, Victor Hugo Vitorino; Leal, Leila Bastos; de Santana, Davi Pereira

2016-07-01

This study proposed to investigate and to compare colloidal carrier systems containing Zidovudine (3'-azido-3'-deoxythymidine) (AZT) for transdermal administration and optimization of antiretroviral therapy. Microemulsion (ME) and lamellar phase (LP) liquid crystal were obtained and selected from pseudoternary diagrams previously developed. Small-angle X-ray scattering and rheology analysis confirmed the presence of typical ME and liquid crystalline structures with lamellar arrangement, respectively. Both colloidal carrier systems, ME, and LP remained stable, homogeneous, and isotropic after AZT addition. In vitro permeation study (using pig ear skin) showed that the amount of permeated drug was higher for ME compared to the control and LP, obtaining a permeation enhancing effect on the order of approximately 2-fold (p < 0.05). Microscopic examination after in vivo skin irritation studies using mice suggested few histological changes in the skin of animals treated with the ME compared to the control group (hydrogel). Thus, ME proved to be adequate and have promising effects, being able to promote the drug permeation without causing apparent skin irritation. On the order hand, LP functioned as a drug reservoir reducing AZT partitioning into the skin. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Nevirapine-Resistant HIV-1 DNA in Breast Milk After Single-Dose Nevirapine With or Without Zidovudine for Prevention of Mother-to-Child Transmission.

PubMed

Gantt, Soren; Payant, Rachel; Carlsson, Jacquelyn; Micek, Mark A; Blanco, Ana Judith; Beck, Ingrid A; Matunha, Laurinda; Montoya, Pablo; Matediana, Eduardo; Gloyd, Stephen; Frenkel, Lisa M

2012-09-01

Among 30 human immunodeficiency virus type 1 (HIV-1)-infected women who received single-dose nevirapine (NVP), 17 (57%) had NVP-resistant HIV-1 detected in breast milk. NVP resistance in breast milk persisted for at least 8 months postpartum and was apparently transmitted to at least 1 infant. NVP resistance was detected less often in women who also received zidovudine. © The Author 2012. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Zidovudine adherence in persons with AIDS. The relation of patient beliefs about medication to self-termination of therapy.

PubMed

Smith, M Y; Rapkin, B D; Morrison, A; Kammerman, S

1997-04-01

To examine the relation of patient beliefs about medication usage and adherence to zidovudine (ZDV) therapy in persons with AIDS. Face-to-face interviews were used to determine attitudes of persons with AIDS toward ZDV and other prescribed medications, history of ZDV usage, and sociodemographics. A public hospital infectious disease clinic, an AIDS day care program, and an inpatient unit in a voluntary hospital where care was provided cooperatively by staff and an informal-care partner. One hundred forty-one people with the acquired immunodeficiency syndrome agreed to be reinterviewed as part of a longitudinal, New York City-based study examining outcomes related to quality of life. Initial recruitment procedures were to approach all active AIDS patients at each of the three sites between January and July of 1992: reinterviews, which were conducted an average of 6 months later, occurred from mid-1992 through May of 1993. The Zidovudine Drug Attitude Inventory was used to assess subjective feelings and attitudes concerning ZDV and prescribed medications in general. Respondents were grouped into five categories on the basis of their ZDV usage history: (1) "short-term" users (i.e., those who had been taking ZDV for 25 months or less); (2) "long-term" users (i.e., those who had been taking ZDV for more than 25 months); (3) self-terminated users; (4) doctor-terminated users; and (5) never users. Long-term users were likely to view ZDV as an illness prophylactic. In contrast, self-terminated users and never users were most likely to believe that ZDV caused adverse side effects and that medicine need not be taken as prescribed. Patients' beliefs about ZDV were significantly associated with adherence-related behavior. In particular, those who had self-terminated ZDV treatment believed that taking the drug was harmful, were skeptical of its ability to prevent illness, and felt that physician's directives about medication usage in general could be disregarded. These findings

In vitro dissolution of generic immediate-release solid oral dosage forms containing BCS class I drugs: comparative assessment of metronidazole, zidovudine, and amoxicillin versus relevant comparator pharmaceutical products in South Africa and India.

PubMed

Reddy, Nallagundla H S; Patnala, Srinivas; Löbenberg, Raimar; Kanfer, Isadore

2014-10-01

Biowaivers are recommended for immediate-release solid oral dosage forms using dissolution testing as a surrogate for in vivo bioequivalence studies. Several guidance are currently available (the World Health Organization (WHO), the US FDA, and the EMEA) where the conditions are described. In this study, definitions, criteria, and methodologies according to the WHO have been applied. The dissolution performances of immediate-release metronidazole, zidovudine, and amoxicillin products purchased in South African and Indian markets were compared to the relevant comparator pharmaceutical product (CPP)/reference product. The dissolution performances were studied using US Pharmacopeia (USP) apparatus 2 (paddle) set at 75 rpm in each of three dissolution media (pH1.2, 4.5, and 6.8). Concentrations of metronidazole, zidovudine, and amoxicillin in each dissolution media were determined by HPLC. Of the 11 metronidazole products tested, only 8 could be considered as very rapidly dissolving products as defined by the WHO, whereas 2 of those products could be considered as rapidly dissolving products but did not comply with the f 2 acceptance criteria in pH 6.8. All 11 zidovudine products were very rapidly dissolving, whereas in the case of the 14 amoxicillin products tested, none of those products met any of the WHO criteria. This study indicates that not all generic products containing the same biopharmaceutics classification system (BCS) I drug and in similar strength and dosage form are necessarily in vitro equivalent. Hence, there is a need for ongoing market surveillance to determine whether marketed generic products containing BCS I drugs meet the release requirements to confirm their in vitro bioequivalence to the respective reference product.

Dideoxynucleoside resistance emerges with prolonged zidovudine monotherapy. The RV43 Study Group.

PubMed Central

Mayers, D L; Japour, A J; Arduino, J M; Hammer, S M; Reichman, R; Wagner, K F; Chung, R; Lane, J; Crumpacker, C S; McLeod, G X

1994-01-01

Human immunodeficiency virus type 1 (HIV-1) isolates resistant to zidovudine (ZDV) have previously been demonstrated to exhibit in vitro cross-resistance to other similar dideoxynucleoside agents which contain a 3'-azido group. However, cross-resistance to didanosine (ddI) or dideoxycytidine (ddC) has been less well documented. ZDV, ddI, and ddC susceptibility data have been collected from clinical HIV-1 isolates obtained by five clinical centers and their respective retrovirology laboratories. All subjects were treated only with ZDV. Clinical HIV-1 isolates were isolated, amplified, and assayed for drug susceptibility in standardized cultures of phytohemagglutinin-stimulated donor peripheral blood mononuclear cells obtained from healthy seronegative donors. All five cohorts showed a correlation between decreased in vitro susceptibility to ZDV and decreased susceptibility to ddI and ddC. For each 10-fold decrease in ZDV susceptibility, an average corresponding decrease of 2.2-fold in ddI susceptibility was observed (129 isolates studied; P < 0.001, Fisher's test of combined significance). Similarly, susceptibility to ddC decreased 2.0-fold for each 10-fold decrease in ZDV susceptibility (82 isolates studied; P < 0.001, Fisher's test of combined significance). These data indicate that a correlation exists between HIV-1 susceptibilities to ZDV and ddI or ddC for clinical HIV-1 isolates. PMID:8192457

Placental Transport of Zidovudine in the Rhesus Monkey

PubMed Central

King, Thomas S.; Henderson, George I.; Schenker, Steven; Schenken, Robert S.

1993-01-01

Objective: This study was undertaken to characterize the pharmacokinetics of zidovudine (ZDV) and ZDV-glucuronide (ZDVG) in the material and :fetal circulations of the rhesus monkey. Methods: Cannulas were placed in the maternal external jugular and the fetal internal jugular and carotid artery in 8 pregnant monkeys at .120–130 days gestation. ZDV (3.5 mg/kg) was administered to 5 monkeys and ZDVG (3.5 mg/kg) to 3 monkeys as single intravenous bolus infusions through the maternal catheter. Maternal and fetal blood , samples were collected every 20 min for the first 2 h and then every hour for the next 4 h. Maternal and fetal concentrations of ZDV and ZDVG were determined using high, performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Results: In monkeys who received ZDV, the terminal half-life (T1/2) for ZDV was 37±15 and 33 ± 13 min in the maternal and fetal compartments, respectively. The apparent T1/2 for maternal ZDVG was 124 ± 44 and 142 ± 50 min in the maternal and fetal compartments, respectively. Peak levels of ZDV and ZDVG in the fetal compartment were reached 40 min after injection. The mean fetal/maternal concentration ratios for ZDV and ZDVG ranged from 0.20 ± 0.20 at 20 min to a maximum of 0.74 ± 1.0 at 120 min and from 0.28 ± 0.08 at 20 min to 1.4 ± 1.3 at 180 min, respectively. In monkeys who received ZDVG, the T1/2 for ZDWG in the maternal and fetal compartments was 47 ± 26 and 119 ± 164 min, respectively. ZDVG reached its peak in the fetal compartment at 60 min post-injection. The fetal/maternal rafio ranged from 0.08 ± 0.11 at 20 min to 4.2 ± 4.2 at 180 min post-injection. Conclusions: These data demonstrate that 1) ZDV and ZDVG rapidly cross the placenta to the fetal compartment, 2) ZDV crosses more rapidly than ZDVG, and 3) some metabolism of ZDV to ZDVG occurs in the fetal compartment. PMID:18475334

Comparative Application of PLS and PCR Methods to Simultaneous Quantitative Estimation and Simultaneous Dissolution Test of Zidovudine - Lamivudine Tablets.

PubMed

Üstündağ, Özgür; Dinç, Erdal; Özdemir, Nurten; Tilkan, M Günseli

2015-01-01

In the development strategies of new drug products and generic drug products, the simultaneous in-vitro dissolution behavior of oral dosage formulations is the most important indication for the quantitative estimation of efficiency and biopharmaceutical characteristics of drug substances. This is to force the related field's scientists to improve very powerful analytical methods to get more reliable, precise and accurate results in the quantitative analysis and dissolution testing of drug formulations. In this context, two new chemometric tools, partial least squares (PLS) and principal component regression (PCR) were improved for the simultaneous quantitative estimation and dissolution testing of zidovudine (ZID) and lamivudine (LAM) in a tablet dosage form. The results obtained in this study strongly encourage us to use them for the quality control, the routine analysis and the dissolution test of the marketing tablets containing ZID and LAM drugs.

Vitamin C prevents zidovudine-induced NAD(P)H oxidase activation and hypertension in the rat.

PubMed

Papparella, Italia; Ceolotto, Giulio; Berto, Laura; Cavalli, Maurizio; Bova, Sergio; Cargnelli, Gabriella; Ruga, Ezia; Milanesi, Ornella; Franco, Lorenzo; Mazzoni, Martina; Petrelli, Lucia; Nussdorfer, Gastone G; Semplicini, Andrea

2007-01-15

Cardiovascular risk is increased among HIV-infected patients receiving antiretroviral therapy due to the development of hypertension and metabolic abnormalities. In this study, we investigated the effects of long-term treatment with zidovudine (AZT) and vitamin C, alone and in combination, on blood pressure and on the chain of events linking oxidative stress to cardiac damage in the rat. Six adult Wistar Kyoto rats received AZT (1 mg/ml) in the drinking water for 8 months, six vitamin C (10 g/kg of food) and AZT, six vitamin C alone, and six served as controls. AZT increased systolic blood pressure, expression of gp91(phox) and p47(phox) subunits of NAD(P)H oxidase, and protein kinase C (PKC) delta activation and reduced antioxidant power of plasma and cardiac homogenates. AZT also caused morphological alterations in cardiac myocyte mitochondria, indicative of functional damage. All of these effects were prevented by vitamin C. Chronic AZT administration increases blood pressure and promotes cardiovascular damage through a NAD(P)H oxidase-dependent mechanism that involves PKC delta. Vitamin C antagonizes these adverse effects of AZT in the cardiovascular system.

Zidovudine for the prevention of vertical HIV transmission: a decision analytic approach.

PubMed

Rouse, D J; Owen, J; Goldenberg, R L; Vermund, S H

1995-08-01

The purpose of this study was to quantify the benefits of maternal-neonatal zidovudine (ZDV) administration for the prevention of vertical human immunodeficiency virus (HIV) transmission against the potential risks of drug-induced complications in uninfected children. A decision analysis model was created with use of a Markov cohort simulation, for evaluating both survival and quality of life for two hypothetical cohorts of HIV-exposed neonates: one with in utero and neonatal exposure to preventive ZDV therapy and the other not exposed. The model included the probability of congenital HIV infection with and without ZDV treatment (estimates derived from AIDS Clinical Trials Group study 076), the yearly probability of death with and without congenital HIV infection, a range of probabilities of adverse effects from ZDV use, and a range of ages in life when any adverse effect would manifest. In a series of scenarios, the impact of different estimates for the quality-of-life decrement from any adverse ZDV effect in HIV-uninfected children was assessed, and threshold values for this estimate were established, i.e., critical values below which withholding ZDV would be the preferred choice. Across a wide range of estimates for multiple contingencies, ZDV use was associated with a greater number of quality-adjusted life years than was non-use. Only in implausible, pessimistic scenarios (i.e., a high incidence of profound adverse effects beginning early in life) would withholding ZDV be the rational choice for an asymptomatic HIV-infected pregnant woman.(ABSTRACT TRUNCATED AT 250 WORDS)

Naringin improves zidovudine- and stavudine-induced skeletal muscle complications in rats.

PubMed

Adebiyi, O O; Adebiyi, O A; Owira, Pmo

2016-03-22

Chronic use of nucleoside reverse transcriptase inhibitors (NRTIs) in managing human immunodeficiency virus (HIV) infection has been associated with several complications. Available management options for these complications have yielded controversial results, thus the need to urgently find newer alternatives. Naringin, a plant-derived flavonoid, has been shown to possess antioxidant and antiapoptotic properties which can be exploited in managing NRTI-induced complications. This study therefore investigated the effects of naringin on some NRTI-induced complications. Forty-nine rats (200-250 g) were divided into seven groups and were orally treated with stavudine (d4T)-only, d4T + naringin, d4T + vitamin E, zidovudine (AZT)-only, AZT + naringin, AZT + vitamin E, and distilled water, respectively. Drugs were administered once daily for 56 days, and oral glucose tolerance tests conducted on day 54 of the experiments and rats were thereafter sacrificed on day 56 by halothane overdose. Plasma samples and the left gastrocnemius muscles were stored at -80°C for further analysis. There was significant glucose intolerance, insulin resistance, oxidative stress, and apoptosis in the skeletal muscles of AZT- or d4T-only-treated rats. Naringin, however, significantly reduced fasting blood glucose and fasting plasma insulin concentrations, mitigated glucose intolerance, and insulin resistance in addition to reducing malondialdehyde and carbonyl protein concentrations when coadministered with either NRTIs. Furthermore, naringin improved antioxidant enzyme activities, reduced skeletal muscle BCL-2-associated X protein expression, and improved B-cell lymphoma-2 protein expression compared to AZT- or d4T-only-treated rats. Naringin ameliorated AZT- and d4T-induced complications and therefore should be further investigated as a possible nutritional supplement in managing HIV infection. © The Author(s) 2016.

Meta-analysis of two randomized controlled trials comparing combined zidovudine and didanosine therapy with combined zidovudine, didanosine, and nevirapine therapy in patients with HIV. INCAS study team.

PubMed

Raboud, J M; Rae, S; Vella, S; Harrigan, P R; Bucciardini, R; Fragola, V; Ricciardulli, D; Montaner, J S

1999-11-01

To extend the range of CD4 counts in which a plasma viral load nadir (pVL) <20 copies/ml was known to be predictive of the duration of virologic response. To determine whether baseline pVL is predictive of virologic response during the study periods. A meta-analysis was conducted of the original individual patient data from two randomized controlled trials comparing zidovudine (ZDV)/didanosine (ddI) with ZDV/ddI/nevirapine (NVP). In total, 87 patients received ZDV/ddI and 83 received ZDV/ddI/NVP. Study subjects on triple therapy with baseline pVL <100,000 copies/ml were more likely to achieve a pVL <400 copies/ml (odds ratio [OR] = 2.49; p = .02) and <20 copies/ml (OR = 4.76; p = .001) during the trial than those with baseline pVL > 100,000 copies/ml. Among triple therapy patients, the relative risk of virologic failure was higher for patients with higher baseline pVL (rate ratio [RR] = 2.51/log10 copies/ ml; p = .01), after controlling for compliance and pVL nadir. The relative risks of virologic failure associated with pVL nadir <20 copies/ml and between 21 and 400 copies/ml were .04 (p = .0001) and .56 (p = .26), respectively, compared with patients with a pVL nadir >400 copies/ml. We have extended our earlier results that achieving a pVL nadir <20 copies/ml is important for maintaining virologic suppression. In particular, we have demonstrated that a pVL nadir <20 copies/ml is at least fivefold more protective against virologic failure than achieving a pVL nadir between 20 and 400 copies/ml. Baseline pVL is significantly associated with the probability of achieving and sustaining virologic suppression.

Expression profiles of adult T-cell leukemia–lymphoma and associations with clinical responses to zidovudine and interferon α

PubMed Central

ALIZADEH, ASH A.; BOHEN, SEAN P.; LOSSOS, CHEN; MARTINEZ-CLIMENT, JOSE A.; RAMOS, JUAN CARLOS; CUBEDO-GIL, ELENA; HARRINGTON, WILLIAM J.; LOSSOS, IZIDORE S.

2014-01-01

Adult T-cell leukemia–lymphoma (ATLL) is an HTLV-1-associated lymphoproliferative malignancy that is frequently fatal. We compared gene expression profiles (GEPs) of leukemic specimens from nine patients with ATLL at the time of diagnosis and immediately after combination therapy with zidovudine (AZT) and interferon α (IFNα). GEPs were also related to genetic aberrations determined by comparative genomic hybridization. We identified several genes anomalously over-expressed in the ATLL leukemic cells at the mRNA level, including LYN, CSPG2, and LMO2, and confirmed LMO2 expression in ATLL cells at the protein level. In vivo AZT–IFNα therapy evoked a marked induction of interferon-induced genes accompanied by repression of cell-cycle regulated genes, including those encoding ribosomal proteins. Remarkably, patients not responding to AZT–IFNα differed most from responding patients in lower expression of these same IFN-responsive genes, as well as components of the antigen processing and presentation apparatus. Demonstration of specific gene expression signatures associated with response to AZT–IFNα therapy may provide novel insights into the mechanisms of action in ATLL. PMID:20370541

Biphasic Elimination of Tenofovir Diphosphate and Nonlinear Pharmacokinetics of Zidovudine Triphosphate in a Microdosing Study

PubMed Central

Chen, Jianmeng; Flexner, Charles; Liberman, Rosa G.; Skipper, Paul L.; Louissaint, Nicolette; Tannenbaum, Steven R.; Hendrix, Craig; Fuchs, Edward

2012-01-01

Objective Phase 0 studies can provide initial pharmacokinetics (PK) data in humans and help to facilitate early drug development, but their predictive value for standard dosing is controversial. To evaluate the prediction of microdosing for active intracellular drug metabolites, we compared the PK profile of two antiretroviral drugs, zidovudine (ZDV) and tenofovir (TFV), in microdose and standard dosing regimens. Study Design We administered a microdose (100 μg) of 14C-labeled drug (ZDV or tenofovir disoproxil fumarate (TDF)) with or without a standard unlabelled dose (300 mg) to healthy volunteers. Both the parent drug in plasma and the active metabolite, ZDV-triphosphate (ZDV-TP) or TFV-diphosphate (TFV-DP) in PBMCs and CD4+ cells were measured by AMS. Results The intracellular ZDV-TP concentration increased less than proportionally over the dose range studied (100 μg to 300 mg), while the intracellular TFV-DP PK were linear over the same dose range. ZDV-TP concentrations were lower in CD4+ cells versus total peripheral blood mononuclear cells (PBMCs), while TFV-DP concentrations were not different in CD4+ cells and PBMCs. Conclusion Our data were consistent with a rate-limiting step in the intracellular phosphorylation of ZDV but not TFV. AMS shows promise for predicting the PK of active intracellular metabolites of nucleosides, but nonlinearity of PK may be seen with some drugs. PMID:23187888

Response to antiretroviral therapy (ART): comparing women with previous use of zidovudine monotherapy (ZDVm) in pregnancy with ART naïve women.

PubMed

Huntington, Susie; Thorne, Claire; Anderson, Jane; Newell, Marie-Louise; Taylor, Graham P; Pillay, Deenan; Hill, Teresa; Tookey, Pat; Sabin, Caroline

2014-03-04

Short-term zidovudine monotherapy (ZDVm) remains an option for some pregnant HIV-positive women not requiring treatment for their own health but may affect treatment responses once antiretroviral therapy (ART) is subsequently started. Data were obtained by linking two UK studies: the UK Collaborative HIV Cohort (UK CHIC) study and the National Study of HIV in Pregnancy and Childhood (NSHPC). Treatment responses were assessed for 2028 women initiating ART at least one year after HIV-diagnosis. Outcomes were compared using logistic regression, proportional hazards regression or linear regression. In adjusted analyses, ART-naïve (n = 1937) and ZDVm-experienced (n = 91) women had similar increases in CD4 count and a similar proportion achieving virological suppression; both groups had a low risk of AIDS. In this setting, antenatal ZDVm exposure did not adversely impact on outcomes once ART was initiated for the woman's health.

From research to practice: use of short course zidovudine to prevent mother-to-child HIV transmission in the context of routine health care in Northern Thailand.

PubMed

Thaineua, V; Sirinirund, P; Tanbanjong, A; Lallemant, M; Soucat, A; Lamboray, J L

1998-09-01

Thailand has made remarkable progress in battling the HIVepidemic, as the decreases in HIV prevalence and changes in sexual behavior attest. Yet, in Phayao, a northern province severely affected by HIV, approximately 280 HIV-infected women, or 5% of all pregnant women, gave birth to an estimated 70 infected children in 1997. As many of these infants die within their first year of life, the infant mortality rate is on the rise after years of decline. The province, however, responded quickly to this crisis. Since July 1997, the Ministry of Public Health (MOPH) offers through Phayao's seven public hospitals a short regimen of zidovudine to all consenting HIV-infected women to prevent mother-to-child transmission of the virus. The overall prophylactic coverage for the province reached 68% of all HIV-infected pregnant women in the fourth quarter of 1997, either through the MOPH program or through the North Thailand Perinatal HIV Prevention Trial, the parallel clinical trial conducted by the MOPH and the Ministry of University Affairs. Analysis of the data collected showed that compliance to the intervention was excellent, around 90%. This was achieved at an additional cost of US$ 0.13 per capita per year, affordable even in the context of the economic crisis, and represents less than 1% of public health expenditures in Thailand. The cost per Disability Adjusted Life Years saved is approximately US$35, making it highly cost-effective. In less than a year, the MOPH implemented this program on a large scale in this relatively poor province, with limited external support. Women receive pretest counseling at their first prenatal visit, are offered HIV testing and, if they accept, return for posttest counseling two weeks later. In the case of a positive test result, a confirmation test is performed at the provincial hospital. HIV-infected women are offered zidovudine the 34th week of pregnancy or as soon as possible thereafter. Before starting treatment, the women

High exposure to zidovudine during the first 2 weeks of life and concentration-toxicity relationships.

PubMed

Hirt, Déborah; Warszawski, Josiane; Firtion, Ghislaine; Giraud, Carole; Chappuy, Hélène; Lechenadec, Jérôme; Benaboud, Sihem; Urien, Saïk; Blanche, Stéphane; Tréluyer, Jean-Marc

2013-08-15

The aims of the study were in a large group of neonates to identify the relative effect of bodyweight, postnatal age, and gestational age on zidovudine (ZDV) pharmacokinetics; to link concentrations with lactate and hemoglobin levels; and to find the more appropriate neonatal ZDV dose. In 484 neonates aged 3-30 days, born to HIV-infected mothers, 767 ZDV and 417 ZDV glucuronide concentrations were collected. Using a population approach, ZDV clearance per kilogram increased with postnatal age but not with gestational age. High neonatal exposures were found as follows: 14,025 ng/mL·h the first week and 6528 ng/mL·h the second week in comparison to 3000 ng/mL·h in adults. At month 1, median lactate level was 2.8 mmol/L (60%, ≥2.5 mmol/L) and median hemoglobin was 10.1 g/dL (90%, <12 g/dL). ZDV trough concentrations at first sampling (days 3-7) or at last sampling (day 20 ± 10) were significantly negatively correlated to hemoglobin at months 1, 3, and 6 (P < 0.02). ZDV maximal or trough concentrations at days 3-7 and at day 20 ± 10 were significantly positively correlated to lactate levels at months 3 and 6, respectively. To obtain an exposure comparable to adults, which should reduce neonatal toxicity, doses should to be decreased during the first 2 weeks of life.

Zidovudine Induces Downregulation of Mitochondrial Deoxynucleoside Kinases: Implications for Mitochondrial Toxicity of Antiviral Nucleoside Analogs

PubMed Central

Sun, Ren; Eriksson, Staffan

2014-01-01

Mitochondrial thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK) catalyze the initial phosphorylation of deoxynucleosides in the synthesis of the DNA precursors required for mitochondrial DNA (mtDNA) replication and are essential for mitochondrial function. Antiviral nucleosides are known to cause toxic mitochondrial side effects. Here, we examined the effects of 3′-azido-2′,3′-dideoxythymidine (AZT) (zidovudine) on mitochondrial TK2 and dGK levels and found that AZT treatment led to downregulation of mitochondrial TK2 and dGK in U2OS cells, whereas cytosolic deoxycytidine kinase (dCK) and thymidine kinase 1 (TK1) levels were not affected. The AZT effects on mitochondrial TK2 and dGK were similar to those of oxidants (e.g., hydrogen peroxide); therefore, we examined the oxidative effects of AZT. We found a modest increase in cellular reactive oxygen species (ROS) levels in the AZT-treated cells. The addition of uridine to AZT-treated cells reduced ROS levels and protein oxidation and prevented the degradation of mitochondrial TK2 and dGK. In organello studies indicated that the degradation of mitochondrial TK2 and dGK is a mitochondrial event. These results suggest that downregulation of mitochondrial TK2 and dGK may lead to decreased mitochondrial DNA precursor pools and eventually mtDNA depletion, which has significant implications for the regulation of mitochondrial nucleotide biosynthesis and for antiviral therapy using nucleoside analogs. PMID:25182642

A Single Zidovudine (AZT) Administration Delays Hepatic Cell Proliferation by Altering Oxidative State in the Regenerating Rat Liver.

PubMed

Butanda-Ochoa, Armando; Hernández-Espinosa, Diego Rolando; Olguín-Martínez, Marisela; Sánchez-Sevilla, Lourdes; Rodríguez, Mario R; Chávez-Rentería, Benito; Aranda-Fraustro, Alberto; Hernández-Muñoz, Rolando

2017-01-01

The 3'-azido-3'-deoxythymidine or Zidovudine (AZT) was the first antiretroviral drug used in the treatment of HIV patients, which has good effectiveness but also hepatotoxic side effects that include cell cycle arrest and oxidative/nitrative mitochondrial damage. Whether such an oxidative damage may affect the proliferative-regenerative capacity of liver remains to be clearly specified at doses commonly used in the clinical practice. In this study, we described the oxidative-proliferative effect of AZT administered at a common clinical dose in rat liver submitted to 70% partial hepatectomy (PH). The results indicate that AZT significantly decreased DNA synthesis and the number of mitosis in liver subjected to PH in a synchronized way with the promotion of organelle-selective lipid peroxidation events (especially those observed in plasma membrane and cytosolic fractions) and with liver enzyme release to the bloodstream. Then at the dose used in clinical practice AZT decreased liver regeneration but stimulates oxidative events involved during the proliferation process in a way that each membrane system inside the cell preserves its integrity in order to maintain the cell proliferative process. Here, the induction of large amounts of free ammonia in the systemic circulation could become a factor capable of mediating the deleterious effects of AZT on PH-induced rat liver regeneration.

Simultaneous determination of the HIV nucleoside analogue reverse transcriptase inhibitors lamivudine, didanosine, stavudine, zidovudine and abacavir in human plasma by reversed phase high performance liquid chromatography.

PubMed

Verweij-van Wissen, C P W G M; Aarnoutse, R E; Burger, D M

2005-02-25

A reversed phase high performance liquid chromatography method was developed for the simultaneous quantitative determination of the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine, didanosine, stavudine, zidovudine and abacavir in plasma. The method involved solid-phase extraction with Oasis MAX cartridges from plasma, followed by high performance liquid chromatography with a SymmetryShield RP 18 column and ultraviolet detection set at a wavelength of 260 nm. The assay was validated over the concentration range of 0.015-5 mg/l for all five NRTIs. The average accuracies for the assay were 92-102%, inter- and intra-day coefficients of variation (CV) were <2.5% and extraction recoveries were higher than 97%. This method proved to be simple, accurate and precise, and is currently in use in our laboratory for the quantitative analysis of NRTIs in plasma.

Continuous wavelet transforms for the simultaneous quantitative analysis and dissolution testing of lamivudine-zidovudine tablets.

PubMed

Dinç, Erdal; Özdemir, Nurten; Üstündağ, Özgür; Tilkan, Müşerref Günseli

2013-01-01

Dissolution testing has a very vital importance for a quality control test and prediction of the in vivo behavior of the oral dosage formulation. This requires the use of a powerful analytical method to get reliable, accurate and precise results for the dissolution experiments. In this context, new signal processing approaches, continuous wavelet transforms (CWTs) were improved for the simultaneous quantitative estimation and dissolution testing of lamivudine (LAM) and zidovudine (ZID) in a tablet dosage form. The CWT approaches are based on the application of the continuous wavelet functions to the absorption spectra-data vectors of LAM and ZID in the wavelet domain. After applying many wavelet functions, the families consisting of Mexican hat wavelet with the scaling factor a=256, Symlets wavelet with the scaling factor a=512 and the order of 5 and Daubechies wavelet at the scale factor a=450 and the order of 10 were found to be suitable for the quantitative determination of the mentioned drugs. These wavelet applications were named as mexh-CWT, sym5-CWT and db10-CWT methods. Calibration graphs for LAM and ZID in the working range of 2.0-50.0 µg/mL and 2.0-60.0 µg/mL were obtained measuring the mexh-CWT, sym5-CWT and db10-CWT amplitudes at the wavelength points corresponding to zero crossing points. The validity and applicability of the improved mexh-CWT, sym5-CWT and db10-CWT approaches was carried out by the analysis of the synthetic mixtures containing the analyzed drugs. Simultaneous determination of LAM and ZID in tablets was accomplished by the proposed CWT methods and their dissolution profiles were graphically explored.

A Single Zidovudine (AZT) Administration Delays Hepatic Cell Proliferation by Altering Oxidative State in the Regenerating Rat Liver

PubMed Central

Butanda-Ochoa, Armando; Hernández-Espinosa, Diego Rolando; Olguín-Martínez, Marisela; Sánchez-Sevilla, Lourdes; Rodríguez, Mario R.; Chávez-Rentería, Benito; Aranda-Fraustro, Alberto

2017-01-01

The 3′-azido-3′-deoxythymidine or Zidovudine (AZT) was the first antiretroviral drug used in the treatment of HIV patients, which has good effectiveness but also hepatotoxic side effects that include cell cycle arrest and oxidative/nitrative mitochondrial damage. Whether such an oxidative damage may affect the proliferative-regenerative capacity of liver remains to be clearly specified at doses commonly used in the clinical practice. In this study, we described the oxidative-proliferative effect of AZT administered at a common clinical dose in rat liver submitted to 70% partial hepatectomy (PH). The results indicate that AZT significantly decreased DNA synthesis and the number of mitosis in liver subjected to PH in a synchronized way with the promotion of organelle-selective lipid peroxidation events (especially those observed in plasma membrane and cytosolic fractions) and with liver enzyme release to the bloodstream. Then at the dose used in clinical practice AZT decreased liver regeneration but stimulates oxidative events involved during the proliferation process in a way that each membrane system inside the cell preserves its integrity in order to maintain the cell proliferative process. Here, the induction of large amounts of free ammonia in the systemic circulation could become a factor capable of mediating the deleterious effects of AZT on PH-induced rat liver regeneration. PMID:28479956

Pharmacokinetic evaluation of the effects of ribavirin on zidovudine triphosphate formation: ACTG 5092s Study Team.

PubMed

Aweeka, F T; Kang, M; Yu, J-Y; Lizak, P; Alston, B; Chung, R T

2007-07-01

Ribavirin (RBV) is used for the treatment of hepatitis C virus (HCV) infection in subjects with HIV-1 infection who may require antiretroviral treatment (ART) with nucleoside reverse transcriptase inhibitors including zidovudine (ZDV). We sought to investigate the potential antagonism between RBV and ZDV by evaluating the impact of RBV on the formation of intracellular ZDV triphosphate (TP) in HIV-infected patients receiving ZDV who were treated for HCV infection. Serial plasma and intracellular ZDV TP pharmacokinetics (PK) were determined in 14 subjects at entry (within 2 weeks prior to RBV administration) and at 8 weeks following initiation of RBV. Intracellular ZDV TP in peripheral blood mononuclear cells (PBMC) was quantified by a validated cartridge/liquid chromatography/tandem mass spectrometry method. PK exposure was estimated from the steady-state area under the concentration vs time curve (AUC(0-12 h)) in plasma and PBMC. Ribavirin did not have a statistically significant impact on ZDV TP AUC(0-12 h), plasma ZDV AUC(0-12 h) or the ratio of ZDV TP AUC(0-12 h) to plasma ZDV AUC(0-12 h), although there was a trend towards an increase post-RBV ratio compared with pre-RBV. There was extensive variability in the ZDV TP AUC(0-12 h). Ribavirin did not inhibit formation of ZDV TP in PBMC in 14 patients receiving ZDV as part of ART and RBV-based HCV therapy for 8 weeks. These results are consistent with those of a previously published limited study in seven subjects. These PK findings should be weighed carefully against emerging clinical reports of significant anaemia associated with combination ZDV and high-dose RBV therapy.

Specific, sensitive, and rapid assay for human immunodeficiency virus type 1 pol mutations associated with resistance to zidovudine and didanosine.

PubMed Central

Frenkel, L M; Wagner, L E; Atwood, S M; Cummins, T J; Dewhurst, S

1995-01-01

The effectiveness of antiretroviral therapy may be limited by the development of human immunodeficiency virus type 1 (HIV-1) resistance. Monitoring for resistance will perhaps allow changes in therapy prior to deterioration in the patient's clinical or immunologic status. Our objective was to develop a rapid, specific, and sensitive genotypic assay for HIV-1 resistance to zidovudine (ZDV) and didanosine (ddI) which is simple to perform. In our assay the DNA of HIV-1 pol was amplified by PCR using two sets of nested oligonucleotide primers. Mutations of reverse transcriptase (RT) encoding amino acids (aa) 74 and 41, 70, and 215 which have been associated with HIV-1 resistance to ddI and ZDV, respectively, were detected with a ligase detection reaction (LDR) and indicated colorimetrically. The RT genotypes of 35 patient specimens (140 codons) blindly assessed for these mutations were in agreement by PCR-LDR and by dideoxynucleotide sequencing. To evaluate the limits of the assay, other specimens with mutations close to the ligation site were evaluated by PCR-LDR. The assay was sensitive and specific for all specimens except when mutations occurred within 2 bases on either side of the ligation site. In summary, this PCR-LDR assay specifically, sensitively, and rapidly detected pol mutations (RT aa 74, 41, 70, and 215) associated with HIV-1 resistance to ddI and ZDV. PMID:7714190

Dysregulation of autophagy in rat liver with mitochondrial DNA depletion induced by the nucleoside analogue zidovudine.

PubMed

Santos-Llamas, Ana; Monte, Maria J; Marin, Jose J G; Perez, Maria J

2018-03-28

The nucleoside reverse transcriptase inhibitor zidovudine (AZT), used in HIV infection treatment, induces mitochondrial DNA (mtDNA) depletion. A cause-effect relationship between mtDNA status alterations and autophagy has been reported. Both events are common in several liver diseases, including hepatocellular carcinoma. Here, we have studied autophagy activation in rat liver with mtDNA depletion induced by AZT administration in drinking water for 35 days. AZT at a concentration of 1 mg/ml, but not 0.5 mg/ml in the drinking water, decreased mtDNA levels in rat liver and extrahepatic tissues. In liver, mtDNA-encoded cytochrome c oxidase 1 protein levels were decreased. Although serum biomarkers of liver and kidney toxicity remained unaltered, β-hydroxybutyrate levels were increased in liver of AZT-treated rats. Moreover, autophagy was dysregulated at two levels: (i) decreased induction signalling of this process as indicated by increases in autophagy inhibitors activity (AKT/mTOR), and absence of changes (Beclin-1, Atg5, Atg7) or decreases (AMPK/ULK1) in the expression/activity of pro-autophagy proteins; and (ii) reduced autophagosome degradation as indicated by decreases in the lysosome abundance (LAMP2 marker) and the transcription factor TFEB controlling lysosome biogenesis. This resulted in increased autophagosome abundance (LC3-II marker) and accumulation of the protein selectively degraded by autophagy p62, and the transcription factor Nrf2 in liver of AZT-treated rats. Nrf2 was activated as indicated by the up-regulation of antioxidant target genes Nqo1 and Hmox-1. In conclusion, rat liver with AZT-induced mtDNA depletion presented dysregulations in autophagosome formation and degradation balance, which results in accumulation of these structures in parenchymal liver cells, favouring hepatocarcinogenesis.

Maternal characteristics associated with antenatal, intrapartum, and neonatal zidovudine use in four US cities, 1994-1998.

PubMed

Orloff, S L; Bulterys, M; Vink, P; Nesheim, S; Abrams, E J; Schoenbaum, E; Palumbo, P; Steketee, R W; Simonds, R J

2001-09-01

To evaluate implementation of 1994 United States Public Health Service guidelines for zidovudine (ZDV) use in HIV-infected women and their newborns by describing the prevalence of use of perinatal ZDV and other antiretrovirals and by investigating determinants of not receiving perinatal ZDV. The Perinatal AIDS Collaborative Transmission Study is a prospective cohort study designed to collect information related to mother-to-child HIV transmission that was conducted in New York City (NY), Newark (NJ), Baltimore (MD), and Atlanta (GA), U.S.A. The current analysis was restricted to infants born between July 1994 and June 1998. Utilization rates for antenatal, intrapartum, and neonatal ZDV increased from 41% to 70% during the 4-year period. Use of combination antiretrovirals increased from fewer than 2% of women in 1994 to 1995 to 35% in 1997 to 1998. Antenatal and neonatal ZDV use increased each year, but intrapartum ZDV use reached a plateau after 1996. Mother-infant pairs with the following characteristics were less likely to have received a complete 3-part ZDV regimen: older maternal age, CD4 count >500 cells/microl, preterm birth, cocaine or heroin use during pregnancy, positive newborn drug screen test result, and smoking or alcohol use during pregnancy. By multivariate logistic regression adjusted for hospital and year of birth, cocaine or heroin use during pregnancy (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.6-3.3), maternal CD4 count (OR, 0.4; 95% CI, 0.2-0.8; comparing <200 with >500 cells/microl), and preterm birth (OR, 1.6; 95% CI, 1.1-2.5) remained independently associated with not receiving the complete ZDV regimen. ZDV use by pregnant HIV-infected women and their infants has increased dramatically since publication of the 1994 guidelines. Nevertheless, women who abuse substances, give birth preterm, or have less advanced immunosuppression, were at substantial risk of not receiving the complete ZDV regimen.

Determination of Zidovudine Triphosphate Intracellular Concentrations in Peripheral Blood Mononuclear Cells from Human Immunodeficiency Virus-Infected Individuals by Tandem Mass Spectrometry

PubMed Central

Font, Eva; Rosario, Osvaldo; Santana, Jorge; García, Hermes; Sommadossi, Jean-Pierre; Rodriguez, Jose F.

1999-01-01

Nucleoside reverse transcriptase inhibitors (NRTIs) used against the human immunodeficiency virus (HIV) need to be activated intracellularly to their triphosphate moiety to inhibit HIV replication. Intracellular concentrations of these NRTI triphosphates, especially zidovudine triphosphate (ZDV-TP), are relatively low (low numbers of femtomoles per 106 cells) in HIV-infected patient peripheral blood mononuclear cells. Recently, several methods have used either high-performance liquid chromatography (HPLC) or solid-phase extraction (SPE) coupled with radioimmunoassay to obtain in vivo measurements of ZDV-TP. The limit of detection (LOD) by these methods ranged from 20 to 200 fmol/106 cells. In this report, we describe the development of a method to determine intracellular ZDV-TP concentrations in HIV-infected patients using SPE and HPLC with tandem mass spectrometry for analysis. The LOD by this method is 4.0 fmol/106 cells with a linear concentration range of at least 4 orders of magnitude from 4.0 to 10,000 fmol/106 cells. In hispanic HIV-infected patients, ZDV-TP was detectable even when the sampling time after drug administration was 15 h. Intracellular ZDV-TP concentrations in these patients ranged from 41 to 193 fmol/106 cells. The low LOD obtained with this method will provide the opportunity for further in vivo pharmacokinetic studies of intracellular ZDV-TP in different HIV-infected populations. Furthermore, this methodology could be used to perform simultaneous detection of two or more NRTIs, such as ZDV-TP and lamivudine triphosphate. PMID:10582890

Determination of lamivudine and zidovudine permeability using a different ex vivo method in Franz cells.

PubMed

Dezani, André Bersani; Pereira, Thaisa Marinho; Caffaro, Arthur Massabki; Reis, Juliana Mazza; Serra, Cristina Helena Dos Reis

2013-01-01

The major processes that control the absorption of orally administered drugs are dissolution and gastrointestinal permeation. These processes depend on two main properties: solubility and permeability. Based on these characteristics, the Biopharmaceutical Classification System (BCS) was proposed as a tool to assist in biowaiver and bioavailability prediction of drugs. The purpose of the present study was to evaluate the permeability of lamivudine (3TC) and zidovudine (AZT) using a different ex vivo method in Franz cells. A segment of jejunum was inserted in a Franz cells apparatus, in order to assess drug permeability in the apical-basolateral (A-B) and basolateral-apical (B-A) directions. Each drug was added to the donor chamber, collected from the acceptor chamber and analyzed by HPLC. Fluorescein (FLU) and metoprolol (METO) were used as low and high permeability markers, respectively. The apparent permeability (Papp) results for the A-B direction were: Papp FLU A-B=0.54×10(-4)cm·s(-1), Papp METO A-B=7.99×10(-4)cm·s(-1), Papp 3TC A-B=4.58×10(-4)cm·s(-1) and Papp AZT A-B=5.34×10(-4)cm·s(-1). For the B-A direction, the Papp results were: Papp FLU B-A=0.56×10(-4)cm·s(-1), Papp METO B-A=0.25×10(-4)cm·s(-1), Papp 3TC B-A=0.24×10(-4)cm·s(-1) and Papp AZT B-A=0.19×10(-4)cm·s(-1). For the A-B direction, the Papp results of fluorescein and metoprolol show low and high permeability, respectively, indicating that the membranes were appropriate for permeability studies. For the A-B direction, the Papp results of 3TC and AZT suggest that these antiretroviral drugs have permeability values close to metoprolol. Nevertheless, for the B-A direction the Papp results do not suggest efflux mechanism for any of the drugs. Thereby, the different ex vivo methods using Franz cells can be successfully applied in drug permeability studies, in particular for drug biopharmaceutical classification. Copyright © 2013 Elsevier Inc. All rights reserved.

Evaluation of in-vitro cytotoxicity and cellular uptake efficiency of zidovudine-loaded solid lipid nanoparticles modified with Aloe Vera in glioma cells.

PubMed

K S, Joshy; Sharma, Chandra P; Kalarikkal, Nandakumar; Sandeep, K; Thomas, Sabu; Pothen, Laly A

2016-09-01

Zidovudine loaded solid lipid nanoparticles of stearic acid modified with Aloe Vera (AV) have been prepared via simple emulsion solvent evaporation method which showed excellent stability at room temperature and refrigerated condition. The nanoparticles were examined by Fourier transform infrared spectroscopy (FT-IR), which revealed the overlap of the AV absorption peak with the absorption peak of modified stearic acid nanoparticles. The inclusion of AV to stearic acid decreased the crystallinity and improved the hydrophilicity of lipid nanoparticles and thereby improved the drug loading efficacy of lipid nanoparticles. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) imaging revealed that, the average particle size of unmodified (bare) nanoparticles was 45.66±12.22nm and modified solid lipid nanoparticles showed an average size of 265.61±80.44nm. Solid lipid nanoparticles with well-defined morphology were tested in vitro for their possible application in drug delivery. Cell culture studies using C6 glioma cells on the nanoparticles showed enhanced growth and proliferation of cells without exhibiting any toxicity. In addition, normal cell morphology and improved uptake were observed by fluorescence microscopy images of rhodamine labeled modified solid lipid nanoparticles compared with unmodified nanoparticles. The cellular uptake study suggested that these nanoparticles could be a promising drug delivery system to enhance the uptake of antiviral drug by brain cells and it could be a suitable drug carrier system for the treatment of HIV. Copyright © 2016 Elsevier B.V. All rights reserved.

Development and characterization of PLGA nanoparticles as delivery systems of a prodrug of zidovudine obtained by its conjugation with ursodeoxycholic acid.

PubMed

Dalpiaz, Alessandro; Contado, Catia; Mari, Lara; Perrone, Daniela; Pavan, Barbara; Paganetto, Guglielmo; Hanuskovà, Miriam; Vighi, Eleonora; Leo, Eliana

2014-05-01

Zidovudine (AZT) is employed against AIDS and hepatitis; its use is limited by active efflux transporters (AETs) that induce multidrug resistance for intracellular therapies and hamper AZT to reach the brain. Ursodeoxycholic acid (UDCA) conjugation with AZT (prodrug UDCA-AZT) allows to elude the AET systems. To investigate the effect of the Pluronic F68 coating on the loading, release and stability of poly(D,L lactide-co-glicolide) nanoparticles (NPs) embedded with UDCA-AZT. The mean diameter of the NP prepared by nanoprecipitation or emulsion/solvent evaporation methods was determined using both photon correlation spectroscopy and sedimentation field-flow fractionation; particle morphology was detected by scanning electron microscope. The stability of the free and encapsulated UDCA-AZT was evaluated in rat liver homogenates by high-performance liquid chromatography analysis. The mean diameter of the NPs was found to be ∼ 600 nm with a relatively high polydispersity. The NPs obtained by emulsion/solvent evaporation were not able to control the prodrug release, differently from NPs obtained by nanoprecipitation. The presence of the Pluronic coating did not substantially modify the kinetics of the drug release, or the extent of the burst effect that were instead only influenced by the preparation parameters. UDCA-AZT incorporated in the NPs was more stable in the rat liver homogenates than the free prodrug and no influence of the Pluronic coating was observed. Considering the different potential applications of nanoparticles coated and uncoated with Pluronic (brain and macrophage targeting, respectively), both of these nanoparticle systems could be useful in the therapies against HIV.

Contribution of different antiretroviral regimens containing zidovudine, lamivudine and ritonavir-boosted lopinavir on HIV viral load reduction during pregnancy.

PubMed

Sripan, Patumrat; Le Coeur, Sophie; Ingsrisawang, Lily; Cressey, Tim R; Bouazza, Naïm; Foissac, Frantz; Ngo-Giang-Huong, Nicole; Traisathit, Patrinee; Srirompotong, Ussanee; Ayudhaya, Orada Patamasingh Na; Puangsombat, Achara; Jungpipun, Jantana; Jittayanun, Kanokwan; Tréluyer, Jean-Marc; Jourdain, Gonzague; Lallemant, Marc; Urien, Saïk

2016-01-01

Antiretroviral (ARV) regimens used for the prevention of mother-to-child transmission of HIV have evolved over time. We evaluated the contribution of different ARV regimens on the reduction of the plasma HIV RNA viral load (VL) during pregnancy. A total of 1,833 VL measurements from ARV-naive pregnant women participating in perinatal prevention trials in Thailand were included. Women received either zidovudine (ZDV) monotherapy, ZDV plus lopinavir/ritonavir (LPV/r), or ZDV plus lamivudine (3TC) plus LPV/r. VL time-course during pregnancy was described as a function of pretreatment VL and treatment duration using an Emax non-linear mixed-effect model. VL reduction and median time to achieve a VL<50 copies/ml were estimated for each regimen. Among 745 women, 279 (37%), 145 (20%) and 321 (43%) received ZDV monotherapy, ZDV+LPV/r and ZDV+3TC+LPV/r, respectively. The predicted VL reduction from baseline to delivery after a median of 10 weeks of treatment were 0.5, 2.7 and 2.9 log10 copies/ml with ZDV monotherapy, ZDV+LPV/r and ZDV+3TC+LPV/r, respectively. At delivery, 1%, 57% and 63% of women receiving ZDV monotherapy, ZDV+LPV/r or ZDV+3TC+LPV/r had a VL<50 copies/ml. The addition of 3TC to ZDV+LPV/r reduced the time to achieve a VL<50 copies/ml and the higher the pretreatment VL, the larger the effect 3TC had on reducing the time to VL<50 copies/ml. The addition of 3TC to ZDV+LPV/r was associated with a slight further VL reduction but the time to reach a VL<50 copies/ml was shorter. This beneficial effect of 3TC is crucial for prevention of mother-to-child transmission in women who receive ARVs late and with high pretreatment VL.

Nevirapine/zidovudine/lamivudine has superior immunological and virological responses not reflected in clinical outcomes in a 48-week randomized comparison with abacavir/zidovudine/lamivudine in HIV-infected Ugandan adults with low CD4 cell counts.

PubMed

Munderi, P; Walker, A S; Kityo, C; Babiker, A G; Ssali, F; Reid, A; Darbyshire, J H; Grosskurth, H; Mugyenyi, P; Gibb, D M; Gilks, C F

2010-05-01

Triple nucleoside reverse transcriptase inhibitor regimens have advantages as first-line antiretroviral therapy (ART), avoiding hepatotoxicity and interactions with anti-tuberculosis therapy, and sparing two drug classes for second-line ART. Concerns exist about virological potency; efficacy has not been assessed in Africa. A safety trial comparing nevirapine with abacavir was conducted in two Ugandan Development of Antiretroviral Therapy in Africa (DART) centres: 600 symptomatic antiretroviral-naïve HIV-infected adults with CD4 counts <200 cells/microL were randomized to zidovudine/lamivudine plus abacavir or nevirapine (placebo-controlled to 24-week primary toxicity endpoint, and then open-label). Documented World Health Organization (WHO) stage 4 events were independently reviewed and plasma HIV-1 RNA assayed retrospectively. Exploratory efficacy analyses are intention-to-treat. The median pre-ART CD4 count was 99 cells/microL, and the median pre-ART viral load was 284 600 HIV-1 RNA copies/mL. A total of 563 participants (94%) completed 48 weeks of follow-up, 25 (4%) died and 12 (2%) were lost to follow-up. The randomized drug was substituted in 21 participants (7%) receiving abacavir vs. 34 (11%) receiving nevirapine (P=0.09). At 48 weeks, 62% of participants receiving abacavir vs. 77% of those receiving nevirapine had viral loads <50 copies/mL (P<0.001), and mean CD4 count increases from baseline were +147 vs. +173 cells/microL, respectively (P=0.006). Nine participants (3%) receiving abacavir vs. 16 (5%) receiving nevirapine died [hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.24-1.25; P=0.15]; 20 receiving abacavir vs. 32 receiving nevirapine developed new or recurrent WHO 4 events or died (HR=0.60; 95% CI 0.34-1.05; P=0.07) and 48 receiving abacavir vs. 68 receiving nevirapine developed new or recurrent WHO 3 or 4 events or died (HR=0.67; 95% CI 0.46-0.96; P=0.03). Seventy-one participants (24%) receiving abacavir experienced 91 grade 4 adverse

Three postpartum antiretroviral regimens to prevent intrapartum HIV infection.

PubMed

Nielsen-Saines, Karin; Watts, D Heather; Veloso, Valdilea G; Bryson, Yvonne J; Joao, Esau C; Pilotto, Jose Henrique; Gray, Glenda; Theron, Gerhard; Santos, Breno; Fonseca, Rosana; Kreitchmann, Regis; Pinto, Jorge; Mussi-Pinhata, Marisa M; Ceriotto, Mariana; Machado, Daisy; Bethel, James; Morgado, Marisa G; Dickover, Ruth; Camarca, Margaret; Mirochnick, Mark; Siberry, George; Grinsztejn, Beatriz; Moreira, Ronaldo I; Bastos, Francisco I; Xu, Jiahong; Moye, Jack; Mofenson, Lynne M

2012-06-21

The safety and efficacy of adding antiretroviral drugs to standard zidovudine prophylaxis in infants of mothers with human immunodeficiency virus (HIV) infection who did not receive antenatal antiretroviral therapy (ART) because of late identification are unclear. We evaluated three ART regimens in such infants. Within 48 hours after their birth, we randomly assigned formula-fed infants born to women with a peripartum diagnosis of HIV type 1 (HIV-1) infection to one of three regimens: zidovudine for 6 weeks (zidovudine-alone group), zidovudine for 6 weeks plus three doses of nevirapine during the first 8 days of life (two-drug group), or zidovudine for 6 weeks plus nelfinavir and lamivudine for 2 weeks (three-drug group). The primary outcome was HIV-1 infection at 3 months in infants uninfected at birth. A total of 1684 infants were enrolled in the Americas and South Africa (566 in the zidovudine-alone group, 562 in the two-drug group, and 556 in the three-drug group). The overall rate of in utero transmission of HIV-1 on the basis of Kaplan-Meier estimates was 5.7% (93 infants), with no significant differences among the groups. Intrapartum transmission occurred in 24 infants in the zidovudine-alone group (4.8%; 95% confidence interval [CI], 3.2 to 7.1), as compared with 11 infants in the two-drug group (2.2%; 95% CI, 1.2 to 3.9; P=0.046) and 12 in the three-drug group (2.4%; 95% CI, 1.4 to 4.3; P=0.046). The overall transmission rate was 8.5% (140 infants), with an increased rate in the zidovudine-alone group (P=0.03 for the comparisons with the two- and three-drug groups). On multivariate analysis, zidovudine monotherapy, a higher maternal viral load, and maternal use of illegal substances were significantly associated with transmission. The rate of neutropenia was significantly increased in the three-drug group (P<0.001 for both comparisons with the other groups). In neonates whose mothers did not receive ART during pregnancy, prophylaxis with a two- or three

Zidovudine ameliorates pathology in the mouse model of Duchenne muscular dystrophy via P2RX7 purinoceptor antagonism.

PubMed

Al-Khalidi, Rasha; Panicucci, Chiara; Cox, Paul; Chira, Natalia; Róg, Justyna; Young, Christopher N J; McGeehan, Rhiannon E; Ambati, Kameshwari; Ambati, Jayakrishna; Zabłocki, Krzysztof; Gazzerro, Elisabetta; Arkle, Stephen; Bruno, Claudio; Górecki, Dariusz C

2018-04-11

Duchenne muscular dystrophy (DMD) is the most common inherited muscle disorder that causes severe disability and death of young men. This disease is characterized by progressive muscle degeneration aggravated by sterile inflammation and is also associated with cognitive impairment and low bone density. Given that no current treatment can improve the long-term outcome, approaches with a strong translational potential are urgently needed. Duchenne muscular dystrophy (DMD) alters P2RX7 signaling in both muscle and inflammatory cells and inhibition of this receptor resulted in a significant attenuation of muscle and non-muscle symptoms in DMD mdx mouse model. As P2RX7 is an attractive target in a range of human diseases, specific antagonists have been developed. Yet, these will require lengthy safety testing in the pediatric population of Duchenne muscular dystrophy (DMD) patients. In contrast, Nucleoside Reverse Transcriptase Inhibitors (NRTIs) can act as P2RX7 antagonists and are drugs with an established safety record, including in children. We demonstrate here that AZT (Zidovudine) inhibits P2RX7 functions acting via the same allosteric site as other antagonists. Moreover, short-term AZT treatment at the peak of disease in DMD mdx mice attenuated the phenotype without any detectable side effects. Recovery was evident in the key parameters such as reduced sarcolemma permeability confirmed by lower serum creatine kinase levels and IgG influx into myofibres, decreased inflammatory cell numbers and inflammation markers in leg and heart muscles of treated mice. Moreover, this short-term therapy had some positive impact on muscle strength in vivo and no detrimental effect on mitochondria, which is the main side-effect of Nucleoside Reverse Transcriptase Inhibitors (NRTIs). Given these results, we postulate that AZT could be quickly re-purposed for the treatment of this highly debilitating and lethal disease. This approach is not constrained by causative DMD mutations and

Placental Mitochondrial Toxicity, Oxidative Stress, Apoptosis, and Adverse Perinatal Outcomes in HIV Pregnancies Under Antiretroviral Treatment Containing Zidovudine.

PubMed

Hernández, Sandra; Catalán-García, Marc; Morén, Constanza; García-Otero, Laura; López, Marta; Guitart-Mampel, Mariona; Milisenda, José; Coll, Oriol; Cardellach, Francesc; Gratacós, Eduard; Miró, Òscar; Garrabou, Glòria

2017-08-01

To determine whether mitochondrial, oxidative, and apoptotic abnormalities in placenta derived from HIV and combined antiretroviral therapy (cART) containing zidovudine (AZT) could be associated with adverse perinatal outcome. Cross-sectional, controlled, observational study. We studied obstetric results and mitochondrial, oxidative, and apoptotic state in placenta of 24 treated HIV-infected and 32 -uninfected pregnant women. We measured mitochondrial DNA (mtDNA) content by quantitative reverse transcriptase-polymerase chain reaction (mtND2/n18SrRNA), oxidative stress by the spectrophotometric quantification of lipid peroxidation and apoptosis by Western blot analysis of active caspase-3 respect to β-actin content and analysis of the terminal deoxynucleotidyl transferase dUTP nick end labeling. Global adverse perinatal outcome (defined as preterm delivery or/and small newborns for gestational age) was significantly increased in HIV pregnancies [or 6.7 (1.3-33.2); P < 0.05]. mtDNA content in HIV-infected women was significantly depleted (39.20% ± 2.78%) with respect to controls (0.59 ± 0.03 vs. 0.97 ± 0.07; P < 0.001). A significant 29.50% ± 9.14% increase in oxidative stress was found in placentas of HIV-infected women (23.23 ± 1.64 vs. 17.94 ± 1.03; P < 0.01). A trend toward 41.18% ± 29.41% increased apoptosis active caspase-3/β-actin was found in HIV patients (0.48 ± 0.10 vs. 0.34 ± 0.05; P = not significant), confirmed by transferase dUTP nick end labeling assay. Adverse perinatal outcome did not correlate mitochondrial, oxidative, or apoptotic findings. Placentas of HIV-infected pregnant women under AZT cART showed evidence of mtDNA depletion, increased oxidative stress levels, and apoptosis suggestive of secondary mitochondrial failure, potential base of associated adverse perinatal outcome. Despite the fact that further demonstration of causality would need new approaches and bigger sample sizes, AZT-sparing cART should be considered in the context

Intracellular zidovudine (ZDV) and ZDV phosphates as measured by a validated combined high-pressure liquid chromatography-radioimmunoassay procedure.

PubMed Central

Slusher, J T; Kuwahara, S K; Hamzeh, F M; Lewis, L D; Kornhauser, D M; Lietman, P S

1992-01-01

In vitro studies of zidovudine (ZDV) phosphorylation may not accurately reflect the in vivo dose-response relationship, which is crucial to determining the relationship between ZDV exposure, efficacy, and toxicity. However, measurement of ZDV phosphorylated anabolites in peripheral blood mononuclear cells (PBMCs) from ZDV-treated human immunodeficiency virus (HIV)-infected patients would be extremely useful in the more appropriate utilization of ZDV in the treatment of HIV infection. We developed a specific and sensitive combined high-pressure liquid chromatography (HPLC)-radioimmunoassay (RIA) procedure for the determination of ZDV, ZDV-monophosphate, ZDV-diphosphate, and ZDV-triphosphate in PBMCs taken from ZDV-treated HIV-infected patients. ZDV and its anabolites were extracted from washed, Ficoll-Paque-isolated PBMCs and then separated by HPLC using a strong anion-exchange column. The anabolites were then hydrolyzed to ZDV with acid phosphatase. ZDV was then measured by using a modified commercially available RIA protocol. Our method was validated by measuring [3H]ZDV anabolites generated in Molt-4 cells radioisotopically and simultaneously by the combined HPLC-RIA procedure. The ZDV determinations correlated well (r2 = 0.97) over the range of 0.037 to 5.2 pmol (10 to 1,400 pg) per assay tube. Furthermore, we defined the stability of ZDV anabolites during ficoll isolation and the recovery after extraction and cleanup. We then measured intracellular parent ZDV and its phosphorylated anabolites in PBMCs from six ZDV-treated HIV-infected patients (PBMCs were taken 2 h after a 300-mg oral dose). The mean concentrations ( +/- standard deviations) of parent and of mono-, di-, and triphosphates were 0.15 +/- 0.08, 1.4 +/-, 0.082 +/- 0.02, and 0.081 +/- 0.03 pmol/10(6) PBMC, respectively (one pmol/10(6) PBMC represents a concentration of approximately 1 microm). Concurrent serum ZDV concentrations were between 1.3 and 7.1 microm. This method should provide a useful

Higher placental anti-inflammatory IL-10 cytokine expression in HIV-1 infected women receiving longer zidovudine prophylaxis associated with nevirapine.

PubMed

Pornprasert, Sakorn; Mary, Jean-Yves; Faye, Albert; Leechanachai, Pranee; Limtrakul, Aram; Rugpao, Sungwal; Sirivatanapa, Pannee; Gomuthbutra, Vorapin; Matanasaravoot, Wanmanee; Le Coeur, Sophie; Lallemant, Marc; Barré-Sinoussi, Françoise; Menu, Elisabeth; Ngo-Giang-Huong, Nicole

2009-03-01

Placental cytokine balance may be critical for the control of mother-to-child transmission (MTCT) of HIV. We assessed whether the type and duration of antiretrovirals used for prevention of HIV-1-MTCT modified the inflammatory cytokine profile. We investigated the levels of cytokine expression in the placentas of 61 HIV-1-infected women who received zidovudine (ZDV) plus single dose nevirapine (SD-NVP) or ZDV only for prevention of MTCT. Placentas of 38 HIV-1-uninfected women were included as controls. All placentas were obtained after vaginal delivery. Levels of mRNA and cytokine expression were quantified using real-time PCR and ELISA, respectively, in placental explants and 24-hour culture supernatants and analyzed in relation to the women's characteristics and the type and duration of antiretroviral prophylaxis. HIV-1-infected and uninfected women did not show any differences in the expression of placental cytokine secretion except for a trend toward lower TNF-alpha mRNA levels in HIV-1-infected women. Within the HIV-1-infected group, women who were exposed to a long duration of ZDV (>72 days) or received SD-NVP less than 5h prior to delivery, more frequently expressed detectable levels of IL-10 in their placentas (32% versus 7% (p = 0.01) and 32% versus 5% (p = 0.02), respectively). No infant was found to be HIV-1-infected. Our results showed a normalization of the placental cytokine balance in HIV-1-infected women receiving antiretroviral prophylaxis. Furthermore, the type and duration of antiretroviral prophylaxis have an impact on the placental anti-inflammatory IL-10 expression level, which may contribute to controlling HIV replication at the placental level, thus reducing MTCT of HIV-1.

The potential toxicological insights about the anti-HIV drug azidothymidine-derived monoselenides in human leukocytes: Toxicological insights of new selenium-azidothymidine analogs.

PubMed

Mariano, Doc; de Souza, D; Meinerz, D F; Allebrandt, J; de Bem, A F; Hassan, W; Rodrigues, Oed; da Rocha, Jbt

2017-09-01

Acquired immunodeficiency syndrome (AIDS) is a worldwide disease characterized by impairments of immune function. AIDS can be associated with oxidative stress (OS) that can be linked to selenium (Se) deficiency. Se is fundamental for the synthesis of selenoproteins, such as glutathione peroxidase and thioredoxin reductase. These enzymes catalyze the decomposition of reactive oxygen species and contribute to maintain equilibrium in cell redox status. Literature data indicate that organoselenium compounds, such as ebselen and diphenyl diselenide, have antioxidant properties in vitro and in vivo models associated with OS. Nevertheless, selenocompounds can also react and oxidize thiols groups, inducing toxicity in mammals. Here, we tested the potential cytotoxic and genotoxic properties of six analogs of the prototypal anti-HIV drug azidothymidine (AZT) containing Se (5'-Se-(phenyl)zidovudine; 5'-Se-(1,3,5-trimethylphenyl)zidovudine; 5'-Se-(1-naphtyl)zidovudine; 5'-Se-(4-chlorophenyl)zidovudine) (C4); 5'-Se-(4-methylphenyl)zidovudine (C5); and 5'-(4-methylbenzoselenoate)zidovudine). C5 increased the rate of dithiothreitol oxidation (thiol oxidase activity) and C2-C4 and C6 (at 100 µM) increased DNA damage index (DI) in human leukocytes. Moreover, C5 (200 µM) decreased human leukocyte viability to about 50%. Taken together, these results indicated the low in vitro toxicity in human leukocytes of some Se-containing analogs of AZT.

Gelatin modified lipid nanoparticles for anti- viral drug delivery.

PubMed

K S, Joshy; S, Snigdha; Kalarikkal, Nandakumar; Pothen, Laly A; Thomas, Sabu

2017-10-01

The major challenges to clinical application of zidovudine are its moderate aqueous solubility and relative short half-life and serious side effects due to frequent administrations. We investigated the preparation of zidovudine-loaded nanoparticles based on lipids which were further modified with the polymer gelatin. Formulation and stability of the modified nanoparticles were analysed from the physico-chemical characterizations. The interactions of nanoparticles with blood components were tested by haemolysis and aggregation studies. The drug content and entrapment efficiencies were assessed by UV analysis. The effect of nanoparticles on protein adsorption was assessed by native polyacrylamide gel electrophoresis (PAGE). In vitro release studies showed a sustained release profile of zidovudine. In vitro cytotoxicity and cellular uptake of the zidovudine-loaded nanoparticles were performed in MCF-7 and neuro 2a brain cells. The enhanced cellular internalization of drug loaded modified nanoparticles in both the cell lines were revealed by fluorescence microscopy. Hence the present study focuses on the feasibility of zidovudine-loaded polymer modified lipid nanoparticles as carriers for safe and efficient HIV/AIDS therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Zidovudine/Lamivudine vs. Abacavir/Lamivudine vs. Tenofovir/Emtricitabine in fixed-dose combinations as initial treatment for HIV patients: a systematic review and network meta-analysis

PubMed Central

Duque Molina, Marcela María; García García, Héctor Iván

2017-01-01

Abstract Introduction: Initial treatment of the HIV is based on the use of three drugs, two of which are nucleoside analog reverse-transcriptase inhibitors. There are three combinations of these drugs which have been approved by different guidelines, each with divergent results in terms of efficacy and safety. Objective: To compare the efficacy and safety of these three combinations. Methods: Systematic review and network meta-analysis of randomized clinical trials comparing fixed doses of Tenofovir Disoproxil Fumarate / Emtricitabine (TDF/FTC), Abacavir / Lamivudine (ABC/3TC) and Zidovudine / Lamivudine (ZDV/3TC). Results: Seven clinical trials met the eligibility criteria. The results suggested higher efficacy with TDF/FTC vs. ABC/3TC at 96 weeks and vs. ZDV/3TC at 48 weeks. However, there is clinical and statistical heterogeneity. Subgroup analysis were performed by third drug and by level of viral load prior to treatment, and found no differences in virological control. Network meta-analysis could only be carried out with TDF/FTC vs. ZDV/3TC, and the proportion of patients with virological response, with no differences at 48 weeks nor at 96 weeks. Direct comparisons showed an increased risk of bone marrow suppression of ZDV/3TC vs. TDF/FTC and of ABC/3TC hypersensitivity reactions vs. ZDV/3TC Conclusions: The results did not show differences in effectiveness among the interventions. However, due to the heterogeneity of the third drug and the follow-up time between the included studies, this result is not definitive. The results raise the need for further studies to help improve treatment recommendations in patients infected with HIV. PMID:29021641

High Plasma Concentrations of Zidovudine (AZT) Do Not Parallel Intracellular Concentrations of AZT-Triphosphates in Infants During Prevention of Mother-to-Child HIV-1 Transmission.

PubMed

Kinai, Ei; Kato, Shingo; Hosokawa, Shinichi; Sadatsuki, Miyuki; Gatanaga, Hiroyuki; Kikuchi, Yoshimi; Lam, Nguyen Van; Ha, Do Quan; Kinh, Nguyen Van; Liem, Nguyen Thanh; Oka, Shinichi

2016-07-01

Zidovudine (AZT) is mainly used to prevent mother-to-child HIV-1 transmission (PMTCT). Despite serious concerns on AZT-associated toxicity, there is little information on pharmacokinetics of intracellular AZT metabolites in infants. We conducted a prospective study in 31 HIV-uninfected infants who received AZT for PMTCT. Blood samples were obtained from 14 infants on postdelivery days (PDD) 1, 7, 14, and 28 and from 17 infants at 0 and 4 hours after dosing on PDD-1. Plasma AZT concentrations (pAZT) and intracellular concentrations of AZT-monophosphate (icAZT-MP), diphosphate (icAZT-DP), and triphosphate (icAZT-TP) were determined. Plasma AZT and icAZT-MP concentrations were 2713 nmol/L and 79 fmol/10 cells in PDD-1, but decreased to 1437 nmol/L and 31 fmol/10 cells by PDD-28 (P = 0.02 and P = 0.07 for all PDDs, respectively), whereas those of icAZT-DP and icAZT-TP remained low throughout the sampling period (P = 0.29 and P = 0.61 for all PDDs, respectively) There were no differences in icAZT-TP between infants of the 2 mg/kg 4 times a day dose and 4 mg/kg twice daily dose (P = 0.25), whereas pAZT and icAZT-MP levels were higher in the latter (P < 0.01 and <0.01, respectively). The pAZT and icAZT-MP significantly increased from 0 to 4 hours after dosing (P < 0.001 and <0.001, respectively), whereas icAZT-DP, icAZT-TP levels were not changed (P = 0.41 and 0.33, respectively). The level of icAZT-TP did not change with age, time, or a single dose despite the wide range of pAZT concentration. A safer dosage needs to be determined because high pAZT levels do not parallel those of icAZT-TP.

Metabolism and pharmacokinetics of the combination Zidovudine plus Lamivudine in the adult Erythrocebus patas monkey determined by liquid chromatography-tandem mass spectrometric analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Divi, Rao L.; Doerge, Daniel R.; Twaddle, Nathan C.

2008-01-15

Because of their similarity to humans, non-human primates constitute useful preclinical models in which to examine potential human drug toxicities. Antiretroviral nucleoside reverse transcriptase inhibitor (NRTI) toxicity is currently under investigation in Erythrocebus patas monkeys, and whereas NRTI pharmacokinetics have been studied in other monkey species, pharmacokinetics for Zidovudine plus Lamivudine (AZT/3TC) dosing have not been reported in the patas. Here we present 24 h serum pharmacokinetic parameters after a single oral exposure to the combination of AZT (40 mg) and 3TC (24 mg), doses equivalent to a human daily dose of Combivir (registered) . The patas (n = 3)more » AZT/3TC pharmacokinetic profiles were similar to those seen in other primate species. Average maximum serum concentrations (C{sub max}) for AZT and 3TC were 2.35 and 2.65 {mu}g/ml, respectively, and were observed at 0.83 h (T{sub max}). C{sub max} was 13.34 {mu}g/ml for the AZT-glucuronide (AZT-G) and was 0.023 {mu}g/ml for the potentially toxic minor metabolite 3'-amino-3'-deoxythymidine (AMT), both occurring at about 1 h after dosing. Similar elimination half-times, 0.70 and 0.68 h{sup -1}, were found for AZT and AZT-G, respectively, while 3TC was eliminated about half as fast (0.33 h{sup -1}) resulting in AUC{sub (0-{infinity})} values of 6.97 {mu}g/ml h for 3TC, 2.99 {mu}g/ml h for AZT, 20.5 {mu}g/ml h for AZT-G and 0.002 for AMT 6.97 {mu}g/ml h. This study shows similar metabolism and pharmacokinetics for oral administration of AZT/3TC in the adult patas monkey, other primate species and humans. The data validate the use of the patas monkey for studies of NRTI toxicity.« less

Anaemia and zidovudine-containing antiretroviral therapy in paediatric antiretroviral programmes in the IeDEA Paediatric West African Database to evaluate AIDS.

PubMed

Renner, Lorna A; Dicko, Fatoumata; Kouéta, Fla; Malateste, Karen; Gueye, Ramatoulaye D; Aka, Edmond; Eboua, Tanoh K; Azondékon, Alain; Okomo, Uduok; Touré, Pety; Ekouévi, Didier; Leroy, Valeriane

2013-09-17

There is a risk of anaemia among HIV-infected children on antiretroviral therapy (ART) containing zidovudine (ZDV) recommended in first-line regimens in the WHO guidelines. We estimated the risk of severe anaemia after initiation of a ZDV-containing regimen in HIV-infected children included in the IeDEA West African database. Standardized collection of data from HIV-infected children (positive PCR<18 months or positive serology ≥ 18 months) followed up in HIV programmes was included in the regional IeDEA West Africa collaboration. Ten clinical centres from seven countries contributed (Benin, Burkina Faso, Côte d'Ivoire, Gambia, Ghana, Mali and Senegal) to this collection. Inclusion criteria were age <16 years and starting ART. We explored the data quality of haemoglobin documentation over time and the incidence and predictors of severe anaemia (Hb<7 g/dL) per 100 child-years of follow-up over the duration of first-line antiretroviral therapy. As of December 2009, among the 2933 children included in the collaboration, 45% were girls, median age was five years; median CD4 cell percentage was 13%; median weight-for-age z-score was-2.7; and 1772 (60.4%) had a first-line ZDV-containing regimen. At baseline, 70% of the children with a first-line ZDV-containing regimen had a haemoglobin measure available versus 76% in those not on ZDV (p ≤ 0.01): the prevalence of severe anaemia was 3.0% (n=38) in the ZDV group versus 10.2% (n=89) in those without (p<0. 01). Over the first-line follow-up, 58.9% of the children had ≥ 1 measure of haemoglobin available in those exposed to ZDV versus 60.4% of those not (p=0.45). Severe anaemia occurred in 92 children with an incidence of 2.47 per 100 child-years of follow-up in those on a ZDV-containing regimen versus 4.25 in those not (p ≤ 0.01). Adjusted for age at ART initiation and first-line regimen, a weight-for-age z-score ≤-3 was a strong predictor associated with a 5.59 times risk of severe anaemia (p<0.01). Severe

Anaemia and zidovudine-containing antiretroviral therapy in paediatric antiretroviral programmes in the IeDEA Paediatric West African Database to evaluate AIDS

PubMed Central

Renner, Lorna A; Dicko, Fatoumata; Kouéta, Fla; Malateste, Karen; Gueye, Ramatoulaye D; Aka, Edmond; Eboua, Tanoh K; Azondékon, Alain; Okomo, Uduok; Touré, Pety; Ekouévi, Didier; Leroy, Valeriane

2013-01-01

Introduction There is a risk of anaemia among HIV-infected children on antiretroviral therapy (ART) containing zidovudine (ZDV) recommended in first-line regimens in the WHO guidelines. We estimated the risk of severe anaemia after initiation of a ZDV-containing regimen in HIV-infected children included in the IeDEA West African database. Methods Standardized collection of data from HIV-infected children (positive PCR<18 months or positive serology ≥18 months) followed up in HIV programmes was included in the regional IeDEA West Africa collaboration. Ten clinical centres from seven countries contributed (Benin, Burkina Faso, Côte d'Ivoire, Gambia, Ghana, Mali and Senegal) to this collection. Inclusion criteria were age <16 years and starting ART. We explored the data quality of haemoglobin documentation over time and the incidence and predictors of severe anaemia (Hb<7g/dL) per 100 child-years of follow-up over the duration of first-line antiretroviral therapy. Results As of December 2009, among the 2933 children included in the collaboration, 45% were girls, median age was five years; median CD4 cell percentage was 13%; median weight-for-age z-score was −2.7; and 1772 (60.4%) had a first-line ZDV-containing regimen. At baseline, 70% of the children with a first-line ZDV-containing regimen had a haemoglobin measure available versus 76% in those not on ZDV (p≤0.01): the prevalence of severe anaemia was 3.0% (n=38) in the ZDV group versus 10.2% (n=89) in those without (p<0. 01). Over the first-line follow-up, 58.9% of the children had ≥1 measure of haemoglobin available in those exposed to ZDV versus 60.4% of those not (p=0.45). Severe anaemia occurred in 92 children with an incidence of 2.47 per 100 child-years of follow-up in those on a ZDV-containing regimen versus 4.25 in those not (p≤0.01). Adjusted for age at ART initiation and first-line regimen, a weight-for-age z-score ≤−3 was a strong predictor associated with a 5.59 times risk of severe

Nucleoside reverse transcriptase inhibitor resistance mutations associated with first-line stavudine-containing antiretroviral therapy: programmatic implications for countries phasing out stavudine.

PubMed

Tang, Michele W; Rhee, Soo-Yon; Bertagnolio, Silvia; Ford, Nathan; Holmes, Susan; Sigaloff, Kim C; Hamers, Raph L; de Wit, Tobias F Rinke; Fleury, Herve J; Kanki, Phyllis J; Ruxrungtham, Kiat; Hawkins, Claudia A; Wallis, Carole L; Stevens, Wendy; van Zyl, Gert U; Manosuthi, Weerawat; Hosseinipour, Mina C; Ngo-Giang-Huong, Nicole; Belec, Laurent; Peeters, Martine; Aghokeng, Avelin; Bunupuradah, Torsak; Burda, Sherri; Cane, Patricia; Cappelli, Giulia; Charpentier, Charlotte; Dagnra, Anoumou Y; Deshpande, Alaka K; El-Katib, Ziad; Eshleman, Susan H; Fokam, Joseph; Gody, Jean-Chrysostome; Katzenstein, David; Koyalta, Donato D; Kumwenda, Johnstone J; Lallemant, Marc; Lynen, Lutgarde; Marconi, Vincent C; Margot, Nicolas A; Moussa, Sandrine; Ndung'u, Thumbi; Nyambi, Phillipe N; Orrell, Catherine; Schapiro, Jonathan M; Schuurman, Rob; Sirivichayakul, Sunee; Smith, Davey; Zolfo, Maria; Jordan, Michael R; Shafer, Robert W

2013-06-15

The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure. We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance. Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥ two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M. Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy.

Variable uptake of recommended interventions to reduce mother-to-child transmission of HIV in Australia, 1982-2005.

PubMed

Giles, Michelle L; McDonald, Ann M; Elliott, Elizabeth J; Ziegler, John B; Hellard, Margaret E; Lewin, Sharon R; Kaldor, John M

2008-08-04

To analyse the uptake of interventions known to reduce the risk of perinatal HIV transmission among Australian women with HIV infection (who knew their HIV status before delivery), and identify predictors of uptake. Retrospective analysis of perinatal HIV surveillance data in Australia. Women reported as having HIV infection and having given birth to a child (1982-2005) were identified through three mechanisms: an informal network of clinicians (1982-1993); an active surveillance program through paediatricians (since 1993); and state health department reports of children born to women newly diagnosed with HIV (since 1995). Uptake of interventions - avoidance of breastfeeding (after 1985), use of zidovudine during pregnancy (after 1994), and elective caesarean section (after 1999). Factors associated with uptake of these interventions were identified by univariate and multivariate analyses. 367 live births were reported in 291 women with HIV infection. Among the subgroup diagnosed with HIV infection before delivery, 4/255 (1.6%) elected to breastfeed (post 1985), 44/185 (24%) did not receive zidovudine (after 1994), and 41/118 (35%) did not have an elective caesarean section (after 1999). In multivariate analysis, there were significant differences in uptake of zidovudine and elective caesarean section according to year of birth and state in which the birth took place. In Australia between 1982 and 2005, uptake of interventions to reduce mother-to-child transmission of HIV was high. There were significant differences associated with use of zidovudine and mode of delivery according to location of delivery and year of birth.

Prophylaxis and treatment of HIV-1 infection in pregnancy: Swedish recommendations 2010.

PubMed

Navér, Lars; Albert, Jan; Belfrage, Erik; Flamholc, Leo; Gisslén, Magnus; Gyllensten, Katarina; Josephson, Filip; Karlström, Olof; Lindgren, Susanne; Pettersson, Karin; Svedhem, Veronica; Sönnerborg, Anders; Westling, Katarina; Yilmaz, Aylin; Swedish Reference Group for Antiviral Therapy

2011-07-01

Prophylaxis and treatment with antiretroviral drugs and the use of elective caesarean section have resulted in a very low mother-to-child transmission of human immunodeficiency virus (HIV) during recent years. The availability of new antiretroviral drugs, updated general treatment guidelines and increasing knowledge of the importance of drug resistance, have necessitated regular revisions of the "Prophylaxis and treatment of HIV-1 infection in pregnancy" recommendations. For these reasons, The Swedish Reference Group for Antiviral Therapy (RAV) updated the 2007 recommendations at an expert meeting that took place on 25 March 2010. The most important revisions from the previous recommendations are: (1) it is recommended that treatment during pregnancy starts at the latest at gestational week 14-18; (2) ongoing efficient treatment at confirmed pregnancy may, with a few exceptions, be continued; (3) lopinavir/r and atazanavir/r are equally recommended protease inhibitors; (4) if maternal HIV RNA is >50 copies/ml close to delivery, a planned caesarean section, intravenous zidovudine, oral nevirapine for the mother and post-exposure prophylaxis for the infant with 3 antiretroviral drugs are recommended; (5) for delivery at <34 gestational weeks, intravenous zidovudine and oral nevirapine for the mother and at 48-72 h for the infant is recommended, in addition to other prophylaxis; (6) intravenous zidovudine is not recommended when HIV RNA is <50 copies/ml and a caesarean section is performed; (7) it is recommended that prophylaxis for the infant is started within 4 h; (8) prophylactic zidovudine for the infant may be administered twice daily instead of 4 times a day, as was the case previously; and (9) the number of sampling occasions for the infant has been decreased.

Derivative Spectrophotometric Method for Estimation of Antiretroviral Drugs in Fixed Dose Combinations

PubMed Central

P.B., Mohite; R.B., Pandhare; S.G., Khanage

2012-01-01

Purpose: Lamivudine is cytosine and zidovudine is cytidine and is used as an antiretroviral agents. Both drugs are available in tablet dosage forms with a dose of 150 mg for LAM and 300 mg ZID respectively. Method: The method employed is based on first order derivative spectroscopy. Wavelengths 279 nm and 300 nm were selected for the estimation of the Lamovudine and Zidovudine respectively by taking the first order derivative spectra. The conc. of both drugs was determined by proposed method. The results of analysis have been validated statistically and by recovery studies as per ICH guidelines. Result: Both the drugs obey Beer’s law in the concentration range 10-50 μg mL-1,for LAM and ZID; with regression 0.9998 and 0.9999, intercept – 0.0677 and – 0.0043 and slope 0.0457 and 0.0391 for LAM and ZID, respectively.The accuracy and reproducibility results are close to 100% with 2% RSD. Conclusion: A simple, accurate, precise, sensitive and economical procedures for simultaneous estimation of Lamovudine and Zidovudine in tablet dosage form have been developed. PMID:24312779

Higher rates of metabolic syndrome among women taking zidovudine as compared to tenofovir in rural Africa: preliminary data from the CART-1 study.

PubMed

Labhardt, Niklaus Daniel; Cheleboi, Molisana; Faturyiele, Olatunbosun; Motlatsi, Mokete M; Pfeiffer, Karolin; Lejone, Thabo Ismael; Cerutti, Bernard; Muser, Jürgen; Gupta, Ravi Shankar; Lynen, Lutgarde; Hatz, Christoph

2014-01-01

Due to its side effects stavudine (D4T) has been replaced by zidovudine (AZT) and tenofovir (TDF) in most low- and middle-income countries (LMICs). In 2014 about 38% of adult first-line regimens contain AZT and 62% TDF [1]. Whereas the unfavourable metabolic outcomes of D4T in comparison to TDF have been described extensively, studies from LMICs comparing metabolic profiles between patients on AZT and TDF are scarce. Given the high number of patients in LMICs still taking AZT, data on their metabolic profile are needed. We present rates of metabolic syndrome (MS) in adult patients taking either AZT- or TDF-containing first-line, non-nucleoside reverse transcriptase (NNRTI)-based regimens. Data derived from a cross-sectional multi-disease screening conducted in ten facilities in two rural districts of Lesotho, Southern Africa [2]. Patients were eligible if aged ≥25 years and on NNRTI-containing first-line ART ≥6 months. The MS definition for Africa of the International Diabetes Federation was applied [3]. Assessed potential predictors for MS were age, time on ART, virologic suppression, body-mass index (BMI), alcohol consumption, wealth quintile, NNRTI (nevirapine (NVP) or Efavirenz (EFV)), history of previous D4T exposure and ART-backbone (AZT or TDF). Statistical analyses - stratified for sex - comprised univariate logistic regression for each predictor variable with subsequent construction of a multivariate model including all predictors with an association to MS at a significance level<0.1 in univariate analysis. Out of 1026 patients, 660 (64.3%) were female. MS prevalence was 9.8% (95% CI 6.9-13.4) in men and 22.9% (19.7-26.3) in women. In women, aged ≥35 years, AZT-backbone, NVP-base, BMI ≥25kg/m2 and taking ART for ≥4.5 years were associated with MS in univariate analysis. In the multivariate model only AZT (adjusted odds-ratio: 2.2, 95% CI 1.4-3.6; p=0.001) and BMI ≥25kg/m2 (9.8; 2.8-34.1, p<0.001) were associated with MS. For men, age, higher

Improvement in vitamin D deficiency following antiretroviral regime change: Results from the MONET trial.

PubMed

Fox, Julie; Peters, Barry; Prakash, Manyu; Arribas, Jose; Hill, Andrew; Moecklinghoff, Christiane

2011-01-01

Low levels of vitamin D are reported in HIV-infected individuals. In HIV-negative people, low vitamin D levels have been associated with an increased risk of cardiovascular disease and cancer and with worse survival. The MONET trial recruited 256 European patients with HIV RNA <50 copies/ml at screening, while taking either NNRTI- or PI-based HAART. Patients were switched to DRV/r 800/100 mg once daily, either as monotherapy or with two NRTIs. In all, 221 patients were measured for 25-hydroxyvitamin D at a central laboratory before randomized treatment started and at week 96. Multiple regression was used to correlate vitamin D levels with gender, season, ethnic group, treatment group, and use of antiretrovirals. Overall, 80% of patients were male and 91% were white, with a mean age of 44 years. At screening, 170/221 (77%) patients had vitamin D deficiency (<50 nmol/liter). At the screening visit, lower vitamin D levels were significantly associated with calendar month (p = 0.0067), black ethnicity (p = 0.013), use of efavirenz (p = 0.0062), and use of zidovudine (p = 0.015). Mean vitamin D levels were lowest from January to April (mean = 35.8 nmol/liter) and highest in September (mean = 45.4 nmol/liter). Increases in vitamin D between screening and week 96 were significantly greater for patients who discontinued efavirenz or zidovudine before the MONET trial versus those who stopped other antiretrovirals. At screening, lower vitamin D levels were associated with season, race, and use of efavirenz and/or zidovudine. Switching from efavirenz and/or zidovudine to darunavir/ritonavir during the trial led to increases in vitamin D levels. Routine screening of HIV-positive patients for vitamin D should be considered and the optimal management further defined.

Synthesis, molecular structure and physicochemical properties of bis(3‧-azido-3‧-deoxythymidin-5‧-yl) carbonate

NASA Astrophysics Data System (ADS)

Raviolo, Mónica A.; Williams, Patricia A. M.; Etcheverry, Susana B.; Piro, Oscar E.; Castellano, Eduardo E.; Gualdesi, Maria S.; Briñón, Margarita C.

2010-04-01

3'-Azido-3'-deoxythymidine (zidovudine, AZT), a synthetic analog of natural nucleoside thymidine, has been used extensively in AIDS treatments. We report here the synthesis, X-ray crystal and molecular structure, NMR, IR and Raman spectra and the thermal behavior of a novel carbonate of AZT [(AZT-O) 2C dbnd O], prepared by the reaction of zidovudine with carbonyldiimidazole. The carbonate compound, C 21H 24N 10O 9, crystallizes in the tetragonal space group P4 12 12 with a = b = 15.284(1), c = 21.695(1) Å, and Z = 8 molecules per unit cell. It consists of two AZT moieties of closely related conformations which are bridged by a carbonyl group to adopt a folded Z-like shape.

Decreased human immunodeficiency virus type 1 plasma viremia during antiretroviral therapy reflects downregulation of viral replication in lymphoid tissue.

PubMed Central

Cohen, O J; Pantaleo, G; Holodniy, M; Schnittman, S; Niu, M; Graziosi, C; Pavlakis, G N; Lalezari, J; Bartlett, J A; Steigbigel, R T

1995-01-01

Although several immunologic and virologic markers measured in peripheral blood are useful for predicting accelerated progression of human immunodeficiency virus (HIV) disease, their validity for evaluating the response to antiretroviral therapy and their ability to accurately reflect changes in lymphoid organs remain unclear. In the present study, changes in certain virologic markers have been analyzed in peripheral blood and lymphoid tissue during antiretroviral therapy. Sixteen HIV-infected individuals who were receiving antiretroviral therapy with zidovudine for > or = 6 months were randomly assigned either to continue on zidovudine alone or to add didanosine for 8 weeks. Lymph node biopsies were performed at baseline and after 8 weeks. Viral burden (i.e., HIV DNA copies per 10(6) mononuclear cells) and virus replication in mononuclear cells isolated from peripheral blood and lymph node and plasma viremia were determined by semiquantitative polymerase chain reaction assays. Virologic and immunologic markers remained unchanged in peripheral blood and lymph node of patients who continued on zidovudine alone. In contrast, a decrease in virus replication in lymph nodes was observed in four of six patients who added didanosine to their regimen, and this was associated with a decrease in plasma viremia. These results indicate that decreases in plasma viremia detected during antiretroviral therapy reflect downregulation of virus replication in lymphoid tissue. Images Fig. 1 Fig. 2 Fig. 3 PMID:7597072

Didanosine, lamivudine, and efavirenz versus zidovudine, lamivudine, and efavirenz for the initial treatment of HIV type 1 infection: final analysis (48 weeks) of a prospective, randomized, noninferiority clinical trial, GESIDA 3903.

PubMed

Berenguer, Juan; González, Juan; Ribera, Esteban; Domingo, Pere; Santos, Jesús; Miralles, Pilar; Angels Ribas, M; Asensi, Víctor; Gimeno, Juan Luis; Pérez-Molina, José Antonio; Terrón, José Alberto; Santamaría, Juan Miguel; Pedrol, Enric

2008-10-15

The combination of didanosine, lamivudine, and efavirenz (ddI/3TC/EFV) for the initial treatment of human immunodeficiency virus type 1 (HIV-1) infection has been insufficiently analyzed in clinical trials. We conducted an open-label, randomized study to compare the noninferiority of ddI/3TC/EFV with the lamivudine-zidovudine tablet and EFV (COM/EFV), both administered with food to improve tolerability and convenience. Patients were stratified by HIV-1 RNA level of <5.0 log(10) or > or =5.0 log(10) copies/mL. The primary end point was the percentage of patients with an HIV-1 RNA level of <50 copies/mL at week 48, determined by intention-to-treat analysis. Three hundred sixty-nine patients were randomized: 186 for ddI/3TC/EFV treatment and 183 for COM/EFV treatment. Both groups were well matched in terms of baseline characteristics; 19.3% of patients received a Centers for Disease Control and Prevention assessment of clinical category C, median HIV RNA level was 5.0 log(10) copies/mL, and median CD4(+) cell count was 208 cells/microL. At week 48, by intention-to-treat analysis, 70% of patients in the ddI/3TC/EFV group and 63% of patients in the COM/EFV group had an HIV-1 RNA level of <50 copies/mL (treatment difference, 7.1%; 95% confidence interval, -2.39% to 16.59%). Fourteen patients (8%) in the ddI/3TC/EFV arm (not the COM/EFV arm) and 26 patients (14%) in the COM/EFV arm (not the ddI/3TC/EFV arm) [corrected] discontinued the study medication because of adverse events (P = .046). One patient (1%) in the ddI/3TC/EFV arm and 11 patients (6%) in the COM/EFV arm discontinued medication because of hematological toxicity (P = .003). At week 48, ddI/3TC/EFV administered once per day with food did not have results inferior to those of COM/EFV treatment. A statistically significantly higher proportion of patients in the COM/EFV arm than in the ddI/3TC/EFV arm discontinued therapy because of adverse events, mainly because of hematological toxicity. NCT00256828.

Comparative safety and effectiveness of perinatal antiretroviral therapies for HIV-infected women and their children: Systematic review and network meta-analysis including different study designs.

PubMed

Veroniki, Areti Angeliki; Antony, Jesmin; Straus, Sharon E; Ashoor, Huda M; Finkelstein, Yaron; Khan, Paul A; Ghassemi, Marco; Blondal, Erik; Ivory, John D; Hutton, Brian; Gough, Kevin; Hemmelgarn, Brenda R; Lillie, Erin; Vafaei, Afshin; Tricco, Andrea C

2018-01-01

Nearly all newly infected children acquire Human Immunodeficiency virus (HIV) via mother-to-child transmission (MTCT) during pregnancy, labour or breastfeeding from untreated HIV-positive mothers. Antiretroviral therapy (ART) is the standard care for pregnant women with HIV. However, evidence of ART effectiveness and harms in infants and children of HIV-positive pregnant women exposed to ART has been largely inconclusive. The aim of our systematic review and network meta-analysis (NMA) was to evaluate the comparative safety and effectiveness of ART drugs in children exposed to maternal HIV and ART (or no ART/placebo) across different study designs. We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (inception until December 7, 2015). Primary outcomes were any congenital malformations (CMs; safety), including overall major and minor CMs, and mother-to-child transmission (MTCT; effectiveness). Random-effects Bayesian pairwise meta-analyses and NMAs were conducted. After screening 6,468 citations and 1,373 full-text articles, 90 studies of various study designs and 90,563 patients were included. The NMA on CMs (20 studies, 7,503 children, 16 drugs) found that none of the ART drugs examined here were associated with a significant increase in CMs. However, zidovudine administered with lamivudine and indinavir was associated with increased risk of preterm births, zidovudine administered with nevirapine was associated with increased risk of stillbirths, and lamivudine administered with stavudine and efavirenz was associated with increased risk of low birth weight. A NMA on MTCT (11 studies, 10,786 patients, 6 drugs) found that zidovudine administered once (odds ratio [OR] = 0.39, 95% credible interval [CrI]: 0.19-0.83) or twice (OR = 0.43, 95% CrI: 0.21-0.68) was associated with significantly reduced risk of MTCT. Our findings suggest that ART drugs are not associated with an increased risk of CMs, yet some may increase adverse birth events

National Institutes of Health Clinical Alerts and Advisories

MedlinePlus

... Health & Toxicology Health Services Research & Public Health Health Information Technology NLM for You Grants & Funding Meaningful Use Tools Training & Outreach Network of Medical Libraries Regional ... Important Therapeutic Information on the Benefit of Zidovudine (AZT) for the ...

Interferon-α (IFN-α) suppresses HTLV-1 gene expression and cell cycling, while IFN-α combined with zidovudin induces p53 signaling and apoptosis in HTLV-1-infected cells

PubMed Central

2013-01-01

Background Human T-cell leukemia virus type-1 (HTLV-1) is the causative retrovirus of adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 gene expression is maintained at low levels in vivo by unknown mechanisms. A combination therapy of interferon-α (IFN-α) and zidovudin (AZT) shows therapeutic effects in ATL patients, although its mechanism is also obscure. We previously found that viral gene expression in IL-2-dependent HTLV-1-infected T-cells (ILTs) derived from ATL patients was markedly suppressed by stromal cells through a type I IFN response. Here, we investigated the effects of IFN-α with or without AZT on viral gene expression and cell growth in ILTs. Results ILTs expressed variable but lower amounts of HTLV-1 Tax protein than HTLV-1-transformed HUT102 cells. Following the addition of IFN-α, the amounts of HTLV-1 p19 in the supernatants of these cells decreased in three days, while HTLV-1 gene expression decreased only in ILTs but not HUT102 cells. IFN-α also suppressed the spontaneous HTLV-1 induction in primary ATL cells cultured for 24 h. A time course study using ILTs revealed that the levels of intracellular Tax proteins decreased in the first 24 h after addition of IFN-α, before the reduction in HTLV-1 mRNA levels. The initial decreases of Tax protein following IFN-α treatment were observed in 6 of 7 ILT lines tested, although the reduction rates varied among ILT lines. An RNA-dependent protein kinase (PKR)-inhibitor reversed IFN-mediated suppression of Tax in ILTs. IFN-α also induced cell cycle arrest at the G0/G1 phase and suppressed NF-κB activities in these cells. AZT alone did not affect HTLV-1 gene expression, cell viability or NF-κB activities. AZT combined with IFN-α markedly induced cell apoptosis associated with phosphorylation of p53 and induction of p53-responsive genes in ILTs. Conclusions IFN-α suppressed HTLV-1 gene expression at least through a PKR

Racial differences in virologic failure associated with adherence and quality of life on efavirenz-containing regimens for initial HIV therapy: results of ACTG A5095.

PubMed

Schackman, Bruce R; Ribaudo, Heather J; Krambrink, Amy; Hughes, Valery; Kuritzkes, Daniel R; Gulick, Roy M

2007-12-15

Blacks had higher rates of virologic failure than whites on efavirenz-containing regimens in the AIDS Clinical Trials Group (ACTG) A5095 study; preliminary analyses also suggested an association with adherence. We rigorously examined associations over time among race, virologic failure, 4 self-reported adherence metrics, and quality of life (QOL). ACTG A5095 was a double-blind placebo-controlled study of treatment-naive HIV-positive patients randomized to zidovudine/lamivudine/abacavir versus zidovudine/lamivudine plus efavirenz versus zidovudine/lamivudine/abacavir plus efavirenz. Virologic failure was defined as confirmed HIV-1 RNA >or=200 copies/mL at >or=16 weeks on study. The zidovudine/lamivudine/abacavir arm was discontinued early because of virologic inferiority. We examined virologic failure differences for efavirenz-containing arms according to missing 0 (adherent) versus at least 1 dose (nonadherent) during the past 4 days, alternative self-reported adherence metrics, and QOL. Analyses used the Fisher exact, log rank tests, and Cox proportional hazards models. The study population included white (n = 299), black (n = 260), and Hispanic (n = 156) patients with >or=1 adherence evaluation. Virologic failure was associated with week 12 nonadherence during the past 4 days for blacks (53% nonadherent failed vs. 25% adherent; P < 0.001) but not for whites (20% nonadherent failed vs. 20% adherent; P = 0.91). After adjustment for baseline covariates and treatment, there was a significant interaction between race and week 12 adherence (P = 0.02). In time-dependent Cox models using self-reports over time to reflect recent adherence, there was a significantly higher failure risk for nonadherent subjects (hazard ratio [HR] = 2.07; P < 0.001). Significant race-adherence interactions were seen in additional models of adherence: missing at least 1 medication dose ever (P = 0.04), past month (P < 0.01), or past weekend (P = 0.05). Lower QOL was significantly associated

The history of antiretrovirals: key discoveries over the past 25 years.

PubMed

De Clercq, Erik

2009-09-01

Within 25 years after zidovudine (3'-azido-2',3'-dideoxythymidine, AZT) was first described as an inhibitor of HIV replication, 25 anti-HIV drugs have been formally approved for clinical use in the treatment of HIV infections: seven nucleoside reverse transcriptase inhibitors (NRTIs): zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine; one nucleotide reverse transcriptase inhibitor (NtRTI): tenofovir [in its oral prodrug form: tenofovir disoproxil fumarate (TDF)]; four non-nucleoside reverse transcriptase inhibitors (NNRTIs): nevirapine, delavirdine, efavirenz and etravirine; ten protease inhibitors (PIs): saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir and darunavir; one fusion inhibitor (FI): enfuvirtide; one co-receptor inhibitor (CRI): maraviroc and one integrase inhibitor (INI): raltegravir. These compounds are used in various drug combination (some at fixed dose) regimens so as to achieve the highest possible benefit and tolerability, and to diminish the risk of virus-drug resistance development. (c) 2009 John Wiley & Sons, Ltd.

Single-Dose Pharmacokinetics and Safety of Abacavir (1592U89), Zidovudine, and Lamivudine Administered Alone and in Combination in Adults with Human Immunodeficiency Virus Infection

PubMed Central

Wang, Laurene H.; Chittick, Gregory E.; McDowell, James A.

1999-01-01

Abacavir (1592U89), a nucleoside reverse transcriptase inhibitor with in vitro activity against human immunodeficiency virus type-1 (HIV-1), has been evaluated for efficacy and safety in combination regimens with other nucleoside analogs, including zidovudine (ZDV) and lamivudine (3TC). To evaluate the potential pharmacokinetic interactions between these agents, 15 HIV-1-infected adults with a median CD4+ cell count of 347 cells/mm3 (range, 238 to 570 cells/mm3) were enrolled in a randomized, seven-period crossover study. The pharmacokinetics and safety of single doses of abacavir (600 mg), ZDV (300 mg), and 3TC (150 mg) were evaluated when each drug was given alone or when any two or three drugs were given concurrently. The concentrations of all drugs in plasma and the concentrations of ZDV and its 5′-glucuronide metabolite, GZDV, in urine were measured for up to 24 h postdosing, and pharmacokinetic parameter values were calculated by noncompartmental methods. The maximum drug concentration (Cmax), the area under the concentration-time curve from time zero to infinity (AUC0–∞), time to Cmax (Tmax), and apparent elimination half-life (t1/2) of abacavir in plasma were unaffected by coadministration with ZDV and/or 3TC. Coadministration of abacavir with ZDV (with or without 3TC) decreased the mean Cmax of ZDV by approximately 20% (from 1.5 to 1.2 μg/ml), delayed the median Tmax for ZDV by 0.5 h, increased the mean AUC0–∞ for GZDV by up to 40% (from 11.8 to 16.5 μg · h/ml), and delayed the median Tmax for GZDV by approximately 0.5 h. Coadministration of abacavir with 3TC (with or without ZDV) decreased the mean AUC0–∞ for 3TC by approximately 15% (from 5.1 to 4.3 μg · h/ml), decreased the mean Cmax by approximately 35% (from 1.4 to 0.9 μg/ml), and delayed the median Tmax by approximately 1 h. While these changes were statistically significant, they are similar to the effect of food intake (for ZDV) or affect an inactive metabolite (for GZDV) or are

Identification of transformation products of antiviral drugs formed during biological wastewater treatment and their occurrence in the urban water cycle.

PubMed

Funke, Jan; Prasse, Carsten; Ternes, Thomas A

2016-07-01

The fate of five antiviral drugs (abacavir, emtricitabine, ganciclovir, lamivudine and zidovudine) was investigated in biological wastewater treatment. Investigations of degradation kinetics were accompanied by the elucidation of formed transformation products (TPs) using activated sludge lab experiments and subsequent LC-HRMS analysis. Degradation rate constants ranged between 0.46 L d(-1) gSS(-1) (zidovudine) and 55.8 L d(-1) gSS(-1) (abacavir). Despite these differences of the degradation kinetics, the same main biotransformation reaction was observed for all five compounds: oxidation of the terminal hydroxyl-moiety to the corresponding carboxylic acid (formation of carboxy-TPs). In addition, the oxidation of thioether moieties to sulfoxides was observed for emtricitabine and lamivudine. Antiviral drugs were detected in influents of municipal wastewater treatment plants (WWTPs) with concentrations up to 980 ng L(-1) (emtricitabine), while in WWTP effluents mainly the TPs were found with concentration levels up to 1320 ng L(-1) (carboxy-abacavir). Except of zidovudine none of the original antiviral drugs were detected in German rivers and streams, whereas the concentrations of the TPs ranged from 16 ng L(-1) for carboxy-lamivudine up to 750 ng L(-1) for carboxy-acyclovir. These concentrations indicate an appreciable portion from WWTP effluents present in rivers and streams, as well as the high environmental persistence of the carboxy-TPs. As a result three of the carboxylic TPs were detected in finished drinking water. Copyright © 2016 Elsevier Ltd. All rights reserved.

Rational design of molecularly imprinted polymer: the choice of cross-linker.

PubMed

Muhammad, Turghun; Nur, Zohre; Piletska, Elena V; Yimit, Osmanjan; Piletsky, Sergey A

2012-06-07

The paper describes a rational approach for the selection of cross-linkers during the development of molecularly imprinted polymers (MIPs). As a model system for this research MIPs specific for the drug zidovudine (AZT) were designed and tested. Three cross-linkers trimethylolpropane trimethacrylate (TRIM), ethylene glycol dimethacrylate (EGDMA) and divinylbenzene (DVB) were studied. The analogue of zidovudine (AZT) ester (AZT-ES) was used as a dummy template. The imprinting factors for all of the polymers in the static adsorption experiments were calculated. The data on the AZT adsorption by control polymers (CP), which were prepared with different cross-linkers without a functional monomer, was also analyzed. DVB was found to be more inert towards zidovudine than EGDMA and TRIM, which was confirmed by both molecular modelling and adsorption experiments. It was demonstrated that DVB-based polymers had a higher imprinting factor (I = 1.85) compared with other tested cross-linked polymers. It was suggested that the selection of the cross-linker should be based on the strength of the interaction with the template: the cross-linker which displays lower binding of the template should be preferential because it generates MIPs with lower non-specific binding and a higher imprinting factor, and therefore specificity. Which cross-linker to use for the preparation of any particular MIP can be determined by analysis of the interactions between the cross-linker and template. This could be done either virtually using computational modelling or by template adsorption using a small library of polymers prepared using different cross-linkers.

Risk Factors for Early and Late Transmission of HIV via Breast-Feeding among Infants Born to HIV-Infected Women in a Randomized Clinical Trial in Botswana

PubMed Central

Shapiro, Roger L.; Smeaton, Laura; Lockman, Shahin; Thior, lbou; Rossenkhan, Raabya; Wester, Carolyn; Stevens, Lisa; Moffat, Claire; Arimi, Peter; Ndase, Patrick; Asmelash, Aida; Leidner, Jean; Novitsky, Vladimir; Makhema, Joseph; Essex, Max

2009-01-01

Risk factors for mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) via breast-feeding were evaluated in a randomized trial. HIV-infected women and their infants received zidovudine as well as single-dose nevirapine or placebo. Infants were randomized to formula-feed (FF) or breast-feed (BF) in combination with zidovudine prophylaxis. Of 1116 at-risk infants, 6 (1.1%) in the FF group and 7 (1.3%) in the BF group were infected between birth and 1 month)P = .99). Maternal receipt of nevirapine did not predict early MTCT in the BF group (P = .45). Of 547 infants in the BF group at risk for late MTCT, 24 (4.4%) were infected. Maternal HIV-1 RNA levels in plasma (P<.001) and breast milk (P<.001) predicted late MTCT. These findings support the safety of 1 month of breast-feeding in combination with maternal and infant antiretroviral prophylaxis. PMID:19090775

Pregnancy outcomes in HIV-positive women in Ukraine, 2000-12 (European Collaborative Study in EuroCoord): an observational cohort study.

PubMed

Bagkeris, Emmanouil; Malyuta, Ruslan; Volokha, Alla; Cortina-Borja, Mario; Bailey, Heather; Townsend, Claire L; Thorne, Claire

2015-09-01

Women living with HIV are potentially at increased risk of adverse pregnancy outcomes, due to a range of factors, including immunosuppression, use of combination antiretroviral therapy (ART), and injecting drug use. Rates of mother-to-child transmission of HIV in Ukraine have declined to around 2-4%, but little is known about other pregnancy outcomes in this setting. We used data from an observational prospective cohort study to assess pregnancy outcomes among HIV-positive women in Ukraine. The European Collaborative Study (ECS) in EuroCoord is a continuing cohort study, established in Ukraine in 2000. Eligible women are those with a diagnosis of HIV infection before or during pregnancy (including intrapartum) who deliver liveborn babies at seven sites. Maternal sociodemographic, HIV-related, and delivery (mother and infant) data were collected with study-specific questionnaires. We used Poisson regression models to identify factors associated with preterm delivery (before 37 weeks' gestation) and small weight for gestational age (less than the tenth percentile of weight for gestational age), based on complete cases. Between January, 2000, and July, 2012, data were collected on 8884 HIV-positive mother and liveborn infant pairs. Median maternal age was 26·5 years (IQR 23·1-30·3). 832 (11%) women had WHO stage 3 or 4 HIV and 1474 (17%) had a history of injecting drug use. 7348 (83%) had received antenatal ART. Among 7435 for whom ART type was available, 4396 (50%) had received zidovudine monotherapy and 2949 (33%) combination ART. Preterm delivery was seen in 780 (9%, 95% CI 8-9) of 8860 births overall and in 77 (9%, 7-11) of 889 babies with small size for gestational age. Factors associated with preterm delivery were history of injecting drug use (adjusted risk ratio 1·64, 95% CI 1·38-1·95), no ART (2·94, 2·43-3·57 vs zidovudine monotherapy), antenatal combination ART (1·40, 1·14-1·73 vs zidovudine monotherapy), WHO stage 4 HIV (2·42, 1·71-3·41 vs

Prophylaxis and treatment of HIV-1 infection in pregnancy: Swedish recommendations 2013.

PubMed

Navér, Lars; Albert, Jan; Böttiger, Ylva; Carlander, Christina; Flamholc, Leo; Gisslén, Magnus; Josephson, Filip; Karlström, Olof; Lindborg, Lena; Svedhem-Johansson, Veronica; Svennerholm, Bo; Sönnerborg, Anders; Yilmaz, Aylin; Pettersson, Karin

2014-06-01

Prophylaxis and treatment with antiretroviral drugs and elective caesarean section delivery have resulted in very low mother-to-child transmission of HIV during recent years. Updated general treatment guidelines and increasing knowledge about mother-to-child transmission have necessitated regular revisions of the recommendations for the prophylaxis and treatment of HIV-1 infection in pregnancy. The Swedish Reference Group for Antiviral Therapy (RAV) updated the recommendations from 2010 at an expert meeting on 11 September 2013. The most important revisions are the following: (1) ongoing efficient treatment at confirmed pregnancy may, with a few exceptions, be continued; (2) if treatment is initiated during pregnancy, the recommended first-line therapy is essentially the same as for non-pregnant women; (3) raltegravir may be added to achieve rapid reduction in HIV RNA; (4) vaginal delivery is recommended if at > 34 gestational weeks and HIV RNA is < 50 copies/ml and no obstetric contraindications exist; (5) if HIV RNA is < 50 copies/ml and delivery is at > 34 gestational weeks, intravenous zidovudine is not recommended regardless of the delivery mode; (6) if HIV RNA is > 50 copies/ml close to delivery, it is recommended that the mother should undergo a planned caesarean section, intravenous zidovudine, and oral nevirapine, and the infant should receive single-dose nevirapine at 48-72 h of age and post-exposure prophylaxis with 2 drugs; (7) if delivery is preterm at < 34 gestational weeks, a caesarean section delivery should if possible be performed, with intravenous zidovudine and oral nevirapine given to the mother, and single-dose nevirapine given to the infant at 48-72 h of age, as well as post-exposure prophylaxis with 2 additional drugs.

Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission.

PubMed

Kumwenda, Newton I; Hoover, Donald R; Mofenson, Lynne M; Thigpen, Michael C; Kafulafula, George; Li, Qing; Mipando, Linda; Nkanaunena, Kondwani; Mebrahtu, Tsedal; Bulterys, Marc; Fowler, Mary Glenn; Taha, Taha E

2008-07-10

Effective strategies are urgently needed to reduce mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) through breast-feeding in resource-limited settings. Women with HIV-1 infection who were breast-feeding infants were enrolled in a randomized, phase 3 trial in Blantyre, Malawi. At birth, the infants were randomly assigned to one of three regimens: single-dose nevirapine plus 1 week of zidovudine (control regimen) or the control regimen plus daily extended prophylaxis either with nevirapine (extended nevirapine) or with nevirapine plus zidovudine (extended dual prophylaxis) until the age of 14 weeks. Using Kaplan-Meier analyses, we assessed the risk of HIV-1 infection among infants who were HIV-1-negative on DNA polymerase-chain-reaction assay at birth. Among 3016 infants in the study, the control group had consistently higher rates of HIV-1 infection from the age of 6 weeks through 18 months. At 9 months, the estimated rate of HIV-1 infection (the primary end point) was 10.6% in the control group, as compared with 5.2% in the extended-nevirapine group (P<0.001) and 6.4% in the extended-dual-prophylaxis group (P=0.002). There were no significant differences between the two extended-prophylaxis groups. The frequency of breast-feeding did not differ significantly among the study groups. Infants receiving extended dual prophylaxis had a significant increase in the number of adverse events (primarily neutropenia) that were deemed to be possibly related to a study drug. Extended prophylaxis with nevirapine or with nevirapine and zidovudine for the first 14 weeks of life significantly reduced postnatal HIV-1 infection in 9-month-old infants. (ClinicalTrials.gov number, NCT00115648.) 2008 Massachusetts Medical Society

HIV-1 induction-maintenance at the lymph node level: the "Apollo-97" Study.

PubMed

Lafeuillade, A; Poggi, C; Chadapaud, S; Hittinger, G; Chouraqui, M; Delbeke, E

2001-10-01

To assess the effects of five-drug combination therapy on HIV-1 load in lymph nodes and subsequent maintenance with four and three drugs. Ten pharmacotherapeutically naive patients received a combination of zidovudine, lamivudine, didanosine, ritonavir, and saquinavir for 24 weeks, then zidovudine, lamivudine, didanosine, and saquinavir for the next 24 weeks, and finally zidovudine, lamivudine, and saquinavir for the last 24 weeks. HIV-1 RNA in lymph nodes was measured using quantitative polymerase chain reaction (PCR) at baseline, after 12, 24, 48, and 78 weeks. Plasma HIV-1 RNA, proviral DNA in peripheral blood mononuclear cells (PBMCs), circulating lymphocyte subsets, and protease inhibitor levels in blood were also regularly measured. Genotypic resistance was assessed in the different compartments in 2 patients who were failed by therapy. HIV-1 RNA decreased in lymph nodes in 9 patients and was stable in 1 despite initial control of plasma replication <20 copies/ml in each patient. Lymph node levels rebounded in 1 patient at week 72 as a result of lack of adherence and remained stable in the 8 others despite maintenance regimens. This represents a mean drop of -3.17 log in lymph nodes for the 8 patients maintaining undetectable viremia at 72 weeks. In the patient with stable lymph node viral RNA, selection of the M184V mutation was demonstrated at this level before detection in plasma and low blood saquinavir levels were found throughout the study. Continuous improvements in immune parameters were observed in all cases, although PBMC proviral DNA levels either showed a continuous decrease or stabilized to a plateau. More complex regimens do not perform better in lymph nodes than classic triple therapy. The persistence of HIV-1 RNA in lymph nodes could be related with cellular resistance mechanisms rather than an insufficient potency of the regimens.

Current use of anti-HIV drugs in AIDS.

PubMed

Clumeck, N

1993-07-01

Since 1987 major advances have been made in our understanding of the pathogenesis of infection and the possible inhibition of the HIV virus. Various drugs targeted to the different steps of viral replication have been selected, but drugs such as soluble CD4 or dextran derivatives aimed to inhibit or interfere with the GP120-CD4 attachment step have shown little or no clinical benefit. Protease inhibitors or interferons acting at the post-transcriptional level are currently under phase I to II investigation. The only group of compounds clinically active belong to the nucleosides analogues that act as DNA chain terminators and by inhibiting viral reverse transcriptase. Zidovudine (AZT), didanosine (ddI) and dideoxycytidine (ddC) have been extensively studied, and used on a large clinical scale. Stavudine (D4T), deoxyfluorothymidine (FLT) and 3'thiacytidine (3TC) are entering phase I-II studies. Being the first nucleoside analogue discovered and used since early 1985, zidovudine remains the gold standard of anti-HIV therapy. Zidovudine is indicated at a dosage varying between 500 and 1000 mg in patients with AIDS and ARC, in asymptomatic patients with CD4 < 200/mm3 and in asymptomatic patients with CD4 between 200 and 500 cells/mm3 with a rapid decrease of CD4 cell count or a positive P24 circulating antigen. There is as yet no consensus concerning patients with more than 500 cell/mm3. ddI and ddC are currently indicated for patients intolerant to AZT or in those who have not responded (clinically or biologically) to AZT. Emergence of resistance to AZT has been reported in 30 to 80% of patients at various stages of the disease and after six to nine months of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Initial therapy with protease inhibitor-sparing regimens: evaluation of nevirapine and delavirdine.

PubMed

Conway, B

2000-06-01

We have compared the results (on-treatment analyses) of 2 randomized clinical trials of protease inhibitor-sparing regimens in drug-naive patients. In the INCAS (Italy, Netherlands, Canada, Australia) study, the mean decrease in plasma viral load over 52 weeks was 2.2 log(10) copies/mL in 40 patients who were receiving zidovudine/didanosine/nevirapine (18 [45%] had maximal suppression), with a mean increase in CD4 T cell counts of 139 cells/microL. In protocol 0021 Part II, the mean decrease in plasma viral load over 52 weeks was 2.1 log(10) copies/mL in 34 patients who were receiving zidovudine/lamivudine/delavirdine (20 [59%] had maximal suppression), with a mean increase in CD4 T cell counts of 88 cells/microL. The virologic and immunologic efficacy of the 2 triple-drug regimens are similar. Until results of long-term studies are available to establish whether a preferred approach to initial therapy exists, nonnucleoside reverse transcriptase inhibitors may be a valuable alternative to protease inhibitors in the initial therapy of antiretroviral-naive, moderately immunosuppressed patients.

Abacavir Pharmacokinetics During Chronic Therapy in HIV-1-Infected Adolescents and Young Adults

PubMed Central

Sleasman, JW; Robbins, BL; Cross, SJ; Lindsey, JC; Kraimer, JM; Heckman, BE; Sprenger, HL; Tustin, NB; Rose, CH; Poston, PA; Neal, EF; Pakes, GE; Nikanjam, M; Capparelli, EV

2009-01-01

The pharmacokinetics of abacavir and its metabolites were investigated in 30 human immunodeficiency virus (HIV)-infected adolescents and young adults 13-25 years of age, equally divided into two groups: <18 years of age and ≥18 years of age. All the subjects received the recommended adult dose of 300 mg twice daily. The area under the plasma concentration-time curve (AUC) and half-life of abacavir did not differ significantly between the age groups or by gender or race, and there were only modest associations of age with apparent abacavir clearance and with volume of distribution. There were no significant correlations of carboxylate or glucuronide metabolite levels with age or gender, although glucuronide AUC was higher in Hispanic subjects than in African-American subjects. Zidovudine and lamivudine concentration profiles were also similar in the two age groups. A novel aspect of the study included an assessment of intracellular carbovir, zidovudine, and lamivudine triphosphate levels, and these were found to be similar in the two age-based groups. Overall, these findings suggest that current recommendations relating to adult dosages are appropriate for adolescents and young adults. PMID:19118380

One-by-one imprinting in two eccentric layers of hollow core-shells: Sequential electroanalysis of anti-HIV drugs.

PubMed

Singh, Kislay; Jaiswal, Swadha; Singh, Richa; Fatma, Sana; Prasad, Bhim Bali

2018-07-15

Double layered one-by-one imprinted hollow core-shells@ pencil graphite electrode was fabricated for sequential sensing of anti-HIV drugs. For this, two eccentric layers were developed on the surface of vinylated silica nanospheres to obtain double layered one-by-one imprinted solid core-shells. This yielded hollow core-shells on treatment with hydrofluoric acid. The modified hollow core-shells (single layered dual imprinted) evolved competitive diffusion of probe/analyte molecules. However, the corresponding double layered one-by-one imprinted hollow core-shells (outer layer imprinted with Zidovudine, and inner layer with Lamivudine) were found relatively better owing to their bilateral diffusions into molecular cavities, without any competition. The entire work is based on differential pulse anodic stripping voltammetry at double layered one-by-one imprinted hollow core-shells. This resulted in indirect detection of electro inactive targets with limits of detection as low as 0.91 and 0.12 (aqueous sample), 0.94 and 0.13 (blood serum), and 0.99 and 0.20 ng mL -1 (pharmaceutics) for lamivudine and zidovudine, respectively in anti-HIV drug combination. Copyright © 2018 Elsevier B.V. All rights reserved.

Highly active antiretroviral therapy during gestation: effects on a rat model of pregnancy.

PubMed

Carvalho, L P F; Simões, R S; Araujo Júnior, E; Oliveira Filho, R M; Kulay Júnior, L; Nakamura, M U

2014-04-01

To assess the adverse effects of the chronic use of zidovudine/lopinavir/ritonavir in a rat pregnancy model.Type of article: Original paper. A prospective experimental study. Department of Obstetrics, São Paulo Federal University (UNIFESP). 40 pregnant EPM-1 albino rats were randomly allocated into four groups of 10 animals each: control (Ctrl) group (untreated) and three experimental groups (Exp1, Exp2 and Exp3), which received zidovudine/lopinavir/ritonavir in the corresponding doses of 10/13.3/3.3; 30/39.9/9.9 and 90/119.7/29.7 mg/Kg/day from the first up to the 20th day of pregnancy, respectively. The rats were treated by gavage daily. Body weights were recorded on days 0, 7, 14 and 20. At term, the rats were sacrificed and the implantation sites, number of live and dead fetuses and placentas, resorptions and fetal and placental weights were recorded. The fetuses were evaluated for external abnormalities under a stereomicroscope. The chi-square test was used to compare death rates between groups. Weight gain during pregnancy no showed significant differences between groups. Average weight gains between the 7th and 20th day were 45.70 ± 5.27 g for Ctrl; 48.49 ± 3.64 g for Exp1; 45.39 ± 6.22 g for Exp2 and 44.19 ± 6.78 g for Exp3. However, the percentage weight gain in the 7th was lower in groups Exp2 and Exp3 and in the 14th in the Group Exp2. All other parameters assessed did not differ significantly between groups. Exp2 and Exp3 in relation of the others. The chronic exposure of pregnant rats to high doses of zidovudine/lopinavir/ritonavir in association resulted in a significant reduction in maternal body weight gain but was not associated with significant adverse fetal parameters.

Anemia among HIV-Infected Patients Initiating Antiretroviral Therapy in South Africa: Improvement in Hemoglobin regardless of Degree of Immunosuppression and the Initiating ART Regimen.

PubMed

Takuva, Simbarashe; Maskew, Mhairi; Brennan, Alana T; Sanne, Ian; Macphail, A Patrick; Fox, Mathew P

2013-01-01

Among those with HIV, anemia is a strong risk factor for disease progression and death independent of CD4 count and viral load. Understanding the role of anemia in HIV treatment is critical to developing strategies to reduce morbidity and mortality. We conducted a prospective analysis among 10,259 HIV-infected adults initiating first-line ART between April 2004 and August 2009 in Johannesburg, South Africa. The prevalence of anemia at ART initiation was 25.8%. Mean hemoglobin increased independent of baseline CD4. Females, lower BMI, WHO stage III/IV, lower CD4 count, and zidovudine use were associated with increased risk of developing anemia during follow-up. After initiation of ART, hemoglobin improved, regardless of regimen type and the degree of immunosuppression. Between 0 and 6 months on ART, the magnitude of hemoglobin increase was linearly related to CD4 count. However, between 6 and 24 months on ART, hemoglobin levels showed a sustained overall increase, the magnitude of which was similar regardless of baseline CD4 level. This increase in hemoglobin was seen even among patients on zidovudine containing regimens. Since low hemoglobin is an established adverse prognostic marker, prompt identification of anemia may result in improved morbidity and mortality of patients initiating ART.

Antiretroviral Treatment for Children with Peripartum Nevirapine Exposure

PubMed Central

Palumbo, Paul; Lindsey, Jane C.; Hughes, Michael D.; Cotton, Mark F.; Bobat, Raziya; Meyers, Tammy; Bwakura-Dangarembizi, Mutsawashe; Chi, Benjamin H.; Musoke, Philippa; Kamthunzi, Portia; Schimana, Werner; Purdue, Lynette; Eshleman, Susan H.; Abrams, Elaine J.; Millar, Linda; Petzold, Elizabeth; Mofenson, Lynne M.; Jean-Philippe, Patrick; Violari, Avy

2010-01-01

BACKGROUND Single-dose nevirapine is the cornerstone of the regimen for prevention of mother-to-child transmission of human immunodeficiency virus (HIV) in resource-limited settings, but nevirapine frequently selects for resistant virus in mothers and children who become infected despite prophylaxis. The optimal antiretroviral treatment strategy for children who have had prior exposure to single-dose nevirapine is unknown. METHODS We conducted a randomized trial of initial therapy with zidovudine and lamivudine plus either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 6 to 36 months of age, in six African countries, who qualified for treatment according to World Health Organization (WHO) criteria. Results are reported for the cohort that included children exposed to single-dose nevirapine prophylaxis. The primary end point was virologic failure or discontinuation of treatment by study week 24. Enrollment in this cohort was terminated early on the recommendation of the data and safety monitoring board. RESULTS A total of 164 children were enrolled. The median percentage of CD4+ lymphocytes was 19%; a total of 56% of the children had WHO stage 3 or 4 disease. More children in the nevirapine group than in the ritonavir-boosted lopinavir group reached a primary end point (39.6% vs. 21.7%; weighted difference, 18.6 percentage-points; 95% confidence interval, 3.7 to 33.6; nominal P = 0.02). Baseline resistance to nevirapine was detected in 18 of 148 children (12%) and was predictive of treatment failure. No significant between-group differences were seen in the rate of adverse events. CONCLUSIONS Among children with prior exposure to single-dose nevirapine for perinatal prevention of HIV transmission, antiretroviral treatment consisting of zidovudine and lamivudine plus ritonavir-boosted lopinavir resulted in better outcomes than did treatment with zidovudine and lamivudine plus nevirapine. Since nevirapine is used for both treatment and perinatal

Patterns of adverse drug reaction signals in NAFDAC Pharmacovigilance activities from September to November, 2014.

PubMed

Awodele, Olufunsho; Ibrahim, Ali; Orhii, Paul

2016-03-16

Adverse drug reaction signals are reported information on possible causal relationships between an adverse event and a drug. The National Pharmacovigilance Centre (NPC) in Nigeria has over 3,000 reported adverse drug reaction cases which have been adequately entered into the ADR data bank. Data mining of ADR reports from September to November, 2014 were carried out in this present study with the intention to describe the pattern of ADRs and generate possible signals. A total of about 100 reported cases with arrays of adverse drug reactions were reported between September and November, 2014 and the data were analyzed using SPSS version 17. Efavirenz/Tenofovir/Lamivudine combination was the highest reported drugs (24.2%) while efavirenz alone was reported in 8 times (8.8%) and HIV (63.3%) was the highest reported indication of drug use. Efavirenz caused central nervous system adverse reactions as revealed in the ADRs analyses. Zidovudine/Lamivudine/Nevirapine combination in concomitant use with Cotrimoxazole were reported 8 times with generalized maculopapular rashes on the trunk with some area of hyper pigmentation with intense itching documented twice and big/swollen rashes all over the faces. Zidovudine was also reported four times to cause severe anaemia. More surveillance is advocated so as to ascertain the consistency of the observed ADRs and thereafter establish appropriate signals.

Maraviroc: perspectives for use in antiretroviral-naive HIV-1-infected patients.

PubMed

Vandekerckhove, Linos; Verhofstede, Chris; Vogelaers, Dirk

2009-06-01

Maraviroc (Pfizer's UK-427857, Selzentry or Celsentri outside the USA) is the first agent in the new class of oral HIV-1 entry inhibitors to acquire approval by the US Food and Drug Administration and the European Medicine Agency. Considering the mechanism of action, it is expected that this drug will be effective only in a subpopulation of HIV-1-infected people, namely those harbouring the R5 virus. The favourable toxicity profile of the drug has been demonstrated in Phase III clinical trials in treatment-naive (MERIT) and treatment-experienced (MOTIVATE) patients. In the latter population, maraviroc showed a superior antiviral efficacy and immunological activity compared with optimized backbone therapy + placebo. However, in MERIT, a prospective double-blind, randomized trial in treatment-naive patients, maraviroc + zidovudine/lamivudine failed to prove non-inferiority to efavirenz + zidovudine/lamivudine as standard of care regimen in the 48 week intention-to-treat analysis. Using an assay with higher sensitivity for minority CXCR4-using (X4) HIV variants (the enhanced Trofile assay-Monogram), non-inferiority was reached for the maraviroc- versus efavirenz-based combination. These data indicate the important impact of the sensitivity of tropism testing on treatment outcome of maraviroc-containing regimens. This paper discusses both the prospective and retrospective analyses of the MERIT data and highlights the impact of these results on daily practice in HIV care.

The burden of anaemia and associated factors in HIV positive Nigerian women.

PubMed

Ezechi, O C; Kalejaiye, O O; Gab-Okafor, C V; Oladele, D A; Oke, B; Ekama, S O; Odunukwe, N N; Ujah, I A O

2013-02-01

Anaemia is the most common complication of pregnancy and a predictor of poor maternal and foetal outcomes. HIV infection is now recognized as one of the major contributors to anaemia in pregnancy. It is therefore important to determine the burden and risk factors of anaemia in maternal HIV infection in others to plan effective prevention strategies as well as optimize management outcomes. To determine the prevalence and risk factors of anaemia in pregnant HIV positive Nigerians. The prevalence and possible risk factors of anaemia were investigated in HIV positive pregnant Nigerian women at a large HIV treatment clinic in southwestern Nigeria using a cross-sectional design between January 2006 and December 2011. Nine hundred and eighty-five (42.5 %) women of 2,318 HIV positive pregnant women seen during the period were anaemic by WHO standard defined by haemoglobin <11 g/dl. Majority were of mild to moderate severity (97.9 %). Short inter birth interval (p = 0.002), presence of opportunistic infections (OIs), (p = 0.001), use of zidovudine containing regimen (p = 0.0005) and CD4 cell count <200 cells/mm(3) (p = 0.001) were found to be independently associated with anaemia in HIV positive pregnant women after controlling for confounding variables. Anaemia was found to be high at 42.5 % among the HIV positive women studied and was found to be independently associated with short inter birth interval, presence of OIs, advanced HIV disease and use of zidovudine containing HAART regimen.

HIV among women in developing countries.

PubMed

Decarlo, P

1999-01-01

In South Africa, a pregnant woman infected with HIV took zidovudine to protect her fetus, but the child later developed HIV because the woman was not told about breast milk transmission. Women in developing countries have been hit hard by the AIDS epidemic because social inequalities that make it impossible for them to negotiate for safer sex or even to choose their sexual partners. In most developing countries, the only treatment women have access to is the zidovudine that is available only during their participation in clinical trials on prenatal transmission. Activists have expressed concern over programs that attempt to save the lives of babies with no regard for their mothers or other women. Women with HIV need access to health care, to information, and to counselors who can help them make choices. Women must be able to assess whether to risk breast feeding or attempt costly bottle feeding, which may lead to higher levels of infant mortality from bacteria in contaminated water. Women must also be educated so that they can protect their sexual health. In some settings, the topics of sex and sexuality still must be introduced into public discourse. Strong prevention programs are reducing HIV-infection rates among young women in parts of Tanzania, among pregnant women and prostitutes in Dakar, among prostitutes in Thailand and Nepal, and among street children in Brazil. Effective programs must consider AIDS a social issue and address education, equality, and information access.

Abacavir and didanosine induce the interaction between human leukocytes and endothelial cells through Mac-1 upregulation.

PubMed

De Pablo, Carmen; Orden, Samuel; Apostolova, Nadezda; Blanquer, Amando; Esplugues, Juan V; Alvarez, Angeles

2010-06-01

Abacavir and didanosine are nucleoside reverse transcriptase inhibitors (NRTI) widely used in therapy for HIV-infection but which have been linked to cardiovascular complications. The objective of this study was to analyze the effects of clinically relevant doses of abacavir and didanosine on human leukocyte-endothelium interactions and to compare them with those of other NRTIs. The interactions between human leukocytes - specifically peripheral blood polymorphonuclear (PMN) or mononuclear (PBMC) cells - and human umbilical vein endothelial cells were evaluated in a flow chamber system that reproduces conditions in vivo. The expression of adhesion molecules was analyzed by flow cytometry. Abacavir induced a dose-dependent increase in PMN and PBMC rolling and adhesion. This was reproduced by didanosine but not by lamivudine or zidovudine. Both abacavir and didanosine increased Mac-1 expression in neutrophils and monocytes, but produced no effects on either lymphocytes or the expression of endothelial adhesion molecules. The PMN/PBMC rolling and adhesion induced by abacavir or didanosine did not occur when antibodies against Mac-1 or its ligand ICAM-1 were blocked. Abacavir induces significant human leukocyte accumulation through the activation of Mac-1, which in turn interacts with its endothelial ligand ICAM-1. The fact that didanosine exhibits similar effects and that lamivudine and zidovudine do not points to a relationship between the chemical structure of NRTIs and the induction of leukocyte/endothelial cell interactions. This mechanism may be especially relevant to the progression of the vascular damage associated with atherosclerosis and myocardial infarction in abacavir and didanosine-treated patients.

Challenges in the concurrent management of malaria and HIV in pregnancy in sub-Saharan Africa.

PubMed

Brentlinger, Paula E; Behrens, Christopher B; Micek, Mark A

2006-02-01

Approximately one million pregnancies are complicated by both malaria and HIV infection in sub-Saharan Africa annually. Both infections have been associated with maternal and infant morbidity and mortality. Intermittent preventive treatment, usually with sulfadoxine-pyrimethamine, has been shown to prevent pregnancy-related malaria and its complications. Several different regimens of antiretroviral therapy are now available to prevent mother-to-child transmission of HIV and/or progression of maternal HIV infection during pregnancy. However, no published studies have yet shown whether standard intermittent preventive treatment and antiretroviral regimens are medically and operationally compatible in pregnancy. We reviewed existing policies regarding prevention and treatment of HIV and malaria in pregnancy, as well as published literature on adverse effects of antiretrovirals and antimalarials commonly used in pregnancy in developing countries, and found that concurrent prescription of sulfadoxine-pyrimethamine, co-trimoxazole (trimethoprim-sulfamethoxazole), and antiretroviral agents including nevirapine and zidovudine per existing protocols for prevention of malaria and vertical HIV transmission may result in adverse drug interactions or overlapping, diagnostically challenging drug toxicities. Insecticide-treated bednets should be provided for HIV-infected pregnant women at risk for malaria. Sulfadoxine-pyrimethamine should be prescribed cautiously in women concurrently receiving daily nevirapine and/or zidovudine, and should be avoided in women on daily co-trimoxazole. Further research is urgently needed to define safe and effective protocols for concurrent management of HIV and malaria in pregnancy, and to define appropriate interventions for different populations subject to differing levels of malaria transmission and antimalarial drug resistance.

Antiretroviral Drugs in Meconium: Detection for Different Gestational Periods of Exposure.

PubMed

Himes, Sarah K; Tassiopoulos, Katherine; Yogev, Ram; Huestis, Marilyn A

2015-08-01

To determine whether antiretroviral (ARV) medications can be detected in meconium from second or third trimester, labor and delivery (L&D), or postnatal exposures. Twenty ARV medications were quantified by liquid chromatography-tandem mass spectrometry in 598 meconium samples from uninfected infants born to pregnant women with HIV enrolled in the Pediatric HIV/AIDS Cohort Study. ARV detection in meconium following third trimester exposure was 85.7%-94.4% for all ARVs except stavudine (0%, n = 2), likely because of low doses and a high limit for quantification. Of 107 samples with some second trimester only ARV exposures, meconium was positive for only lopinavir, tenofovir, or efavirenz in 11.8%-14.3% of exposed neonates; administration of these ARVs occurred between gestational weeks 25-28 in the positive samples. Days without lopinavir or tenofovir before delivery significantly correlated with decreasing concentrations of lopinavir and tenofovir in meconium. Tenofovir and lamivudine concentrations significantly correlated with increasing gestational age among infants with continuous second and third trimester exposure. Zidovudine given during L&D or for neonatal prophylaxis was detected in 95.1% and 94.6% of meconium samples, respectively. Changes in ARV treatments during pregnancy offered a unique opportunity to investigate ARV detection in meconium. ARVs in meconium primarily reflect third trimester ARV exposures, although 6 of 107 second trimester only exposures were detected. Zidovudine administration during L&D was detected in meconium indicating potential urine contamination or rapid incorporation into meconium. These data will improve interpretation of meconium drug test results. Published by Elsevier Inc.

Pharmacokinetics of antiretroviral drugs in anatomical sanctuary sites: the male and female genital tract.

PubMed

Else, Laura J; Taylor, Stephen; Back, David J; Khoo, Saye H

2011-01-01

HIV resides within anatomical 'sanctuary sites', where local drug exposure and viral dynamics may differ significantly from the systemic compartment. Suboptimal antiretroviral concentrations in the genital tract may result in compartmentalized viral replication, selection of resistant mutations and possible re-entry of wild-type/resistant virus into the systemic circulation. Therefore, achieving adequate antiretroviral exposure in the genital tract has implications for the prevention of sexual and vertical transmission of HIV. Penetration of antiretrovirals in the genital tract is expressed by accumulation ratios derived from the measurement of drug concentrations in time-matched seminal plasma/cervicovaginal fluid and plasma samples. Penetration varies by gender and may be drug (as opposed to class) specific with high interindividual variability. Concentrations in seminal plasma are highest for nucleoside analogues and lowest for protease inhibitors and efavirenz. Seminal accumulation of newer agents, raltegravir and maraviroc, is moderate (rank order of accumulation is nucleoside/nucleotide reverse transcriptase inhibitors [lamivudine/zidovudine/tenofovir/didanosine > stavudine/abacavir] > raltegravir > indinavir/maraviroc/nevirapine > efavirenz/protease inhibitors [amprenavir/atazanavir/darunavir > lopinavir/ritonavir > saquinavir] > enfuvirtide). In the female genital tract, the nucleoside analogues exhibit high accumulation ratios, whereas protease inhibitors have limited penetration; however, substantial variability exists between individuals and study centres. Second generation non-nucleoside reverse transcriptase inhibitor etravirine, and maraviroc and raltegravir, demonstrate effective accumulation in cervicovaginal secretions (rank order of accumulation is nucleoside/nucleotide reverse transcriptase inhibitor [zidovudine/lamivudine/didanosine > emtricitabine/tenofovir] > indinavir > maraviroc/raltegravir/darunavir/etravirine > nevirapine

Evidence-based guideline: Antiepileptic drug selection for people with HIV/AIDS

PubMed Central

Birbeck, G.L.; French, J.A.; Perucca, E.; Simpson, D.M.; Fraimow, H.; George, J.M.; Okulicz, J.F.; Clifford, D.B.; Hachad, H.; Levy, R.H.

2012-01-01

Objective: To develop guidelines for selection of antiepileptic drugs (AEDs) among people with HIV/AIDS. Methods: The literature was systematically reviewed to assess the global burden of relevant comorbid entities, to determine the number of patients who potentially utilize AEDs and antiretroviral agents (ARVs), and to address AED-ARV interactions. Results and Recommendations: AED-ARV administration may be indicated in up to 55% of people taking ARVs. Patients receiving phenytoin may require a lopinavir/ritonavir dosage increase of ∼50% to maintain unchanged serum concentrations (Level C). Patients receiving valproic acid may require a zidovudine dosage reduction to maintain unchanged serum zidovudine concentrations (Level C). Coadministration of valproic acid and efavirenz may not require efavirenz dosage adjustment (Level C). Patients receiving ritonavir/atazanavir may require a lamotrigine dosage increase of ∼50% to maintain unchanged lamotrigine serum concentrations (Level C). Coadministration of raltegravir/atazanavir and lamotrigine may not require lamotrigine dosage adjustment (Level C). Coadministration of raltegravir and midazolam may not require midazolam dosage adjustment (Level C). Patients may be counseled that it is unclear whether dosage adjustment is necessary when other AEDs and ARVs are combined (Level U). It may be important to avoid enzyme-inducing AEDs in people on ARV regimens that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors, as pharmacokinetic interactions may result in virologic failure, which has clinical implications for disease progression and development of ARV resistance. If such regimens are required for seizure control, patients may be monitored through pharmacokinetic assessments to ensure efficacy of the ARV regimen (Level C). PMID:22218281

Oral adverse effects due to the use of Nevirapine.

PubMed

Moura, Mariela Dutra Gontijo; Senna, Maria Inês Barreiros; Madureira, Davidson Fróis; Fonseca, Linaena Merícy Silva; Mesquita, Ricardo Alves

2008-01-01

The aim of this article is to present the clinical characteristics and management of an oral adverse effect stemming from the use of the antiretroviral medication Nevirapine (NVP). NVP is a non-nucleoside reverse transcriptase inhibitor used in the treatment of Human Immunodeficiency Virus (HIV) infection. A 29-year-old black man, HIV-infected since 1996, began highly active antiretroviral therapy (HAART) with zidovudine, lamivudine, and indinavir. From 1996 to 2002 several medications were changed due to their adverse effects: indinavir (renal colic and fever), nelfinavir (cutaneous rash), and efavirenz (nausea and temporary memory loss). When the patient presented to our service he was taking NVP, zidovudine, and lamivudine. A whitish plaque in the lips and bilateral buccal mucosa, burning, taste disturbance, and xerostomia were observed. The discontinuation of HAART led to the complete resolution of signs and symptoms. The patient has received follow-up treatment for three years and five months without local or systemic effects observed. Unfortunately, the clinical features of the oral adverse effect from NVP are not well known. This paper contributed to the identification of possible reactions in the oral cavity due to antiretroviral medication. Although HAART is very important in the treatment of HIV, its side effects are responsible for patients' non-adherence to medications. While more studies are needed to better understand the mechanism of action after suspending HAART, the complete resolution of the signs and symptoms was observed. Therefore, physicians and dentists alike must understand how to identify and prevent these adverse effects in order to further improve HIV patient treatments.

Prospective Double-Blind Study of Zidovudine (AZT) in Early Stage HIV infection

DTIC Science & Technology

1988-05-01

cell numbers, cytomegalovirus and toxoplasmosis IgG levels, Beta-2-microglobulin levels, and a variety of psychological tests. Over 200 military and...Toxoplasmic encephalitis in patients with acquired immune deficiency syndrome. JAMA, 252:913, 1984. 22. McCabe R, Remington JS: Toxoplasmosis : The

Landmark Estimation of Survival and Treatment Effect in a Randomized Clinical Trial

PubMed Central

Parast, Layla; Tian, Lu; Cai, Tianxi

2013-01-01

Summary In many studies with a survival outcome, it is often not feasible to fully observe the primary event of interest. This often leads to heavy censoring and thus, difficulty in efficiently estimating survival or comparing survival rates between two groups. In certain diseases, baseline covariates and the event time of non-fatal intermediate events may be associated with overall survival. In these settings, incorporating such additional information may lead to gains in efficiency in estimation of survival and testing for a difference in survival between two treatment groups. If gains in efficiency can be achieved, it may then be possible to decrease the sample size of patients required for a study to achieve a particular power level or decrease the duration of the study. Most existing methods for incorporating intermediate events and covariates to predict survival focus on estimation of relative risk parameters and/or the joint distribution of events under semiparametric models. However, in practice, these model assumptions may not hold and hence may lead to biased estimates of the marginal survival. In this paper, we propose a semi-nonparametric two-stage procedure to estimate and compare t-year survival rates by incorporating intermediate event information observed before some landmark time, which serves as a useful approach to overcome semi-competing risks issues. In a randomized clinical trial setting, we further improve efficiency through an additional calibration step. Simulation studies demonstrate substantial potential gains in efficiency in terms of estimation and power. We illustrate our proposed procedures using an AIDS Clinical Trial Protocol 175 dataset by estimating survival and examining the difference in survival between two treatment groups: zidovudine and zidovudine plus zalcitabine. PMID:24659838

Survival of HIV/AIDS patients with antiretroviral therapy in association with first-line regimens from 2007 – 2010 in Haji AdamMalik general hospital Medan

NASA Astrophysics Data System (ADS)

Kembaren, T.; Ginting, Y.; Saragih, R. H.

2018-03-01

The mortality related to AIDS have decreased dramatically among HIV infected patients taking HAART. HAART is the combination of at least 3 antiretroviral drugs based on the recommendation of WHO. The recent guideline for 1st line therapy recommended by the Indonesian Ministry of Health was Zidovudine/Lamivudine/Nevirapine (ZDV+3TC+NVP), Zidovudine/Lamivudine/Efavirenz (ZDV+3TC+EFV), Stavudine/Lamivudine/Nevirapine (d4T+3TC+NVP), Stavudine/Lamivudine/Efavirenz (d4T+3TC+EFV). Due to a side effect of Stavudine, Ministry of Health plan to pass out Stavudin from the regimens for 1stline therapy.We wanted to evaluate the survival of HIV/AIDS patients with first-line regimens in HAM general hospital Medan. A cohort retrospective study was conducted to evaluate the survival of HIV/AIDS patients taking a combination of 1st line antiretroviral therapy between January 2007 and December 2010. From 2007-2010, among 609 HIV/AIDS patients with first-line ARV medication, 77.5% were male, and 22.5% were female. The most common risk infection was heterosexual. The majority of the patients were in 25-34 years old group. Most of the patients with CD4 1-50 cell/mm3. 2 years survival rate in HIV/AIDS patients taking ZDV+3TC+NVP, ZDV+3TC+EFV, d4T+3TC+NVP, d4T+3TC+EFV were 61.5%, 61.2%, 57.5% and 59.3% respectively. There were no significant differences of 24 months survival in both regiment with or without d4T, 61.8% vs 63.6%.

Treatment-limiting toxicities associated withnucleoside analogue reverse transcriptase inhibitor therapy: A prospective, observational study**

PubMed Central

Palacios, Rosario; Santos, Jesús; Camino, Xavier; Arazo, Piedad; Torres Perea, Rafael; Echevarrfa, Santiago; Ribera, Esteban; Sánchez de la Rosa, Rainel; Moreno Guillen, Santiago

2005-01-01

Background: The Recover Study is an ongoing, prospective study designed 10 to assess toxicity associated with the use of nucleoside analogue reverse transcriptase inhibitors (NRTIs) (stavudine, zidovudine, lamivudine, didanosine, abacavir) in HIV-1-infected patients receiving highly active antiretroviral therapy (HAART) in routine clinical practice. This project is being conducted at 120 HIV units at teaching hospitals across Spain. Objective: The aim of this study was to identify the most common treatment-limiting 10 moderate to severe clinical and laboratory adverse effects (AEs), and the individual NRTIs involved in the development of these effects, in HIV-1-infected patients receiving HAART who discontinued use of an NRTI in the Recover Study. Methods: Patients eligible for participation in the Recover Study are aged10 ≥18 years; have virologically documented HIV-1 infection; have sustained viral suppression (viral load <200 cells/mL or stable, heavily experienced [ie, have received ≥3 antiretroviral regimens] patients with viral load <5000 cells/mL) for ≥6 months; are receiving HAART; are undergoing active follow-up; and have developed 2:1 NRTI-associated AE that, in the opinion of a study investigator and under the conditions of routine clinical practice, justified discontinuation of treatment with the offending drug (principal AE/offending NRTI). The present study included patients recruited for the Recover Study between September 2002 and May 2003. Results: A total of 1391 patients were enrolled (966 men, 425 women; mean 1 age, 42 years [range, 18–67 years]). Five hundred six patients (36.4%) had been diagnosed with AIDS. The mean duration of treatment with the offending NRTI was 74 months (range, 6–156 months). Seven hundred nine patients (51.0%) were receiving fourth-line (or more) therapy. Eight hundred twenty-one patients (59.0%) were receiving nonnucleoside analogues, and 552 patients (39.7%), protease inhibitors, as components of their HAART

Point-of-care CD4 testing to inform selection of antiretroviral medications in south african antenatal clinics: a cost-effectiveness analysis.

PubMed

Ciaranello, Andrea L; Myer, Landon; Kelly, Kathleen; Christensen, Sarah; Daskilewicz, Kristen; Doherty, Katie; Bekker, Linda-Gail; Hou, Taige; Wood, Robin; Francke, Jordan A; Wools-Kaloustian, Kara; Freedberg, Kenneth A; Walensky, Rochelle P

2015-01-01

Many prevention of mother-to-child HIV transmission (PMTCT) programs currently prioritize antiretroviral therapy (ART) for women with advanced HIV. Point-of-care (POC) CD4 assays may expedite the selection of three-drug ART instead of zidovudine, but are costlier than traditional laboratory assays. We used validated models of HIV infection to simulate pregnant, HIV-infected women (mean age 26 years, gestational age 26 weeks) in a general antenatal clinic in South Africa, and their infants. We examined two strategies for CD4 testing after HIV diagnosis: laboratory (test rate: 96%, result-return rate: 87%, cost: $14) and POC (test rate: 99%, result-return rate: 95%, cost: $26). We modeled South African PMTCT guidelines during the study period (WHO "Option A"): antenatal zidovudine (CD4 ≤350/μL) or ART (CD4>350/μL). Outcomes included MTCT risk at weaning (age 6 months), maternal and pediatric life expectancy (LE), maternal and pediatric lifetime healthcare costs (2013 USD), and cost-effectiveness ($/life-year saved). In the base case, laboratory led to projected MTCT risks of 5.7%, undiscounted pediatric LE of 53.2 years, and undiscounted PMTCT plus pediatric lifetime costs of $1,070/infant. POC led to lower modeled MTCT risk (5.3%), greater pediatric LE (53.4 years) and lower PMTCT plus pediatric lifetime costs ($1,040/infant). Maternal outcomes following laboratory were similar to POC (LE: 21.2 years; lifetime costs: $23,860/person). Compared to laboratory, POC improved clinical outcomes and reduced healthcare costs. In antenatal clinics implementing Option A, the higher initial cost of a one-time POC CD4 assay will be offset by cost-savings from prevention of pediatric HIV infection.

High-level cross-resistance to didanosine observed in South African children failing an abacavir- or stavudine-based 1st-line regimen.

PubMed

Steegen, Kim; Levin, Leon; Ketseoglou, Irene; Bronze, Michelle; Papathanasopoulos, Maria A; Carmona, Sergio; Stevens, Wendy

2014-01-01

The knowledge-base of emerging drug resistance profiles in children exposed to abacavir-based antiretroviral regimens in South Africa is very limited. This study investigated the suitability of didanosine-based 2nd-line regimens for children in the context of antiretroviral drug resistance patterns emerging after 1st-line virologic failure. A retrospective dataset of 354 antiretroviral drug resistant genotypes from children failing either abacavir (n = 81) or stavudine (n = 273) based 1st-line regimens, was analysed. Samples were sent to the HIV genotyping laboratory at Charlotte Maxeke Johannesburg Academic Hospital, for routine testing. Pol sequences were submitted to the Stanford HIV drug resistance database for genotypic predictions. Children were exposed to abacavir or stavudine-based 1st-line regimens for an average of 21 and 36 months, respectively. The frequency of reduced susceptibility to didanosine was substantial in the abacavir-exposed group (69.1%).This reduced susceptibility was commonly attributed to L74V/I (n = 44) and to a lesser extent K65R (n = 10) mutations. Didanosine resistance was observed in 43.2% of patients exposed to stavudine-based regimens. In contrast, most children remained susceptible to stavudine regardless of exposure to abacavir (77.8%) or stavudine (74.7%). At least 80% of children remained susceptible to zidovudine irrespective of stavudine or abacavir-exposure. The presence of the K65R mutation was more common after abacavir pressure (12.3% vs 1.8%). Analysis revealed that didanosine-based 2nd-line regimens have limitations for South African children, given the high frequency of mutations that confer cross-resistance to didanosine; especially after abacavir-exposure. This data has influenced South African paediatric treatment guidelines, which now recommend zidovudine-based 2nd-line regimens.

Impact of human immunodeficiency virus type 1 reverse transcriptase inhibitor drug resistance mutation interactions on phenotypic susceptibility.

PubMed

Trivedi, Vinod; Von Lindern, Jana; Montes-Walters, Miguel; Rojo, Daniel R; Shell, Elisabeth J; Parkin, Neil; O'Brien, William A; Ferguson, Monique R

2008-10-01

The role specific reverse transcriptase (RT) drug resistance mutations play in influencing phenotypic susceptibility to RT inhibitors in virus strains with complex resistance interaction patterns was assessed using recombinant viruses that consisted of RT-PCR-amplified pol fragments derived from plasma HIV-1 RNA from two treatment-experienced patients. Specific modifications of key RT amino acids were performed by site-directed mutagenesis. A panel of viruses with defined genotypic resistance mutations was assessed for phenotypic drug resistance. Introduction of M184V into several different clones expressing various RT resistance mutations uniformly decreased susceptibility to abacavir, lamivudine, and didanosine, and increased susceptibility to zidovudine, stavudine, and tenofovir; replication capacity was decreased. The L74V mutation had similar but slightly different effects, contributing to decreased susceptibility to abacavir, lamivudine, and didanosine and increased susceptibility to zidovudine and tenofovir, but in contrast to M184V, L74V contributed to decreased susceptibility to stavudine. In virus strains with the nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E and G190S, the L74V mutation increased replication capacity, consistent with published observations, but replication capacity was decreased in strains without NNRTI resistance mutations. K101E and G190S together tend to decrease susceptibility to all nucleoside RT inhibitors, but the K103N mutation had little effect on nucleoside RT inhibitor susceptibility. Mutational interactions can have a substantial impact on drug resistance phenotype and replication capacity, and this has been exploited in clinical practice with the development of fixed-dose combination pills. However, we are the first to report these mutational interactions using molecularly cloned recombinant strains derived from viruses that occur naturally in HIV-infected individuals.

Impact of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Inhibitor Drug Resistance Mutation Interactions on Phenotypic Susceptibility

PubMed Central

Trivedi, Vinod; Von Lindern, Jana; Montes-Walters, Miguel; Rojo, Daniel R.; Shell, Elisabeth J.; Parkin, Neil; O'Brien, William A.

2008-01-01

Abstract The role specific reverse transcriptase (RT) drug resistance mutations play in influencing phenotypic susceptibility to RT inhibitors in virus strains with complex resistance interaction patterns was assessed using recombinant viruses that consisted of RT-PCR-amplified pol fragments derived from plasma HIV-1 RNA from two treatment-experienced patients. Specific modifications of key RT amino acids were performed by site-directed mutagenesis. A panel of viruses with defined genotypic resistance mutations was assessed for phenotypic drug resistance. Introduction of M184V into several different clones expressing various RT resistance mutations uniformly decreased susceptibility to abacavir, lamivudine, and didanosine, and increased susceptibility to zidovudine, stavudine, and tenofovir; replication capacity was decreased. The L74V mutation had similar but slightly different effects, contributing to decreased susceptibility to abacavir, lamivudine, and didanosine and increased susceptibility to zidovudine and tenofovir, but in contrast to M184V, L74V contributed to decreased susceptibility to stavudine. In virus strains with the nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E and G190S, the L74V mutation increased replication capacity, consistent with published observations, but replication capacity was decreased in strains without NNRTI resistance mutations. K101E and G190S together tend to decrease susceptibility to all nucleoside RT inhibitors, but the K103N mutation had little effect on nucleoside RT inhibitor susceptibility. Mutational interactions can have a substantial impact on drug resistance phenotype and replication capacity, and this has been exploited in clinical practice with the development of fixed-dose combination pills. However, we are the first to report these mutational interactions using molecularly cloned recombinant strains derived from viruses that occur naturally in HIV-infected individuals. PMID:18844463

Antiepileptic drug selection for people with HIV/AIDS: evidence-based guidelines from the ILAE and AAN.

PubMed

Birbeck, Gretchen L; French, Jacqueline A; Perucca, Emilio; Simpson, David M; Fraimow, Henry; George, Jomy M; Okulicz, Jason F; Clifford, David B; Hachad, Houda; Levy, René H

2012-01-01

A joint panel of the American Academy of Neurology (AAN) and the International League Against Epilepsy (ILAE) convened to develop guidelines for selection of antiepileptic drugs (AEDs) among people with HIV/AIDS. The literature was systematically reviewed to assess the global burden of relevant comorbid entities, to determine the number of patients who potentially utilize AEDs and antiretroviral agents (ARVs), and to address AED-ARV interactions. Key findings from this literature search included the following: AED-ARV administration may be indicated in up to 55% of people taking ARVs. Patients receiving phenytoin may require a lopinavir/ritonavir dosage increase of approximately 50% to maintain unchanged serum concentrations (Level C). Patients receiving valproic acid may require a zidovudine dosage reduction to maintain unchanged serum zidovudine concentrations (Level C). Coadministration of valproic acid and efavirenz may not require efavirenz dosage adjustment (Level C). Patients receiving ritonavir/atazanavir may require a lamotrigine dosage increase of approximately 50% to maintain unchanged lamotrigine serum concentrations (Level C). Coadministration of raltegravir/atazanavir and lamotrigine may not require lamotrigine dosage adjustment (Level C). Coadministration of raltegravir and midazolam may not require midazolam dosage adjustment (Level C). Patients may be counseled that it is unclear whether dosage adjustment is necessary when other AEDs and ARVs are combined (Level U). It may be important to avoid enzyme-inducing AEDs in people on ARV regimens that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors because pharmacokinetic interactions may result in virologic failure, which has clinical implications for disease progression and development of ARV resistance. If such regimens are required for seizure control, patients may be monitored through pharmacokinetic assessments to ensure efficacy of the ARV regimen (Level C). Wiley

Increased Risk of Severe Infant Anemia Following Exposure to Maternal HAART, Botswana

PubMed Central

Dryden-Peterson, Scott; Shapiro, Roger L.; Hughes, Michael D.; Powis, Kathleen; Ogwu, Anthony; Moffat, Claire; Moyo, Sikhulile; Makhema, Joseph; Essex, Max; Lockman, Shahin

2011-01-01

Background Maternal highly-active antiretroviral therapy (HAART) reduces mother-to-child HIV transmission (MTCT), but may increase the risk for infant anemia. Methods The incidence of first severe anemia (Grade 3 or 4, Division of AIDS 2004 Toxicity Table) was assessed among HIV-uninfected infants in the Mashi and Mma Bana MTCT prevention trials in Botswana. Severe anemia rates were compared between 3 groups: infants exposed to maternal HAART in utero and during breastfeeding and 1 month of postnatal zidovudine (HAART-BF); infants exposed to maternal zidovudine (ZDV) in utero, 6 months of postnatal ZDV, and breastfeeding (ZDV-BF); and infants exposed to maternal ZDV in utero, 1 month of postnatal ZDV, and formula-feeding (ZDV-FF). Results A total of 1719 infants were analyzed— 691 HAART-BF, 503 ZDV-BF, and 525 ZDV-FF. Severe anemia was detected in 118 infants (7.4%). By 6 months, 12.5% of HAART-BF infants experienced severe anemia, compared with 5.3% of ZDV-BF (P<0.001) and 2.5% of ZDV-FF infants (P<0.001). In adjusted analysis, HAART-BF infants were at greater risk of severe anemia than ZDV-BF or ZDV-FF infants (adjusted odds ratios 2.6 and 5.8, respectively; P < 0.001). Most anemias were asymptomatic and improved with iron/multivitamin supplementation and cessation of ZDV exposure. However, 11 infants (0.6% of all infants) required transfusion for symptomatic anemia. Microcytosis and hypochromia were common among infants with severe anemia. Conclusions Exposure to maternal HAART starting in utero was associated with severe infant anemia. Confirmation of this finding and possible strategies to mitigate hematologic toxicity warrant further study. Trial Registration ClinicalTrials.gov identifiers: NCT00197587 and NCT00270296. PMID:21266910

Natural Variation of Drug Susceptibility in Wild-Type Human Immunodeficiency Virus Type 1

PubMed Central

Parkin, N. T.; Hellmann, N. S.; Whitcomb, J. M.; Kiss, L.; Chappey, C.; Petropoulos, C. J.

2004-01-01

Wild-type viruses from the ViroLogic phenotype-genotype database were evaluated to determine the upper confidence limit of the drug susceptibility distributions, or “biological cutoffs,” for the PhenoSense HIV phenotypic drug susceptibility assay. Definition of the natural variation in drug susceptibility in wild-type human immunodeficiency virus (HIV) type 1 isolates is necessary to determine the prevalence of innate drug resistance and to assess the capability of the PhenoSense assay to reliably measure subtle reductions in drug susceptibility. The biological cutoffs for each drug, defined by the 99th percentile of the fold change in the 50% inhibitory concentration distributions or the mean fold change plus 2 standard deviations, were lower than those previously reported for other phenotypic assays and lower than the clinically relevant cutoffs previously defined for the PhenoSense assay. The 99th percentile fold change values ranged from 1.2 (tenofovir) to 1.8 (zidovudine) for nucleoside reverse transcriptase RT inhibitors (RTIs), from 3.0 (efavirenz) to 6.2 (delavirdine) for nonnucleoside RTIs, and from 1.6 (lopinavir) to 3.6 (nelfinavir) for protease inhibitors. To evaluate the potential role of intrinsic assay variability in the observed variations in the drug susceptibilities of wild-type isolates, 10 reference viruses with different drug susceptibility patterns were tested 8 to 30 times each. The median coefficients of variation in fold change for the reference viruses ranged from 12 to 18% for all drugs except zidovudine (32%), strongly suggesting that the observed differences in wild-type virus susceptibility to the different drugs is related to intrinsic virus variability rather than assay variability. The low biological cutoffs and assay variability suggest that the PhenoSense HIV assay may assist in defining clinically relevant susceptibility cutoffs for resistance to antiretroviral drugs. PMID:14742192

Anaemia in pregnancy is associated with advanced HIV disease.

PubMed

Nandlal, Vikesh; Moodley, Dhayendre; Grobler, Anneke; Bagratee, Jayanthilall; Maharaj, Niren R; Richardson, Paul

2014-01-01

Anaemia is a common clinical finding in HIV infected women and has been associated with advanced disease. The use of antiretroviral drugs such as Zidovudine (ZDV) either for prevention of mother to child transmission (MTCT) of HIV or used in combination with other antiretrovirals have been implicated in the development or increased severity of anaemia. We report the prevalence, type, severity and incidence of anaemia in a cohort of HIV infected women who initiated antiretroviral prophylaxis or treatment during pregnancy. This is a retrospective cohort data analysis of 408 HIV infected pregnant women who participated in a breastfeeding intervention study (HPTN 046 Study, ClinicalTrials.gov NCT 00074412) in South Africa. Women initiated zidovudine prophylaxis for PMTCT or triple antiretroviral treatment in pregnancy according to the standard of care. Laboratory and clinical data in pregnancy, <72 hours and 2 weeks postdelivery were extracted from the main database and analysed. The mean Hb concentration was 10.6 g/dL at baseline and 262/408 (64.2%) women were diagnosed with anaemia (Hb<11 g/dL) in pregnancy, 48/146 (32.9%) subsequently developed anaemia intrapartum or postpartum and 89/310 (28.7%) of all cases of anaemia remained unresolved by 2 weeks postdelivery. In a univariate analysis, CD4 count and gravidity were significant risk factors for anaemia in pregnancy, RR 1.41; 1.23-1.61 (p<0.001) and 1.10; 1.01-1.18 (p = 0.02) respectively. After adjusting for antiretroviral regimen, age and gravidity in a multivariable analysis, only the CD4 count remains a significant risk factor for anaemia in pregnancy and postdelivery. In conclusion, anaemia was most common among women in the advanced stage of HIV infection (CD4<200 cells/mm3). There was no evidence of an association between ZDV or triple ARVs and anaemia.

Operational issues in preventing mother-to-child transmission of HIV-1 in Abidjan, Côte d'Ivoire, 1998-99.

PubMed Central

Msellati, P.; Hingst, G.; Kaba, F.; Viho, I.; Welffens-Ekra, C.; Dabis, F.

2001-01-01

OBJECTIVE: To demonstrate the feasibility, from the public health standpoint, of preventing mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) in Africa. METHODS: Voluntary counselling and HIV serotesting were routinely provided in four health centres in Abidjan, Côte d'Ivoire, for six months in 1998-99. Peripartum treatment with zidovudine and alternatives to breastfeeding were provided free to HIV-infected women. FINDINGS: Of the 4309 pregnant women in the study who attended their first antenatal care visit, 3756 benefited from individual counselling and pretesting (87.2%), and 3452 (80.1%) agreed to undergo HIV serotesting. Overall HIV prevalence was (12.89%) and 5% for women aged under 18 years. Among the 2998 HIV-negative women, 71% returned for their test result, whereas only 60% of the 445 HIV-positive women did so. A total of 124 HIV-positive women were informed of their serostatus and the possibility of preventing mother-to-child transmission of HIV; 100 started treatment and 80 completed zidovudine prophylaxis. At 6 weeks of age, 36 of the 78 liveborn children were being breastfed (46%), two were being mixed-fed and 41 (52%) were being artificially fed. CONCLUSIONS: In Abidjan, voluntary counselling and HIV testing with a view to preventing mother-to-child transmission was feasible in antenatal care units and was well accepted by pregnant women. An insufficient proportion of women returned to obtain their test results. This was especially so among HIV-positive women, the target group for preventing mother-to-child transmission of HIV. Additional staff were required in order to offer voluntary counselling and HIV testing to the study women. Close supervision and strong commitment of health workers were essential. Alternatives to breastfeeding were effectively proposed to HIV-positive women, with active follow-up of children and clinical, nutritional and social support. PMID:11477967

Interventions for preventing late postnatal mother-to-child transmission of HIV.

PubMed

Horvath, Tara; Madi, Banyana C; Iuppa, Irene M; Kennedy, Gail E; Rutherford, George; Read, Jennifer S

2009-01-21

mortality and malnutrition rates during the first two years of life were similar in the two groups. In a trial of early cessation of breastfeeding, HIV-free survival was similar between those children who ceased breastfeeding around four months of age and those who continued breastfeeding. Another trial addressing vitamin supplementation found more cases of HIV infection among children of mothers in the vitamin A arm. Efficacy for other vitamin supplements was not shown. An intervention cohort study evaluated the risk of MTCT according to infant feeding modality, and found increased risks of MTCT among breastfed children who also received solids (hazard ratio = 10.87, p = 0.018) as well as higher 3-month mortality rates (hazard ratio = 2.06) among infants given non- breast milk feedings (instead of exclusive breastfeeding). Three trials evaluated antiretroviral prophylaxis to breastfeeding infants. One trial found that breastfeeding with zidovudine prophylaxis (transmission rate = 9.0%) was not as effective as formula feeding (transmission rate 5.6%) in preventing late postnatal HIV transmission (p = 0.04). Breastfeeding with zidovudine prophylaxis and formula feeding had comparable HIV-free survival rates at 18 months (p = 0.60). Two trials of extended nevirapine prophylaxis demonstrated efficacy. In the first (data combined from trials conducted in three different countries), a six-week course of nevirapine resulted in a lower risk of HIV transmission by six weeks of age (p=0.009), but not at six months of age (p = 0.016). In the second, nevirapine administration until 14 weeks of age (5.2%) or nevirapine with zidovudine until 14 weeks of age (6.4%) resulted in significantly lower risks of MTCT of HIV by 9 months of age than a control regimen of peripartum prophylaxis (10.6%) (p < 0.001). HIV-free survival was significantly better through the age of 9 months in both extended prophylaxis groups, and through the age of 15 months in the extended nevirapine group. Complete

Antiretroviral therapy supply chain quality control and assurance in improving people living with HIV therapeutic outcomes in Cameroon.

PubMed

Djobet, M P Ngogang; Singhe, David; Lohoue, Julienne; Kuaban, Christopher; Ngogang, Jeanne; Tambo, Ernest

2017-04-04

Evaluation of medication efficacy and safety is an essential guarantee to successful therapeutic outcome in public health practices. However, larger distribution chain supply in developing countries such as Cameroon is often challenged by counterfeit drugs, poor manufacturing, storage and degradation leading to health and patient adverse consequences. Yet, access to supply chain management in strengthening ARVs quality assurance and outcomes remains poorly documented. More than 53,000 patients have been enrolled on free ARVs medications, but little is documented on quality assurance and validity of safety for affected populations along the supply chain management since 2008. The cross sectional study was conducted in ARVs distribution units and centers in central, littoral and south west regions of Cameroon. ARVs drugs samples included Nevirapine, Efavirenz, and fixed dose combinations of Zidovudine + Lamivudine, Lamivudine + Stavudine and Zidovudine + Lamivudine + Nevirapine. Drugs packaging and labeling was assessed and galenic assays were performed at National Laboratory of quality Control of Medications and Expertise (LANACOME), Yaoundé, Cameroon. The study covered 16 structures located in eight different towns including the central ARVs store, two regional pharmaceutical procurement centers and thirteen HIV approved treatment centers and management units. A total of 35 ARVs products were collected. Only eight ARVs drugs containing Lamivudine and Stavudine presented with white stains on tablets, however these drugs were standard for all other tests performed. The others 28 ARVs products were standards to all assays performed. We concluded that ARVs drugs freely accessible and distributed to PLWHA are of good quality in Cameroon. However, with the increase number of patients under HAART since 2013, adoption of "Test and Treat" approach to reach the 90-90-90 goals and with the implementation of new national antiretroviral regimen guidelines and molecules

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2006-03-01

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 131I-labetuzumab; Abacavir sulfate, abatacept, adalimumab, ademetionine, adjuvanted influenza vaccine, alefacept, alemtuzumab, amlodipine, amphotericin B, anakinra, aripiprazole, aspirin, axitinib; Betamethasone dipropionate, bevacizumab, biphasic insulin aspart, bortezomib, bosentan, botulinum toxin type B, BQ-123; Calcium folinate, canertinib dihydrochloride, carboplatin, carmustine, cetirizine hydrochloride, cetuximab, cholecalciferol, ciclesonide, ciclosporin, cinacalcet hydrochloride, cisplatin, clarithromycin, clofazimine, cold-adapted influenza vaccine trivalent, CpG-7909; Darbepoetin alfa, darifenacin hydrobromide, DB-289, desloratadine, Dexamet, dicycloverine hydrochloride, dimethyl fumarate, docetaxel, dolastatin 10, drospirenone, drospirenone/estradiol, duloxetine hydrochloride; Ecogramostim, edotecarin, efaproxiral sodium, enalapril maleate, epoetin beta, epoprostenol sodium, epratuzumab, erlotinib hydrochloride, escitalopram oxalate, estradiol, etanercept; Fluconazole, fludarabine phosphate, fluorouracil; Gefitinib, gemcitabine, Ghrelin (human), glibenclamide, glimepiride, GTI-2040; Haloperidol, human insulin, hydrocortisone probutate; Imatinib mesylate, indisulam, influenza vaccine, inhaled insulin, insulin aspart, insulin glulisine, insulin lispro, irinotecan, ispronicline; Lamivudine, lamivudine/zidovudine/abacavir sulfate, lapatinib, letrozole, levocetirizine, lomustine, lonafarnib, lumiracoxib;Magnesium sulfate, MD-1100, melphalan, metformin hydrochloride, methotrexate, metoclopramide hydrochloride, mitiglinide calcium hydrate, monophosphoryl lipid A, montelukast sodium, motexafin gadolinium

HIV-related ocular microangiopathic syndrome and color contrast sensitivity.

PubMed

Geier, S A; Hammel, G; Bogner, J R; Kronawitter, U; Berninger, T; Goebel, F D

1994-06-01

Color vision deficits in patients with acquired immunodeficiency syndrome (AIDS) or human immunodeficiency virus (HIV) disease were reported, and a retinal pathogenic mechanism was proposed. The purpose of this study was to evaluate the association of color vision deficits with HIV-related retinal microangiopathy. A computer graphics system was used to measure protan, deutan, and tritan color contrast sensitivity (CCS) thresholds in 60 HIV-infected patients. Retinal microangiopathy was measured by counting the number of cotton-wool spots, and conjunctival blood-flow sludging was determined. Additional predictors were CD4+ count, age, time on aerosolized pentamidine, time on zidovudine, and Walter Reed staging. The relative influence of each predictor was calculated by stepwise multiple regression analysis (inclusion criterion; incremental P value = < 0.05) using data for the right eyes (RE). The results were validated by using data for the left eyes (LE) and both eyes (BE). The only included predictors in multiple regression analyses for the RE were number of cotton-wool spots (tritan: R = .70; deutan: R = .46; and protan: R = .58; P < .0001 for all axes) and age (tritan: increment of R [Ri] = .05, P = .002; deutan: Ri = .10, P = .004; and protan: Ri = .05, P = .002). The predictors time on zidovudine (Ri = .05, P = .002) and Walter Reed staging (Ri = .03, P = .01) were additionally included in multiple regression analysis for tritan LE. The results for deutan LE were comparable to those for the RE. In the analysis for protan LE, the only included predictor was number of cotton-wool spots. In the analyses for BE, no further predictors were included. The predictors Walter Reed staging and CD4+ count showed a significant association with all three criteria in univariate analysis. Additionally, tritan CCS was significantly associated with conjunctival blood-flow sludging. CCS deficits in patients with HIV disease are primarily associated with the number of cotton

Mutation covariation of HIV-1 CRF07_BC reverse transcriptase during antiretroviral therapy.

PubMed

Li, Zhenpeng; Huang, Yang; Ouyang, Yabo; Xing, Hui; Liao, Lingjie; Jiang, Shibo; Shao, Yiming; Ma, Liying

2013-11-01

To understand the effect of HIV-1 drug resistance mutations in the context of antiretroviral therapy (ART), we compared the prevalence of protease (PR) and reverse transcriptase (RT) mutations in HIV-1 CRF07_BC sequences from blood samples of treatment-naive and ART-treated patients. Mutation covariation in the RT and PR of HIV-1 CRF07_BC viruses from 542 treatment-naive patients and 261 patients treated with lamivudine/zidovudine/nevirapine or lamivudine/zidovudine/efavirenz was analysed. Stratified networks were used to display the mutation covariation. Based on the comparison between treatment-naive and ART-treated patients, three types of featured mutations for RT and PR were initially identified: treatment-associated mutations, treatment-agonistic mutations and overlapping polymorphisms. Twelve significant covariation pairs were found between five treatment-associated mutations (K103N, M184V, Q197K, G190A and Y181C) and nine overlapping polymorphisms (A36E, D39N, Y121H, D123E, R135I, T200A, R277K, L283I and D291E). Meanwhile, three covariation pairs between three treatment-associated mutations (I132L and M184V for RT and I15V for PR) and three overlapping polymorphisms (L10I, L36M and A71V) for PR were also detected. Finally, the overlapping polymorphisms for RT and PR were both found to have significant correlations with treatment-associated mutations, indicating a possible association between polymorphisms and drug resistance. When compared with HIV-1 subtype B under the same regimens as CRF07_BC, the mutation covariations of CRF07_BC showed a distinct pattern of RT and PR mutation covariation. The role of polymorphisms in the development of drug resistance has been widely reported. Here, we found a significant correlation between overlapping polymorphisms for RT and PR and treatment-associated mutations, indicating that polymorphisms exert a global influence on treatment-associated mutations. Polymorphism mutations might therefore be considered before

Anaemia in Pregnancy Is Associated with Advanced HIV Disease

PubMed Central

Nandlal, Vikesh; Moodley, Dhayendre; Grobler, Anneke; Bagratee, Jayanthilall; Maharaj, Niren R.; Richardson, Paul

2014-01-01

Background Anaemia is a common clinical finding in HIV infected women and has been associated with advanced disease. The use of antiretroviral drugs such as Zidovudine (ZDV) either for prevention of mother to child transmission (MTCT) of HIV or used in combination with other antiretrovirals have been implicated in the development or increased severity of anaemia. We report the prevalence, type, severity and incidence of anaemia in a cohort of HIV infected women who initiated antiretroviral prophylaxis or treatment during pregnancy. Methods and Materials This is a retrospective cohort data analysis of 408 HIV infected pregnant women who participated in a breastfeeding intervention study (HPTN 046 Study, ClinicalTrials.gov NCT 00074412) in South Africa. Women initiated zidovudine prophylaxis for PMTCT or triple antiretroviral treatment in pregnancy according to the standard of care. Laboratory and clinical data in pregnancy, <72 hours and 2 weeks postdelivery were extracted from the main database and analysed. Results The mean Hb concentration was 10.6 g/dL at baseline and 262/408 (64.2%) women were diagnosed with anaemia (Hb<11 g/dL) in pregnancy, 48/146 (32.9%) subsequently developed anaemia intrapartum or postpartum and 89/310 (28.7%) of all cases of anaemia remained unresolved by 2 weeks postdelivery. In a univariate analysis, CD4 count and gravidity were significant risk factors for anaemia in pregnancy, RR 1.41; 1.23–1.61 (p<0.001) and 1.10; 1.01–1.18 (p = 0.02) respectively. After adjusting for antiretroviral regimen, age and gravidity in a multivariable analysis, only the CD4 count remains a significant risk factor for anaemia in pregnancy and postdelivery. Conclusion In conclusion, anaemia was most common among women in the advanced stage of HIV infection (CD4<200 cells/mm3). There was no evidence of an association between ZDV or triple ARVs and anaemia. PMID:25222119

An analysis of FDA-approved drugs for infectious disease: HIV/AIDS drugs.

PubMed

Kinch, Michael S; Patridge, Eric

2014-10-01

HIV/AIDS is one of the worst pandemics in history. According to the World Health Organization, 26 million people have died since 1981 - 1.6 million in 2012 alone. The dramatic rise in HIV/AIDS mobilized a swift and impressive coordination among governmental, academic and private sector organizations to identify the virus and develop new treatments. Herein, we assess the arsenal of 28 new molecular entities (NMEs) targeting HIV/AIDS. These data demonstrate that the first approval of zidovudine presaged an expansion of the antiviral repertoire over the following years. Whereas the rate of HIV/AIDS NMEs is rapidly declining, so is the number of organizations developing NMEs. We speculate that decisions to abandon further research reflect, in part, growing costs and time required for development. Copyright © 2014 Elsevier Ltd. All rights reserved.

Susceptibility of recombinant porcine endogenous retrovirus reverse transcriptase to nucleoside and non-nucleoside inhibitors.

PubMed

Wilhelm, M; Fishman, J A; Pontikis, R; Aubertin, A M; Wilhelm, F X

2002-12-01

Transplantation of organs, tissues or cells from pigs to humans could be a potential solution to the shortage of human organs for transplantation. Porcine endogenous retroviruses (PERVs) remain a major safety concern for porcine xenotransplantation. Thus, finding drugs that could be used as virological prophylaxis (or therapy) against PERV replication would be desirable. One of the most effective ways to block retroviral multiplication is to inhibit the enzyme reverse transcriptase (RT) which catalyzes the reverse transcription of viral RNA to proviral double-stranded DNA. We report here the cloning and expression of PERV RT and its susceptibility to several inhibitors. Our data demonstrate PERV susceptibility in vitro to the triphosphorylated nucleoside analog of zidovudine (AZT) and to ddGTP and to a lesser extent to ddTTP but almost no susceptibility to the non-nucleoside RT inhibitors tested.

Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV.

PubMed

De Clercq, Erik

2009-04-01

In 2008, 25 years after the human immunodeficiency virus (HIV) was discovered as the then tentative aetiological agent of acquired immune deficiency syndrome (AIDS), exactly 25 anti-HIV compounds have been formally approved for clinical use in the treatment of AIDS. These compounds fall into six categories: nucleoside reverse transcriptase inhibitors (NRTIs: zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine); nucleotide reverse transcriptase inhibitors (NtRTIs: tenofovir); non-nucleoside reverse transcriptase inhibitors (NNRTIs: nevirapine, delavirdine, efavirenz and etravirine); protease inhibitors (PIs: saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir and darunavir); cell entry inhibitors [fusion inhibitors (FIs: enfuvirtide) and co-receptor inhibitors (CRIs: maraviroc)]; and integrase inhibitors (INIs: raltegravir). These compounds should be used in drug combination regimens to achieve the highest possible benefit, tolerability and compliance and to diminish the risk of resistance development.

In Vitro Evolution of the Human Immunodeficiency Virus Type 1 Gag-Protease Region and Maintenance of Reverse Transcriptase Resistance following Prolonged Drug Exposure†

PubMed Central

La Seta Catamancio, Simona; De Pasquale, Maria Pia; Citterio, Paola; Kurtagic, Semir; Galli, Massimo; Rusconi, Stefano

2001-01-01

We studied the human immunodeficiency virus type 1 phenotypic and genotypic profiles of a dual drug-resistant isolate (isolate 14aPost-DR) selected for zidovudine (ZDV) and lamivudine (3TC) resistance and then cultured in the presence of 3TC and a protease inhibitor: indinavir (IDV), ritonavir, or KNI-272. The IDV-treated virus was highly resistant to 3TC, ZDV, and IDV and accumulated protease mutations at positions M46I and V82F. A change from alanine to valine was observed in 4 of 10 clones in the P2 position of the p7-p1 Gag-protease cleavage site, linked to position M46I in the dominant viral quasispecies. Previous 3TC resistance did not impair the development of additional mutations in the protease and Gag-protease cleavage regions. PMID:11230439

Association between Prenatal Exposure to Antiretroviral Therapy and Birth Defects: An Analysis of the French Perinatal Cohort Study (ANRS CO1/CO11)

PubMed Central

Sibiude, Jeanne; Mandelbrot, Laurent; Blanche, Stéphane; Le Chenadec, Jérôme; Boullag-Bonnet, Naima; Faye, Albert; Dollfus, Catherine; Tubiana, Roland; Bonnet, Damien; Lelong, Nathalie; Khoshnood, Babak; Warszawski, Josiane

2014-01-01

Background Antiretroviral therapy (ART) has major benefits during pregnancy, both for maternal health and to prevent mother-to-child transmission of HIV. Safety issues, including teratogenic risk, need to be evaluated. We estimated the prevalence of birth defects in children born to HIV-infected women receiving ART during pregnancy, and assessed the independent association of birth defects with each antiretroviral (ARV) drug used. Methods and Findings The French Perinatal Cohort prospectively enrolls HIV-infected women delivering in 90 centers throughout France. Children are followed by pediatricians until 2 y of age according to national guidelines. We included 13,124 live births between 1994 and 2010, among which, 42% (n = 5,388) were exposed to ART in the first trimester of pregnancy. Birth defects were studied using both European Surveillance of Congenital Anomalies (EUROCAT) and Metropolitan Atlanta Congenital Defects Program (MACDP) classifications; associations with ART were evaluated using univariate and multivariate logistic regressions. Correction for multiple comparisons was not performed because the analyses were based on hypotheses emanating from previous findings in the literature and the robustness of the findings of the current study. The prevalence of birth defects was 4.4% (95% CI 4.0%–4.7%), according to the EUROCAT classification. In multivariate analysis adjusting for other ARV drugs, maternal age, geographical origin, intravenous drug use, and type of maternity center, a significant association was found between exposure to zidovudine in the first trimester and congenital heart defects: 2.3% (74/3,267), adjusted odds ratio (AOR) = 2.2 (95% CI 1.3–3.7), p = 0.003, absolute risk difference attributed to zidovudine +1.2% (95% CI +0.5; +1.9%). Didanosine and indinavir were associated with head and neck defects, respectively: 0.5%, AOR = 3.4 (95% CI 1.1–10.4), p = 0.04; 0.9%, AOR = 3.8 (95% CI 1.1–13.8), p = 0

Adverse events and adherence to HIV post-exposure prophylaxis: a cohort study at the Korle-Bu Teaching Hospital in Accra, Ghana.

PubMed

Tetteh, Raymond A; Nartey, Edmund T; Lartey, Margaret; Mantel-Teeuwisse, Aukje K; Leufkens, Hubert G M; Nortey, Priscilla A; Dodoo, Alexander N O

2015-06-20

There is strong evidence that post-exposure prophylaxis (PEP) with antiretroviral drugs in the timely management of occupational exposures sustained by healthcare workers decreases the risk of HIV infection and PEP is now widely used. Antiretroviral drugs have well documented toxicities and produce adverse events in patients living with HIV/AIDS. In the era of "highly active antiretroviral therapy", non-adherence to treatment has been closely linked to the occurrence of adverse events in HIV patients and this ultimately influences treatment success but the influence of adverse events on adherence during PEP is less well studied. Following the introduction of a HIV post-exposure prophylaxis program in the Korle-Bu Teaching Hospital in January 2005, the incidence of adverse events and adherence were documented in occupationally-exposed healthcare workers (HCWs) and healthcare students (HCSs). Cohort event monitoring was used in following-up on exposed HCWs/HCSs for the two study outcomes; adverse events and adherence. All adverse events reported were grouped by MedDRA system organ classification and then by preferred term according to prophylaxis regimen. Adherence was determined by the completion of prophylaxis schedule. Cox proportional regression analysis was applied to determine the factors associated with the cohort study outcomes. Differences in frequencies were tested using the Chi square test and p < 0.05 was considered statistically significant. A total of 228 exposed HCWs/HCSs were followed up during the study, made up of 101 exposed HCWs/HCSs administered lamivudine/zidovudine (3TC/AZT) for 3 days; 75 exposed HCWs/HCSs administered lamivudine/zidovudine (3TC/AZT) for 28 days; and 52 exposed HCWs/HCSs administered lamivudine/zidovudine/lopinavir-ritonavir (3TC/AZT/LPV-RTV) for 28 days. The frequency of adverse events was 28% (n = 28) in exposed HCWs/HCSs administered 3TC/AZT for 3 days, 91% (n = 68) in exposed HCWs/HCSs administered 3TC/AZT for

Quantification of HTLV-1 reverse transcriptase activity in ATL patients treated with zidovudine and interferon-α.

PubMed

Macchi, Beatrice; Balestrieri, Emanuela; Frezza, Caterina; Grelli, Sandro; Valletta, Elena; Marçais, Ambroise; Marino-Merlo, Francesca; Turpin, Jocelyn; Bangham, Charles R; Hermine, Olivier; Mastino, Antonio; Bazarbachi, Ali

2017-05-09

The therapeutic efficacy of the AZT and IFN combination in ATL presumably reflects the inhibition of RT-related functions.HTLV-1-RT activity from short-term cultured PBMCs may represent a predictive correlate of clinical response to AZT/IFN in ATL patients.

The public health approach to identify antiretroviral therapy failure: high-level nucleoside reverse transcriptase inhibitor resistance among Malawians failing first-line antiretroviral therapy

PubMed Central

Hosseinipour, Mina C.; van Oosterhout, Joep J.G.; Weigel, Ralf; Phiri, Sam; Kamwendo, Debbie; Parkin, Neil; Fiscus, Susan A.; Nelson, Julie A.E.; Eron, Joseph J.; Kumwenda, Johnstone

2010-01-01

Background Over 150 000 Malawians have started antiretroviral therapy (ART), in which first-line therapy is stavudine/lamivudine/nevirapine. We evaluated drug resistance patterns among patients failing first-line ART on the basis of clinical or immunological criteria in Lilongwe and Blantyre, Malawi. Methods Patients meeting the definition of ART failure (new or progressive stage 4 condition, CD4 cell count decline more than 30%, CD4 cell count less than that before treatment) from January 2006 to July 2007 were evaluated. Among those with HIV RNA of more than 1000 copies/ml, genotyping was performed. For complex genotype patterns, phenotyping was performed. Results Ninety-six confirmed ART failure patients were identified. Median (interquartile range) CD4 cell count, log10 HIV-1 RNA, and duration on ART were 68 cells/μl (23–174), 4.72 copies/ml (4.26–5.16), and 36.5 months (26.6–49.8), respectively. Ninety-three percent of samples had nonnucleoside reverse transcriptase inhibitor mutations, and 81% had the M184V mutation. The most frequent pattern included M184V and nonnucleoside reverse transcriptase inhibitor mutations along with at least one thymidine analog mutation (56%). Twenty-three percent of patients acquired the K70E or K65R mutations associated with tenofovir resistance; 17% of the patients had pan-nucleoside resistance that corresponded to K65R or K70E and additional resistance mutations, most commonly the 151 complex. Emergence of the K65R and K70E mutations was associated with CD4 cell count of less than 100 cells/μl (odds ratio 6.1) and inversely with the use of zidovudine (odds ratio 0.18). Phenotypic susceptibility data indicated that the nucleoside reverse transcriptase inhibitor backbone with the highest activity for subsequent therapy was zidovudine/lamivudine/tenofovir, followed by lamivudine/tenofovir, and then abacavir/didanosine. Conclusion When clinical and CD4 cell count criteria are used to monitor first-line ART failure

Regimen durability in HIV-infected children and adolescents initiating first-line antiretroviral therapy in a large public sector HIV cohort in South Africa.

PubMed

Bonawitz, Rachael; Brennan, Alana T; Long, Lawrence; Heeren, Timothy; Maskew, Mhairi; Sanne, Ian; Fox, Matthew P

2018-06-01

In April 2010, tenofovir and abacavir replaced stavudine in public sector first-line antiretroviral therapy (ART) for children under 20 years old in South Africa. The association of both abacavir and tenofovir with fewer side effects and toxicities compared to stavudine could translate to increased durability of tenofovir or abacavir-based regimens. We evaluated changes over time in regimen durability for paediatric patients 3-19 years of age at eight public sector clinics in Johannesburg, South Africa. Cohort analysis of treatment-naïve, non-pregnant paediatric patients from 3 to 19 years old initiated on ART between April 2004 and December 2013. First-line ART regimens before April 2010 consisted of stavudine or zidovudine with lamivudine and either efavirenz or nevirapine. Tenofovir and/or abacavir was substituted for stavudine after April 2010 in first-line ART. We evaluated the frequency and type of single-drug substitutions, treatment interruptions and switches to second-line therapy. Fine and Gray competing risk regression models were used to evaluate the association of antiretroviral drug type with single-drug substitutions, treatment interruptions and second-line switches in the first 24 months on treatment. Three hundred and ninety-eight (15.3%) single-drug substitutions, 187 (7.2%) treatment interruptions and 86 (3.3%) switches to second-line therapy occurred among 2602 paediatric patients over 24-months on ART. Overall, the rate of single-drug substitutions started to increase in 2009, peaked in 2011 at 25% and then declined to 10% in 2013, well after the integration of tenofovir into paediatric regimens; no patients over the age of 3 were initiated on abacavir for first-line therapy. Competing risk regression models showed patients on zidovudine or stavudine had upwards of a fivefold increase in single-drug substitution vs. patients initiated on tenofovir in the first 24 months on ART. Older adolescents also had a two- to threefold increase in

HIV rapid testing as a key strategy for prevention of mother-to-child transmission in Brazil

PubMed Central

Veloso, Valdiléa G; Bastos, Francisco I; Portela, Margareth Crisóstomo; Grinsztejn, Beatriz; João, Esau Custodio; da Silva Pilotto, Jose Henrique; Araújo, Ana Beatriz Busch; Santos, Breno Riegel; da Fonseca, Rosana Campos; Kreitchmann, Regis; Derrico, Monica; Friedman, Ruth Khalili; Cunha, Cynthia B; Morgado, Mariza Gonçalves; Saines, Karin Nielsen; Bryson, Yvonne J

2015-01-01

OBJECTIVE To assess the feasibility of HIV rapid testing for pregnant women at maternity hospital admission and of subsequent interventions to reduce perinatal HIV transmission. METHODS Study based on a convenience sample of women unaware of their HIV serostatus when they were admitted to delivery in public maternity hospitals in Rio de Janeiro and Porto Alegre, Brazil, between March 2000 and April 2002. Women were counseled and tested using the Determine HIV1/2 Rapid Test. HIV infection was confirmed using the Brazilian algorithm for HIV infection diagnosis. In utero transmission of HIV was determined using HIVDNA-PCR. There were performed descriptive analyses of sociodemographic data, number of previous pregnancies and abortions, number of prenatal care visits, timing of HIV testing, HIV rapid test result, neonatal and mother-to-child transmission interventions, by city studied. RESULTS HIV prevalence in women was 6.5% (N=1,439) in Porto Alegre and 1.3% (N=3.778) in Rio de Janeiro. In Porto Alegre most of women were tested during labor (88.7%), while in Rio de Janeiro most were tested in the postpartum (67.5%). One hundred and forty-four infants were born to 143 HIV-infected women. All newborns but one in each city received at least prophylaxis with oral zidovudine. It was possible to completely avoid newborn exposure to breast milk in 96.8% and 51.1% of the cases in Porto Alegre and Rio de Janeiro, respectively. Injectable intravenous zidovudine was administered during labor to 68.8% and 27.7% newborns in Porto Alegre and Rio de Janeiro, respectively. Among those from whom blood samples were collected within 48 hours of birth, in utero transmission of HIV was confirmed in 4 cases in Rio de Janeiro (4/47) and 6 cases in Porto Alegre (6/79). CONCLUSIONS The strategy proved feasible in maternity hospitals in Rio de Janeiro and Porto Alegre. Efforts must be taken to maximize HIV testing during labor. There is a need of strong social support to provide this

Controversies in targeted therapy of adult T cell leukemia/lymphoma: ON target or OFF target effects?

PubMed

Nasr, Rihab; El Hajj, Hiba; Kfoury, Youmna; de Thé, Hugues; Hermine, Olivier; Bazarbachi, Ali

2011-06-01

Adult T cell leukemia/lymphoma (ATL) represents an ideal model for targeted therapy because of intrinsic chemo-resistance of ATL cells and the presence of two well identified targets: the HTLV-I retrovirus and the viral oncoprotein Tax. The combination of zidovudine (AZT) and interferon-alpha (IFN) has a dramatic impact on survival of ATL patients. Although the mechanism of action remains unclear, arguments in favor or against a direct antiviral effect will be discussed. Yet, most patients relapse and alternative therapies are mandatory. IFN and arsenic trioxide induce Tax proteolysis, synergize to induce apoptosis in ATL cells and cure Tax-driven ATL in mice through specific targeting of leukemia initiating cell activity. These results provide a biological basis for the clinical success of arsenic/IFN/AZT therapy in ATL patients and suggest that both extinction of viral replication (AZT) and Tax degradation (arsenic/IFN) are needed to cure ATL.

Efficacy of Antiretroviral Agents against Murine Replication-Competent Retrovirus Infection in Human Cells

PubMed Central

Powell, Sharon K.; Artlip, Moria; Kaloss, Michele; Brazinski, Scott; Lyons, Russette; McGarrity, Gerard J.; Otto, Edward

1999-01-01

Retroviral vectors for gene therapy are designed to minimize the occurrence of replication-competent retrovirus (RCR); nonetheless, it is possible that a vector-derived RCR could establish an infection in a patient. Since the efficacy of antiretroviral agents can be impacted by interactions between virus, host cell, and drug, five commonly used antiretroviral drugs were evaluated for their abilities to inhibit the replication of a murine leukemia virus (MLV)-derived RCR in human cells. The results obtained indicate that the combination of nucleoside analogs zidovudine and dideoxyinosine with the protease inhibitor indinavir effectively inhibits MLV-derived RCR replication in three human cell lines. In addition, MLV-derived RCR was found to be inherently resistant to the nucleoside analogs lamivudine and stavudine, suggesting that mutations conferring resistance to nucleoside analogs in human immunodeficiency virus type 1 have the same effect even in an alternative viral backbone. PMID:10482636

Correlation of virus load in plasma and lymph node tissue in human immunodeficiency virus infection. INCAS Study Group. Italy, Netherlands, Canada, Australia, and (United) States.

PubMed

Harris, M; Patenaude, P; Cooperberg, P; Filipenko, D; Thorne, A; Raboud, J; Rae, S; Dailey, P; Chernoff, D; Todd, J; Conway, B; Montaner, J S

1997-11-01

The impact of long-term changes in plasma viremia, produced by effective combination antiretroviral therapy, on human immunodeficiency virus (HIV) burden within tissue reservoirs is unknown. Fifteen patients who had received at least 1 year of therapy with two or three drug combinations of zidovudine, didanosine, and nevirapine had suitable samples of lymph node tissue obtained by ultrasound-guided core needle biopsy. HIV RNA was extracted from homogenized tissue samples and quantitated using a modified branched DNA assay. Results were correlated with antiretroviral treatment effect on the basis of plasma virus load measurements over the preceding 12-18 months. A statistically significant negative correlation was observed between magnitude of treatment effect on plasma viremia and lymph node virus load. These data suggest that combinations of antiretroviral drugs that produce sustained suppression of plasma HIV RNA may also be able to reduce the virus burden in lymphoid tissues.

Intracellular studies of the nucleoside reverse transcriptase inhibitor active metabolites: a review.

PubMed

Rodriguez Orengo, J F; Santana, J; Febo, I; Diaz, C; Rodriguez, J L; Garcia, R; Font, E; Rosario, O

2000-03-01

Nucleoside reverse transcriptase inhibitors (NRTIs) plasma concentrations do not correlate with clinical efficacy or toxicity. These agents need to be phosphorylated to become active against HIV-infection. Thus, the characterization of the NRTIs intracellular metabolite pharmacological parameters will provide a better understanding that could lead to the development of more rational dose regimens in the HIV-infected population. Furthermore, intracellular measurements of NRTIs may provide a better marker with respect to clinical efficacy and toxicity than plasma concentrations. Thus, in this article we review the latest information regarding the intracellular pharmacological parameters of zidovudine (ZDV) and lamivudine (3TC) active metabolites in HIV-infected patients including the results from our recent clinical studies. We will start the discussion with ZDV and 3TC clinical efficacy, followed by systemic pharmacokinetics studies. We will then discuss the in vitro and in vivo intracellular studies with particular emphasis in the method development to measure these metabolites and we will conclude with the most current data from our clinical trials.

Alopecia areata associated with abacavir therapy.

PubMed

Kim, Hee-Sung; Shin, Hyoung-Shik

2014-06-01

Abacavir is a nucleoside reverse-transcriptase inhibitor that has been approved for use in combination with other retroviral agents in the treatment of HIV infection. Common adverse reactions include headache, fatigue, nausea, and rash. A fatal hypersensitivity reaction may occur in 5% of patients receiving abacavir; therefore, screening for HLA-B5701 should be performed before starting abacavir. Alopecia areata (AA) is infrequently reported in HIV-infected patients. Certain underlying conditions have been associated with AA, including a decreased CD4:CD8 ratio related to the progression of HIV infection, some opportunistic infections, and syphilis. Several antiretroviral drugs, such as zidovudine, indinavir, indinavir/ritonavir, lopinavir/ritonavir, and atazanavir/ritonavir have been implicated in the development of AA. At present, the occurrence of AA has not been associated with abacavir use. We cannot exclude that the use of abacavir and the development of AA could be coincidental. Nevertheless, patients given abacavir should be monitored for hair loss and the drug discontinued promptly if such signs appear.

Controversies in Targeted Therapy of Adult T Cell Leukemia/Lymphoma: ON Target or OFF Target Effects?

PubMed Central

Nasr, Rihab; Hajj, Hiba El; Kfoury, Youmna; de Thé, Hugues; Hermine, Olivier; Bazarbachi, Ali

2011-01-01

Adult T cell leukemia/lymphoma (ATL) represents an ideal model for targeted therapy because of intrinsic chemo-resistance of ATL cells and the presence of two well identified targets: the HTLV-I retrovirus and the viral oncoprotein Tax. The combination of zidovudine (AZT) and interferon-alpha (IFN) has a dramatic impact on survival of ATL patients. Although the mechanism of action remains unclear, arguments in favor or against a direct antiviral effect will be discussed. Yet, most patients relapse and alternative therapies are mandatory. IFN and arsenic trioxide induce Tax proteolysis, synergize to induce apoptosis in ATL cells and cure Tax-driven ATL in mice through specific targeting of leukemia initiating cell activity. These results provide a biological basis for the clinical success of arsenic/IFN/AZT therapy in ATL patients and suggest that both extinction of viral replication (AZT) and Tax degradation (arsenic/IFN) are needed to cure ATL. PMID:21994752

Early nucleoside reverse transcriptase inhibitors for the treatment of HIV: a brief history of stavudine (D4T) and its comparison with other dideoxynucleosides.

PubMed

Martin, John C; Hitchcock, Michael J M; De Clercq, Erik; Prusoff, William H

2010-01-01

The occasion of this 25th anniversary issue encouraged us to reminisce about the important history of the discovery of the dideoxynucleoside analogues for the treatment of HIV/AIDS and to chronicle our thoughts about a particular exciting and rewarding period of our scientific careers. Following the identification of the anti-HIV activity of zidovudine (AZT), we participated in the urgent quest to discover optimal treatments of HIV infection and AIDS. A number of previously synthesized nucleoside analogues were comparatively evaluated, and stavudine (D4T) emerged as a promising candidate for development. Following clinical evaluation, D4T became a mainstay of the initial antiretroviral combination therapy, prolonging and saving numerous lives. It has only recently been supplanted by better-tolerated treatments. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010. Copyright 2009 Elsevier B.V. All rights reserved.

Antiretroviral Drugs-Loaded Nanoparticles Fabricated by Dispersion Polymerization with Potential for HIV/AIDS Treatment

PubMed Central

Ogunwuyi, Oluwaseun; Kumari, Namita; Smith, Kahli A.; Bolshakov, Oleg; Adesina, Simeon; Gugssa, Ayele; Anderson, Winston A.; Nekhai, Sergei; Akala, Emmanuel O.

2016-01-01

Highly active antiretroviral (ARV) therapy (HAART) for chronic suppression of HIV replication has revolutionized the treatment of HIV/AIDS. HAART is no panacea; treatments must be maintained for life. Although great progress has been made in ARV therapy, HIV continues to replicate in anatomical and intracellular sites where ARV drugs have restricted access. Nanotechnology has been considered a platform to circumvent some of the challenges in HIV/AIDS treatment. Dispersion polymerization was used to fabricate two types (PMM and ECA) of polymeric nanoparticles, and each was successfully loaded with four ARV drugs (zidovudine, lamivudine, nevirapine, and raltegravir), followed by physicochemical characterization: scanning electron microscope, particle size, zeta potential, drug loading, and in vitro availability. These nanoparticles efficiently inhibited HIV-1 infection in CEM T cells and peripheral blood mononuclear cells; they hold promise for the treatment of HIV/AIDS. The ARV-loaded nanoparticles with polyethylene glycol on the corona may facilitate tethering ligands for targeting specific receptors expressed on the cells of HIV reservoirs. PMID:27013886

Lipid levels and changes in body fat distribution in treatment-naive, HIV-1-Infected adults treated with rilpivirine or Efavirenz for 96 weeks in the ECHO and THRIVE trials.

PubMed

Tebas, Pablo; Sension, Michael; Arribas, José; Duiculescu, Dan; Florence, Eric; Hung, Chien-Ching; Wilkin, Timothy; Vanveggel, Simon; Stevens, Marita; Deckx, Henri

2014-08-01

Pooled ECHO/THRIVE lipid and body fat data are presented from the ECHO (Efficacy Comparison in Treatment-Naïve, HIV-Infected Subjects of TMC278 and Efavirenz) and THRIVE (TMC278 Against HIV, in a Once-Daily Regimen Versus Efavirenz) trials. We assessed the 96-week effects on lipids, adverse events (AEs), and body fat distribution (dual-energy x-ray absorptiometry) of rilpivirine (RPV) and EFV plus 2 nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTIs) in treatment-naive adults infected with human immunodeficiency virus type 1 (HIV-1). Rilpivirine produced minimal changes in total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. Compared with RPV, EFV significantly (P < .001) increased lipid levels. Decreases in the TC/HDL-C ratio were similar with RPV and EFV. Background N[t]RTI affected RPV-induced lipid changes; all levels increased with zidovudine/lamivudine (3TC) and abacavir/3TC (except triglycerides, which were unchanged). With emtricitabine/tenofovir, levels of HDL-C were increased, TC and LDL-C were unchanged, and triglycerides were decreased. With EFV, lipid levels increased in each N[t]RTI subgroup (except triglycerides were unchanged with abacavir/3TC). Fewer (P < .001) RPV-treated patients than EFV-treated patients had TC, LDL-C, and triglyceride levels above National Cholesterol Education Program cutoffs. More RPV- than EFV-treated patients had HDL-C values below these cutoffs (P = .02). Dyslipidemia AEs were less common with RPV than with EFV. Similar proportions of patients had a ≥10% decrease in limb fat (16% with RPV and 17% with EFV). Limb fat was significantly (P < .001) increased to a similar extent (by 12% with RPV and 11% with EFV). At week 96, patients receiving zidovudine/3TC had lost limb fat, and those receiving emtricitabine/tenofovir had gained it. Over the course of 96 weeks, RPV-based therapy was associated with lower increases in lipid

Use of dolutegravir in two INI-experienced patients with multiclass resistance resulted in excellent virological and immunological responses

PubMed Central

Marije Hofstra, Laura; Nijhuis, Monique; Mudrikova, Tania; Fun, Axel; Schipper, Pauline; Schneider, Margriet; Wensing, Annemarie

2014-01-01

Introduction Dolutegravir is a second generation integrase inhibitor with a proposed high genetic barrier to resistance. However, in clinical trials, decreased virological response was seen in a subset of patients with prior exposure to raltegravir and multiple integrase resistance mutations. Methods We describe two cases of HIV subtype B-infected patients starting dolutegravir after previous failure on a raltegravir-containing regimen with extensive resistance. Genotypic analysis was performed using population sequencing and 454 ultradeep sequencing of integrase at time of raltegravir exposure. Results Both patients were diagnosed in early 1990s and received mono- and dual therapy, followed by several cART-regimens. Due to presence of extensive resistance, the genotypic susceptibility score of these regimens never reached a score >2 and never resulted in sustained virological suppression despite good adherence. Early 2012, the clinical condition of patient 1 worsened during persistent failure of a mega-cART regimen despite excellent drug levels. Six major PI, six minor PI, seven NRTI, six NNRTI and two INI mutations plus DM-virus were detected (Table 1). Ultra-deep sequencing of integrase showed the selection of Q148R, E138K+Q148K, and N155H variants and phenotypic raltegravir resistance was demonstrated. After addition of dolutegravir and enfuvirtide to the failing regimen (zidovudine, lamivudine, tenofovir, etravirine, darunavir/ritonavir, maraviroc), viral load (VL) decreased from 244,000 to <20 cps/mL within five months, CD4-count increased (33 to 272 mm3) and the clinical condition improved substantially. In patient 2, similar worsening of the clinical condition was observed late 2012 during persistent failure on mega-cART. Five major PI, six minor PI, nine NRTI, seven NNRTI and one INI mutation plus DM-virus were detected. Ultra-deep sequencing showed selection of N155H, followed by Q95K and V151I variants and phenotypic raltegravir resistance was

Molecular Docking and Molecular Dynamics to Identify a Novel Human Immunodeficiency Virus Inhibitor from Alkaloids of Toddalia asiatica

PubMed Central

Priya, R.; Sumitha, Rajendrarao; Doss, C. George Priya; Rajasekaran, C.; Babu, S.; Seenivasan, R.; Siva, R.

2015-01-01

Background: Acquired immunodeficiency syndrome caused by human immunodeficiency virus (HIV) is an immunosuppressive disease. Over the past decades, it has plagued human health due to the grave consequences in its harness. Objective: For this reason, anti-HIV agents are imperative, and the search for the same from natural resources would assure the safety. Materials and Methods: In this investigation we have performed molecular docking, molecular property prediction, drug-likeness score, and molecular dynamics (MD) simulation to develop a novel anti-HIV drug. We have screened 12 alkaloids from a medicinal plant Toddalia asiatica for its probabilistic binding with the active site of the HIV-1-reverse transcriptase (HIV-1-RT) domain (the major contributor to the onset of the disease). Results: The docking results were evaluated based on free energies of binding (ΔG), and the results suggested toddanol, toddanone, and toddalenone to be potent inhibitors of HIV-1-RT. In addition, the alkaloids were subjected to molecular property prediction analysis. Toddanol and toddanone with more rotatable bonds were found to have a drug-likeness score of 0.23 and 0.11, respectively. These scores were comparable with the standard anti-HIV drug zidovudine with a model score 0.28. Finally, two characteristic protein-ligand complexes were exposed to MD simulation to determine the stability of the predicted conformations. Conclusion: The toddanol-RT complex showed higher stability and stronger H-bonds than toddanone-RT complex. Based on these observations, we firmly believe that the alkaloid toddanol could aid in efficient HIV-1 drug discovery. SUMMARY In the present study, the molecular docking and MD simulations are performed to explore the possible binding mode of HIV 1 RT with 12 alkaloids of T. asiatica. Molecular docking by AutoDock4 revealed three alkaloids toddanol, toddanone, and toddalenone with highest binding affinity towards HIV 1 RT. The drug likeness model score revealed

Molecular Docking and Molecular Dynamics to Identify a Novel Human Immunodeficiency Virus Inhibitor from Alkaloids of Toddalia asiatica.

PubMed

Priya, R; Sumitha, Rajendrarao; Doss, C George Priya; Rajasekaran, C; Babu, S; Seenivasan, R; Siva, R

2015-10-01

Acquired immunodeficiency syndrome caused by human immunodeficiency virus (HIV) is an immunosuppressive disease. Over the past decades, it has plagued human health due to the grave consequences in its harness. For this reason, anti-HIV agents are imperative, and the search for the same from natural resources would assure the safety. In this investigation we have performed molecular docking, molecular property prediction, drug-likeness score, and molecular dynamics (MD) simulation to develop a novel anti-HIV drug. We have screened 12 alkaloids from a medicinal plant Toddalia asiatica for its probabilistic binding with the active site of the HIV-1-reverse transcriptase (HIV-1-RT) domain (the major contributor to the onset of the disease). The docking results were evaluated based on free energies of binding (ΔG), and the results suggested toddanol, toddanone, and toddalenone to be potent inhibitors of HIV-1-RT. In addition, the alkaloids were subjected to molecular property prediction analysis. Toddanol and toddanone with more rotatable bonds were found to have a drug-likeness score of 0.23 and 0.11, respectively. These scores were comparable with the standard anti-HIV drug zidovudine with a model score 0.28. Finally, two characteristic protein-ligand complexes were exposed to MD simulation to determine the stability of the predicted conformations. The toddanol-RT complex showed higher stability and stronger H-bonds than toddanone-RT complex. Based on these observations, we firmly believe that the alkaloid toddanol could aid in efficient HIV-1 drug discovery. In the present study, the molecular docking and MD simulations are performed to explore the possible binding mode of HIV 1 RT with 12 alkaloids of T. asiatica. Molecular docking by AutoDock4 revealed three alkaloids toddanol, toddanone, and toddalenone with highest binding affinity towards HIV 1 RT. The drug likeness model score revealed a positive score for toddanol and toddanone which is comparable to the drug

[Results of the implementation of three national guidelines for the prevention of HIV vertical transmission in Instituto Nacional Materno Perinatal. Lima, Peru].

PubMed

Velásquez, Carlos

2011-01-01

A retrospective analysis is performed in three successive periods between the years 1996 and 2009, in order to evaluate the impact of the implementation of three national guidelines for the prevention of the vertical transmission of HIV. 275 births were included in 13 years. Significant statistical differences were found in the percentage of HIV cases in the children exposed to the virus between the three periods: 15% during the period in which only zidovudine (AZT) was administered to the pregnant woman, 6.4% during the second period (administration of AZT to the pregnant woman not fulfilling HAART initiation criteria and HAART to those fulfilling criteria for this treatment), and 4% during the third period in which HAART was applied to all pregnant women with HIV infection. 95% of pregnant women ended their pregnancy by cesarean section and the 100% of children received infant formula. Changes made in national guidelines have produced a positive impact in the decrease of HIV infected children in the Instituto Nacional Materno Perinatal in Peru.

AIDS activists take South African government to court.

PubMed

Baleta, A

2000-08-26

In South Africa, AIDS activists are taking legal action against their government because of its refusal to provide HIV-positive women with drugs to prevent mother-to-child transmission of HIV. The Treatment Action Campaign gave the health department an ultimatum to make moves to change policy on treating infected mothers; however, since the department had not responded, the legal process was set to begin. Mark Heywood, the Campaign's spokesman, said that the campaign is pushing for the implementation of programs on a phased basis to provide zidovudine or nevirapine at facilities where it is possible. It is noted that the government has remained steadfast in its opposition to an expansion of the program to all HIV-positive women attending state health services. Although Health Minister Mantho Tshabalala Msimang said that the drug regulatory authority is reviewing results of studies on nevirapine use, with a view to possible registration of the drug, Heywood argues that such an action continues to question the efficacy of antiretrovirals since these tests have already been done.

Thymidine analogue-sparing highly active antiretroviral therapy (HAART).

PubMed

Nolan, David; Mallal, Simon

2003-02-01

The use of alternative nucleoside reverse transcriptase inhibitors (NRTIs) to the thymidine analogues stavudine (d4T) and zidovudine(ZDV) has been advocated as a means of limiting long-term NRTI-associated toxicity, particularly the development of lipoatrophy or fat wasting. This approach reflects an increasing knowledge of the distinct toxicity profiles of NRTI drugs. However, recent clinical trials have demonstrated that the use of thymidine analogue NRTIs and newer alternative backbone NRTIs, such as tenofovir (TNF) and abacavir (ABC), is associated with comparable short-term efficacy and tolerability. Given the importance of toxicity profile differences in determining clinical management, it is important to recognise that d4T and ZDV cary significantly different risks for long-term NRTI toxicity. Recognising that all NRTIs, including thymidine analogues, have individual toxicity profiles provides a more appropriate basis for selecting optimal antiretroviral therapy. The safety and efficacy of TNF and ABC are also reviewed here, although the available data provide only limited knowledge of the long-term effects of these drugs in terms of toxicity and antiviral durability.

Micronuclei induced by reverse transcriptase inhibitors in mononucleated and binucleated cells as assessed by the cytokinesis-block micronucleus assay

PubMed Central

2010-01-01

This study evaluated the clastogenic and/or aneugenic potential of three nucleoside reverse transcriptase inhibitors (zidovudine - AZT, lamivudine - 3TC and stavudine - d4T) using the cytokinesis-block micronucleus (CBMN) assay in human lymphocyte cultures. All three inhibitors produced a positive response when tested in binucleated cells. The genotoxicity of AZT and 3TC was restricted to binucleated cells since there was no significant increase in the frequency of micronuclei in mononucleated cells. This finding indicated that AZT and 3TC caused chromosomal breakage and that their genotoxicity was related to a clastogenic action. In addition to the positive response observed with d4T in binucleated cells, this drug also increased the frequency of micronuclei in mononucleated cells, indicating clastogenic and aneugenic actions. Since the structural differences between AZT and 3TC and AZT and d4T involve the 3' position in the 2'-deoxyribonucleoside and in an unsaturated 2',3',dideoxyribose, respectively, we suggest that an unsaturated 2', 3', dideoxyribose is responsible for the clastogenic and aneugenic actions of d4T. PMID:21637587

Economic evaluation of 3-drug antiretroviral regimens for the prevention of mother-to-child HIV transmission in Thailand.

PubMed

Werayingyong, Pitsaphun; Phanuphak, Nittaya; Chokephaibulkit, Kulkunya; Tantivess, Sripen; Kullert, Nareeluk; Tosanguan, Kakanang; Butchon, Rukmanee; Voramongkol, Nipunporn; Boonsuk, Sarawut; Pilasant, Songyot; Kulpeng, Wantanee; Teerawattananon, Yot

2015-03-01

The current program for prevention of mother-to-child HIV transmission in Thailand recommends a 2-drugs regimen for HIV-infected pregnant women with a CD4 count >200 cells/mm(3). This study assesses the value for money of 3 antiretroviral drugs compared with zidovudine (AZT)+single-dose nevirapine (sd-NVP). A decision tree was constructed to predict costs and outcomes using the governmental perspective for assessing cost-effectiveness of 3-drug regimens: (1) AZT, lamivudine, and efavirenz and (2) AZT, 3TC, and lopinavir/ritonavir, in comparison with the current protocol, AZT+sd-NVP. The 3-drug antiretroviral regimens yield lower costs and better health outcomes compared with AZT+sd-NVP. Although these 3-drug regimens offer higher program costs and health care costs for premature birth, they save money significantly in regard to pediatric HIV treatment and treatment costs for drug resistance in mothers. The 3-drug regimens are cost-saving interventions. The findings from this study were used to support a policy change in the national recommendation. © 2013 APJPH.

Suppression of Type I Interferon Production by Human T-Cell Leukemia Virus Type 1 Oncoprotein Tax through Inhibition of IRF3 Phosphorylation

PubMed Central

Yuen, Chun-Kit; Chan, Ching-Ping; Fung, Sin-Yee; Wang, Pei-Hui; Wong, Wan-Man; Tang, Hei-Man Vincent; Yuen, Kit-San; Chan, Chi-Ping

2016-01-01

ABSTRACT Infection with human T-cell leukemia virus type 1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and tropical spastic paraparesis. Type I interferons (IFNs) are key effectors of the innate antiviral response, and IFN-α combined with the nucleoside reverse transcriptase inhibitor zidovudine is considered the standard first-line therapy for ATL. HTLV-1 oncoprotein Tax is known to suppress innate IFN production and response but the underlying mechanisms remain to be fully established. In this study, we report on the suppression of type I IFN production by HTLV-1 Tax through interaction with and inhibition of TBK1 kinase that phosphorylates IRF3. Induced transcription of IFN-β was severely impaired in HTLV-1-transformed ATL cells and freshly infected T lymphocytes. The ability to suppress IRF3 activation was ascribed to Tax. The expression of Tax alone sufficiently repressed the induction of IFN production by RIG-I plus PACT, cGAMP synthase plus STING, TBK1, IKKε, IRF3, and IRF7, but not by IRF3-5D, a dominant-active phosphomimetic mutant. This suggests that Tax perturbs IFN production at the step of IRF3 phosphorylation. Tax mutants deficient for CREB or NF-κB activation were fully competent in the suppression of IFN production. Coimmunoprecipitation experiments confirmed the association of Tax with TBK1, IKKε, STING, and IRF3. In vitro kinase assay indicated an inhibitory effect of Tax on TBK1-mediated phosphorylation of IRF3. Taken together, our findings suggested a new mechanism by which HTLV-1 oncoprotein Tax circumvents the production of type I IFNs in infected cells. Our findings have implications in therapeutic intervention of ATL. IMPORTANCE Human T-cell leukemia virus type 1 (HTLV-1) is the cause of adult T-cell leukemia (ATL), an aggressive and fatal blood cancer, as well as another chronic disabling disease of the spinal cord. Treatments are unsatisfactory, and options are limited. A combination of antiviral cellular protein alpha

Suppression of Type I Interferon Production by Human T-Cell Leukemia Virus Type 1 Oncoprotein Tax through Inhibition of IRF3 Phosphorylation.

PubMed

Yuen, Chun-Kit; Chan, Ching-Ping; Fung, Sin-Yee; Wang, Pei-Hui; Wong, Wan-Man; Tang, Hei-Man Vincent; Yuen, Kit-San; Chan, Chi-Ping; Jin, Dong-Yan; Kok, Kin-Hang

2016-04-01

Infection with human T-cell leukemia virus type 1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and tropical spastic paraparesis. Type I interferons (IFNs) are key effectors of the innate antiviral response, and IFN-α combined with the nucleoside reverse transcriptase inhibitor zidovudine is considered the standard first-line therapy for ATL. HTLV-1 oncoprotein Tax is known to suppress innate IFN production and response but the underlying mechanisms remain to be fully established. In this study, we report on the suppression of type I IFN production by HTLV-1 Tax through interaction with and inhibition of TBK1 kinase that phosphorylates IRF3. Induced transcription of IFN-β was severely impaired in HTLV-1-transformed ATL cells and freshly infected T lymphocytes. The ability to suppress IRF3 activation was ascribed to Tax. The expression of Tax alone sufficiently repressed the induction of IFN production by RIG-I plus PACT, cGAMP synthase plus STING, TBK1, IKKε, IRF3, and IRF7, but not by IRF3-5D, a dominant-active phosphomimetic mutant. This suggests that Tax perturbs IFN production at the step of IRF3 phosphorylation. Tax mutants deficient for CREB or NF-κB activation were fully competent in the suppression of IFN production. Coimmunoprecipitation experiments confirmed the association of Tax with TBK1, IKKε, STING, and IRF3.In vitrokinase assay indicated an inhibitory effect of Tax on TBK1-mediated phosphorylation of IRF3. Taken together, our findings suggested a new mechanism by which HTLV-1 oncoprotein Tax circumvents the production of type I IFNs in infected cells. Our findings have implications in therapeutic intervention of ATL. Human T-cell leukemia virus type 1 (HTLV-1) is the cause of adult T-cell leukemia (ATL), an aggressive and fatal blood cancer, as well as another chronic disabling disease of the spinal cord. Treatments are unsatisfactory, and options are limited. A combination of antiviral cellular protein alpha interferon and zidovudine

Drug companies cut HIV drug prices in the developing world.

PubMed

Yamey, G

2000-05-20

The UN has reported that five multinational pharmaceutical companies would cut down HIV drug prices in the developing world. One of these drug companies is GlaxoWellcome, which has promised to reduce the price of zidovudine and lamivudine to US$2 in the poorest nations, a fifth of its price in the US. Although Peter Piot, director of the UN Program on HIV/AIDS, welcomed the companies' promises, he warned that price cuts alone will not curb the epidemic. He stated that this initiative is only one critical factor in what must become a much broader and more urgent effort to help people living with HIV/AIDS. Moreover, health and development agencies expressed concern that AIDS drugs will still be unaffordable for the vast majority of those in need in developing countries. In addition, poor countries lack the infrastructure to deliver these drugs safely and effectively. During the time of the UN announcement, US President Bill Clinton also signed an executive order allowing sub-Saharan Africa to adopt legal measures to obtain cheap HIV drugs. Meanwhile, South Africa's reaction to the offer to cut antiretroviral drug prices has been lukewarm.

Antiviral therapy: current concepts and practices.

PubMed Central

Bean, B

1992-01-01

Drugs capable of inhibiting viruses in vitro were described in the 1950s, but real progress was not made until the 1970s, when agents capable of inhibiting virus-specific enzymes were first identified. The last decade has seen rapid progress in both our understanding of antiviral therapy and the number of antiviral agents on the market. Amantadine and ribavirin are available for treatment of viral respiratory infections. Vidarabine, acyclovir, ganciclovir, and foscarnet are used for systemic treatment of herpesvirus infections, while ophthalmic preparations of idoxuridine, trifluorothymidine, and vidarabine are available for herpes keratitis. For treatment of human immunodeficiency virus infections, zidovudine and didanosine are used. Immunomodulators, such as interferons and colony-stimulating factors, and immunoglobulins are being used increasingly for viral illnesses. While resistance to antiviral drugs has been seen, especially among AIDS patients, it has not become widespread and is being intensely studied. Increasingly, combinations of agents are being used: to achieve synergistic inhibition of viruses, to delay or prevent resistance, and to decrease dosages of toxic drugs. New approaches, such as liposomes carrying antiviral drugs and computer-aided drug design, are exciting and promising prospects for the future. PMID:1576586

TDP1 repairs nuclear and mitochondrial DNA damage induced by chain-terminating anticancer and antiviral nucleoside analogs

PubMed Central

Huang, Shar-yin N.; Murai, Junko; Dalla Rosa, Ilaria; Dexheimer, Thomas S.; Naumova, Alena; Gmeiner, William H.; Pommier, Yves

2013-01-01

Chain-terminating nucleoside analogs (CTNAs) that cause stalling or premature termination of DNA replication forks are widely used as anticancer and antiviral drugs. However, it is not well understood how cells repair the DNA damage induced by these drugs. Here, we reveal the importance of tyrosyl–DNA phosphodiesterase 1 (TDP1) in the repair of nuclear and mitochondrial DNA damage induced by CTNAs. On investigating the effects of four CTNAs—acyclovir (ACV), cytarabine (Ara-C), zidovudine (AZT) and zalcitabine (ddC)—we show that TDP1 is capable of removing the covalently linked corresponding CTNAs from DNA 3′-ends. We also show that Tdp1−/− cells are hypersensitive and accumulate more DNA damage when treated with ACV and Ara-C, implicating TDP1 in repairing CTNA-induced DNA damage. As AZT and ddC are known to cause mitochondrial dysfunction, we examined whether TDP1 repairs the mitochondrial DNA damage they induced. We find that AZT and ddC treatment leads to greater depletion of mitochondrial DNA in Tdp1−/− cells. Thus, TDP1 seems to be critical for repairing nuclear and mitochondrial DNA damage caused by CTNAs. PMID:23775789

Treatment of cytomegalovirus retinitis with intravitreal ganciclovir. Long-term results.

PubMed

Cantrill, H L; Henry, K; Melroe, N H; Knobloch, W H; Ramsay, R C; Balfour, H H

1989-03-01

Long-term management of cytomegalovirus (CMV) retinitis by intravitreal injection of ganciclovir was evaluated in ten patients with acquired immune deficiency syndrome (AIDS). Patients were unable to tolerate systemic ganciclovir because of severe neutropenia (8 cases), catheter-induced sepsis (1 case), or the need to continue therapy for human immunodeficiency virus (HIV) with zidovudine (ZDV) (1 case). All patients had a favorable response to initial treatment. Cytomegalovirus retinitis progressed in four fellow eyes in which treatment was deferred. Vision improved or remained stable in all but one eye. Patients were followed for a mean of 4 months and received an average of 16.6 intravitreal injections in each eye. Relapse occurred late in the course while on maintenance treatment in five eyes (33%). There was no evidence of toxicity from repeated intravitreal injections. Treatment was very well tolerated. The only severe complication in a total of 249 injections was a single case of Staphylococcus epidermidis endophthalmitis which responded to intravitreal antibiotic treatment. Intravitreal ganciclovir is an effective alternative to systemic ganciclovir in those patients with severe neutropenia and in those patients who desire to remain on systemic ZDV.

Effect of changing from first- to second-line antiretroviral therapy on renal function: a retrospective study based on data from a single health facility in Namibia.

PubMed

Kalemeera, Francis; Mbango, Christofina; Mubita, Mwangana; Naikaku, Esther; Gaida, Razia; Godman, Brian

2016-08-01

Tenofovir disoproxil fumarate (TDF) and lopinavir/ritonavir (LPV/r) can cause renal impairment with this combination co-administered during second-line combination antiretroviral therapy (cART) potentially associated with greater risk of nephrotoxicity. As a result, the aim of this study is to assess effects of second-line cART on renal function. Retrospective longitudinal study in patients receiving cART. 71 patients received TDF, zidovudine or stavudine, each combined with 3TC/NVP or 3TC/EFV. Before second-line cART, 46.5% had abnormal kidney function. First-line cART had no relationship with calculated creatinine clearance (CrCl). During second-line cART, more males than females had abnormal renal function and more females experienced increases in CrCl. Calculated CrCl during second-line cART related strongly with CrCl during first-line cART. Time spent on cART had a weak relationship with CrCl. Patients on first-line cART for several years without renal impairment may experience new onset impairment during second line cART. Patients with pre-existing renal impairment just before switching to second-line cART may experience a further decline.

Do non-nucleoside reverse transcriptase inhibitors contribute to lipodystrophy?

PubMed

Nolan, David

2005-01-01

Lipodystrophy complications, including lipoatrophy (pathological fat loss) and metabolic complications, have emerged as important long-term toxicities associated with antiretroviral therapy in the current era. The wealth of data that has accumulated over the past 6 years has now clarified the contribution of specific antiretroviral drugs to the risk of these clinical endpoints, with evidence that lipoatrophy is strongly associated with the choice of nucleoside reverse transcriptase inhibitor therapy (specifically, stavudine and to a lesser extent zidovudine). The aetiological basis of metabolic complications of antiretroviral therapy has proven to be complex, in that the risk appears to be modulated by a number of lifestyle factors that have made the metabolic syndrome highly prevalent in the general population, with additional contributions from HIV disease status itself, as well as from individual drugs within the HIV protease inhibitor class. The currently licensed non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs, efavirenz and nevirapine, have been proven to have a favourable safety profile in terms of lipodystrophy complications. However, it must be noted that NNRTI drugs also have individual toxicity profiles that must be accounted for when considering and/or monitoring their use in the treatment of HIV infection.

Altered Oligodendrocyte Maturation and Myelin Maintenance: The Role of Antiretrovirals in HIV-Associated Neurocognitive Disorders.

PubMed

Jensen, Brigid K; Monnerie, Hubert; Mannell, Maggie V; Gannon, Patrick J; Espinoza, Cagla Akay; Erickson, Michelle A; Bruce-Keller, Annadora J; Gelman, Benjamin B; Briand, Lisa A; Pierce, R Christopher; Jordan-Sciutto, Kelly L; Grinspan, Judith B

2015-11-01

Despite effective viral suppression through combined antiretroviral therapy (cART), approximately half of HIV-positive individuals have HIV-associated neurocognitive disorders (HAND). Studies of antiretroviral-treated patients have revealed persistent white matter abnormalities including diffuse myelin pallor, diminished white matter tracts, and decreased myelin protein mRNAs. Loss of myelin can contribute to neurocognitive dysfunction because the myelin membrane generated by oligodendrocytes is essential for rapid signal transduction and axonal maintenance. We hypothesized that myelin changes in HAND are partly due to effects of antiretroviral drugs on oligodendrocyte survival and/or maturation. We showed that primary mouse oligodendrocyte precursor cell cultures treated with therapeutic concentrations of HIV protease inhibitors ritonavir or lopinavir displayed dose-dependent decreases in oligodendrocyte maturation; however, this effect was rapidly reversed after drug removal. Conversely, nucleoside reverse transcriptase inhibitor zidovudine had no effect. Furthermore, in vivo ritonavir administration to adult mice reduced frontal cortex myelin protein levels. Finally, prefrontal cortex tissue from HIV-positive individuals with HAND on cART showed a significant decrease in myelin basic protein compared with untreated HIV-positive individuals with HAND or HIV-negative controls. These findings demonstrate that antiretrovirals can impact myelin integrity and have implications for myelination in juvenile HIV patients and myelin maintenance in adults on lifelong therapy.

Targets for inhibition of HIV replication: entry, enzyme action, release and maturation.

PubMed

Sierra-Aragón, Saleta; Walter, Hauke

2012-01-01

Inhibition of HIV replication initially targeted viral enzymes, which are exclusively expressed by the virus and not present in the human cell. The development of reverse transcriptase (RT) inhibitors started with the discovery of antiretroviral activity of the nucleoside analog zidovudine in March 1987. Currently, six major classes of antiretroviral drugs are used for the treatment of HIV-infected patients: the RT inhibitors, nucleoside inhibitors and nonnucleoside inhibitors, the protease inhibitors, the integrase inhibitor raltegravir, the fusion inhibitor enfuvirtide (T-20), and the chemokine receptor 5 antagonist maraviroc. A seventh class, the maturation inhibitors, has not yet been approved as their effectiveness is impaired by HIV-1 polymorphisms naturally occurring in 30-40% of HIV-1 therapy-naive isolates. The use of antiretroviral combination therapy has proven to be effective in delaying progression to AIDS and to reconstitute the immune system of HIV-infected individuals. During the last 5 years, the introduction of the newest antiretrovirals has increased treatment efficacy tremendously. However, the development and accumulation of resistance to all antiretroviral drug classes are still a major problem. Additional targets will have to be defined to achieve the ultimate goal: the eradication of the virus from the infected human body. Copyright © 2012 S. Karger AG, Basel.

Quercetin attenuates AZT-induced neuroinflammation in the CNS.

PubMed

Yang, Yi; Liu, Xiaokang; Wu, Ting; Zhang, Wenping; Shu, Jianhong; He, Yulong; Tang, Shao-Jun

2018-04-18

Highly active anti-retroviral therapy (HAART) is very effective in suppressing HIV-1 replication in patients. However, continuous HAART is required to prevent viral rebound, which may have detrimental effects in various tissues, including persistent neuroinflammation in the central nervous system (CNS). Here, we show that quercetin (3,5,7,3',4'-pentahydroxy flavones), a natural antioxidant used in Chinese traditional medicines, suppresses the neuroinflammation that is induced by chronic exposure to Zidovudine (azidothymidine, AZT), a nucleoside reverse transcriptase inhibitor (NRTI) that is commonly part of HAART regimens. We found that the up-regulation of pro-inflammatory cytokines and microglial and astrocytic markers induced by AZT (100 mg/kg/day; 8 days) was significantly inhibited by co-administration of quercetin (50 mg/kg/day) in the mouse cortex, hippocampus and spinal cord. We further showed that quercetin attenuated AZT-induced up-regulation of Wnt5a, a key regulator of neuroinflammation. These results suggest that quercetin has an inhibitory effect on AZT-induced neuroinflammation in the CNS, and Wnt5a signaling may play an important role in this process. Our results may further our understanding of the mechanisms of HAART-related neurotoxicity and help in the development of effective adjuvant therapy.

Developments in early diagnosis and therapy of HIV infection in newborns.

PubMed

Canals, Francisco; Masiá, Mar; Gutiérrez, Félix

2018-01-01

Infants who acquire HIV have an exceptionally high risk of morbidity and mortality if they do not receive antiretroviral therapy (ART). Areas covered: This review aims to summarize the currently available evidence on ART in HIV-infected neonates. Data were obtained from literature searches from PubMed, abstracts from International Conferences (2000-2017), and authors' files. Expert opinion: Current evidence favors early diagnosis and prompt ART of HIV infection in newborns. The precise timing of initiation of ART remains undetermined. Very early (close to birth) ART appears to limit the size of the viral reservoir and may restrict replication-competent virus, but the clinical benefit remains unproven. Among the current options for initial therapy, in full term neonates from 2 weeks of life onwards, a lopinavir/ritonavir-based three-drug regimen is preferred. In term infants, younger than 2 weeks a nevirapine-based regimen is recommended, although there are no clinical trial data supporting that initiating treatment before 2 weeks improves outcome compared to starting afterwards. Existing safety information is insufficient to recommend ART in preterm infants, with pharmacokinetic data available for zidovudine only. If ART is considered in this setting, an individual case assessment of the risk/benefit ratio of treatment should be made.

Hypersusceptibility to substrate analogs conferred by mutations in human immunodeficiency virus type 1 reverse transcriptase.

PubMed

Smith, Robert A; Anderson, Donovan J; Preston, Bradley D

2006-07-01

Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) contains four structural motifs (A, B, C, and D) that are conserved in polymerases from diverse organisms. Motif B interacts with the incoming nucleotide, the template strand, and key active-site residues from other motifs, suggesting that motif B is an important determinant of substrate specificity. To examine the functional role of this region, we performed "random scanning mutagenesis" of 11 motif B residues and screened replication-competent mutants for altered substrate analog sensitivity in culture. Single amino acid replacements throughout the targeted region conferred resistance to lamivudine and/or hypersusceptibility to zidovudine (AZT). Substitutions at residue Q151 increased the sensitivity of HIV-1 to multiple nucleoside analogs, and a subset of these Q151 variants was also hypersusceptible to the pyrophosphate analog phosphonoformic acid (PFA). Other AZT-hypersusceptible mutants were resistant to PFA and are therefore phenotypically similar to PFA-resistant variants selected in vitro and in infected patients. Collectively, these data show that specific amino acid replacements in motif B confer broad-spectrum hypersusceptibility to substrate analog inhibitors. Our results suggest that motif B influences RT-deoxynucleoside triphosphate interactions at multiple steps in the catalytic cycle of polymerization.

An Analysis of Enzyme Kinetics Data for Mitochondrial DNA Strand Termination by Nucleoside Reverse Transcription Inhibitors

PubMed Central

Wendelsdorf, Katherine V.; Song, Zhuo; Cao, Yang; Samuels, David C.

2009-01-01

Nucleoside analogs used in antiretroviral treatment have been associated with mitochondrial toxicity. The polymerase-γ hypothesis states that this toxicity stems from the analogs' inhibition of the mitochondrial DNA polymerase (polymerase-γ) leading to mitochondrial DNA (mtDNA) depletion. We have constructed a computational model of the interaction of polymerase-γ with activated nucleoside and nucleotide analog drugs, based on experimentally measured reaction rates and base excision rates, together with the mtDNA genome size, the human mtDNA sequence, and mitochondrial dNTP concentrations. The model predicts an approximately 1000-fold difference in the activated drug concentration required for a 50% probability of mtDNA strand termination between the activated di-deoxy analogs d4T, ddC, and ddI (activated to ddA) and the activated forms of the analogs 3TC, TDF, AZT, FTC, and ABC. These predictions are supported by experimental and clinical data showing significantly greater mtDNA depletion in cell culture and patient samples caused by the di-deoxy analog drugs. For zidovudine (AZT) we calculated a very low mtDNA replication termination probability, in contrast to its reported mitochondrial toxicity in vitro and clinically. Therefore AZT mitochondrial toxicity is likely due to a mechanism that does not involve strand termination of mtDNA replication. PMID:19132079

[Young women with HIV infection acquired by vertical transmission: Expectations of having uninfected children].

PubMed

Villarroel, Julia; Álvarez, Ana M; Salvador, Francisco; Chávez, Ana; Wu, Elba; Contardo, Verónica

2016-12-01

Pediatric antiretroviral therapy (ART), changed the prognosis of the disease, allowing young women infected by vertical transmission (TV) to be pregnant without risk for their fetus of acquiring this infection. To describe the clinical-immune status in pregnant women that acquired HV by vertical transmission, treatments received, monitoring of pregnancy and newborn characteristics. A protocol was performed, evaluating clinical and immunological parameters during pregnancy, ART used, protocol preventing vertical transmission (PPTV), and follow up of children to 18 months of age. Of 358 HIV-positive patients vertically infected, five women became pregnant, between 14 and 24 years old. Pregnancies were controlled in clinical/immune-stage N2 C3. They had received two to five therapies. Full PPTV was performed in all binomials. Pre-natal undetectable viral loads ranged from 4,700 ARN copies/mL. Five living children were born by Caesarean section, four of them with 37 weeks of completed gestation and one of them with 34 weeks of gestation. All received zidovudine (AZT) for 6 weeks. CD4 at 72 hours of life ranged from 48% to 74.6%. All children were born uninfected with HIV. Only two had mild anemia. Expectations of HIV mothers vertically infected to have healthy children are similar to those infected by horizontal transmission, using PPTV.

Making fair decisions about financing care for persons with AIDS.

PubMed Central

Roper, W L; Winkenwerder, W

1988-01-01

An estimated 40 percent of the nation's 55,000 persons with acquired immunodeficiency syndrome (AIDS) have received care under the Medicaid Program, which is administered by the Health Care Financing Administration (HCFA) and funded jointly by the Federal Government and the States. In fiscal year 1988, Medicaid will spend between $700 and $750 million for AIDS care and treatment. Medicaid spending on AIDS is likely to reach $2.4 billion by fiscal year 1992, an estimate that does not include costs of treatment with zidovudine (AZT). Four policy principles are proposed for meeting this new cost burden in a way that is fair, responsive, efficient, and in harmony with our current joint public-private system of health care financing. The four guidelines are to (a) treat AIDS as any other serious disease, without the creation of a disease-specific entitlement program; (b) bring AIDS treatment financing into the mainstream of the health care financing system, making it a shared responsibility and promoting initiatives such as high-risk insurance pools: (c) give States the flexibility to meet local needs, including Medicaid home care and community-based care services waivers; (d) encourage health care professionals to meet their obligation to care for AIDS patients. PMID:3131823

Amphiphilic lipid derivatives of 3'-hydroxyurea-deoxythymidine: preparation, properties, molecular self-assembly, simulation and in vitro anticancer activity.

PubMed

Li, Miao; Qi, Shuo; Jin, Yiguang; Yao, Weishang; Zhang, Sa; Zhao, Jingyu

2014-11-01

Lipid derivatives of nucleoside analogs and their nanoassemblies have become the research hotspot due to their unique function in cancer therapy. Six lipid derivatives of 3'-hydroxyurea-deoxythymidine were prepared with zidovudine as the raw material. The 5'-substituted lipid chains in the derivatives were from the various fatty acids including octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid and octadecanoic acid corresponding to the derivatives OHT, DHT, DDHT, TDHT, HDHT and ODHT. The amphiphilic derivatives formed Langmuir monolayers at the air/water interface with different surface pressure-molecular area isotherms depending on the length of lipid chains. The nanoassemblies of OHT, DHT, DDHT, TDHT and HDHT and the nanoscale precipitates of ODHT were obtained after we injected their tetrahydrofuran solutions doped with hydrophilic long chained polymers into water. Electron microscopy showed that the morphology of nanoassemblies may be vesicles or nanotubes depending on the length of lipid chains. The shorter the lipid chains were, the softer the nanoassemblies. Computer simulation supported the experimental results. The nanoassemblies and the nanoscale precipitates showed much higher anticancer effects on SW620 cells than the parent drug hydroxyurea. The nanostructures of the derivatives are promising anticancer nanomedicines. Copyright © 2014 Elsevier B.V. All rights reserved.

Health insurance and use of medical services by men infected with HIV.

PubMed

Katz, M H; Chang, S W; Buchbinder, S P; Hessol, N A; O'Malley, P; Doll, L S

1995-01-01

Among 178 HIV-infected men from the San Francisco City Clinic Cohort (SFCCC), we examined the association between health insurance and use of outpatient services and treatment. For men with private insurance, we also assessed the frequency of avoiding the use of health insurance. Men without private insurance reported fewer outpatient visits than men with fee-for-service or managed-care plans. Use of zidovudine for eligible men was similar for those with fee-for-service plans (74%), managed-care plans (77%), or no insurance (61%). Use of Pneumocytstis carinii pneumonia prophylaxis was similar for those with fee-for-service (93%) and managed-care plans (83%) but lower for those with no insurance (63%). Of 149 men with private insurance, 31 (21%) reported that they had avoided using their health insurance for medical expenses in the previous year. In multivariate analysis, the independent predictors of avoiding the use of insurance were working for a small company and living outside the San Francisco Bay Area. Having private insurance resulted in higher use of outpatient services, but the type of private insurance did not appear to affect the use of service or treatment. Fears of loss of coverage and confidentiality may negate some benefits of health insurance for HIV-infected persons.

Predicting survival in AIDS: refining the model.

PubMed

Hutchinson, S J; Brettle, R P; Gore, S M

1997-11-01

We tested the validity of a previously-published AIDS staging system by examining AIDS-defining diseases (ADDs) and CD4 counts as prognostic factors for survival of the 248 AIDS patients in the Edinburgh City Hospital Cohort, of whom 56% were injecting drug-users (IDUs). Cox regression was used to model the proportionality of risk of death as the CD4 count declined and more ADDs were experienced, and dependence upon post-AIDS treatment. Using the system of Mocroft et al. (Lancet 1995; 346:12-17) to grade severity, our data were well enough modelled, but we suggest: (i) regrading of HIV dementia (RR 3.9, 95% CI 2.5-6.0), mainly attributed to the drug users, to a very severe ADD; (ii) reduction in risk from zidovudine (RR 0.7, 95% CI 0.5-1.0) during AIDS follow-up for patients starting treatment at or after AIDS diagnosis; (iii) improved management of first mild ADDs (from 1987-89 to 1994-95: 40% reduction in IDUs appearing with mild index diseases, and an approximate three-fold reduction in risk associated with a mild ADD). This study supports previous findings on the significance of ADDs and lowest CD4 count in predicting the lifetime of AIDS patients.

Optimization of a polymer composite employing molecular mechanic simulations and artificial neural networks for a novel intravaginal bioadhesive drug delivery device.

PubMed

Ndesendo, Valence M K; Pillay, Viness; Choonara, Yahya E; du Toit, Lisa C; Kumar, Pradeep; Buchmann, Eckhart; Meyer, Leith C R; Khan, Riaz A

2012-01-01

This study aimed at elucidating an optimal synergistic polymer composite for achieving a desirable molecular bioadhesivity and Matrix Erosion of a bioactive-loaded Intravaginal Bioadhesive Polymeric Device (IBPD) employing Molecular Mechanic Simulations and Artificial Neural Networks (ANN). Fifteen lead caplet-shaped devices were formulated by direct compression with the model bioactives zidovudine and polystyrene sulfonate. The Matrix Erosion was analyzed in simulated vaginal fluid to assess the critical integrity. Blueprinting the molecular mechanics of bioadhesion between vaginal epithelial glycoprotein (EGP), mucin (MUC) and the IBPD were performed on HyperChem 8.0.8 software (MM+ and AMBER force fields) for the quantification and characterization of correlative molecular interactions during molecular bioadhesion. Results proved that the IBPD bioadhesivity was pivoted on the conformation, orientation, and poly(acrylic acid) (PAA) composition that interacted with EGP and MUC present on the vaginal epithelium due to heterogeneous surface residue distributions (free energy= -46.33 kcalmol(-1)). ANN sensitivity testing as a connectionist model enabled strategic polymer selection for developing an IBPD with an optimally prolonged Matrix Erosion and superior molecular bioadhesivity (ME = 1.21-7.68%; BHN = 2.687-4.981 N/mm(2)). Molecular modeling aptly supported the EGP-MUC-PAA molecular interaction at the vaginal epithelium confirming the role of PAA in bioadhesion of the IBPD once inserted into the posterior fornix of the vagina.

Broad advances in understanding HIV resistance to antiretrovirals: report on the XVII International HIV Drug Resistance Workshop.

PubMed

Mascolini, Mark; Larder, Brendan A; Boucher, Charles A B; Richman, Douglas D; Mellors, John W

2008-01-01

The 2008 International HIV Drug Resistance Workshop explored six topics on viral resistance: new antiretrovirals; clinical implications; epidemiology; new technologies and interpretations; HIV pathogenesis, fitness, and resistance; and mechanisms of resistance. The last of these topics provided a forum for new work on resistance of hepatitis B and C viruses, which were also explored in two poster sessions. Much work focused on resistance to the two most recent antiretroviral classes (integrase inhibitors and CCR5 antagonists), a new set of entry inhibitor candidates and one new class represented by the maturation inhibitor bevirimat. Other research explored two novel non-nucleoside reverse transcriptase inhibitors, etravirine and IDX899. Epidemiological work analysed rates of transmitted resistant virus, multiclass resistance in antiretroviral-experienced patients and a heightened resistance risk in injecting drug users regardless of adherence. New research on resistance technologies involved an enhanced assay for HIV-1 coreceptor determination and improved gene-based tools for predicting coreceptor use. In the pathogenesis arena, a small study of intensification shed light on the likely source of residual viraemia in patients on successful antiretroviral therapy. A large study in Mozambique correlated the timing of infant infection with selection, transmission and persistence of nevirapine resistance mutations. Mechanistic research explored resistance to the integrase inhibitor raltegravir, K65R-mediated resistance to tenofovir and the role of connection domain mutations in resistance to zidovudine.

Summaries from the Eleventh Annual Houston Conference on AIDS in America.

PubMed

1999-07-01

A number of significant papers from the Eleventh Annual Houston Conference on AIDS in America are summarized. Topics include the current concepts in pathogenesis of HIV infection, the use of anti-HIV therapies, and drug interactions in HIV treatment. A session on HIV disease in children focused on the epidemiology and prevention of vertical transmission with Zidovudine, when to initiate therapy, and options for children who have failed current therapies. Studies using immune-based therapy have shown promise in treating HIV disease. New data from a study with sargramostim, an investigational agent for opportunistic infection prophylaxis, shows that the drug reduces viral loads and delays time to treatment failure. Pentafuside (T-20), the first of a new class of HIV drugs, fusion inhibitors, has been found to be safe and effective against HIV, although drug resistance may be associated with its use. Other sessions summarized progress in clearing HIV from viral reservoirs, the ethics of HIV research support from the drug industry and drug marketing, and a review of immune reconstitution studies among people on antiretroviral therapy. Sam Avrett of the AIDS Vaccine Advocacy Coalition (AVAC) summarized in his session the characteristics of a successful HIV vaccine and the need to have more people involved in vaccine advocacy as a means to ending the epidemic. Contact information is provided.

Follow-up on long-term antiretroviral therapy for cats infected with feline immunodeficiency virus.

PubMed

Medeiros, Sheila de Oliveira; Abreu, Celina Monteiro; Delvecchio, Rodrigo; Ribeiro, Anísia Praxedes; Vasconcelos, Zilton; Brindeiro, Rodrigo de Moraes; Tanuri, Amilcar

2016-04-01

Feline immunodeficiency virus (FIV) is a lentivirus that induces AIDS-like disease in cats. Some of the antiretroviral drugs available to treat patients with HIV type 1 are used to treat FIV-infected cats; however, antiretroviral therapy (ART) is not used in cats as a long-term treatment. In this study, the effects of long-term ART were evaluated in domestic cats treated initially with the nucleoside transcriptase reverse inhibitor (NTRI) zidovudine (AZT) over a period ranging from 5-6 years, followed by a regimen of the NTRI lamivudine (3TC) plus AZT over 3 years. Viral load, sequencing of pol (reverse transcriptase [RT]) region and CD4:CD8 lymphocyte ratio were evaluated during and after treatment. Untreated cats were evaluated as a control group. CD4:CD8 ratios were lower, and uncharacterized resistance mutations were found in the RT region in the group of treated cats. A slight increase in viral load was observed in some cats after discontinuing treatment. The data strongly suggest that treated cats were resistant to therapy, and uncharacterized resistance mutations in the RT gene of FIV were selected for by AZT. Few studies have been conducted to evaluate the effect of long-term antiretroviral therapy in cats. To date, resistance mutations have not been described in vivo. © ISFM and AAFP 2015.

Detection and analysis of bovine foamy virus infection by an indicator cell line.

PubMed

Ma, Zhe; Qiao, Wen-tao; Xuan, Cheng-hao; Xie, Jin-hui; Chen, Qi-min; Geng, Yun-qi

2007-07-01

To determine the infectivity and replication strategy of bovine foamy virus (BFV) in different cultured cells using the BFV indicator cell line (BICL) system. BFV infection was induced by the co-culture method or the transient transfection of the infectious BFV plasmid [pCMV (cytomegalovirus) - BFV] clone. The infectivity of BFV was monitored by the percentage of green fluorescent protein-positive cells in the BICL. The effect of reverse transcriptase inhibitor zidovudine (AZT) on BFV replication was also evaluated in the BICL. The titer of BFV in fetal bovine lung cells was 4-5-folds more than that in either 293T or HeLa (Cells from Henrietta lacks) cells using the co-culture method, and in the meantime was significantly higher than that produced by the infectious clone pCMV-BFV in the same cells. AZT had only a minor effect on viral titers when added to cells prior to the virus infection. In contrast, viral titers reduced sharply to the level of the negative control when the virus was produced from cells in the presence of AZT. BICL can be used for the titration of the BFV viral infection in non-cytopathic condition. In addition, we provide important evidence to show that reverse transcription is essential for BFV replication at a late step of viral infection.

Contraceptive use and pregnancy decision making among women with HIV.

PubMed

Smits, A K; Goergen, C A; Delaney, J A; Williamson, C; Mundy, L M; Fraser, V J

1999-12-01

HIV is a growing epidemic among women in the United States. This study seeks to determine if knowledge of HIV infection and of the benefits of prenatal zidovudine (ZDV) to decrease vertical HIV transmission is related to decisions about pregnancy planning, contraceptive and condom use, and pregnancy termination among noninjection drug using (IDU) women with HIV. Eighty-two HIV-infected women were interviewed about their pregnancy decisions, contraceptive and condom use, and pregnancy outcome. Data was verified by structured chart review where available. Awareness of HIV infection or knowledge of the benefits of prenatal ZDV use did not significantly influence pregnancy planning, contraceptive choice, use of contraception, or consideration of pregnancy termination. Condom use was extremely low (14.6% consistent use), the majority of pregnancies (68.0%) were unplanned, contraceptive use was low (50.9%), and few pregnancies were terminated (6.3%). Women on Medicaid were significantly less likely than women with private or no insurance to terminate their pregnancy (2/20, 10% vs. 3/5, 60%, p = 0.04, two-tailed Fisher's exact test). Most women (70.0%) reported the most important reason for carrying the pregnancy to term was the desire for a child. In conclusion, among women in this non-IDU, Midwestern cohort, knowledge of HIV infection was not associated with decisions to plan a pregnancy, use contraception if not planning pregnancy, or terminate an unplanned pregnancy.

Colombia: crusading efforts bring signs of progress.

PubMed

Kendall, S

1989-01-01

Colombia, like many developing countries, has not committed resources to fight the AIDS problem. They have used the media for condom promotion and other sexually transmitted diseases. There have been 151 deaths caused by AIDS by the end of 1988; 344 cases are known, and 130 additional have tested positive to the virus. Health officials were reluctant to recognize the problem, thinking it was outside their country and that they would not be affected by it. Since then, they have tried to target high risk groups and educate them and assist with testing and counseling. There is a move to make the new drug zidovudine available, but few could afford its high price. The authorities have put transvestite prostitutes in jail and kept them for AIDS testing, but few woman prostitutes have been tested. Up until 1986, only 30% of the Red Cross blood bank supplies were being tested; now 80% are, although it comprises only about 40% of the total supply. Drugs are used heavily, but mostly smoked, in Colombia, yet there is some concern about increased use of needles. The majority of cases in Columbia have been homosexual and bisexual men, but prostitution among men and women is prevalent in large cities such as Bogota. Health officials state that education is the best deterrent, but must be perpetuated so people will be constantly reminded.

IRF-4 and c-Rel expression in antiviral-resistant adult T-cell leukemia/lymphoma

PubMed Central

Ramos, Juan Carlos; Ruiz, Phillip; Ratner, Lee; Reis, Isildinha M.; Brites, Carlos; Pedroso, Celia; Byrne, Gerald E.; Toomey, Ngoc L.; Andela, Valentine; Harhaj, Edward W.; Lossos, Izidore S.

2007-01-01

Adult T-cell leukemia/lymphoma (ATLL) is a generally fatal malignancy. Most ATLL patients fare poorly with conventional chemotherapy; however, antiviral therapy with zidovudine (AZT) and interferon alpha (IFN-α) has produced long-term clinical remissions. We studied primary ATLL tumors and identified molecular features linked to sensitivity and resistance to antiviral therapy. Enhanced expression of the proto-oncogene c-Rel was noted in 9 of 27 tumors. Resistant tumors exhibited c-Rel (6 of 10; 60%) more often than did sensitive variants (1 of 9; 11%). This finding was independent of the disease form. Elevated expression of the putative c-Rel target, interferon regulatory factor-4 (IRF-4), was observed in 10 (91%) of 11 nonresponders and in all tested patients with c-Rel+ tumors and occurred in the absence of the HTLV-1 oncoprotein Tax. In contrast, tumors in complete responders did not express c-Rel or IRF-4. Gene rearrangement studies demonstrated the persistence of circulating T-cell clones in long-term survivors maintained on antiviral therapy. The expression of nuclear c-Rel and IRF-4 occurs in the absence of Tax in primary ATLL and is associated with antiviral resistance. These molecular features may help guide treatment. AZT and IFN-α is a suppressive rather than a curative regimen, and patients in clinical remission should remain on maintenance therapy indefinitely. PMID:17138822

Protease inhibitors as potential therapeutic agents for AIDS.

PubMed

Jamjoom, G A

1991-09-01

A decade since the epidemic of the acquired immunodeficiency syndrome (AIDS) was first recognized, a wealth of information has accumulated on the molecular biology of the causative agents, the human immunodeficiency viruses (HIV). Of particular interest is knowledge of the viral enzymes involved in the formation of new virus particles. Such enzymes constitute attractive targets for efforts aimed at selecting agents that interfere with virus multiplication and subsequent spread and pathogenesis. Already, several agents that inhibit the viral reverse transcriptase (e.g., nucleoside analogs such as Zidovudine) have proved to have a beneficial effect on the course off the disease, but their prolonged use has been associated with significant toxicity and the emergence of resistant mutants. A second enzyme that has recently attracted attention is the virus-coded protease. This enzyme is involved in the cleavage of viral precursor polyproteins into the final products that constitute the mature virus particle. Protease inhibitors interfere with the process of virus maturation which is required for the formation of infective virus particles. Several custom-made inhibitors with a high selective action against HIV protease have been produced recently. They are nonhydrolyzable peptide analogs that mimic the cleavage sequences of the natural substrate of the enzyme during the transition state of the cleavage reaction. It is hoped that a similar selectivity in vivo may make protease inhibitors a promising new category of AIDS therapeutics.

Highly active antiretroviral therapy started during pregnancy or postpartum suppresses HIV-1 RNA, but not DNA, in breast milk.

PubMed

Shapiro, Roger L; Ndung'u, Thumbi; Lockman, Shahin; Smeaton, Laura M; Thior, Ibou; Wester, Carolyn; Stevens, Lisa; Sebetso, Gaseene; Gaseitsiwe, Simani; Peter, Trevor; Essex, Max

2005-09-01

The ability of highly active antiretroviral therapy (HAART) to reduce human immunodeficiency virus type 1 (HIV-1) RNA and DNA in breast milk has not been described. We compared breast-milk HIV-1 RNA and DNA loads of women in Botswana who received HAART (nevirapine, lamivudine, and zidovudine) and women who did not receive HAART. Women in the HAART group received treatment for a median of 98 days (range, 67-222 days) at the time of breast-milk sampling; 23 (88%) of 26 had whole breast-milk HIV-1 RNA loads <50 copies/mL, compared with 9 (36%) of 25 women who did not receive HAART (P=.0001). This finding remained significant in a multivariate logistic-regression model (P = .0006). The whole-milk HIV-1 DNA load was unaffected by HAART. Of women who received HAART, 13 (50%) of 26 had HIV-1 DNA loads <10 copies/10(6) cells, compared with 15 (65%) of 23 who did not receive HAART (P = .39). HAART suppressed cell-free HIV-1 RNA in breast milk and may therefore reduce mother-to-child transmission (MTCT) of HIV-1 via breast-feeding. However, HAART initiated during pregnancy or early after delivery had no apparent effect on cell-associated HIV-1 DNA loads in breast milk. Clinical trials to determine MTCT among breast-feeding women receiving HAART are needed.

[HIV encephalopathy due to drug resistance despite 2-year suppression of HIV viremia by cART].

PubMed

Sekiya, Hiroaki; Kawamoto, Michi; Togo, Masaya; Yoshimura, Hajime; Imai, Yukihiro; Kohara, Nobuo

2014-01-01

A 57-year-old man presented with subacute progression of cognitive impairment (MMSE 22/30). He had been diagnosed as AIDS two years before and taking atazanavir, abacavir, and lamivudine. HIV RNA of plasma had been negative. On admission, HIV RNA was 4,700 copy/ml and 5,200 copy/ml in plasma and in cerebrospinal fluid respectively, suggesting treatment failure of cART. The brain magnetic resonance imaging showed high intensity areas in the white matter of the both frontal lobes and brain stem. The drug-resistance test revealed the resistance of lamivudine and abacavir. We introduced the CNS penetration effectiveness (CPE) score to evaluate the drug penetration of HIV drugs. As the former regimen had low points (7 points), we optimized the regimen to raltegravir, zidovudine, and darunavir/ritonavir (scoring 10 points). His cognitive function improved as normal (MMSE 30/30) in 2 weeks and HIV-RNA became undetectable both in plasma and CSF in a month. In spite of the cognitive improvement, the white matter hyperintensity expanded. To rule out malignant lymphoma or glioblastoma, the brain biopsy was performed from the right frontal lobe. It revealed microglial hyperplasia and diffuse perivascular infiltration by CD8+/CD4-lymphocytes. No malignant cells were found and the polymerase chain reaction analyses excluded other viruses. Considering the drug penetration to the central nervous system is important for treating HIV encephalopathy.

Forecasting the personal medical care costs of AIDS from 1988 through 1991.

PubMed Central

Hellinger, F J

1988-01-01

The personal medical care costs of those diagnosed with acquired immunodeficiency syndrome (AIDS) in 1988 are forecast to be $2.2 billion, an amount that will increase to $4.5 billion in 1991. This is the first study to include the cost of purchasing azidothymidine (AZT), also called zidovudine, a palliative treatment for AIDS. The forecasts of this study are lower than those reported by Rice and Scitovsky, and other researchers, because the data are more recent and AIDS patients are receiving more care on an outpatient basis and staying in the hospital fewer days. They are also lower because projections for the number of AIDS cases diagnosed in future years are lower than those made by the Centers for Disease Control (CDC). This study projects that about 38,000 AIDS cases will be diagnosed in 1988 and 73,000 in 1991. The projections in this study are derived using data on the number of AIDS cases reported to CDC from January 1984 to October 1987, while the CDC projections employed by Rice and Scitovsky were derived using data from June 1981 to May 1986. It is also projected that the lifetime cost of treating an AIDS patient will increase from $57,000 in 1988 to $61,800 in 1991 due to the wider use of AZT. PMID:2836880

Clinical Trials and Treatment of ATL

PubMed Central

Tsukasaki, Kunihiro; Tobinai, Kensei

2012-01-01

ATL is a distinct peripheral T-lymphocytic malignancy associated with human T-cell lymphotropic virus type I (HTLV-1). The diversity in clinical features and prognosis of patients with this disease has led to its subtype-classification into four categories, acute, lymphoma, chronic, and smoldering types, defined by organ involvement, and LDH and calcium values. In case of acute, lymphoma, or unfavorable chronic subtypes (aggressive ATL), intensive chemotherapy like the LSG15 regimen (VCAP-AMP-VECP) is usually recommended if outside of clinical trials, based on the results of a phase 3 trial. In case of favorable chronic or smoldering ATL (indolent ATL), watchful waiting until disease progression has been recommended, although the long-term prognosis was inferior to those of, for instance, chronic lymphoid leukemia. Retrospective analysis suggested that the combination of interferon alpha and zidovudine was apparently promising for the treatment of ATL, especially for types with leukemic manifestation. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is also promising for the treatment of aggressive ATL possibly reflecting graft versus ATL effect. Several new agent trials for ATL are ongoing and in preparation, including a defucosylated humanized anti-CC chemokine receptor 4 monoclonal antibody, IL2-fused with diphtheria toxin, histone deacetylase inhibitors, a purine nucleoside phosphorylase inhibitor, a proteasome inhibitor, and lenalidomide. PMID:23259064

Patents for critical pharmaceuticals: the AZT case.

PubMed

Ackiron, E

1991-01-01

Patents and other statutory types of market protections are used in the United States to promote scientific research and innovation. This incentive is especially important in research intensive fields such as the pharmaceutical industry. Unfortunately, these same protections often result in higher monopoly pricing once a successful product is brought to market. Usually this consequence is viewed as the necessary evil of an incentive system that encourages costly research and development by promising large rewards to the successful inventor. However, in the case of the AIDS drug Zidovudine (AZT), the high prices charged by the pharmaceutical company owning the drug have led to public outcry and a re-examination of government incentive systems. This Note traces the evolution of these incentive programs--the patent system, and, to a lesser extent, the orphan drug program--and details the conflicting interests involved in their development. It then demonstrates how the AZT problem brings the interest of providing inventors with incentives for risky innovative efforts into a sharp collision with the ultimate goal of such systems: ensuring that the public has access to the resulting products at a reasonable price. Finally, the Note describes how Congress and the courts have attempted to resolve these problems in the past, and how they might best try to solve the AZT problem in the near future.

[Mutations of resistance of HIV-1 in previously untreated patients at penitentiary centers of the Autonomous Community of Valencia, Spain. REPRICOVA study].

PubMed

García-Guerrero, Julio; Herrero, Agustín; Vera, Enrique; Almenara, José M; Araújo, Rosa; Saurí, Vicente V; Castellano, Juan C; Fernández-Clemente, Luis; Bedia, Miguel; Llorente, María I; González-Morán, Francisco

2002-03-02

Our purpose was to determine the prevalence of mutations of resistance to nucleoside inhibitors of reverse transcriptase (NIRT) and protease inhibitors (PI) in the HIV-1 genotype of naïve infected subjects in the prisons of the Autonomous Community of Valencia, Spain. Multicentric, descriptive, cross-sectional study of prevalence including a systematic stratified and randomised sampling by centres. Demographic, clinical, virological and immunological data were collected. The HIV gene of protease and transcriptase was studied in peripheral blood plasma samples by means of double PCR amplification and subsequent automatic sequence. Reference: wild strain HXB2. Plasma was obtained from 133 individuals (119 men and 14 women). 117 samples were selected and the rest did not have enough copies for transcription. With regard to NIRT, 7 samples (5.2% of total) showed some mutation of resistance: M41L, D67N, L210W and K219Q, all them secondary to and associated with resistance to zidovudine, abacavir as well as group B multinucleoside-resistance. With regard to PI, only one sample showed a primary mutation, M46I, which was associated with resistance to indinavir. Moreover, a further 41 samples were found to express some secondary mutation. In our series, there was a low number of primary mutations of resistance. These results allow us to exclude the systematic use of resistance tests before an initiation antiretroviral therapy.

Insulin resistance and associated factors among HIV-infected patients in sub-Saharan Africa: a cross sectional study from Cameroon.

PubMed

Noumegni, Steve Raoul Ngongang; Nansseu, Jobert Richie; Ama, Vicky Jocelyne Moor; Bigna, Jean Joel; Assah, Felix Kembe; Guewo-Fokeng, Magellan; Leumi, Steve; Katte, Jean-Claude; Dehayem, Mesmin; Kengne, Andre Pascal; Sobngwi, Eugene

2017-08-10

Little is known on the magnitude and correlates of insulin resistance in HIV-infected people in Africa. We determined the prevalence of insulin resistance and investigated associated factors in HIV-infected adult Cameroonians. We conducted a cross-sectional study at the Yaoundé Central Hospital, Cameroon; during which we enrolled HIV-infected people aged 30 to 74 years with no previous history of cardiovascular disease. An homeostatic model assessment of insulin resistance (HOMA-IR) like index served to assess insulin sensitivity with insulin resistance defined by values of 2.1 or higher. We included 452 patients (20% men). Their mean age was 44.4 ± 9.8 years and 88.5% of them were on antiretroviral therapy (93.3% on first line regimen including Zidovudine, lamivudine and Efavirenz/Nevirapine). Of all participants, 28.5% were overweight, 19.5% had obesity and 2.0% had diabetes. The prevalence of insulin resistance was 47.3% without any difference between patients on ART and those ART-naïve (48.5% vs. 38.5%; p = 0.480). Obesity was the only factor independently associated with insulin resistance (adjusted odds ratio: 2.28; 95% confidence interval: 1.10-4.72). Insulin resistance is present in nearly half of HIV-infected patients in Cameroon despite a low prevalence rate of diabetes, and is associated with obesity.

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2002-05-01

hydrochloride, rosuvastatin calcium; Sevoflurane, sildenafil citrate, simvastatin, somatropin; Tacrolimus, tamoxifen citrate, telmisartan, temozolomide, thiopental sodium, tinzaparin sodium, tirofiban hydrochloride, treosulfan, triamcinolone acetonide; Urokinase; Valsartan, vardenafil, vincristine; Warfarin sodium; Ximelagatran; Zidovudine.

Anemia and Red Blood Cell Indices Predict HIV-Associated Neurocognitive Impairment in the Highly Active Antiretroviral Therapy Era

PubMed Central

Kallianpur, Asha R.; Wang, Quan; Jia, Peilin; Hulgan, Todd; Zhao, Zhongming; Letendre, Scott L.; Ellis, Ronald J.; Heaton, Robert K.; Franklin, Donald R.; Barnholtz-Sloan, Jill; Collier, Ann C.; Marra, Christina M.; Clifford, David B.; Gelman, Benjamin B.; McArthur, Justin C.; Morgello, Susan; Simpson, David M.; McCutchan, J. A.; Grant, Igor

2016-01-01

Background. Anemia has been linked to adverse human immunodeficiency virus (HIV) outcomes, including dementia, in the era before highly active antiretroviral therapy (HAART). Milder forms of HIV-associated neurocognitive disorder (HAND) remain common in HIV-infected persons, despite HAART, but whether anemia predicts HAND in the HAART era is unknown. Methods. We evaluated time-dependent associations of anemia and cross-sectional associations of red blood cell indices with neurocognitive impairment in a multicenter, HAART-era HIV cohort study (N = 1261), adjusting for potential confounders, including age, nadir CD4+ T-cell count, zidovudine use, and comorbid conditions. Subjects underwent comprehensive neuropsychiatric and neuromedical assessments. Results. HAND, defined according to standardized criteria, occurred in 595 subjects (47%) at entry. Mean corpuscular volume and mean corpuscular hemoglobin were positively associated with the global deficit score, a continuous measure of neurocognitive impairment (both P < .01), as well as with all HAND, milder forms of HAND, and HIV-associated dementia in multivariable analyses (all P < .05). Anemia independently predicted development of HAND during a median follow-up of 72 months (adjusted hazard ratio, 1.55; P < .01). Conclusions. Anemia and red blood cell indices predict HAND in the HAART era and may contribute to risk assessment. Future studies should address whether treating anemia may help to prevent HAND or improve cognitive function in HIV-infected persons. PMID:26690344

Raltegravir in second-line antiretroviral therapy in resource-limited settings (SELECT): a randomised, phase 3, non-inferiority study.

PubMed

La Rosa, Alberto M; Harrison, Linda J; Taiwo, Babafemi; Wallis, Carole L; Zheng, Lu; Kim, Peter; Kumarasamy, Nagalingeswaran; Hosseinipour, Mina C; Jarocki, Bernadette; Mellors, John W; Collier, Ann C

2016-06-01

For second-line antiretroviral therapy, WHO recommends a boosted protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs). However, concerns about toxicity and cross-resistance motivated a search for regimens that do not contain NRTIs. We aimed to assess whether boosted lopinavir plus raltegravir would be non-inferior to boosted lopinavir plus NRTIs for virological suppression in resource-limited settings. A5273 was a randomised, open-label, phase 3, non-inferiority study at 15 AIDS Clinical Trials Group (ACTG) research sites in nine resource-limited countries (three sites each in India and South Africa, two each in Malawi and Peru, and one each in Brazil, Kenya, Tanzania, Thailand, and Zimbabwe). Adults with plasma HIV-1 RNA concentrations of at least 1000 copies per mL after at least 24 weeks on a regimen based on a non-NRTI inhibitor were randomly assigned (1:1) to receive oral ritonavir-boosted lopinavir (100 mg ritonavir, 400 mg lopinavir) plus 400 mg raltegravir twice a day (raltegravir group) or to ritonavir-boosted lopinavir plus two or three NRTIs selected from an algorithm (eg, zidovudine after failure with tenofovir and vice versa; NRTI group). Randomised group assignment was done with a computer algorithm concealed to site personnel, and stratified by HIV-1 RNA viral load, CD4 cell count, and intention to use zidovudine, with the groups balanced by each site. The primary endpoint was time to confirmed virological failure (two measurements of HIV-1 RNA viral load >400 copies per mL) at or after week 24 in the intention-to-treat population. Non-inferiority (10% margin) was assessed by comparing the cumulative probability of virological failure by 48 weeks. This trial was registered with ClinicalTrials.gov, NCT01352715. Between March 13, 2012, and Oct 2, 2013, we randomly assigned 515 participants: 260 to the raltegravir group and 255 to the NRTI group; two participants in the raltegravir group and one in the NRTI group

Short communication: high prevalence of drug resistance in HIV type 1-infected children born in Honduras and Belize 2001 to 2004.

PubMed

Parham, Leda; de Rivera, Ivette Lorenzana; Murillo, Wendy; Naver, Lars; Largaespada, Natalia; Albert, Jan; Karlsson, Annika C

2011-10-01

Antiretroviral therapy has had a great impact on the prevention of mother-to-child transmission (MTCT) of HIV-1. However, development of drug resistance, which could be subsequently transmitted to the child, is a major concern. In Honduras and Belize the prevalence of drug resistance among HIV-1-infected children remains unknown. A total of 95 dried blood spot samples was obtained from HIV-1-infected, untreated children in Honduras and Belize born during 2001 to 2004, when preventive antiretroviral therapy was often suboptimal and consisted of monotherapy with nevirapine or zidovudine. Partial HIV-1 pol gene sequences were successfully obtained from 66 children (Honduras n=55; Belize n=11). Mutations associated with drug resistance were detected in 13% of the Honduran and 27% of the Belizean children. Most of the mutations detected in Honduras (43%) and all mutations detected in Belize were associated with resistance to nonnucleoside reverse transcriptase inhibitors, which was expected from the wide use of nevirapine to prevent MTCT during the study period. In addition, although several mothers reported that they had not received antiretroviral therapy, mutations associated with resistance to nucleoside reverse transcriptase inhibitors and protease inhibitors were found in Honduras. This suggests prior and unreported use of these drugs, or that these women had been infected with resistant virus. The present study demonstrates, for the first time, the presence of drug resistance-associated mutations in HIV-1-infected Honduran and Belizean children.

Antiretroviral Agents Effectively Block HIV Replication after Cell-to-Cell Transfer

PubMed Central

Permanyer, Marc; Ballana, Ester; Ruiz, Alba; Badia, Roger; Riveira-Munoz, Eva; Gonzalo, Encarna; Clotet, Bonaventura

2012-01-01

Cell-to-cell transmission of HIV has been proposed as a mechanism contributing to virus escape to the action of antiretrovirals and a mode of HIV persistence during antiretroviral therapy. Here, cocultures of infected HIV-1 cells with primary CD4+ T cells or lymphoid cells were used to evaluate virus transmission and the effect of known antiretrovirals. Transfer of HIV antigen from infected to uninfected cells was resistant to the reverse transcriptase inhibitors (RTIs) zidovudine (AZT) and tenofovir, but was blocked by the attachment inhibitor IgGb12. However, quantitative measurement of viral DNA production demonstrated that all anti-HIV agents blocked virus replication with similar potency to cell-free virus infections. Cell-free and cell-associated infections were equally sensitive to inhibition of viral replication when HIV-1 long terminal repeat (LTR)-driven green fluorescent protein (GFP) expression in target cells was measured. However, detection of GFP by flow cytometry may incorrectly estimate the efficacy of antiretrovirals in cell-associated virus transmission, due to replication-independent Tat-mediated LTR transactivation as a consequence of cell-to-cell events that did not occur in short-term (48-h) cell-free virus infections. In conclusion, common markers of virus replication may not accurately correlate and measure infectivity or drug efficacy in cell-to-cell virus transmission. When accurately quantified, active drugs blocked proviral DNA and virus replication in cell-to-cell transmission, recapitulating the efficacy of antiretrovirals in cell-free virus infections and in vivo. PMID:22696642

Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV-associated multicentric Castleman disease

PubMed Central

Polizzotto, Mark N.; Aleman, Karen; Wyvill, Kathleen M.; Marshall, Vickie; Whitby, Denise; Wang, Victoria; Pittaluga, Stefania; O’Mahony, Deirdre; Steinberg, Seth M.; Little, Richard F.; Yarchoan, Robert

2014-01-01

Kaposi sarcoma (KS) herpesvirus–associated multicentric Castleman disease (KSHV-MCD) is a lymphoproliferative disorder, most commonly seen in HIV-infected patients, that has a high mortality if untreated. Concurrent KS is common. Although rituximab has reported activity in KSHV-MCD, its use is often associated with KS progression. Within a natural history study of KSHV-MCD, we prospectively evaluated rituximab 375 mg/m2 combined with liposomal doxorubicin 20 mg/m2 (R-Dox) every 3 weeks in 17 patients. Patients received a median of 4 cycles (range 3-9). All received antiretroviral therapy, 11 received consolidation interferon-α, and 6 received consolidation high-dose zidovudine with valganciclovir. Using NCI KSHV-MCD response criteria, major clinical and biochemical responses were attained in 94% and 88% of patients, respectively. With a median 58 months’ potential follow-up, 3-year event-free survival was 69% and 3-year overall survival was 81%. During R-Dox therapy, cutaneous KS developed in 1 patient, whereas 5 of 6 patients with it had clinical improvement. R-Dox was associated with significant improvement in anemia and hypoalbuminemia. KSHV viral load, KSHV viral interleukin-6, C-reactive protein, human interleukin-6, and serum immunoglobulin free light chains decreased with therapy. R-Dox is effective in symptomatic KSHV-MCD and may be useful in patients with concurrent KS. This trial was registered at www.clinicaltrials.gov as #NCT00092222. PMID:25331113

“Dynamic Range” of Inferred Phenotypic HIV Drug Resistance Values in Clinical Practice

PubMed Central

Swenson, Luke C.; Pollock, Graham; Wynhoven, Brian; Mo, Theresa; Dong, Winnie; Hogg, Robert S.; Montaner, Julio S. G.; Harrigan, P. Richard

2011-01-01

Background ‘Virtual’ or inferred phenotypes (vPhenotypes) are commonly used to assess resistance to antiretroviral agents in patients failing therapy. In this study, we provide a clinical context for understanding vPhenotype values. Methods All HIV-infected persons enrolled in the British Columbia Drug Treatment Program with a baseline plasma viral load (pVL) and follow-up genotypic resistance and pVL results were included up to October 29, 2008 (N = 5,277). Change from baseline pVL was determined as a function of Virco vPhenotype, and the “dynamic range” (defined here by the 10th and 90th percentiles for fold-change in IC50 amongst all patients) was estimated from the distribution of vPhenotye fold-changes across the cohort. Results The distribution of vPhenotypes from a large cohort of HIV patients who have failed therapy are presented for all available antiretroviral agents. A maximum change in IC50 of at least 13-fold was observed for all drugs. The dideoxy drugs, tenofovir and most PIs exhibited small “dynamic ranges” with values of <4-fold change observed in >99% of samples. In contrast, zidovudine, lamivudine, emtricitabine and the non-nucleoside reverse transcriptase inihibitors (excluding etravirine) had large dynamic ranges. Conclusion We describe the populational distribution of vPhenotypes such that vPhenotype results can be interpreted relative to other patients in a drug-specific manner. PMID:21390218

[High activity antiretroviral therapy change associated to adverse drug reactions in a specialized center in Venezuela].

PubMed

Subiela, José D; Dapena, Elida

2016-03-01

Adverse drug reactions (ADRs) represent the first cause of change of the first-line highly active antiretroviral therapy (HAART) regimen, therefore, they constitute the main limiting factor in the long-term follow up of HIV patients in treatment. A retrospective study was carried out in a specialized center in Lara State, Venezuela, including 99 patients over 18 years of age who had change of first-line HAART regimen due to ADRs, between 2010 and 2013. The aims of this research were to describe the sociodemographic and clinical variables, frequency of ADRs related to change of HAART, duration of the first-line HAART regimen, to determine the drugs associated with ARVs and to identify the risk factors. The ADRs constituted 47.5% of all causes of change of first-line HAART regimen, the median duration was 1.08±0.28 years. The most frequent ADRs were anemia (34.3%), hypersensitivity reactions (20.2%) and gastrointestinal intolerance (13.1%). The most frequent ARV regimen type was the protease inhibitors-based regimen (59.6%), but zidovudine was the ARV most linked to ADRs (41.4%). The regression analysis showed increased risk of ADRs in singles and students in the univariate analysis and heterosexuals and homosexuals in multivariate analysis; and decreased risk in active workers. The present work shows the high prevalence of ADRs in the studied population and represents the first case-based study that describes the pharmacoepidemiology of a cohort of HIV-positive patients treated in Venezuela.

HIV-1 Viral Escape in Cerebrospinal Fluid of Subjects on Suppressive Antiretroviral Treatment

PubMed Central

Edén, Arvid; Fuchs, Dietmar; Hagberg, Lars; Nilsson, Staffan; Spudich, Serena; Svennerholm, Bo; Price, Richard W.; Gisslén, Magnus

2010-01-01

Background. Occasional cases of viral escape in cerebrospinal fluid (CSF) despite suppression of plasma human immunodeficiency virus type 1 (HIV-1) RNA have been reported. We investigated CSF viral escape in subjects treated with commonly used antiretroviral therapy regimens in relation to intrathecal immune activation and central nervous system penetration effectiveness (CPE) rank. Methods. Sixty-nine neurologically asymptomatic subjects treated with antiretroviral therapy >6 months and plasma HIV-1 RNA <50 copies/mL were cross-sectionally included in the analysis. Antiretroviral therapy regimens included efavirenz, lopinavir/ritonavir or atazanavir/ritonavir combined with tenofovir, abacavir, or zidovudine and emtricitabine or lamivudine. HIV-1 RNA was analyzed with real-time polymerase chain reaction assays. Neopterin was analyzed by enzyme-linked immunosorbent assay. Results. Seven (10%) of the 69 subjects had detectable CSF HIV-1 RNA, in median 121 copies/mL (interquartile range, 54–213 copies/mL). Subjects with detectable CSF virus had significantly higher CSF neopterin and longer duration of treatment. Previous treatment interruptions were more common in subjects with CSF escape. Central nervous system penetration effectiveness rank was not a significant predictor of detectable CSF virus or CSF neopterin levels. Conclusions. Viral escape in CSF is more common than previously reported, suggesting that low-grade central nervous system infection may continue in treated patients. Although these findings need extension in longitudinal studies, they suggest the utility of monitoring CSF responses, as new treatment combinations and strategies modify clinical practice. PMID:21050119

Adoption of new HIV treatment guidelines and drug substitutions within first-line as a measure of quality of care in rural Lesotho: health centers and hospitals compared.

PubMed

Labhardt, Niklaus D; Sello, Motlalepula; Lejone, Thabo; Ehmer, Jochen; Mokhantso, Mohlaba; Lynen, Lutgarde; Pfeiffer, Karolin

2012-10-01

In 2007, Lesotho launched new national antiretroviral treatment (ART) guidelines, prioritising tenofovir and zidovudine over stavudine as a backbone together with lamivudine. We compared the rate of adoption of these new guidelines and substitution of first-line drugs by health centers (HC) and hospitals in two catchment areas in rural Lesotho. Retrospective cohort analysis. Patients aged ≥16 years were stratified into a HC- and a hospital-group. Type of backbone at ART-initiation (i), substitutions within first line (ii) and type of backbone among patients retained by December 2010 (iii). A multiple logistic regression model including HC vs. hospital, patient characteristics (sex, age, WHO-stage, baseline CD4-count, concurrent pregnancy, concurrent tuberculosis treatment) and year of ART-start, was used. Of 3936 adult patients initiated on ART between 2007 and 2010, 1971 started at hospitals and 1965 at HCs. Hospitals were more likely to follow the new guidelines as measured by prescription of backbones without stavudine (Odds-ratio 1.55; 95%CI: 1.32-1.81) and had a higher rate of drug substitutions while on first-line ART (2.39; 1.83-3.13). By December 2010, patients followed at health centres were more likely to still receive stavudine (2.28; 1.83-2.84). Health centers took longer to adopt the new guidelines and substituted drugs less frequently. Decentralised ART-programmes need close support, supervision and mentoring to absorb new guidelines and to adhere to them. © 2012 Blackwell Publishing Ltd.

Studies on Antiretroviral Drug Concentrations in Breast Milk: Validation of a Liquid Chromatography–Tandem Mass Spectrometric Method for the Determination of 7 Anti-Human Immunodeficiency Virus Medications

PubMed Central

Rezk, Naser L.; White, Nicole; Bridges, Arlene S.; Abdel-Megeed, Mohamed F.; Mohamed, Tarek M.; Moselhy, Said S.; Kashuba, Angela D. M.

2010-01-01

Studying the pharmacokinetics of antiretroviral drugs in breast milk has important implications for the health of both the mother and the infant, particularly in resource-poor countries. Breast milk is a highly complex biological matrix, yet it is necessary to develop and validate methods in this matrix, which simultaneously measure multiple analytes, as women may be taking any number of drug combinations to combat human immunodeficiency virus infection. Here, we report a novel extraction method coupled to high-performance liquid chromatography and tandem mass spectrometry for the accurate, precise, and specific measurement of 7 antiretroviral drugs currently prescribed to infected mothers. Using 200 µL of human breast milk, simultaneous quantification of lamivudine (3TC), stavudine (d4T), zidovudine (ZDV), nevirapine (NVP), nelfinavir (NFV), ritonavir, and lopinavir was validated over the range of 10–10,000 ng/mL. Intraday accuracy and precision for all analytes were 99.3% and 5.0 %, respectively. Interday accuracy and precision were 99.4 % and 7.8%, respectively. Cross-assay validation with UV detection was performed using clinical breast milk samples, and the results of the 2 assays were in good agreement (P = 0.0001, r = 0.97). Breast milk to plasma concentration ratios for the different antiretroviral drugs were determined as follows: 3TC = 2.96, d4T = 1.73, ZDV = 1.17, NVP = 0.82, and NFV = 0.21. PMID:18758393

Comparison of adherence to generic multi-tablet regimens vs. brand multi-tablet and brand single-tablet regimens likely to incorporate generic antiretroviral drugs by breaking or not fixed-dose combinations in HIV-infected patients.

PubMed

Rwagitinywa, Joseph; Lapeyre-Mestre, Maryse; Bourrel, Robert; Montastruc, Jean-Louis; Sommet, Agnès

2018-03-05

Adherence to antiretroviral (ARV) is crucial to achieve viral load suppression in HIV-infected patients. This study aimed to compare adherence to generic multi-tablet regimens (MTR) vs. brand MTR likely to incorporate ARV drugs without breaking fixed-dose combinations (FDC) and brand single-tablet regimens (STR) likely to incorporate generics by breaking the FDC. Patients aged of 18 years or over exposed to one of the generic or the brand of lamivudine (3TC), zidovudine/lamivudine (AZT/TC), nevirapine (NVP), or efavirenz (EFV), or the brand STR of efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF). Adherence was measured by medication possession ratio (MPR) using both defined daily dose (DDD) and daily number of tablet recommended for adults (DNT). Adherence to generic MTR vs. brand MTR and brand STR was compared using Kruskal-Wallis. The overall median adherence was 0.97 (IQR 0.13) by DNT method and 0.97 (0.14) by DDD method. Adherence in patients exposed to generic MTR (n = 165) vs. brand MTR (n = 481) and brand STR (n = 470) was comparable by DNT and DDD methods. In conclusion, adherence to generic MTR was high and comparable with adherence to brand MTR and to STR. Utilization of DDD instead DNT to measure the MPR led to small but nonsignificant difference that has no clinical impact. © 2018 Société Française de Pharmacologie et de Thérapeutique.

Naringin Reverses Hepatocyte Apoptosis and Oxidative Stress Associated with HIV-1 Nucleotide Reverse Transcriptase Inhibitors-Induced Metabolic Complications

PubMed Central

Adebiyi, Oluwafeyisetan O.; Adebiyi, Olubunmi A.; Owira, Peter M. O.

2015-01-01

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) have not only improved therapeutic outcomes in the treatment of HIV infection but have also led to an increase in associated metabolic complications of NRTIs. Naringin’s effects in mitigating NRTI-induced complications were investigated in this study. Wistar rats, randomly allotted into seven groups (n = 7) were orally treated daily for 56 days with 100 mg/kg zidovudine (AZT) (groups I, II III), 50 mg/kg stavudine (d4T) (groups IV, V, VI) and 3 mL/kg of distilled water (group VII). Additionally, rats in groups II and V were similarly treated with 50 mg/kg naringin, while groups III and VI were treated with 45 mg/kg vitamin E. AZT or d4T treatment significantly reduced body weight and plasma high density lipoprotein concentrations but increased liver weights, plasma triglycerides and total cholesterol compared to controls, respectively. Furthermore, AZT or d4T treatment significantly increased oxidative stress, adiposity index and expression of Bax protein, but reduced Bcl-2 protein expression compared to controls, respectively. However, either naringin or vitamin E significantly mitigated AZT- or d4T-induced weight loss, dyslipidemia, oxidative stress and hepatocyte apoptosis compared to AZT- or d4T-only treated rats. Our results suggest that naringin reverses metabolic complications associated with NRTIs by ameliorating oxidative stress and apoptosis. This implies that naringin supplements could mitigate lipodystrophy and dyslipidemia associated with NRTI therapy. PMID:26690471

Evaluation of an antiretroviral medication attitude scale and relationships between medication attitudes and medication nonadherence.

PubMed

Viswanathan, Hema; Anderson, Rodney; Thomas, Joseph

2005-05-01

The objectives of this study were to refine a scale designed to assess attitudes toward antiretroviral medication, to examine variation in medication attitudes across clinical and demographic characteristics, and to assess relationships between medication attitudes and medication nonadherence. A cross-sectional design was used to survey individuals at least 18 years of age, currently on antiretroviral therapy, and served by a regional HIV/AIDS center. The survey was administered by pharmacy students using convenience sampling between February 2002 and August 2002. Nonadherence was measured using a nine-item scale with a higher score indicative of higher nonadherence. An antiretroviral medication attitude scale was developed based on revision of a zidovudine attitude inventory. The sample of 99 patients was predominantly male (79.8%), had an annual income of less than $10,000 (74%), and was comprised of 50% whites and 40.8% blacks. Participants were between 18 and 70 years old. Item reduction using item-total correlations and factor analytic techniques resulted in a 15-item medication attitude scale with good internal consistency (Cronbach alpha coefficient = 0.84). A multiple regression model showed a significant negative relationship between attitude toward medication and medication nonadherence after controlling for covariates including age, education, gender, ethnicity, work status, social support, CD4 cell count and number of antiretroviral medications, suggesting that more positive the attitude toward medication, lower the medication nonadherence. Findings underscore the importance of attitude toward medication as a modifiable factor that can be targeted to improve medication adherence.

The effect of individual antiretroviral drugs on body composition in HIV-infected persons initiating highly active antiretroviral therapy.

PubMed

Shlay, Judith C; Sharma, Shweta; Peng, Grace; Gibert, Cynthia L; Grunfeld, Carl

2009-07-01

To examine the long-term effects of individual antiretroviral drugs on body composition among 416 persons initiating antiretroviral therapy (ART). In a substudy of a clinical trial of persons initiating ART, changes in body composition attributable to individual ART were examined. ARTs assessed were as follows: indinavir, ritonavir, nelfinavir, efavirenz, nevirapine, stavudine (d4T), zidovudine (ZDV), lamivudine (3TC), didanosine, and abacavir. Skinfolds and circumferences were measured at baseline and every 4 months. Mid arm, mid thigh, and waist subcutaneous tissue areas and nonsubcutaneous tissue areas were calculated. Rates of change per year of exposure to each individual ART drug were determined using multivariate longitudinal regression. d4T and ZDV use was associated with losses in subcutaneous tissue area and skinfold thickness. 3TC use was associated with gains in all subcutaneous tissue areas and skinfold thickness, whereas abacavir use was associated with an increase in waist subcutaneous tissue area. Indinavir was associated with gains in waist subcutaneous tissue area, whereas indinavir, efavirenz, and nevirapine were associated with increases in upper back skinfolds. d4T use was also associated with increases in all nonsubcutaneous tissue areas; 3TC use was associated with the greatest increase in waist nonsubcutaneous tissue area. In this prospective nonrandomized evaluation, the nucleoside reverse transcriptase inhibitors d4T and ZDV were associated with decreases in subcutaneous tissue areas, whereas 3TC use was associated with increased subcutaneous tissue areas and waist nonsubcutaneous tissue area.

Computational Analysis of Molecular Interaction Networks Underlying Change of HIV-1 Resistance to Selected Reverse Transcriptase Inhibitors

PubMed Central

Kierczak, Marcin; Dramiński, Michał; Koronacki, Jacek; Komorowski, Jan

2010-01-01

Motivation Despite more than two decades of research, HIV resistance to drugs remains a serious obstacle in developing efficient AIDS treatments. Several computational methods have been developed to predict resistance level from the sequence of viral proteins such as reverse transcriptase (RT) or protease. These methods, while powerful and accurate, give very little insight into the molecular interactions that underly acquisition of drug resistance/hypersusceptibility. Here, we attempt at filling this gap by using our Monte Carlo feature selection and interdependency discovery method (MCFS-ID) to elucidate molecular interaction networks that characterize viral strains with altered drug resistance levels. Results We analyzed a number of HIV-1 RT sequences annotated with drug resistance level using the MCFS-ID method. This let us expound interdependency networks that characterize change of drug resistance to six selected RT inhibitors: Abacavir, Lamivudine, Stavudine, Zidovudine, Tenofovir and Nevirapine. The networks consider interdependencies at the level of physicochemical properties of mutating amino acids, eg,: polarity. We mapped each network on the 3D structure of RT in attempt to understand the molecular meaning of interacting pairs. The discovered interactions describe several known drug resistance mechanisms and, importantly, some previously unidentified ones. Our approach can be easily applied to a whole range of problems from the domain of protein engineering. Availability A portable Java implementation of our MCFS-ID method is freely available for academic users and can be obtained at: http://www.ipipan.eu/staff/m.draminski/software.htm. PMID:21234299

Análisis de Minimización de Costo e Impacto Presupuestario del Tratamiento ARV con Abacavir/Lamivudina para el VIH/SIDA en México.

PubMed

Rely, Kely; Martínez Valverde, Silvia; Salinas Escudero, Guillermo

2013-12-01

In Mexico, health authorities have raised reach the total of people living with HIV/ AIDS who need treatment have access to it, with the proper use of the best ARV therapies. Evaluate health spending would mean the management of patients with HIV/AIDS with the first-line therapy of abacavir/lamivudine with respect to tenofovir/emtricitabine and lamivudine-zidovudine. A literature review was conducted to seek evidence from clinical studies that demonstrated similar efficacy of ARV treatment between abacavir-lamivudine medications compared with other options. To calculate the incremental cost between these treatments, there was a Budget Impact Analysis and a pharmacoeconomic model was constructed to estimate the economic benefits by increasing its market share. Increased market penetration of abacavir/lamivudine represent a save of $ 44.8 million for the National Health System in Mexico during the years 2012-2017, without compromising the quality and effectiveness of treatment. Furthermore, this increase in market share with abacavir-lamivudine, the National Health System could get an additional benefit to deal on average 5.197 with HIV patients by 5 years with ARV therapies in Mexico. The use of abacavir/lamivudine in ARV treatment of patients with HIV/AIDS is a cost saving for the Mexican health System, which leads to a potential reduction in resources of US$44.8 million in treatment costs in the five projected years. Copyright © 2013 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Computational Analysis of Molecular Interaction Networks Underlying Change of HIV-1 Resistance to Selected Reverse Transcriptase Inhibitors.

PubMed

Kierczak, Marcin; Dramiński, Michał; Koronacki, Jacek; Komorowski, Jan

2010-12-12

Despite more than two decades of research, HIV resistance to drugs remains a serious obstacle in developing efficient AIDS treatments. Several computational methods have been developed to predict resistance level from the sequence of viral proteins such as reverse transcriptase (RT) or protease. These methods, while powerful and accurate, give very little insight into the molecular interactions that underly acquisition of drug resistance/hypersusceptibility. Here, we attempt at filling this gap by using our Monte Carlo feature selection and interdependency discovery method (MCFS-ID) to elucidate molecular interaction networks that characterize viral strains with altered drug resistance levels. We analyzed a number of HIV-1 RT sequences annotated with drug resistance level using the MCFS-ID method. This let us expound interdependency networks that characterize change of drug resistance to six selected RT inhibitors: Abacavir, Lamivudine, Stavudine, Zidovudine, Tenofovir and Nevirapine. The networks consider interdependencies at the level of physicochemical properties of mutating amino acids, eg,: polarity. We mapped each network on the 3D structure of RT in attempt to understand the molecular meaning of interacting pairs. The discovered interactions describe several known drug resistance mechanisms and, importantly, some previously unidentified ones. Our approach can be easily applied to a whole range of problems from the domain of protein engineering. A portable Java implementation of our MCFS-ID method is freely available for academic users and can be obtained at: http://www.ipipan.eu/staff/m.draminski/software.htm.

HIV-1 viral escape in cerebrospinal fluid of subjects on suppressive antiretroviral treatment.

PubMed

Edén, Arvid; Fuchs, Dietmar; Hagberg, Lars; Nilsson, Staffan; Spudich, Serena; Svennerholm, Bo; Price, Richard W; Gisslén, Magnus

2010-12-15

Occasional cases of viral escape in cerebrospinal fluid (CSF) despite suppression of plasma human immunodeficiency virus type 1 (HIV-1) RNA have been reported. We investigated CSF viral escape in subjects treated with commonly used antiretroviral therapy regimens in relation to intrathecal immune activation and central nervous system penetration effectiveness (CPE) rank. Sixty-nine neurologically asymptomatic subjects treated with antiretroviral therapy >6 months and plasma HIV-1 RNA <50 copies/mL were cross-sectionally included in the analysis. Antiretroviral therapy regimens included efavirenz, lopinavir/ritonavir or atazanavir/ritonavir combined with tenofovir, abacavir, or zidovudine and emtricitabine or lamivudine. HIV-1 RNA was analyzed with real-time polymerase chain reaction assays. Neopterin was analyzed by enzyme-linked immunosorbent assay. Seven (10%) of the 69 subjects had detectable CSF HIV-1 RNA, in median 121 copies/mL (interquartile range, 54-213 copies/mL). Subjects with detectable CSF virus had significantly higher CSF neopterin and longer duration of treatment. Previous treatment interruptions were more common in subjects with CSF escape. Central nervous system penetration effectiveness rank was not a significant predictor of detectable CSF virus or CSF neopterin levels. Viral escape in CSF is more common than previously reported, suggesting that low-grade central nervous system infection may continue in treated patients. Although these findings need extension in longitudinal studies, they suggest the utility of monitoring CSF responses, as new treatment combinations and strategies modify clinical practice.

Postmarketing in vitro/in vivo assessment of fixed dose combination products of first line antiretrovirals.

PubMed

Joshi, A; Esseku, F; Silva, L; Igwilo, C; Oqua, D; Kunle, B; Obodozie, O; Inyang, U; Adeyeye, Moji C

2010-06-01

The purpose of this study was to evaluate the postmarket pharmaceutical equivalence, stability and bioequivalence of generic and innovator fixed dose combination products of lamivudine (3TC) and zidovudine (AZT) 150/300 mg tablets available in Nigeria. An isocratic HPLC-UV method was developed and validated for the quantitative determination of 3TC and AZT in human plasma and pharmaceutical samples. The model independent f(2) similarity factor was used to compare the dissolution profiles of the two products stored at accelerated and long-term stability conditions for 6 months. The f(2) values for 3TC and AZT in both products were found to be greater than 51. Also, the tablets were stable according to the USP potency and drug dissolution criteria with more than 80% of drug dissolution in 30 min indicating the pharmaceutical equivalence of the two products. The 90% confidence interval for the ratios of generic/innovator pharmacokinetic parameters for 3TC/AZT were 73.5-112.6/63.4-95.8 (C(max)); 68.5-105.6/68.0-114.8 (AUC(0-t)); and 64.2-106.2/80.1-120.3 (AUC(0-infinity)) respectively. The pharmacokinetic parameters failed to fully demonstrate bioequivalence between the products. The results underscored the importance of assessing the quality of the combination drug products that would ensure the safety and efficacy of the generic drug products available in the market. (c) 2010 Wiley-Liss, Inc. and the American Pharmacists Association

Simultaneous quantification of four antiretroviral drugs in breast milk samples from HIV-positive women by an ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method

PubMed Central

Rodríguez-Delgado, Rosa Georgina; Figueroa-Damián, Ricardo; Domínguez-Castro, Mauricio; López-Martínez, Margarita; Flores-García, Zayra

2018-01-01

The primary strategy to avoid mother-to-child transmission of human immunodeficiency virus (HIV) through breastfeeding is administration of highly active antiretroviral therapy (HAART) to HIV-positive pregnant women. Because significant changes in the pharmacokinetics of antiretroviral (ARV) drugs occur during pregnancy, quantifying HAART and the viral load in breast milk in this population is essential. Here, we developed an analytical assay for the simultaneous quantification of four ARV drugs in breast milk using ultra-performance liquid chromatography coupled to tandem mass spectrometry. We validated this method following Mexican and international guidelines. ARV drugs. We extracted the ARV drugs from 200 μL samples of breast milk and detected these drugs in a triple quadrupole mass spectrometer with positive electrospray ionization. The validated concentration ranges (ng/mL) for zidovudine, lamivudine, lopinavir, and ritonavir were 12.5–750, 50–2500, 100–5000 and 5 to 250, respectively. Additionally, the absolute recovery percentages (and matrix effects) were 91.4 (8.39), 88.78 (28.75), 91.38 (11.77) and 89.78 (12.37), respectively. We determined that ARV drugs are stable for 24 h at 8°C and 24°C for 15 days at –80°C. This methodology had the capacity for simultaneous detection; separation; and accurate, precise quantification of ARV drugs in human breast milk samples according to Mexican standard laws and United States Food and Drug Administration guidelines. PMID:29351333

Trends in procurement costs for HIV commodities: a 7-year retrospective analysis of global fund data across 125 countries.

PubMed

Wafula, Francis; Agweyu, Ambrose; Macintyre, Kate

2014-04-01

Nearly 40% of Global Fund money goes toward procurement. However, no analyses have been published to show how costs vary across regions and time, despite the availability of procurement data collected through the Global Fund's price and quality reporting system. We analyzed data for the 3 most widely procured commodities for the prevention, diagnosis, and treatment of HIV. These were male condoms, HIV rapid tests, and the antiretroviral (ARV) combination of lamivudine/nevirapine/zidovudine. The compared costs, first across time (2005-2012), then across regions, and finally, between individual procurement reported through the price and quality reporting and pooled procurement reported through the Global Fund's voluntary pooled procurement system. All costs were adjusted for inflation and reported in US dollars. There were 2337 entries from 578 grants in 125 countries. The procurement cost for the ARV dropped substantially over the period, whereas those for condoms and HIV tests remained relatively stable. None of the commodity prices increased. Regional variations were pronounced for HIV tests, but minimal for condoms and the ARV. The unit cost for the 3-table ARV combination, for instance, varied between US$0.15 and US$0.23 in South Asia and the Eastern Europe/Central Asia regions, respectively, compared with a range of $0.23 (South Asia)-$1.50 (Eastern Europe/Central Asia) for a single diagnostic test. Pooled procurement lowered costs for condoms but not the other commodities. We showed how global procurement costs vary by region and time. Such analyses should be done more often to identify and correct market insufficiencies.

Coconut Oil Extract Mitigates Testicular Injury Following Adjuvant Treatment with Antiretroviral Drugs

PubMed Central

Ogedengbe, Oluwatosin O; Jegede, Ayoola I; Onanuga, Ismail O; Offor, Ugochukwu; Naidu, Edwin CS; Peter, Aniekan I; Azu, Onyemaechi O

2016-01-01

Increased access to highly active antiretroviral therapy (HAART) has made the management of drug toxicities an increasingly crucial component of HIV. This study investigated the effects of adjuvant use of coconut oil and HAART on testicular morphology and seminal parameters in Sprague- Dawley rats. Twelve adult male Sprague-Dawley rats, weighing 153~169 g were distributed into four groups (A–D) and treated as follows: A served as control (distilled water); B (HAART cocktail- Zidovudine, Lamivudine and Nevirapine); C (HAART + Virgin coconut oil 10 mL/kg) and D (Virgin coconut oil 10 mL/kg). After 56 days of treatment, animals were killed and laparotomy to exercise the epididymis for seminal fluid analyses done whilst testicular tissues were processed for histomorphometric studies. Result showed a significant decline in sperm motility (P < 0.05) and count (P < 0.0001) in HAART-treated animals while there was insignificant changes in other parameters in groups C and D except count that was reduced (P < 0.0001) when compared with controls. Histomorphological studies showed HAART caused disorders in seminiferous tubular architecture with significant (P < 0.01) decline in epithelial height closely mirrored by extensive reticulin framework and positive PAS cells. Adjuvant Virgin coconut oil + HAART resulted in significant decrease in seminiferous tubular diameter (P < 0.05), but other morphometric and histological parameters were similar to control or Virgin coconut oil alone (which showed normal histoarchitecture levels). While derangements in testicular and seminal fluid parameters occurred following HAART, adjuvant treatment with Virgin coconut oil restored the distortions emanating thereof. PMID:27818734

Neuropsychiatric adverse events after switching from an antiretroviral regimen containing efavirenz without tenofovir to an efavirenz regimen containing tenofovir: a report of nine cases.

PubMed

Allavena, Clotilde; Le Moal, Gwenael; Michau, Christophe; Chiffoleau, Anne; Raffi, François

2006-01-01

The combination of tenofovir (TDF) and efavirenz (EFV) has not been associated with any pharmakokinetic interaction or with enhancement of neuropsychiatric disturbances. We report nine cases of neuropsychiatric intolerance occurring early after a switch from an antiretroviral regimen without TDF to an EFV and TDF-containing regimen. Nine HIV-1-infected patients were treated with an EFV-containing regimen for a median duration of 31 months without any EFV-related central nervous system (CNS) effects. They were switched to an EFV-TDF-containing regimen because of lipodystrophy (n=2) and/or the wish to simplify to a once-daily regimen (n=9). Moderate to severe neuropsychiatric events occurred immediately (<48 hours) after TDF initiation in five patients and 2 weeks to 24 months after the switch in the remaining four patients. Treatment modifications occurred in six patients (switch to EFV-nevirapine [n=3], TDF-zidovudine [n=2] or treatment discontinuation [n=1]), leading to a marked improvement of CNS intolerance. Treatment remained unchanged in three patients; two patients experienced chronic persistent sleeping disorders and one patient underwent a spontaneous improvement of symptoms within 2 weeks. EFV plasma concentrations, which were available in two patients before the switch and in four patients after the switch, remained in the therapeutic range. Although the exact mechanism of these symptoms remains hypothetical, neuropsychiatric disorders could be either a consequence of an unexplained interaction between EFV and TDF or an infrequent TDF-related side effect. The incidence of these side effects needs to be evaluated in large databases or pharmacokinetic studies.

Influence of mitochondrion-toxic agents on the cardiovascular system.

PubMed

Finsterer, Josef; Ohnsorge, Peter

2013-12-01

Cardiovascular disease may be induced or worsened by mitochondrion-toxic agents. Mitochondrion-toxic agents may be classified as those with or without a clinical effect, those which induce cardiac disease only in humans or animals or both, as prescribed drugs, illicit drugs, exotoxins, or nutritiants, as those which affect the heart exclusively or also other organs, as those which are effective only in patients with a mitochondrial disorder or cardiac disease or also in healthy subjects, or as solid, liquid, or volatile agents. In humans, cardiotoxic agents due to mitochondrial dysfunction include anthracyclines (particularly doxorubicin), mitoxantrone, cyclophosphamide, cisplatin, fluorouracil, imatinib, bortezomib, trastuzumab, arsenic trioxide, cyclosporine-A, zidovudine, lamotrigine, glycosides, lidocain, isoproterenol, nitroprusside, pivalic acid, alcohol, cocaine, pesticides, cadmium, mycotoxins, cyanotoxins, meat meal, or carbon monoxide. Even more agents exhibit cardiac abnormalities due to mitochondrion-toxicity only in animals or tissue cultures. The mitochondrion-toxic effect results from impairment of the respiratory chain, the oxidative phosphorylation, the Krebs cycle, or the β-oxidation, from decrease of the mitochondrion-membrane potential, from increased oxidative stress, reduced anti-oxidative capacity, or from induction of apoptosis. Cardiac abnormalities induced via these mechanisms include cardiomyopathy, myocarditis, coronary heart disease, arrhythmias, heart failure, or Takotsubo syndrome. Discontinuation of the cardiotoxic agent results in complete recovery in the majority of the cases. Antioxidants and nutritiants may be of additional help. Particularly coenzyme-Q, riboflavin, vitamin-E, vitamin-C, L-carnitine, vitamin-D, thiamin, folic acid, omega-3 fatty acids, and D-ribose may alleviate mitochondrial cardiotoxic effects. Copyright © 2013 Elsevier Inc. All rights reserved.

The Kinetic Effects on Thymidine Kinase 2 by Enzyme-Bound dTTP May Explain the Mitochondrial Side Effects of Antiviral Thymidine Analogs▿†

PubMed Central

Wang, Liya; Sun, Ren; Eriksson, Staffan

2011-01-01

Mitochondrial thymidine kinase 2 (TK2) is a key enzyme in the salvage of pyrimidine deoxynucleosides needed for mitochondrial DNA synthesis. TK2 phosphorylates thymidine (dThd), deoxycytidine (dCyd), and many other antiviral pyrimidine nucleoside analogs. Zidovudine (AZT) is the first nucleoside analog approved for anti-HIV therapy, and it is still used in combination with other drugs. One of the side effects of long-term treatment with nucleoside analogs is mitochondrial DNA depletion, which has been ascribed to competition by AZT for the endogenous dThd phosphorylation carried out by TK2. Here we studied the kinetics of AZT and 3′-fluorothymidine phosphorylation by recombinant human TK2 and the effects of these and other pyrimidine nucleoside analogs on the phosphorylation of dThd and dCyd. Thymidine analogs strongly inhibited dThd phosphorylation but not dCyd phosphorylation, which instead was stimulated ∼30%. We found that recombinant human TK2 contained the feedback inhibitor dTTP in a 1:1 molar ratio and that incubation with dThd and AZT could completely remove the enzyme-bound dTTP, but dCyd was less efficient in this regard. The release of feedback inhibitor by dThd and dThd analogs most likely accounts for the observed kinetics. Similar effects were also observed with native rat liver mitochondrial TK2, strongly indicating a physiologic role for this process, which most likely is an important factor in the mitochondrial toxicity observed with antiviral nucleoside analogs. PMID:21444706

Novel nonnucleoside inhibitors that select nucleoside inhibitor resistance mutations in human immunodeficiency virus type 1 reverse transcriptase.

PubMed

Zhang, Zhijun; Walker, Michelle; Xu, Wen; Shim, Jae Hoon; Girardet, Jean-Luc; Hamatake, Robert K; Hong, Zhi

2006-08-01

Mutations in and around the catalytic site of the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) are associated with resistance to nucleoside RT inhibitors (NRTIs), whereas changes in the hydrophobic pocket of the RT are attributed to nonnucleoside RT inhibitor (NNRTI) resistance. In this study, we report a novel series of nonnucleoside inhibitors of HIV-1, exemplified by VRX-329747 and VRX-413638, which inhibit both NNRTI- and NRTI-resistant HIV-1 isolates. Enzymatic studies indicated that these compounds are HIV-1 RT inhibitors. Surprisingly, however, following prolonged (6 months) tissue culture selection, this series of nonnucleoside inhibitors did not select NNRTI-resistant mutations in HIV-1 RT. Rather, four mutations (M41L, A62T/V, V118I, and M184V) known to cause resistance to NRTIs and two additional novel mutations (S68N and G112S) adjacent to the catalytic site of the enzyme were selected. Although the M184V mutation appears to be the initial mutation to establish resistance, this mutation alone confers only a two- to fourfold decrease in susceptibility to VRX-329747 and VRX-413638. At least two additional mutations must accumulate for significant resistance. Moreover, while VRX-329747-selected viruses are resistant to lamivudine and emtricitabine due to the M184V mutation, they remain susceptible to zidovudine, stavudine, dideoxyinosine, abacavir, tenofovir, and efavirenz. These results directly demonstrate that VRX-329747 and VRX-413638 are novel nonnucleoside inhibitors of HIV-1 RT with the potential to augment current therapies.

Novel Nonnucleoside Inhibitors That Select Nucleoside Inhibitor Resistance Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase

PubMed Central

Zhang, Zhijun; Walker, Michelle; Xu, Wen; Shim, Jae Hoon; Girardet, Jean-Luc; Hamatake, Robert K.; Hong, Zhi

2006-01-01

Mutations in and around the catalytic site of the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) are associated with resistance to nucleoside RT inhibitors (NRTIs), whereas changes in the hydrophobic pocket of the RT are attributed to nonnucleoside RT inhibitor (NNRTI) resistance. In this study, we report a novel series of nonnucleoside inhibitors of HIV-1, exemplified by VRX-329747 and VRX-413638, which inhibit both NNRTI- and NRTI-resistant HIV-1 isolates. Enzymatic studies indicated that these compounds are HIV-1 RT inhibitors. Surprisingly, however, following prolonged (6 months) tissue culture selection, this series of nonnucleoside inhibitors did not select NNRTI-resistant mutations in HIV-1 RT. Rather, four mutations (M41L, A62T/V, V118I, and M184V) known to cause resistance to NRTIs and two additional novel mutations (S68N and G112S) adjacent to the catalytic site of the enzyme were selected. Although the M184V mutation appears to be the initial mutation to establish resistance, this mutation alone confers only a two- to fourfold decrease in susceptibility to VRX-329747 and VRX-413638. At least two additional mutations must accumulate for significant resistance. Moreover, while VRX-329747-selected viruses are resistant to lamivudine and emtricitabine due to the M184V mutation, they remain susceptible to zidovudine, stavudine, dideoxyinosine, abacavir, tenofovir, and efavirenz. These results directly demonstrate that VRX-329747 and VRX-413638 are novel nonnucleoside inhibitors of HIV-1 RT with the potential to augment current therapies. PMID:16870771

Antiretroviral treatment sequencing strategies to overcome HIV type 1 drug resistance in adolescents and adults in low-middle-income countries.

PubMed

De Luca, Andrea; Hamers, Raphael L; Schapiro, Jonathan M

2013-06-15

Antiretroviral treatment (ART) is expanding to human immunodeficiency virus type 1 (HIV-1)-infected persons in low-middle income countries, thanks to a public health approach. With 3 available drug classes, 2 ART sequencing lines are programmatically foreseen. The emergence and transmission of viral drug resistance represents a challenge to the efficacy of ART. Knowledge of HIV-1 drug resistance selection associated with specific drugs and regimens and the consequent activity of residual drug options are essential in programming ART sequencing options aimed at preserving ART efficacy for as long as possible. This article determines optimal ART sequencing options for overcoming HIV-1 drug resistance in resource-limited settings, using currently available drugs and treatment monitoring opportunities. From the perspective of drug resistance and on the basis of limited virologic monitoring data, optimal sequencing seems to involve use of a tenofovir-containing nonnucleoside reverse-transcriptase inhibitor-based first-line regimen, followed by a zidovudine-containing, protease inhibitor (PI)-based second-line regimen. Other options and their consequences are explored by considering within-class and between-class sequencing opportunities, including boosted PI monotherapies and future options with integrase inhibitors. Nucleoside reverse-transcriptase inhibitor resistance pathways in HIV-1 subtype C suggest an additional reason for accelerating stavudine phase out. Viral load monitoring avoids the accumulation of resistance mutations that significantly reduce the activity of next-line options. Rational use of resources, including broader access to viral load monitoring, will help ensure 3 lines of fully active treatment options, thereby increasing the duration of ART success.

Twenty-Five Years of Lamivudine: Current and Future Use for the Treatment of HIV-1 Infection.

PubMed

Quercia, Romina; Perno, Carlo-Federico; Koteff, Justin; Moore, Katy; McCoig, Cynthia; St Clair, Marty; Kuritzkes, Daniel

2018-06-01

Innovation in medicine is a dynamic, complex, and continuous process that cannot be isolated to a single moment in time. Anniversaries offer opportunities to commemorate crucial discoveries of modern medicine, such as penicillin (1928), polio vaccination (inactivated, 1955; oral, 1961), the surface antigen of the hepatitis B virus (1967), monoclonal antibodies (1975), and the first HIV antiretroviral drugs (zidovudine, 1987). The advent of antiretroviral drugs has had a profound effect on the progress of the epidemiology of HIV infection, transforming a terminal, irreversible disease that caused a global health crisis into a treatable but chronic disease. This result has been driven by the success of antiretroviral drug combinations that include nucleoside reverse transcriptase inhibitors such as lamivudine. Lamivudine, an L-enantiomeric analog of cytosine, potently affects HIV replication by inhibiting viral reverse transcriptase enzymes at concentrations without toxicity against human polymerases. Although lamivudine was approved more than 2 decades ago, it remains a key component of first-line therapy for HIV because of its virological efficacy and ability to be partnered with other antiretroviral agents in traditional and novel combination therapies. The prominence of lamivudine in HIV therapy is highlighted by its incorporation in recent innovative treatment strategies, such as single-tablet regimens that address challenges associated with regimen complexity and treatment adherence and 2-drug regimens being developed to mitigate cumulative drug exposure and toxicities. This review summarizes how the pharmacologic and virologic properties of lamivudine have solidified its role in contemporary HIV therapy and continue to support its use in emerging therapies.

Early versus delayed initiation of antiretroviral therapy for Indian HIV-Infected individuals with tuberculosis on antituberculosis treatment.

PubMed

Sinha, Sanjeev; Shekhar, Rahul C; Singh, Gurjeet; Shah, Nipam; Ahmad, Hafiz; Kumar, Narendra; Sharma, Surendra K; Samantaray, J C; Ranjan, Sanjai; Ekka, Meera; Sreenivas, Vishnu; Mitsuyasu, Ronald T

2012-07-31

For antiretroviral therapy (ART) naive human immunodeficiency virus (HIV) infected adults suffering from tuberculosis (TB), there is uncertainty about the optimal time to initiate highly active antiretroviral therapy (HAART) after starting antituberculosis treatment (ATT), in order to minimize mortality, HIV disease progression, and adverse events. In a randomized, open label trial at All India Institute of Medical Sciences, New Delhi, India, eligible HIV positive individuals with a diagnosis of TB were randomly assigned to receive HAART after 2-4 or 8-12 weeks of starting ATT, and were followed for 12 months after HAART initiation. Participants received directly observed therapy short course (DOTS) for TB, and an antiretroviral regimen comprising stavudine or zidovudine, lamivudine, and efavirenz. Primary end points were death from any cause, and progression of HIV disease marked by failure of ART. A total of 150 patients with HIV and TB were initiated on HAART: 88 received it after 2-4 weeks (early ART) and 62 after 8-12 weeks (delayed ART) of starting ATT. There was no significant difference in mortality between the groups after the introduction of HAART. However, incidence of ART failure was 31% in delayed versus 16% in early ART arm (p = 0.045). Kaplan Meier disease progression free survival at 12 months was 79% for early versus 64% for the delayed ART arm (p = 0.05). Rates of adverse events were similar. Early initiation of HAART for patients with HIV and TB significantly decreases incidence of HIV disease progression and has good tolerability. CTRI/2011/12/002260.

The pricing and procurement of antiretroviral drugs: an observational study of data from the Global Fund.

PubMed Central

Vasan, Ashwin; Hoos, David; Mukherjee, Joia S.; Farmer, Paul E.; Rosenfield, Allan G.; Perriëns, Joseph H.

2006-01-01

The Purchase price report released in August 2004 by the Global Fund to Fight AIDS, Tuberculosis, and Malaria (Global Fund) was the first publication of a significant amount of real transaction purchase data for antiretrovirals (ARVs). We did an observational study of the ARV transaction data in the Purchase price report to examine the procurement behaviour of principal recipients of Global Fund grants in developing countries. We found that, with a few exceptions for specific products (e.g. lamivudine) and regions (e.g. eastern Europe), prices in low-income countries were broadly consistent or lower than the lowest differential prices quoted by the research and development sector of the pharmaceutical industry. In lower middle-income countries, prices were more varied and in several instances (lopinavir/ritonavir, didanosine, and zidovudine/lamivudine) were very high compared with the per capita income of the country. In all low- and lower middle-income countries, ARV prices were still significantly high given limited local purchasing power and economic strength, thus reaffirming the need for donor support to achieve rapid scale-up of antiretroviral therapy. However, the price of ARVs will have to decrease to render scale-up financially sustainable for donors and eventually for governments themselves. An important first step in reducing prices will be to make available in the public domain as much ARV transaction data as possible to provide a factual basis for discussions on pricing. The price of ARVs has considerable implications for the sustainability of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) treatment in the developing world. PMID:16710550

Crystal structure of a concentrative nucleoside transporter from Vibrio cholerae at 2.4;#8201;Å

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, Zachary Lee; Cheong, Cheom-Gil; Lee, Seok-Yong

2012-07-11

Nucleosides are required for DNA and RNA synthesis, and the nucleoside adenosine has a function in a variety of signalling processes. Transport of nucleosides across cell membranes provides the major source of nucleosides in many cell types and is also responsible for the termination of adenosine signalling. As a result of their hydrophilic nature, nucleosides require a specialized class of integral membrane proteins, known as nucleoside transporters (NTs), for specific transport across cell membranes. In addition to nucleosides, NTs are important determinants for the transport of nucleoside-derived drugs across cell membranes. A wide range of nucleoside-derived drugs, including anticancer drugsmore » (such as Ara-C and gemcitabine) and antiviral drugs (such as zidovudine and ribavirin), have been shown to depend, at least in part, on NTs for transport across cell membranes. Concentrative nucleoside transporters, members of the solute carrier transporter superfamily SLC28, use an ion gradient in the active transport of both nucleosides and nucleoside-derived drugs against their chemical gradients. The structural basis for selective ion-coupled nucleoside transport by concentrative nucleoside transporters is unknown. Here we present the crystal structure of a concentrative nucleoside transporter from Vibrio cholerae in complex with uridine at 2.4 {angstrom}. Our functional data show that, like its human orthologues, the transporter uses a sodium-ion gradient for nucleoside transport. The structure reveals the overall architecture of this class of transporter, unravels the molecular determinants for nucleoside and sodium binding, and provides a framework for understanding the mechanism of nucleoside and nucleoside drug transport across cell membranes.« less

Activities of the human immunodeficiency virus type 1 (HIV-1) protease inhibitor nelfinavir mesylate in combination with reverse transcriptase and protease inhibitors against acute HIV-1 infection in vitro.

PubMed

Patick, A K; Boritzki, T J; Bloom, L A

1997-10-01

Nelfinavir mesylate (formerly AG1343) is a potent and selective, nonpeptidic inhibitor of human immunodeficiency virus type 1 (HIV-1) protease that was discovered by protein structure-based design methodologies. We evaluated the antiviral and cytotoxic effects of two-drug combinations of nelfinavir with the clinically approved antiretroviral therapeutics zidovudine (ZDV), lamivudine (3TC), dideoxycytidine (ddC; zalcitabine), stavudine (d4T), didanosine (ddI), indinavir, saquinavir, and ritonavir and a three-drug combination of nelfinavir with ZDV and 3TC against an acute HIV-1 strain RF infection of CEM-SS cells in vitro. Quantitative assessment of drug interaction was evaluated by a universal response surface approach (W. R. Greco, G. Bravo, and J. C. Parsons, Pharm. Rev. 47:331-385, 1995) and by the method of M. N. Prichard and C. Shipman (Antiviral Res. 14:181-206, 1990). Both analytical methods yielded similar results and showed that the two-drug combinations of nelfinavir with the reverse transcriptase inhibitors ZDV, 3TC, ddI, d4T, and ddC and the three-drug combination with ZDV and 3TC resulted in additive to statistically significant synergistic interactions. In a similar manner, the combination of nelfinavir with the three protease inhibitors resulted in additive (ritonavir and saquinavir) to slightly antagonistic (indinavir) interactions. In all combinations, minimal cellular cytotoxicity was observed with any drug alone and in combination. These results suggest that administration of combinations of the appropriate doses of nelfinavir with other currently approved antiretroviral therapeutic agents in vivo may result in enhanced antiviral activity with no associated increase in cellular cytotoxicity.

Anti-infective properties of the melanin-glucan complex obtained from medicinal tinder bracket mushroom, Fomes fomentarius (L.: Fr.) Fr. (Aphyllophoromycetideae).

PubMed

Seniuk, Olga F; Gorovoj, Leontiy F; Beketova, Galina V; Savichuk, Hatalia O; Rytik, Petr G; Kucherov, Igor I; Prilutskay, Alla B; Prilutsky, Alexandr I

2011-01-01

The goal of this investigation was to comparatively study the efficiency of traditionally used anti-infective drugs and biopolymer complexes originated from the medicinal mushroom Fomes fomentarius (L.:Fr.) Fr.: 1) water-soluble melanin-glucan complex (MGC; -80% melanins and -20% beta-glucans) and 2) insoluble chitin-glucan-melanin complex (ChGMC; -70% chitin, -20% beta-glucans, and -10% melanins). Infectious materials (Helicobacter pylori, Candida albicans, and Herpes vulgaris I and HIV-1(zmb) were used in pure cultures of in vitro and in vivo models on experimental animals. Comparison studies of fungal biopolymers and effective modern antifungal, antibacterial, and antiviral drugs were used in in vitro models. The comparative clinical efficiency of ChGMC and of etiotropic pharmaceuticals in models of H. pylori, C. albicans, and H. vulgaris I infection contamination were studied. Using in vitro models, it was established that MGC completely depresses growth of C. albicans. MGC had an antimicrobial effect on H. pylori identical to erythromycin in all concentrations, and had a stronger action on this bacterium than other tested antibiotics. Tested MGC possesses simultaneously weak toxicity and high anti-HIV-1 activity in comparison with zidovudine (Retrovir). The obtained results show that CLUDDT therapy in Wistar rats with the application of ChGMC is, on average, 1.35-1.43 times as effective as a traditional one. Considering the absence of MGC and ChGMC toxic properties on blood cells even in very high concentrations, these complexes may be used as a source of biopolymers for the creation of essentially new agents for wide application in infectious pathology.

Estimating HIV-1 Fitness Characteristics from Cross-Sectional Genotype Data

PubMed Central

Gopalakrishnan, Sathej; Montazeri, Hesam; Menz, Stephan; Beerenwinkel, Niko; Huisinga, Wilhelm

2014-01-01

Despite the success of highly active antiretroviral therapy (HAART) in the management of human immunodeficiency virus (HIV)-1 infection, virological failure due to drug resistance development remains a major challenge. Resistant mutants display reduced drug susceptibilities, but in the absence of drug, they generally have a lower fitness than the wild type, owing to a mutation-incurred cost. The interaction between these fitness costs and drug resistance dictates the appearance of mutants and influences viral suppression and therapeutic success. Assessing in vivo viral fitness is a challenging task and yet one that has significant clinical relevance. Here, we present a new computational modelling approach for estimating viral fitness that relies on common sparse cross-sectional clinical data by combining statistical approaches to learn drug-specific mutational pathways and resistance factors with viral dynamics models to represent the host-virus interaction and actions of drug mechanistically. We estimate in vivo fitness characteristics of mutant genotypes for two antiretroviral drugs, the reverse transcriptase inhibitor zidovudine (ZDV) and the protease inhibitor indinavir (IDV). Well-known features of HIV-1 fitness landscapes are recovered, both in the absence and presence of drugs. We quantify the complex interplay between fitness costs and resistance by computing selective advantages for different mutants. Our approach extends naturally to multiple drugs and we illustrate this by simulating a dual therapy with ZDV and IDV to assess therapy failure. The combined statistical and dynamical modelling approach may help in dissecting the effects of fitness costs and resistance with the ultimate aim of assisting the choice of salvage therapies after treatment failure. PMID:25375675

Cognitive and language outcomes in HIV-uninfected infants exposed to combined antiretroviral therapy in utero and through extended breast-feeding.

PubMed

Ngoma, Mary S; Hunter, Jennifer A; Harper, Jessica A; Church, Paige T; Mumba, Scholastica; Chandwe, Mulapati; Côté, Hélène C F; Albert, Arianne Y K; Smith, Mary-Lou; Selemani, Chisomo; Sandstrom, Paul A; Bandenduck, Lucas; Ndlovu, Utsile; Khan, Sara; Roa, Lina; Silverman, Michael S

2014-07-01

To determine whether there is a higher risk for cognitive or language delay among HIV-exposed uninfected (HEU) children exposed to cART (zidovudine/lamivudine/lopinavir/ritonavir) in utero and through 1 year of breast-feeding (World health Organization Option B+), compared with the control children born to HIV-uninfected mothers. This is a double cohort study from Lusaka, Zambia. HEU (n = 97) and control (n = 103) children aged 15-36 months were assessed on their early nonverbal problem-solving and language skills using the standardized Capute Scales. A score of less than 85 on the Capute Full-Scale Developmental Quotient (FSDQ) was considered indicative of developmental delay and was the primary outcome of interest. An FSDQ of less than 85 was found in eight (8.3%) of HEU participants and 15 (14.6%) of controls. In univariate logistic regressions, lower income [odds ratio (OR) = 0.93, P = 0.02], older infant age (OR = 1.08, P = 0.03), lower birth weight (OR = 0.16, P < 0.001), and less maternal education (OR = 0.41, P = 0.047) were associated with the probability of FSDQ less than 85, whereas Group (control/HEU) was not (OR = 1.88, P = 0.16). In the multivariable analysis, only lower birth weight (OR = 0.15, P < 0.001) remained associated with FSDQ less than 85. Our study did not support the presence of an adverse effect on cognitive and language development with prolonged antepartum and postpartum cART e/xposure. Larger studies and studies of older HEU children will be required to confirm these reassuring findings.

Coconut Oil Extract Mitigates Testicular Injury Following Adjuvant Treatment with Antiretroviral Drugs.

PubMed

Ogedengbe, Oluwatosin O; Jegede, Ayoola I; Onanuga, Ismail O; Offor, Ugochukwu; Naidu, Edwin Cs; Peter, Aniekan I; Azu, Onyemaechi O

2016-10-01

Increased access to highly active antiretroviral therapy (HAART) has made the management of drug toxicities an increasingly crucial component of HIV. This study investigated the effects of adjuvant use of coconut oil and HAART on testicular morphology and seminal parameters in Sprague- Dawley rats. Twelve adult male Sprague-Dawley rats, weighing 153~169 g were distributed into four groups (A-D) and treated as follows: A served as control (distilled water); B (HAART cocktail- Zidovudine, Lamivudine and Nevirapine); C (HAART + Virgin coconut oil 10 mL/kg) and D (Virgin coconut oil 10 mL/kg). After 56 days of treatment, animals were killed and laparotomy to exercise the epididymis for seminal fluid analyses done whilst testicular tissues were processed for histomorphometric studies. Result showed a significant decline in sperm motility ( P < 0.05) and count ( P < 0.0001) in HAART-treated animals while there was insignificant changes in other parameters in groups C and D except count that was reduced ( P < 0.0001) when compared with controls. Histomorphological studies showed HAART caused disorders in seminiferous tubular architecture with significant ( P < 0.01) decline in epithelial height closely mirrored by extensive reticulin framework and positive PAS cells. Adjuvant Virgin coconut oil + HAART resulted in significant decrease in seminiferous tubular diameter ( P < 0.05), but other morphometric and histological parameters were similar to control or Virgin coconut oil alone (which showed normal histoarchitecture levels). While derangements in testicular and seminal fluid parameters occurred following HAART, adjuvant treatment with Virgin coconut oil restored the distortions emanating thereof.

The pricing and procurement of antiretroviral drugs: an observational study of data from the Global Fund.

PubMed

Vasan, Ashwin; Hoos, David; Mukherjee, Joia S; Farmer, Paul E; Rosenfield, Allan G; Perriëns, Joseph H

2006-05-01

The Purchase price report released in August 2004 by the Global Fund to Fight AIDS, Tuberculosis, and Malaria (Global Fund) was the first publication of a significant amount of real transaction purchase data for antiretrovirals (ARVs). We did an observational study of the ARV transaction data in the Purchase price report to examine the procurement behaviour of principal recipients of Global Fund grants in developing countries. We found that, with a few exceptions for specific products (e.g. lamivudine) and regions (e.g. eastern Europe), prices in low-income countries were broadly consistent or lower than the lowest differential prices quoted by the research and development sector of the pharmaceutical industry. In lower middle-income countries, prices were more varied and in several instances (lopinavir/ritonavir, didanosine, and zidovudine/lamivudine) were very high compared with the per capita income of the country. In all low- and lower middle-income countries, ARV prices were still significantly high given limited local purchasing power and economic strength, thus reaffirming the need for donor support to achieve rapid scale-up of antiretroviral therapy. However, the price of ARVs will have to decrease to render scale-up financially sustainable for donors and eventually for governments themselves. An important first step in reducing prices will be to make available in the public domain as much ARV transaction data as possible to provide a factual basis for discussions on pricing. The price of ARVs has considerable implications for the sustainability of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) treatment in the developing world.

Antiviral Screening of Multiple Compounds against Ebola Virus.

PubMed

Dowall, Stuart D; Bewley, Kevin; Watson, Robert J; Vasan, Seshadri S; Ghosh, Chandradhish; Konai, Mohini M; Gausdal, Gro; Lorens, James B; Long, Jason; Barclay, Wendy; Garcia-Dorival, Isabel; Hiscox, Julian; Bosworth, Andrew; Taylor, Irene; Easterbrook, Linda; Pitman, James; Summers, Sian; Chan-Pensley, Jenny; Funnell, Simon; Vipond, Julia; Charlton, Sue; Haldar, Jayanta; Hewson, Roger; Carroll, Miles W

2016-10-27

In light of the recent outbreak of Ebola virus (EBOV) disease in West Africa, there have been renewed efforts to search for effective antiviral countermeasures. A range of compounds currently available with broad antimicrobial activity have been tested for activity against EBOV. Using live EBOV, eighteen candidate compounds were screened for antiviral activity in vitro. The compounds were selected on a rational basis because their mechanisms of action suggested that they had the potential to disrupt EBOV entry, replication or exit from cells or because they had displayed some antiviral activity against EBOV in previous tests. Nine compounds caused no reduction in viral replication despite cells remaining healthy, so they were excluded from further analysis (zidovudine; didanosine; stavudine; abacavir sulphate; entecavir; JB1a; Aimspro; celgosivir; and castanospermine). A second screen of the remaining compounds and the feasibility of appropriateness for in vivo testing removed six further compounds (ouabain; omeprazole; esomeprazole; Gleevec; D-LANA-14; and Tasigna). The three most promising compounds (17-DMAG; BGB324; and NCK-8) were further screened for in vivo activity in the guinea pig model of EBOV disease. Two of the compounds, BGB324 and NCK-8, showed some effect against lethal infection in vivo at the concentrations tested, which warrants further investigation. Further, these data add to the body of knowledge on the antiviral activities of multiple compounds against EBOV and indicate that the scientific community should invest more effort into the development of novel and specific antiviral compounds to treat Ebola virus disease.

Phenotype, Genotype, and Drug Resistance in Subtype C HIV-1 Infection.

PubMed

Derache, Anne; Wallis, Carole L; Vardhanabhuti, Saran; Bartlett, John; Kumarasamy, Nagalingeswaran; Katzenstein, David

2016-01-15

Virologic failure in subtype C is characterized by high resistance to first-line antiretroviral (ARV) drugs, including efavirenz, nevirapine, and lamivudine, with nucleoside resistance including type 2 thymidine analog mutations, K65R, a T69del, and M184V. However, genotypic algorithms predicting resistance are mainly based on subtype B viruses and may under- or overestimate drug resistance in non-B subtypes. To explore potential treatment strategies after first-line failure, we compared genotypic and phenotypic susceptibility of subtype C human immunodeficiency virus 1 (HIV-1) following first-line ARV failure. AIDS Clinical Trials Group 5230 evaluated patients failing an initial nonnucleoside reverse-transcriptase inhibitor (NNRTI) regimen in Africa and Asia, comparing the genotypic drug resistance and phenotypic profile from the PhenoSense (Monogram). Site-directed mutagenesis studies of K65R and T69del assessed the phenotypic impact of these mutations. Genotypic algorithms overestimated resistance to etravirine and rilpivirine, misclassifying 28% and 32%, respectively. Despite K65R with the T69del in 9 samples, tenofovir retained activity in >60%. Reversion of the K65R increased susceptibility to tenofovir and other nucleosides, while reversion of the T69del showed increased resistance to zidovudine, with little impact on other NRTI. Although genotype and phenotype were largely concordant for first-line drugs, estimates of genotypic resistance to etravirine and rilpivirine may misclassify subtype C isolates compared to phenotype. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Suboptimal etravirine activity is common during failure of nevirapine-based combination antiretroviral therapy in a cohort infected with non-B subtype HIV-1.

PubMed

Taiwo, Babafemi; Chaplin, Beth; Penugonda, Sudhir; Meloni, Seema; Akanmu, Sulaimon; Gashau, Wadzani; Idoko, John; Adewole, Isaac; Murphy, Robert; Kanki, Phyllis

2010-04-01

The primary objective of this study was to estimate etravirine activity in a cohort of patients infected with non-B subtype HIV-1 and failing nevirapine-based therapy. Genotypic resistance testing was performed if viral load was >OR= 1,000 copies/ml after receiving at least six months of therapy. Suboptimal response to etravirine was predicted by a score >OR= 2.5 on the Tibotec weighting schema, >OR= 4 in the Monogram schema, or classification as high to low-level resistant by a modification of the Stanford HIVdb algorithm (Version 5.1.2). Bivariate and multivariate analyses were conducted to determine the risk factors for suboptimal etravirine activity. The patients (n=91) were receiving nevirapine and lamivudine plus stavudine (57.1%) or zidovudine (42.9%). Median duration of nevirapine exposure was 53 weeks (IQR 46-101 weeks). The most common etravirine resistance associated mutations were Y181C (42.9%), G190A (25.3%), H221Y (19.8%), A98G (18.7%), K101E (16.5%), and V90I (12.1%). Suboptimal etravirine activity was predicted in 47.3 to 56.0%. There were disparities in mutations listed in Tibotec versus Monogram Schemas. Predicted suboptimal activity was not associated with nucleoside reverse transcriptase inhibitor (NRTI) used, gender, pretreatment or current CD4 cell count or viral load, subtype or NRTI mutations. Etravirine has compromised activity in approximately half of the patients failing nevirapine-based first-line treatment in this cohort, which supports guidelines that caution against using it with NRTIs alone in such patients.

High exposure to nevirapine in plasma is associated with an improved virological response in HIV-1-infected individuals.

PubMed

Veldkamp, A I; Weverling, G J; Lange, J M; Montaner, J S; Reiss, P; Cooper, D A; Vella, S; Hall, D; Beijnen, J H; Hoetelmans, R M

2001-06-15

To explore relationships between exposure to nevirapine and the virological response in HIV-1-infected individuals participating in the INCAS trial. The elimination rate constant of plasma HIV-1 RNA (k) was calculated during the first 2 weeks of treatment with nevirapine, zidovudine and didanosine in 51 antiretroviral-naive HIV-1-infected patients. The relationships between the value of k, the time to reach an undetectable HIV-1 RNA concentration in plasma (< 20 copies/ml) and the success of therapy after 52 weeks of treatment as dependent variables and the exposure to nevirapine, baseline HIV-1 RNA and baseline CD4 cell count as independent variables, were explored using linear regression analyses, proportional hazard models and logistic analyses, respectively. The value of k for HIV-1 RNA in plasma was positively and significantly associated with the mean plasma nevirapine concentration during the first 2 weeks of therapy (P = 0.011) and the baseline HIV-1 RNA (P = 0.008). Patients with a higher exposure to nevirapine reached undetectable levels of HIV-1 RNA in plasma more rapidly (P = 0.03). From 12 weeks on, the median nevirapine plasma concentration was significantly correlated with success of therapy after 52 weeks (P < 0.02). A high exposure to nevirapine (in a twice daily regimen) is significantly associated with improved virological response in the short as well as in the long term. These findings suggest that optimization of nevirapine concentration might be used as a tool to improve virological outcome in (antiretroviral-naive) patients treated with nevirapine.

Determination of nucleoside analog mono-, di-, and tri-phosphates in cellular matrix by solid phase extraction and ultra-sensitive LC-MS/MS detection.

PubMed

Bushman, Lane R; Kiser, Jennifer J; Rower, Joseph E; Klein, Brandon; Zheng, Jia-Hua; Ray, Michelle L; Anderson, Peter L

2011-09-10

An ultra-sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) assay was developed and validated to facilitate the assessment of clinical pharmacokinetics of nucleotide analogs from lysed intracellular matrix. The method utilized a strong anion exchange isolation of mono-(MP), di-(DP), and tri-phosphates (TP) from intracellular matrix. Each fraction was then dephosphorylated to the parent moiety yielding a molar equivalent to the original nucleotide analog intracellular concentration. The analytical portion of the methodology was optimized in specific nucleoside analog centric modes (i.e. tenofovir (TFV) centric, zidovudine (ZDV) centric), which included desalting/concentration by solid phase extraction and detection by LC-MS/MS. Nucleotide analog MP-, DP-, and TP-determined on the TFV centric mode of analysis include TFV, lamivudine (3TC), and emtricitibine (FTC). The quantifiable linear range for TFV was 2.5-2000 fmol/sample, and that for 3TC/FTC was 0.1 200 pmol/sample. Nucleoside analog MP-, DP-, and TP-determined on the ZDV centric mode of analysis included 3TC and ZDV. The quantifiable linear range for 3TC was 0.1 100 pmol/sample, and 5-2000 fmol/sample for ZDV. Stable labeled isotopic internal standards facilitated accuracy and precision in alternative cell matrices, which supported the intended use of the method for MP, DP, and TP determinations in various cell types. The method was successfully applied to clinical research samples generating novel intracellular information for TFV, FTC, ZDV, and 3TC nucleotides. This document outlines method development, validation, and application to clinical research. Copyright © 2011 Elsevier B.V. All rights reserved.

Substrate mimicry: HIV-1 reverse transcriptase recognizes 6-modified-3′-azido-2′,3′-dideoxyguanosine-5′-triphosphates as adenosine analogs

PubMed Central

Herman, Brian D.; Schinazi, Raymond F.; Zhang, Hong-wang; Nettles, James H.; Stanton, Richard; Detorio, Mervi; Obikhod, Aleksandr; Pradère, Ugo; Coats, Steven J.; Mellors, John W.; Sluis-Cremer, Nicolas

2012-01-01

β-D-3′-Azido-2′,3′-dideoxyguanosine (3′-azido-ddG) is a potent inhibitor of HIV-1 replication with a superior resistance profile to zidovudine. Recently, we identified five novel 6-modified-3′-azido-ddG analogs that exhibit similar or superior anti-HIV-1 activity compared to 3′-azido-ddG in primary cells. To gain insight into their structure–activity–resistance relationships, we synthesized their triphosphate (TP) forms and assessed their ability to inhibit HIV-1 reverse transcriptase (RT). Steady-state and pre-steady-state kinetic experiments show that the 6-modified-3′-azido-ddGTP analogs act as adenosine rather than guanosine mimetics in DNA synthesis reactions. The order of potency of the TP analogs against wild-type RT was: 3′-azido-2,6-diaminopurine >3′-azido-6-chloropurine; 3′-azido-6-N-allylaminopurine > 2-amino-6-N,N-dimethylaminopurine; 2-amino-6-methoxypurine. Molecular modeling studies reveal unique hydrogen-bonding interactions between the nucleotide analogs and the template thymine base in the active site of RT. Surprisingly, the structure–activity relationship of the analogs differed in HIV-1 RT ATP-mediated excision assays of their monophosphate forms, suggesting that it may be possible to rationally design a modified base analog that is efficiently incorporated by RT but serves as a poor substrate for ATP-mediated excision reactions. Overall, these studies identify a promising strategy to design novel nucleoside analogs that exert profound antiviral activity against both WT and drug-resistant HIV-1. PMID:21914723

Antiretroviral pharmacokinetics in mothers and breastfeeding infants from 6 to 24 weeks post partum: results of the BAN Study

PubMed Central

Corbett, Amanda H; Kayira, Dumbani; White, Nicole R; Davis, Nicole L; Kourtis, Athena P; Chasela, Charles; Martinson, Francis; Phiri, Grace; Musisi, Bonaface; Kamwendo, Deborah; Hudgens, Michael G; Hosseinipour, Mina C; Nelson, Julie AE; Ellington, Sascha R; Jamieson, Denise J; van der Horst, Charles; Kashuba, Angela

2014-01-01

Background An intensive, prospective, open-label pharmacokinetic (PK) study in a subset of HIV-infected mothers and their uninfected infants enrolled in the Breastfeeding, Antiretroviral, and Nutrition study was performed to describe drug exposure and antiviral response. Methods Women using Combivir®[zidovudine (ZDV)+ lamivudine (3TC)]+Aluvia®[lopinavir/ritonavir(LPV/RTV)] were enrolled. Breast milk (BM) and mother and infant plasma (MP, IP) samples were obtained over 6hrs after observed dosing at 6, 12, or 24wks post-partum for drug concentrations and HIV RNA. Results 30 mother/infant pairs (10 each at 6, 12,and 24wks post-partum) were enrolled. Relative to MP, BM concentrations of ZDV and 3TC were 35% and 21% higher, while LPV and RTV were 80% lower. Only 3TC was detected in IP with concentrations 96% and 98% lower than MP and BM, respectively. Concentrations in all matrices were similar at 6-24wks. The majority (98.3%) of BM concentrations were >HIVwt IC50, with one having detectable virus. There was no association between PK parameters and MP or BM HIV RNA. Conclusions ZDV and 3TC concentrated in BM while LPV and RTV did not, possibly due to protein binding and drug transporter affinity. Undetectable to low ARV concentrations in IP suggests prevention of transmission while breast feeding may be due to ARV effects on systemic or BM HIV RNA in the mother. Low IP 3TC exposure may predispose an infected infant to HIV resistance, necessitating testing and treating infants early. PMID:24464632

Standardized peripheral blood mononuclear cell culture assay for determination of drug susceptibilities of clinical human immunodeficiency virus type 1 isolates. The RV-43 Study Group, the AIDS Clinical Trials Group Virology Committee Resistance Working Group.

PubMed Central

Japour, A J; Mayers, D L; Johnson, V A; Kuritzkes, D R; Beckett, L A; Arduino, J M; Lane, J; Black, R J; Reichelderfer, P S; D'Aquila, R T

1993-01-01

A standardized antiviral drug susceptibility assay for clinical human immunodeficiency virus type 1 (HIV-1) isolates has been developed for use in clinical trials. The protocol is a two-step procedure that first involves cocultivation of patient infected peripheral blood mononuclear cells (PBMC) with seronegative phytohemagglutinin-stimulated donor PBMC to obtain an HIV-1 stock. The virus stock is titrated for viral infectivity (50% tissue culture infective dose) by use of serial fourfold virus dilutions in donor PBMC. A standardized inoculum of 1,000 50% tissue culture infective doses per 10(6) cells is used in the second step of the procedure to acutely infect seronegative donor PBMC in a 7-day microtiter plate assay with triplicate wells containing zidovudine (ZDV) concentrations ranging from 0 to 5.0 microM. The ZDV 50% inhibitory concentrations (IC50) for reference ZDV-susceptible and ZDV-resistant HIV-1 isolates ranged from 0.002 to 0.113 microM and from 0.15 to > 5.0 microM, respectively. Use of this consensus protocol reduced interlaboratory variability for ZDV IC50 determinations with reference HIV-1 isolates. Among eight laboratories, the coefficient of variation ranged from 0.85 to 1.25 with different PBMC protocols and was reduced to 0.39 to 0.98 with the standardized assay. Among the clinical HIV-1 isolates assayed by the standardized drug susceptibility assay, the median ZDV IC50 increased gradually with more ZDV therapy. This protocol provides an efficient and reproducible means to assess the in vitro susceptibility to antiretroviral agents of virtually all clinical HIV-1 isolates. PMID:8517697

Adverse Drug Reactions to Antiretroviral Therapy in HIV-Infected Patients at the Largest Public Hospital in Nicaragua.

PubMed

Lorío, Marco; Colasanti, Jonathan; Moreira, Sumaya; Gutierrez, Gamaliel; Quant, Carlos

2014-01-01

Adverse drug reactions (ADRs) to antiretroviral therapy (ART) are an important cause of hospitalization, treatment discontinuation, and regimen changes in both developed and developing countries. This study is the first to examine and understand ADRs in HIV-infected patients in Nicaragua. A retrospective descriptive study was conducted from May 2010 to March 2011, in a cohort of HIV-infected patients receiving ART at the largest public hospital in Managua, Nicaragua. Patients were identified based on ADRs reporting on a standardized antiretroviral pharmacotherapy form. Subsequently, chart reviews of these patients were performed in order to document the specific ADRs. Six hundred ninety-two patients on ART were included. The incidence of ADRs was 6.4% (95% confidence interval [CI] 4.5-8.2). Females demonstrated a higher incidence, that is, 10.2% (95% CI 5.3-15.1, P = .020). Patients treated with combinations of zidovudine (ZDV)/lamivudine (3TC) and emtricitabine (FTC)/tenofovir (TDF) had fewer ADRs (P < .01) than those using other combinations. Five patients were hospitalized or had a prolonged hospitalization secondary to ADRs, with no mortality attributed to ADR. The most common manifestations of ADRs were central nervous system (20 of 44), gastrointestinal (12 of 44), and dermatologic (8 of 44) reactions. Adverse drug reactions were classified as "likely ADRs" (25 of 44) and "possible ADRs" (19 of 44). No ADRs were preventable. Adverse drug reactions most frequently affected the central nervous system. No ADR was life threatening. The frequency of ADRs in this Nicaraguan patient population was less than that reported from other studies in resource-limited settings. © The Author(s) 2014.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jules-Elysee, K.M.; Stover, D.E.; Zaman, M.B.

The objective of this study was to determine the effect of previous aerosolized pentamidine therapy on diagnosis and presentation of Pneumocystis carinii pneumonia. This was a retrospective study of fifty-two consecutive patients with P. carinii pneumonia and underlying infection with the human immunodeficiency virus (HIV) who had bronchoscopy. Twenty-one patients who were on aerosolized pentamidine therapy served as the study group. Thirty-one patients who had not received the drug served as the control group. The yield of bronchoalveolar lavage for P. carinii pneumonia was 62% for the study group and 100% for the control group (P less than 0.05). Thismore » lower yield was significant for the subset of patients having their first episode of P. carinii pneumonia. The yield of transbronchial biopsy was similar for both groups of patients (81% compared with 84%). The yield of bronchoscopy was not influenced by use of zidovudine. Review of lavage specimen slides suggested that there may be fewer organisms present in patients receiving aerosolized pentamidine. An atypical roentgenographic presentation of upper lobe predominant infiltrates was seen in 38% of the study patients and 7% of the control patients. In addition, pneumothoraces and cystic changes were also frequently seen in the study patients. Gallium scans, when done, were also atypical in the study group. Markers of the severity of disease, however, were similar in both groups. The yield of bronchoalveolar lavage for P. carinii pneumonia in HIV-infected patients is lower in patients receiving aerosolized pentamidine. Unusual roentgenographic presentations and atypical gallium scans are also found in this setting.« less

Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naive HIV-1-infected patients: pooled results from the phase 3 double-blind randomized ECHO and THRIVE Trials.

PubMed

Cohen, Calvin J; Molina, Jean-Michel; Cahn, Pedro; Clotet, Bonaventura; Fourie, Jan; Grinsztejn, Beatriz; Wu, Hao; Johnson, Margaret A; Saag, Michael; Supparatpinyo, Khuanchai; Crauwels, Herta; Lefebvre, Eric; Rimsky, Laurence T; Vanveggel, Simon; Williams, Peter; Boven, Katia

2012-05-01

Pooled analysis of phase 3, double-blind, double-dummy ECHO and THRIVE trials comparing rilpivirine (TMC278) and efavirenz. Treatment-naive HIV-1-infected adults were randomized 1:1 to rilpivirine 25 mg once daily or efavirenz 600 mg once daily, with background tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) (ECHO) or TDF/FTC, zidovudine/lamivudine, or abacavir/lamivudine (THRIVE). The primary endpoint was confirmed response [viral load <50 copies per milliliter; intent-to-treat time-to-loss-of-virologic-response (ITT-TLOVR) algorithm] at week 48. The pooled data set enabled analyses of subgroups and predictors of response/virologic failure. Confirmed responses were 84% (rilpivirine) and 82% (efavirenz). The difference in response rates (95% confidence interval) was 2.0% (-2.0% to 6.0%). The incidence of virologic failure was 9% (rilpivirine) versus 5% (efavirenz). Responses in ITT-TLOVR and ITT-snapshot analyses were consistent. Responses were similar for rilpivirine and efavirenz by background regimen, gender, race and clade. Suboptimal adherence and higher baseline viral load resulted in lower responses, higher virologic failure, and development of resistance in both groups; the effects on virologic failure were more apparent with rilpivirine. CD4 cell count increased over time in both groups. Rilpivirine compared with efavirenz gave smaller incidences of adverse events leading to discontinuation (3% vs. 8%, respectively), treatment-related grade 2-4 adverse events (16% vs. 31%), rash (3% vs. 14%), dizziness (8% vs. 26%), abnormal dreams/nightmares (8% vs. 13%), and grade 2-4 lipid abnormalities. At week 48, rilpivirine 25 mg once daily and efavirenz 600 mg once daily had comparable response rates. Rilpivirine had more virologic failures and improved tolerability versus efavirenz.

[Factors predicting lack of adherence to highly active antiretroviral treatment].

PubMed

Martín-Sánchez, Vicente; Ortega-Valín, Luis; Pérez-Simón, María del Rosario; Mostaza-Fernández, José Luis; Ortiz de Urbina-González, Juan José; Rodríguez-María, Miriam; Carro-Fernández, José Antonio; Cuevas-González, María José; Alcoba-Leza, Manuel

2002-12-01

Knowledge of adherence to highly active antiretroviral treatment (HAART) and the variables associated with poor compliance is useful for the follow-up of HIV infected patients. Patients were consecutively recruited from the HIV outpatient clinics of the Hospitals of Leon and El Bierzo from January to June 2000. Patients were considered non-adherent to treatment if they failed to take 10% or more of their prescribed total dose of at least one drug during the 4 days before the interview, or if they had accumulated a delay of more than 9 days over the previous 3 months in picking up their prescribed drugs from the hospital pharmacy. Logistic regression analysis was performed with variables found to be associated with adherence in the univariate analysis. The methods used to determine adherence had a Kappa index of 12.6%. Among the 206 patients interviewed, 108 were considered non-adherent (52.4%; CI 95% 5 45.6-59.2). Multivariate analysis showed that the following factors were associated with poor treatment adherence: cocaine consumption in the previous six months (adjusted OR 5 5.1); patients unsure about the proper way to take prescribed treatment; (adjusted OR 5 2.5); and patients not prescribed the zidovudine-lamivudine combination (adjusted OR 5 1.9). Over one-third of patients with no variable associated with treatment adherence were considered non-compliant. Measurement of medication adherence and its predictive factors involved methodological difficulties. With the criteria used in the present study more than half the patients were considered non-compliant. The variables found to be related to poor adherence can be modified by social, psychological or health care interventions.

Brief Report: High Sensitivity and Specificity of the Cepheid Xpert HIV-1 Qualitative Point-of-Care Test Among Newborns in Botswana.

PubMed

Ibrahim, Maryanne; Moyo, Sikhulile; Mohammed, Terence; Mupfumi, Lucy; Gaseitsiwe, Simani; Maswabi, Kenneth; Ajibola, Gbolahan; Gelman, Rebecca; Batlang, Oganne; Sakoi, Maureen; Auletta-Young, Chloe; Makhema, Joseph; Lockman, Shahin; Shapiro, Roger L

2017-08-15

HIV point-of-care (POC) testing allows for early infant HIV diagnosis and treatment, but POC accuracy at birth and in the setting of antiretroviral prophylaxis for the prevention of mother-to-child HIV transmission is unknown. We evaluated the Cepheid Xpert HIV-1 Qual POC test against the Roche Taqman HIV-1 DNA polymerase chain reaction (PCR) platform using dried blood spots from 15 HIV-infected and 75 HIV-exposed uninfected newborns. These infants were screened for HIV at <96 hours of life at 5 hospital maternity wards in Botswana; all infants received postexposure antiretroviral prophylaxis with single-dose nevirapine and zidovudine, and most mothers received 3-drug antiretroviral therapy in pregnancy and at delivery. Fourteen of the 15 PCR positive samples tested positive by Cepheid POC, yielding a sensitivity of 93.3% (95% confidence interval: 68.1 to 99.8). Baseline viral load among positive infants ranged from <40 to >10,000,000 copies/mL, with a median of 2403 copies/mL. The HIV RNA for the infant with false-negative POC testing was 1661 copies/mL. Of note, 2 infants with low HIV RNA (<40 and 272 copies/mL) were correctly identified as HIV positive by Cepheid POC. All the 75 PCR-negative samples tested negative by Cepheid POC, yielding a specificity of 100% (95% confidence interval: 96.1 to 100). Our study demonstrates high sensitivity and specificity for the Cepheid POC assay in the first week of life despite early infection and antiretroviral prophylaxis. This platform may be a useful approach for adding early infant HIV diagnosis to current testing programs.

LC-MS/MS determination of antiretroviral drugs in influents and effluents from wastewater treatment plants in KwaZulu-Natal, South Africa.

PubMed

Abafe, Ovokeroye A; Späth, Jana; Fick, Jerker; Jansson, Stina; Buckley, Chris; Stark, Annegret; Pietruschka, Bjoern; Martincigh, Bice S

2018-06-01

South Africa has the largest occurrence of the human immune deficiency virus (HIV) in the world but has also implemented the largest antiretroviral (ARV) treatment programme. It was therefore of interest to determine the presence and concentrations of commonly used antiretroviral drugs (ARVDs) and, also, to determine the capabilities of wastewater treatment plants (WWTPs) for removing ARVDs. To this end, a surrogate standard based LC-MS/MS method was optimized and applied for the detection of thirteen ARVDs used in the treatment and management of HIV/acquired immune deficiency syndrome (HIV/AIDS) in two major and one modular WWTP in the eThekwini Municipality in KwaZulu-Natal, South Africa. The method was validated and the detection limits fell within the range of 2-20 ng L -1 . The analytical recoveries for the ARVDs were mainly greater than 50% with acceptable relative standard deviations. The concentration values ranged from zidovudine were almost completely removed from the effluents, atazanavir, efavirenz, lopinavir and nevirapine persisted in the effluents from all three WWTPs. To estimate the ecotoxicological risks associated with the discharge of ARVDs, a countrywide survey focussing on the occurrence of ARVDs in WWTPs, surface and fresh water bodies, and aquatic organisms, is necessary. Copyright © 2018 Elsevier Ltd. All rights reserved.

Science and ethics of human immunodeficiency virus/acquired immunodeficiency syndrome controversies in Africa.

PubMed

Brewster, David

2011-09-01

The human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic in Africa has raised important ethical issues for both researchers and clinicians. The most notorious controversy has been related to the zidovudine (AZT) trials in Africa in the late 1990s, in which the control groups were given a placebo rather than an effective drug to prevent vertical transmission. This raised concerns in the sponsoring country about exploitation of subjects, injustice and an ethical double standard between donor countries and resource-poor settings. However, the real double standard is between clinical practice standards in Western versus African countries, which must be addressed as part of the increasing global inequity of wealth both between countries and also within countries. There are important limitations to ethical declarations, principles and guidelines on their own without contextual ethical reasoning. The focus on research ethics with the HIV epidemic has led to a relative neglect of ethical issues in clinical practice. Although the scientific advances in HIV/AIDS have changed the ethical issues since the 1990s, there has also been progress in the bioethics of HIV/AIDS in terms of ethical review capability by local committees as well as in exposure to ethical issues by clinicians and researchers in Africa. However, serious concerns remain about the overregulation of research by bureaucratic agencies which could discourage African research on specifically African health issues. There is also a need for African academic institutions and researchers to progressively improve their research capacity with the assistance of research funders and donor agencies. © 2011 The Author. Journal of Paediatrics and Child Health © 2011 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

Absence of a universal mechanism of mitochondrial toxicity by nucleoside analogs.

PubMed

Lund, Kaleb C; Peterson, LaRae L; Wallace, Kendall B

2007-07-01

Nucleoside analogs are associated with various mitochondrial toxicities, and it is becoming increasingly difficult to accommodate these differences solely in the context of DNA polymerase gamma inhibition. Therefore, we examined the toxicities of zidovudine (AZT) (10 and 50 microM; 2.7 and 13.4 microg/ml), didanosine (ddI) (10 and 50 microM; 2.4 and 11.8 microg/ml), and zalcitabine (ddC) (1 and 5 microM; 0.21 and 1.1 microg/ml) in HepG2 and H9c2 cells without the presumption of mitochondrial DNA (mtDNA) depletion. Ethidium bromide (EtBr) (0.5 microg/ml; 1.3 microM) was used as a positive control. AZT treatment resulted in metabolic disruption (increased lactate and superoxide) and increased cell mortality with decreased proliferation, while mtDNA remained unchanged or increased (HepG2 cells; 50 microM AZT). ddC caused pronounced mtDNA depletion in HepG2 cells but not in H9c2 cells and increased mortality in HepG2 cells, but no significant metabolic disruption in either cell type. ddI caused a moderate depletion of mtDNA in both cell types but showed no other effects. EtBr exposure resulted in metabolic disruption, increased cell mortality with decreased cell proliferation, and mtDNA depletion in both cell types. We conclude that nucleoside analogs display unique toxicities within and between culture models, and therefore, care should be taken when generalizing about the mechanisms of nucleoside reverse transcriptase inhibitor toxicity. Additionally, mtDNA abundance does not necessarily correlate with metabolic disruption, especially in cell culture; careful discernment is recommended in this regard.

Activities of the human immunodeficiency virus type 1 (HIV-1) protease inhibitor nelfinavir mesylate in combination with reverse transcriptase and protease inhibitors against acute HIV-1 infection in vitro.

PubMed Central

Patick, A K; Boritzki, T J; Bloom, L A

1997-01-01

Nelfinavir mesylate (formerly AG1343) is a potent and selective, nonpeptidic inhibitor of human immunodeficiency virus type 1 (HIV-1) protease that was discovered by protein structure-based design methodologies. We evaluated the antiviral and cytotoxic effects of two-drug combinations of nelfinavir with the clinically approved antiretroviral therapeutics zidovudine (ZDV), lamivudine (3TC), dideoxycytidine (ddC; zalcitabine), stavudine (d4T), didanosine (ddI), indinavir, saquinavir, and ritonavir and a three-drug combination of nelfinavir with ZDV and 3TC against an acute HIV-1 strain RF infection of CEM-SS cells in vitro. Quantitative assessment of drug interaction was evaluated by a universal response surface approach (W. R. Greco, G. Bravo, and J. C. Parsons, Pharm. Rev. 47:331-385, 1995) and by the method of M. N. Prichard and C. Shipman (Antiviral Res. 14:181-206, 1990). Both analytical methods yielded similar results and showed that the two-drug combinations of nelfinavir with the reverse transcriptase inhibitors ZDV, 3TC, ddI, d4T, and ddC and the three-drug combination with ZDV and 3TC resulted in additive to statistically significant synergistic interactions. In a similar manner, the combination of nelfinavir with the three protease inhibitors resulted in additive (ritonavir and saquinavir) to slightly antagonistic (indinavir) interactions. In all combinations, minimal cellular cytotoxicity was observed with any drug alone and in combination. These results suggest that administration of combinations of the appropriate doses of nelfinavir with other currently approved antiretroviral therapeutic agents in vivo may result in enhanced antiviral activity with no associated increase in cellular cytotoxicity. PMID:9333041

Antiretroviral therapy provided to HIV-infected Malawian women in a randomized trial diminishes the positive effects of lipid-based nutrient supplements on breast-milk B vitamins.

PubMed

Allen, Lindsay H; Hampel, Daniela; Shahab-Ferdows, Setareh; York, Emily R; Adair, Linda S; Flax, Valerie L; Tegha, Gerald; Chasela, Charles S; Kamwendo, Debbie; Jamieson, Denise J; Bentley, Margaret E

2015-12-01

Little information is available on B vitamin concentrations in human milk or on how they are affected by maternal B vitamin deficiencies, antiretroviral therapy, or maternal supplementation. The objective was to evaluate the effects of antiretroviral therapy and/or lipid-based nutrient supplements (LNSs) on B vitamin concentrations in breast milk from HIV-infected women in Malawi. Breast milk was collected from 537 women recruited within the Breastfeeding, Antiretrovirals, and Nutrition study at 2 or 6 wk and 24 wk postpartum. Women were assigned to receive antiretrovirals and LNSs, antiretrovirals only, LNSs only, or a control. Antiretrovirals and LNSs were given to the mothers from weeks 0 to 28. The antiretrovirals were zidovudine/lamivudine and nelfinavir or lopinavir/ritonavir. LNSs provided 93-118% of the Recommended Dietary Allowances of thiamin, riboflavin, niacin, pyridoxine, and vitamin B-12. Infants were exclusively breastfed. LNSs increased milk concentrations of all vitamins except thiamin, whereas antiretrovirals lowered concentrations of nicotinamide, pyridoxal, and vitamin B-12. Although antiretrovirals alone had no significant effect on riboflavin concentrations, they negatively affected the LNS-induced increase in this vitamin. Thiamin was not influenced by the study interventions. Concentrations of all B vitamins were much lower than usually accepted values. All B vitamins were low in milk, and all but thiamin were increased by maternal supplementation with LNSs. Antiretrovirals alone decreased concentrations of some B vitamins in milk. When LNS was given in addition to antiretrovirals, the negative effect of antiretrovirals offset the positive effect of LNSs for all vitamins except thiamin. This trial was registered at clinicaltrials.gov as NCT00164762. © 2015 American Society for Nutrition.

Incidence of anaemia among HIV-infected patients treated with highly active antiretroviral therapy.

PubMed

Curkendall, S M; Richardson, J T; Emons, M F; Fisher, A E; Everhard, F

2007-11-01

The aim of the study was to compare the incidence of anaemia in patients treated with zidovudine (ZDV) with that in patients treated with highly active antiretroviral therapy (HAART) not including ZDV. Using HIV Insight, a database of abstracted US HIV care centre medical charts, ZDV-naïve patients starting ZDV-containing HAART were compared with those starting non-ZDV, nucleoside reverse transcriptase inhibitor-containing HAART. Cohorts were divided as follows: group 1: without baseline anaemia [haemoglobin (Hb) >or=11 g/dL]; group 2: with baseline anaemia (Hb <11 g/dL). The incidence of anaemia (anaemia diagnosis, Hb <11 g/dL, erythropoietic therapy or blood transfusion) was computed for group 1. The anaemia hazard ratio (HR) was adjusted using Cox regression. The rate of worsening anaemia (Hb decrease >or=1.0 g/dL) was computed for group 2. In group 1, the incidence of anaemia was 24.3 and 8.1 per 100 person-years in the ZDV and non-ZDV cohorts, respectively, after 6 months of follow-up, and 12.5 and 5.3 per 100 person-years after 24 months. Significant predictors of anaemia were ZDV, low initial Hb, injecting drug use, CD4 count <200 cells/microL and AIDS. The adjusted HR for ZDV was 1.6 (P=0.005). In group 2, the ZDV/non-ZDV risk ratio for worsening anaemia was 2.2 (95% confidence interval 1.1-4.3). Patients initiating ZDV-containing HAART are at greater risk of developing new anaemia or worsening anaemia than patients initiating non-ZDV-containing HAART.

The feasibility of voluntary counselling and HIV testing for pregnant women using community volunteers in Zimbabwe.

PubMed

Shetty, Avinash K; Mhazo, Miriam; Moyo, Sostain; von Lieven, Andrea; Mateta, Patrick; Katzenstein, David A; Maldonado, Yvonne; Hill, David; Bassett, Mary T

2005-11-01

The purpose of this pilot project was to assess the feasibility and acceptability of voluntary counselling and HIV testing (VCT) by pregnant women using community volunteers in Zimbabwe to prevent mother to child transmission (MTCT) of HIV. From July 1999 to June 2001, a short-course zidovudine (ZDV)-based perinatal HIV prevention programme was initiated in two antenatal clinics. Community volunteers, recruited from local community organizations, underwent a two-week training course in VCT, which included HIV/AIDS facts, systematic counselling approach, and practical counselling techniques using scripts and role-play. Rapid HIV testing was performed after informed consent. Lay counsellors conducted individual pre- and post-test counselling for HIV. A total of 35 women community volunteers were trained in VCT; 34 graduated and committed to work four hours per week in the clinic. Of the 6051 pregnant women presenting for antenatal clinics (ANC), 1824 (30%) underwent pre-test counselling and 1547 (26%) were tested, and 429 (28%) were HIV infected. Overall, 1283 (83%) returned for their test results including 406 (95%) of HIV-infected women. Of the 406 HIV-infected women who collected their test results, only 203 (50%) opted for ZDV prophylaxis to prevent MTCT of HIV. Over the two-year study period, two counsellors died and three sought employment at other organizations. Adherence to duty roster was 97% and no breach of confidentiality was reported. Despite many challenges, VCT delivered by community volunteers is feasible and acceptable for pregnant women aiming to reduce their risk of transmitting HIV to their infants. This programme is being implemented at several urban and rural MTCT sites in Zimbabwe and can serve as a model for other resource-poor countries.

Adherence to HAART therapy measured by electronic monitoring in newly diagnosed HIV patients in Botswana.

PubMed

Vriesendorp, Reinout; Cohen, Adam; Kristanto, Paulus; Vrijens, Bernard; Rakesh, Pande; Anand, Bene; Iwebor, Henry Uchechukwaka; Stiekema, Jacobus

2007-12-01

This pilot study was designed to evaluate the feasibility and benefits of electronic adherence monitoring of antiretroviral medications in HIV patients who recently started Highly Active Anti Retroviral Therapy (HAART) in Francistown, Botswana and to compare this with self-reporting. Dosing histories were compiled electronically using Micro Electro Mechanical Systems (MEMS) monitors to evaluate adherence to prescribed therapies. Thirty patients enrolled in the antiretroviral treatment program were monitored over 6 weeks. These patients were all antiretroviral (ARV) naïve. After each visit (mean three times) to the pharmacy, the data compiled by the monitors were downloaded. Electronic monitoring of adherence was compared to patient self-reports of adherence. The mean individual medication adherence level measured with the electronic device was 85% (range 21-100%). The mean adherence level measured by means of self-reporting was 98% (range 70-100%). Medication prescribed on a once-a-day dose base was associated with a higher adherence level (97.9% for efavirenz) compared with a twice-a-day regimen (88.4% for Lamivudine/Zidovudine). It is feasible to assess treatment adherence of patients living in a low resource setting on HAART by using electronic monitors. Adherence, even in the early stages of treatment, appears to be insufficient in some patients and may be below the level required for continuous inhibition of viral replication. This approach may lead to improved targeting of counselling about their medication intake of such patients in order to prevent occurrence of resistant viral strains due to inadequate inhibition of viral replication. In this pilot study a significant difference between the data recorded through the electronic monitors and those provided by self-reporting was observed.

Herb–drug interaction prediction based on the high specific inhibition of andrographolide derivatives towards UDP-glucuronosyltransferase (UGT) 2B7

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma, Hai-Ying, E-mail: cmu4h-mhy@126.com; Sun, Dong-Xue; Cao, Yun-Feng

2014-05-15

Herb–drug interaction strongly limits the clinical application of herbs and drugs, and the inhibition of herbal components towards important drug-metabolizing enzymes (DMEs) has been regarded as one of the most important reasons. The present study aims to investigate the inhibition potential of andrographolide derivatives towards one of the most important phase II DMEs UDP-glucuronosyltransferases (UGTs). Recombinant UGT isoforms (except UGT1A4)-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation were employed to firstly screen the andrographolide derivatives' inhibition potential. High specific inhibition of andrographolide derivatives towards UGT2B7 was observed. The inhibition type and parameters (K{sub i}) were determined for themore » compounds exhibiting strong inhibition capability towards UGT2B7, and human liver microsome (HLMs)-catalyzed zidovudine (AZT) glucuronidation probe reaction was used to furtherly confirm the inhibition behavior. In combination of inhibition parameters (K{sub i}) and in vivo concentration of andrographolide and dehydroandrographolide, the potential in vivo inhibition magnitude was predicted. Additionally, both the in vitro inhibition data and computational modeling results provide important information for the modification of andrographolide derivatives as selective inhibitors of UGT2B7. Taken together, data obtained from the present study indicated the potential herb–drug interaction between Andrographis paniculata and the drugs mainly undergoing UGT2B7-catalyzed metabolic elimination, and the andrographolide derivatives as potential candidates for the selective inhibitors of UGT2B7. - Highlights: • Specific inhibition of andrographolide derivatives towards UGT2B7. • Herb-drug interaction related withAndrographis paniculata. • Guidance for design of UGT2B7 specific inhibitors.« less

Birth defects among children born to HIV-infected women: Pediatric AIDS Clinical Trials Protocols 219 and 219C

PubMed Central

Brogly, Susan B.; Abzug, Mark J.; Watts, D. Heather; Cunningham, Coleen K.; Williams, Paige L.; Oleske, James; Conway, Daniel; Sperling, Rhoda S.; Spiegel, Hans; Van Dyke, Russell B.

2010-01-01

Background Some studies have detected associations between in utero antiretroviral therapy (ARV) exposure and birth defects but evidence is inconclusive. Methods 2,202 HIV-exposed children enrolled in the Pediatric AIDS Clinical Trials Group 219 and 219C protocols before one year of age were included. Birth defects were classified using the Metropolitan Atlanta Congenital Defects Program (MACDP) coding. Logistic regression models were used to evaluate associations between first trimester in utero ARV exposure and birth defects. Results 117 live-born children had birth defects for a prevalence of 5.3% (95% CI: 4.4, 6.3). Prevalence did not differ by HIV infection status or overall ARV exposure; rates were 4.8% (95% CI: 3.7, 6.1) and 5.8% (95% CI: 4.2, 7.8) in children without and with first trimester ARV exposure, respectively. The defect rate was higher among children with first trimester efavirenz exposure (5/32, 15.6%) versus children without first trimester efavirenz exposure [adjusted odds ratio (aOR)=4.31 (95% CI: 1.56, 11.86)]. Protective effects of first trimester zidovudine exposure on musculoskeletal defects were detected [aOR=0.24 (95% CI: 0.08, 0.69)], while a higher risk of heart defects was found [aOR=2.04 (95% CI: 1.03, 4.05)]. Conclusion The prevalence of birth defects was higher in this cohort of HIV-exposed children than in other pediatric cohorts. There was no association with overall ARV exposure, but there were some associations with specific agents including efavirenz. Additional studies are needed to rule out confounding and to evaluate newer ARV agents. PMID:20539252

Zinc blocks SOS-induced antibiotic resistance via inhibition of RecA in Escherichia coli.

PubMed

Bunnell, Bryan E; Escobar, Jillian F; Bair, Kirsten L; Sutton, Mark D; Crane, John K

2017-01-01

Zinc inhibits the virulence of diarrheagenic E. coli by inducing the envelope stress response and inhibiting the SOS response. The SOS response is triggered by damage to bacterial DNA. In Shiga-toxigenic E. coli, the SOS response strongly induces the production of Shiga toxins (Stx) and of the bacteriophages that encode the Stx genes. In E. coli, induction of the SOS response is accompanied by a higher mutation rate, called the mutator response, caused by a shift to error-prone DNA polymerases when DNA damage is too severe to be repaired by canonical DNA polymerases. Since zinc inhibited the other aspects of the SOS response, we hypothesized that zinc would also inhibit the mutator response, also known as hypermutation. We explored various different experimental paradigms to induce hypermutation triggered by the SOS response, and found that hypermutation was induced not just by classical inducers such as mitomycin C and the quinolone antibiotics, but also by antiviral drugs such as zidovudine and anti-cancer drugs such as 5-fluorouracil, 6-mercaptopurine, and azacytidine. Zinc salts inhibited the SOS response and the hypermutator phenomenon in E. coli as well as in Klebsiella pneumoniae, and was more effective in inhibiting the SOS response than other metals. We then attempted to determine the mechanism by which zinc, applied externally in the medium, inhibits hypermutation. Our results show that zinc interferes with the actions of RecA, and protects LexA from RecA-mediated cleavage, an early step in initiation of the SOS response. The SOS response may play a role in the development of antibiotic resistance and the effect of zinc suggests ways to prevent it.

Epidemiology, clinical features, and outcome of HTLV-1–related ATLL in an area of prevalence in the United States

PubMed Central

Pimentel, Agustin; Reis, Isildinha M.; Gotuzzo, Eduardo; Lekakis, Lazaros; Komanduri, Krishna; Harrington, Thomas; Barber, Glen N.

2018-01-01

Adult T-cell leukemia/lymphoma (ATLL) is a fatal disease caused by human T-cell leukemia virus type 1 (HTLV-1). We retrospectively analyzed 195 patients with ATLL (lymphomatous n = 96, acute n = 80, unfavorable chronic n = 7, chronic n = 5, smoldering n = 3, and unclassified n = 4) diagnosed between 1987 and 2016 (median age 52 years, 77% Afro-Caribbean). Hypercalcemia was associated with acute ATLL (65%, vs 23% lymphomatous) (P = .012). The median survival for patients treated with modern therapies between 2000 and 2016 was 4.1 months for acute, 10.2 months for lymphomatous, 72 months for chronic/smoldering, and not reached for unfavorable chronic type, with 4-year survival rates of 10%, 4%, 60%, and 83%, respectively. The overall response rate (ORR) after first-line multiagent chemotherapy was 78% (complete response [CR] 39%) for acute vs 67% (CR 33%) for lymphomatous ATLL. First-line zidovudine interferon-α (AZT-IFN) resulted in ORR of 56% (CR 23%) for acute (n = 43), 33% (CR 16.5%) for lymphomatous (n = 6), and 86% (CR 29%) for unfavorable chronic ATLL. The median progression-free survival (PFS) in patients with aggressive ATLL who achieved CR after AZT-IFN was 48 months vs 11 months after chemotherapy (P = .003). Allogeneic hematopoietic stem cell transplant (allo-HSCT) resulted in a PFS of 24 and 28 months in 2 patients with lymphomatous ATLL. Our results suggest high-dose AZT-IFN is a reasonable up-front option for patients with aggressive leukemic ATLL followed by chemotherapy switch in nonresponders, whereas chemotherapy should be used in lymphomatous type followed by allo-HSCT when feasible. PMID:29545256

Efavirenz DuPont Pharmaceuticals Co.

PubMed

Dong, B J

1998-10-01

Efavirenz is the lead compound of a series of benzoxazinones originally developed by DuPont Merck. It is a non-nucleoside reverse transcriptase inhibitor (NNRTI) under development for the potential treatment of viral infections, including HIV. In June 1998, the company submitted an NDA to the US FDA for the use of efavirenz (as Sustiva) for the treatment of HIV infection [289361]. In July 1998, DuPont purchased Merck's interest in DuPont Merck and the company's name changed to DuPont Pharmaceuticals. The two companies decided to continue to share marketing rights to Sustiva (to be marketed by Merck as Stocrin outside the US, Canada, and certain European countries) [291738]. As of October 1997, triple combination studies of efavirenz were ongoing, or planned, with nelfinavir, indinavir or ritonavir, or other retroviral inhibitors, for the treatment of opportunistic and pediatric viral infections [265945]. Efavirenz is also being evaluated as monotherapy and in combination with zidovudine (Retrovir, AZT) and lamivudine (Epivir, 3TC) (qv). Results of a study in eight HIV-infected patients, reported at the 12th World AIDS Conference in July 1998, showed that efavirenz administration, in dual and triple combinations, achieved HIV-RNA levels in plasma and cerebrospinal fluid (CSF) below the level of detection (fewer than 400 copies/ml) [290881,293994]. In March 1998, Merck signed a letter of intent with Trimeris to conduct a trial of efavirenz in combination with Trimeris's HIV fusion inhibitor, T-20, (qv). The trial will enroll up to 48 HIV-infected individuals at three sites in the US. All enrolled patients will be those who have begun to fail their existing triple combination therapy. Prior exposure to NNRTIs and protease inhibitors, other than indinavir, will be among the exclusion criteria for the study. The first 10 days of the study were planned as a dose-optimization period to assess the safety, pharmacokinetics and antiviral activity of multiple ascending doses

Nevirapine Resistance by Timing of HIV Type 1 Infection in Infants Treated with Single-Dose Nevirapine

PubMed Central

Micek, Mark A.; Blanco, Ana Judith; Beck, Ingrid A.; Dross, Sandra; Matunha, Laurinda; Montoya, Pablo; Seidel, Kristy; Gantt, Soren; Matediane, Eduardo; Jamisse, Lilia; Gloyd, Stephen; Frenkel, Lisa M.

2011-01-01

Background In women, single-dose nevirapine for prophylaxis against mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) selects for nevirapine-resistant HIV-1, which subsequently decays rapidly. We hypothesized that the selection, acquisition, and decay of nevirapine-resistant HIV-1 differs in infants, varying by the timing of HIV-1 infection. Methods We conducted a prospective, observational study of 740 Mozambican infants receiving single-dose nevirapine prophylaxis and determined the timing of infection and concentrations of nevirapine-resistant HIV-1 over time. Results Infants with established in utero infection had a high rate (87.0%) of selection of nevirapine-resistant HIV-1 mutants, which rapidly decayed to undetectable levels. The few without nevirapine resistance received zidovudine with single-dose nevirapine and/or their mothers took alternative antiretroviral drugs. Infants with acute in utero infection had a lower rate of nevirapine-resistant HIV-1 (33.3%; P =.006, compared with established in utero infection), but mutants persisted over time. Infants with peripartum infection also had a lower rate of nevirapine-resistant HIV-1 (38.1%; P =.001, compared with established in utero infection) but often acquired 100% mutant virus that persisted over time (P =.017, compared with established in utero infection). Conclusions The detection and persistence of nevirapine-resistant HIV-1 in infants after single-dose nevirapine therapy vary by the timing of infection and the antiretroviral regimen. In infants with persistent high-level nevirapine-resistant HIV-1, nevirapine-based antiretroviral therapy is unlikely to ever be efficacious because of concentrations in long-lived viral reservoirs. However, the absence or decay of nevirapine-resistant HIV-1 in many infants suggests that nevirapine antiretroviral therapy may be effective if testing can identify these individuals. PMID:20384494

Tenofovir disoproxil fumarate safety for women and their infants during pregnancy and breastfeeding.

PubMed

Mofenson, Lynne M; Baggaley, Rachel C; Mameletzis, Ioannis

2017-01-14

Pregnant/lactating women in some sub-Saharan Africa settings are at substantial risk of HIV acquisition and could benefit from preexposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF), but safety data in pregnancy/lactation are limited. Systematic data review through August 2016. We reviewed research reports/conference abstracts with maternal/child adverse outcome data in HIV-infected and HIV-uninfected pregnant/lactating women receiving TDF alone or in combination with other drugs compared with non-TDF regimens. In total, 26 articles in HIV-infected and seven in HIV-uninfected women were identified. No statistically significant differences were observed between TDF and comparison non-TDF regimens in pregnancy incidence, stillbirth/pregnancy loss, preterm delivery less than 37 weeks, low birth weight <2500/<1500 g, small for gestational age, birth defects, or infant (>14 days) or maternal mortality. One study reported significantly higher very preterm delivery (<34 weeks) and neonatal mortality with TDF versus non-TDF antiretroviral therapy (ART), but no significant difference between TDF ART and zidovudine/single-dose nevirapine. Most studies report normal infant linear growth; one study showed slightly lower, and one higher 1-year length-for-age z-score in TDF ART-exposed infants. No significant differences were reported in abnormal laboratory values or bone markers between TDF and non-TDF-exposed infants in four studies. Lower maternal bone mineral density was observed at 74 weeks postpartum in breastfeeding women on TDF ART compared with no ART in one study. Given available safety data, there does not appear to be a safety-related rationale for prohibiting PrEP during pregnancy/lactation or for discontinuing PrEP in HIV-uninfected women receiving PrEP who become pregnant and are at continuing risk of HIV acquisition.

Postpartum weight change among HIV-infected mothers by antiretroviral prophylaxis and infant feeding modality in a research setting.

PubMed

Cames, Cecile; Cournil, Amandine; de Vincenzi, Isabelle; Gaillard, Philippe; Meda, Nicolas; Luchters, Stanley; Nduati, Ruth; Naidu, Kevindra; Newell, Marie-Louise; Read, Jennifer S; Bork, Kirsten

2014-01-02

To assess the relationship between infant feeding, triple-antiretroviral prophylaxis and weight from 2 weeks (baseline) to 6 months postpartum among HIV-infected mothers in a mother-to-child transmission (MTCT) of HIV-prevention trial in five sub-Saharan African sites. HIV-infected pregnant women with CD4 cell counts of 200-500 cells/μl were counselled to choose breastfeeding to 6 months or replacement feeding from delivery. They were randomized to receive perinatal zidovudine and single-dose nevirapine or triple-antiretroviral MTCT prophylaxis until breastfeeding cessation. Mixed-effect linear models were used to compare maternal weight trajectories over time by infant feeding mode. Antiretroviral prophylaxis and BMI at baseline were examined as potential effect modifiers. Among 797 mothers, 620 (78%) initiated breastfeeding. Wasting (BMI <18.5) was rare at baseline (2%), whereas overweight/obesity (BMI ≥ 25) was common (40%). In the model including all women, breastfeeding was not associated with weight loss up to 6 months, irrespective of baseline BMI and antiretroviral prophylaxis. Triple-antiretroviral prophylaxis was associated with weight gain among replacement-feeding mothers with baseline BMI at least 25 (+0.54 kg/month; P < 0.0001). In the model including breastfeeding mothers only, triple-antiretroviral prophylaxis was associated with weight gain among mothers with baseline BMI at least 25 who ceased breastfeeding before 3 months postpartum (+0.33 kg/month; P = 0.03). The results suggest that breastfeeding up to 6 months postpartum is not detrimental for postpartum weight among well nourished HIV-infected mothers at intermediate-disease stage. In the absence of breastfeeding or after weaning, triple-antiretroviral prophylaxis is associated with weight gain among women with high BMI, even after cessation of prophylaxis.

Time trends in drug resistant HIV-1 infections in the United Kingdom up to 2009: multicentre observational study.

PubMed

Dolling, David; Sabin, Caroline; Delpech, Valerie; Smit, Erasmus; Pozniak, Anton; Asboe, David; Brown, Andrew Leigh; Churchill, Duncan; Williams, Ian; Geretti, Anna Maria; Phillips, Andrew; Mackie, Nicola; Murphy, Gary; Castro, Hannah; Pillay, Deenan; Cane, Patricia; Dunn, David; Dolling, David

2012-08-21

To evaluate whether the prevalence of HIV-1 transmitted drug resistance has continued to decline in infections probably acquired within the United Kingdom. Multicentre observational study. All UK public laboratories conducting tests for genotypic HIV resistance as a part of routine care. 14,584 patients infected with HIV-1 subtype B virus, who were first tested for resistance before receiving antiretroviral therapy between January 2002 and December 2009. Prevalence of transmitted drug resistance, defined as one or more resistance mutations from the surveillance list recommended by the World Health Organization. 1654 (11.3%, 95% confidence interval 10.8% to 11.9%) patients had one or more mutations associated with transmitted HIV-1 drug resistance; prevalence was found to decline from 15.5% in 2002 to 9.6% in 2007, followed by a slight increase to 10.9% in 2009 (P=0.21). This later rise was mainly a result of increases in resistance to nucleos(t)ide reverse transcriptase inhibitors (from 5.4% in 2007 to 6.6% in 2009, P=0.24) and protease inhibitors (1.5% to 2.1%, P=0.12). Thymidine analogue mutations, including T215 revertants, remained the most frequent mutations associated with nucleos(t)ide reverse transcriptase inhibitors, despite a considerable fall in stavudine and zidovudine use between 2002 and 2009 (from 29.4% of drug regimens in 2002 to 0.8% in 2009, from 47.9% to 8.8%, respectively). The previously observed decline in the prevalence of transmitted drug resistance in HIV-1 infections probably acquired in the UK seems to have stabilised. The continued high prevalence of thymidine analogue mutations suggests that the source of this resistance may be increasingly from patients who have not undergone antiretroviral therapy and who harbour resistant viruses. Testing of all newly diagnosed HIV-1 positive people should be continued.

Diabetes mellitus reduces activity of human UDP-glucuronosyltransferase 2B7 in liver and kidney leading to decreased formation of mycophenolic acid acyl-glucuronide metabolite.

PubMed

Dostalek, Miroslav; Court, Michael H; Hazarika, Suwagmani; Akhlaghi, Fatemeh

2011-03-01

Mycophenolic acid (MPA) is an immunosuppressive agent commonly used after organ transplantation. Altered concentrations of MPA metabolites have been reported in diabetic kidney transplant recipients, although the reason for this difference is unknown. We aimed to compare MPA biotransformation and UDP-glucuronosyltransferase (UGT) expression and activity between liver (n = 16) and kidney (n = 8) from diabetic and nondiabetic donors. Glucuronidation of MPA, as well as the expression and probe substrate activity of UGTs primarily responsible for MPA phenol glucuronide (MPAG) formation (UGT1A1 and UGT1A9), and MPA acyl glucuronide (AcMPAG) formation (UGT2B7), was characterized. We have found that both diabetic and nondiabetic human liver microsomes and kidney microsomes formed MPAG with similar efficiency; however, AcMPAG formation was significantly lower in diabetic samples. This finding is supported by markedly lower glucuronidation of the UGT2B7 probe zidovudine, UGT2B7 protein, and UGT2B7 mRNA in diabetic tissues. UGT genetic polymorphism did not explain this difference because UGT2B7*2 or *1c genotype were not associated with altered microsomal UGT2B7 protein levels or AcMPAG formation. Furthermore, mRNA expression and probe activities for UGT1A1 or UGT1A9, both forming MPAG but not AcMPAG, were comparable between diabetic and nondiabetic tissues, suggesting the effect may be specific to UGT2B7-mediated AcMPAG formation. These findings suggest that diabetes mellitus is associated with significantly reduced UGT2B7 mRNA expression, protein level, and enzymatic activity of human liver and kidney, explaining in part the relatively low circulating concentrations of AcMPAG in diabetic patients.

Characteristics of pregnancy with human immuno-deficiency virus (HIV) and perinatal transmission in Nakornping Hospital.

PubMed

Gomutbutra, Vorapin

2008-02-01

The HIV infected pregnancy delivered at Nakornping Hospital was common. To reduce and prevent HIV infection in pregnancy and perinatal transmission, the understanding of characteristics of HIV pregnancy and neonatal infective outcome were needed for proper strategy and policy making. To study the characteristics of HIV pregnancy and neonatal infective outcome in a hospital in the northern part of Thailand. This retrospective descriptive study was conducted at the Department of Obstetrics and Gynecology Unit, Nakornping Hospital, Chiang Mai Province, Thailand. Medical records of HIV infected pregnancy from the labor unit during October 2002 and September 2005 was scrutinized. The relevant data of the characteristics of HIV infected mother, pregnancy and neonatal infective outcome were collected and analyzed. There were 172 HIV infected mothers among 7,872 parturients (2.2%). The mean age was 28.2 years (range 14-44 years). Most of the cases were between 25-29 years (40%). 45 pregnancies (26%) delivered before 37 weeks. About half (50.6%) delivered via cesarean section. 22% of their newborn weighted below 2,500 grams. With antiviral regimen of Navirapine and Zidovudine for both mothers and their neonate the overall perinatal transmission rate was 4%. In mothers having ANC group the transmission rate was 3.2% compared to 11.7% in no ANC group. (X2 = 1.092 p = 0.296 Cl 0.04-1.4) RR of ANC group = 0.274 compare to no ANC. Many of HIV infected mothers were in the young age group. High preterm labor rate was observed. The no ANC group had about 4 folds infective neonate compared to the ANC group. No antiviral drug during pregnancy in no ANC group may be a factor. This information was vital for strategic ANC planning to prevent and reduce this problem.

Metabolic effects of protease inhibitor-sparing antiretroviral regimens given as initial treatment of HIV-1 Infection (AIDS Clinical Trials Group Study A5095).

PubMed

Shikuma, Cecilia M; Yang, Yang; Glesby, Marshall J; Meyer, William A; Tashima, Karen T; Ribaudo, Heather J; Webb, Nancy; Bastow, Barbara; Kuritzkes, Daniel R; Gulick, Roy M

2007-04-15

To assess metabolic changes after initiation of protease inhibitor (PI)-sparing regimens in antiretroviral-naive patients. Metabolic changes were analyzed within the triple-nucleoside (zidovudine [ZDV]/lamivudine [3TC]/abacavir [ABC])-containing, 3-drug efavirenz (EFV) [ZDV/3TC + EFV]-containing, and 4-drug EFV [ZDV/3TC/ABC + EFV]-containing arms of the AIDS Clinical Trials Group multicenter trial A5095. Metabolic values were compared with published US general population norms. From week 0 to week 24, all arms exhibited similar mild median increases in glucose and decreases in insulin sensitivity, whereas changes in lipids were greater in the ZDV/3TC + EFV and ZDV/3TC/ABC + EFV arms than in the ZDV/3TC/ABC arm: triglyceride (TG; 7, 18, and -1 mg/dL, respectively), total cholesterol (TC; 23, 28, and 5 mg/dL, respectively), low-density lipoprotein cholesterol (LDL-C; 9, 14, and 1 mg/dL, respectively), and high-density lipoprotein cholesterol (HDL-C; 10, 10, and 5 mg/dL, respectively). Adjusted mean study lipid values of all study participants at week 0 and week 96 compared with those of the National Health and Nutrition Examination Survey (NHANES) 1999 through 2002 values were: TG (148, 187, and 123 mg/dL, respectively), TC (164, 195, and 203 mg/dL, respectively), HDL-C (35, 47, and 51 mg/dL, respectively), and LDL-C (101, 117, and 123 mg/dL, respectively) (P < or = 0.005 for each value vs. NHANES values). Similar mild increases in glucose and decreases in insulin sensitivity were observed in all regimens, whereas lipids were modestly higher in the EFV-containing arms. Compared with general population norms, the metabolic dysfunctions of concern after these PI-sparing therapies were increasingly abnormal TC and lower (but improved relative to baseline) HDL-C levels.

A pilot study to evaluate the safety and feasibility of the administration of AZT/3TC fixed dose combination to HIV infected pregnant women and their infants in Rio de Janeiro, Brazil

PubMed Central

Lambert, J; Nogueira, S; Abreu, T; Machado, E; Costa, T; Bondarovsky, M; Andrade, M; Halpern, M; Barbosa, R; Perez, M

2003-01-01

Objectives: To evaluate the safety and feasibility of zidovudine and lamivudine (AZT/3TC) given to HIV infected pregnant women and their infants in Rio de Janeiro, Brazil. Methods: This open label phase II study enrolled 40 HIV infected antiretroviral naive women ⩾20 weeks gestation, CD4 <500 cells x106/l, from two public hospitals. Treatment: fixed dose AZT 300 mg/3TC 150 mg by mouth every 12 hours until labour; AZT 300 mg by mouth every 3 hours until delivery; infants: AZT 4 mg/kg every 12 hours plus 3TC 2 mg/kg every 12 hours for 6 weeks. Blood haematology and chemistry were monitored; adherence evaluated by pills count; efficacy measured by changes in lymphocyte (CD4) and viral load, and by HIV RNA-PCR tests performed at birth, 6 and 12 weeks, to diagnose infant infection. No women breast fed. Results: Patient characteristics: mean age 24.48 (SD 3.5) years; gestational age 24.5 (4.5) weeks; AZT/3TC duration 14.4 (4.4) weeks; vaginal delivery: 11/39; caesarean section: 28/39. Entry and pre-labour CD4: 310/486 cells x106/l (p<0.001); entry and pre-labour viral load: 53 818/2616 copies/ml (p<0.001). Thirty nine women tolerated treatment with >80% adherence; one was lost to follow up. Five newborns were excluded from 3TC receipt. All 39 babies were uninfected. Haematological toxicity in newborns was common: anaemia in 27; neutropenia in five (two severe); platelets counts <100 000 in two. All values recovered on study completion. Conclusions: Fixed dose AZT/3TC is well accepted, gives improvements in CD4 and viral load; no infants were HIV infected. Haematological toxicity in infants needs careful monitoring. PMID:14663118

Some clinical aspects of HIV infection in Africa.

PubMed

Harries, A

1991-07-01

WHO has estimated the cumulative number of AIDS cases in Africa to have grown from 2978 (1986) to 81,019 (1990). The actual numbers are probably much higher due to under reporting, under diagnosis, and delays in notification. Pathogenicity and clinical features of HIV 2, found mainly in west Africa, are similar to those of HIV 1. 2nd generation HIV-ELISA tests can check for both viruses' antigens. These and other ELISA tests can be used to rapidly identify HIV, but clinical criteria alone can usually determine an accurate diagnosis. In developed countries, AZT (zidovudine) shows some promise of stemming the onset of AIDS in asymptomatic patients. Other promising antiretrovirus drugs are being developed, but are all too expensive for Africa. Almost 33% of HIV positive patients in Africa also have tuberculosis (TB) and, up to 1988, around 40% of TB patients tested HIV positive. In Uganda, Zambia, and Malawi the percentages ranged from 50-65% in TB patients. HIV positive TB patients have a substantial higher mortality than HIV negative TB patients. In some areas of Africa, 66% of AIDS patients have chronic, watery diarrhea and weight loss. The most common pathogens include Cryptosporidium and Isopora belli. Cryptosporidium does not respond to treatment, so there is a concern of a hospital based outbreak in AIDS patients. Cytomegalovirus also causes gastrointestinal illness in African AIDS patients as well as pulmonary disease. Toxoplasma and Cryptococcus often attack the central nervous system of AIDS patients. Oral fluconazole can provide some initial relief from cryptococcal meningitis. Bacteremia is also common. Little evidence exists to suggest an important interaction between HIV and traditional tropical diseases. Unlike Western nations, pneumocystosis and Mycobacterium avium intracellular are uncommon in Africa.

Hematological parameters of human immunodeficiency virus positive pregnant women on antiretroviral therapy in Aminu Kano Teaching Hospital Kano, North Western Nigeria.

PubMed

Abdulqadir, Ibrahim; Ahmed, Sagir Gumel; Kuliya, Aisha Gwarzo; Tukur, Jamilu; Yusuf, Aminu Abba; Musa, Abubakar Umar

2018-01-01

Human immunodeficiency virus (HIV) scourge continues to affect young women within the reproductive age group and pregnancy is a recognized indication for the use antiretroviral (ARV) drugs among HIV-positive women. The aim is to determine the combined effect of pregnancy, HIV and ARV drugs on the hematological parameters of the pregnant women. This was a comparative cross-sectional study conducted among 70 each of HIV-positive and negative pregnant women. Bio-demographic and clinical data were extracted from the client folder and 4 ml of blood sample was obtained from each participant. Full blood count was generated using Swelab automatic hematology analyzer while reticulocyte count and erythrocyte sedimentation rate (ESR) were conducted manually. Data analysis was performed using SPSS version software 16 while P < 0.05 was considered statistically significant. Pregnant women with HIV had statistically significant lower hematocrit and white blood cell (WBC) and higher ESR than pregnant women without HIV ( P < 0.000). There was no statistically significant difference between the two groups in terms of platelet and reticulocyte ( P > 0.05). However, among HIV positive pregnant women, those with CD4 count <350/μL had statistically significant lower WBC and lymphocyte count than those with CD4 count ≥350/μL ( P < 0.05), whereas, those on zidovudine (AZT)-containing treatment had statistically significant lower hematocrit and higher mean cell volume than those on non-AZT-containing treatment ( P < 0.05), but there was no statistically significant difference in any of the hematological parameters ( P > 0.050) between women on first- and second-line ARV regimens. There is a significant difference in terms of hematological parameters between HIV-positive and HIV-negative pregnant women in this environment.

Previous antiretroviral therapy for prevention of mother-to-child transmission of HIV does not hamper the initial response to PI-based multitherapy during subsequent pregnancy.

PubMed

Briand, Nelly; Mandelbrot, Laurent; Blanche, Stéphane; Tubiana, Roland; Faye, Albert; Dollfus, Catherine; Le Chenadec, Jérôme; Benhammou, Valérie; Rouzioux, Christine; Warszawski, Josiane

2011-06-01

Few data are available on the possible long-term negative effects of a short exposure to antiretroviral therapy (ART) for prevention of mother-to-child transmission (PMTCT). To determine whether ART for PMTCT, discontinued after delivery, affects the virological response to highly active antiretroviral therapy (HAART) administered during subsequent pregnancies. All current pregnancies of HIV-1-infected women enrolled in the French Perinatal Cohort (ANRS CO-01 EPF) between 2005 and 2009 and not receiving ART at the time of conception were eligible. We studied the association between history of exposure to ART during a previous pregnancy and detectable viral load (VL) under multitherapy at current delivery (VL ≥ 50 copies/mL). Among 1116 eligible women, 869 were ART naive and 247 had received PMTCT during a previous pregnancy. Previous ART was protease inhibitor (PI)-based HAART in 48%, non-PI-based HAART in 4%, nucleoside reverse transcriptase inhibitor bitherapy in 19% and zidovudine monotherapy in 29% of the women. At current pregnancy, women with or without prior exposure to ART had similar CD4 cell counts and VL before ART initiation. PI-based HAART was initiated in 90% of the women. VL was undetectable (<50 copies/mL) at delivery in 65% of previously ART-naive women, 72% of women previously exposed to HAART, 62% previously exposed to bitherapy, and 67% previously exposed to monotherapy for prophylaxis (P = 0.42). Detectable VL was not associated with previous exposure in multivariate analysis (adjusted OR for previous versus no previous exposure to ART: 0.92; 0.95% confidence interval: 0.59 to 1.44). Efficacy of PI-based combinations is not decreased in women previously exposed to various regimens of antiretroviral PMTCT.

Effect of gender and race on the week 48 findings in treatment-naïve, HIV-1-infected patients enrolled in the randomized, phase III trials ECHO and THRIVE.

PubMed

Hodder, S; Arasteh, K; De Wet, J; Gathe, J; Gold, J; Kumar, P; Mohapi, L; Short, W; Crauwels, H; Vanveggel, S; Boven, K

2012-08-01

A week 48 efficacy and safety analysis with respect to gender and race was conducted using pooled data from the phase III, double-blind, double-dummy efficacy comparison in treatment-naïve, HIV-infected subjects of TMC278 and efavirenz (ECHO) and TMC278 against HIV, in a once-daily regimen versus efavirenz (THRIVE) trials. Treatment-naïve, HIV-1-infected adults were randomized to receive rilpivirine (RPV; TMC278) 25 mg once a day (qd), or efavirenz (EFV) 600 mg qd, plus tenofovir/emtricitabine (ECHO) or tenofovir/emtricitabine, zidovudine/lamivudine or abacavir/lamivudine (THRIVE). A total of 1368 participants (76% male and 61% White, of those with available race data) were randomized and treated. No gender-related differences in response rate (percentage of patients with HIV-1 viral load < 50 HIV-1 RNA copies/mL, using an intent-to-treat, time-to-loss-of-virological-response algorithm) were observed (RPV: men, 85%; women, 83%; EFV: men, 82%; women, 83%). Response rates were lower in Black compared with Asian and White participants (RPV: 75% vs. 95% and 85%, respectively; EFV: 74% vs. 93% and 83%, respectively); this finding was mostly a result of higher discontinuation and virological failure rates in Black patients. Safety findings were generally similar across race and gender subgroups. However, nausea occurred more commonly in women than in men in both treatment groups. In men, diarrhoea was more frequent in the EFV group, and abnormal dreams/nightmares were more frequent in men in both the EFV and RPV groups. Overall response rates were high for both RPV and EFV. No gender differences were observed. However, response rates were lower among Black patients, regardless of treatment group. Gender appeared to influence the incidence of gastrointestinal adverse events and abnormal dreams/nightmares for both treatments. © 2012 British HIV Association.

Impact of expanded access to combination antiretroviral therapy in pregnancy: results from a cohort study in Ukraine

PubMed Central

Bailey, Heather; Townsend, Claire L; Semenenko, Igor; Malyuta, Ruslan; Cortina-Borja, Mario

2013-01-01

Abstract Objective To investigate the scale-up of antenatal combination antiretroviral therapy (cART) in Ukraine since this became part of the national policy for the prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV). Methods Data on 3535 HIV-positive pregnant women who were enrolled into the Ukraine European Collaborative Study in 2008–2010 were analysed. Factors associated with receipt of zidovudine monotherapy (AZTm) – rather than cART – and rates of mother-to-child transmission (MTCT) of HIV were investigated. Findings cART coverage increased significantly, from 22% of deliveries in 2008 to 61% of those in 2010. After adjusting for possible confounders, initiation of antenatal AZTm – rather than cART – was associated with cohabiting (versus being married; adjusted prevalence ratio, aPR: 1.09; 95% confidence interval, CI: 1.02–1.16), at least two previous live births (versus none; aPR: 1.22; 95% CI: 1.11–1.35) and a diagnosis of HIV infection during the first or second trimester (versus before pregnancy; aPR: 1.11; 95% CI: 1.03–1.20). The overall MTCT rate was 4.1% (95% CI: 3.4–4.9); 42% (49/116) of the transmissions were from the 8% (n = 238) of women without antenatal ART. Compared with AZTm, cART was associated with a 70% greater reduction in the risk of MTCT (adjusted odds ratio: 0.30; 95% CI: 0.16–0.56). Conclusion Between 2008 and 2010, access to antenatal cART improved substantially in Ukraine, but implementation of the World Health Organization’s Option-B policy was slow. For MTCT to be eliminated in Ukraine, improvements in the retention of women in HIV care and further roll-out of Option B are urgently needed. PMID:23825876

Impact of expanded access to combination antiretroviral therapy in pregnancy: results from a cohort study in Ukraine.

PubMed

Bailey, Heather; Townsend, Claire L; Semenenko, Igor; Malyuta, Ruslan; Cortina-Borja, Mario; Thorne, Claire

2013-07-01

To investigate the scale-up of antenatal combination antiretroviral therapy (cART) in Ukraine since this became part of the national policy for the prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV). Data on 3535 HIV-positive pregnant women who were enrolled into the Ukraine European Collaborative Study in 2008-2010 were analysed. Factors associated with receipt of zidovudine monotherapy (AZTm) - rather than cART - and rates of mother-to-child transmission (MTCT) of HIV were investigated. cART coverage increased significantly, from 22% of deliveries in 2008 to 61% of those in 2010. After adjusting for possible confounders, initiation of antenatal AZTm - rather than cART - was associated with cohabiting (versus being married; adjusted prevalence ratio, aPR: 1.09; 95% confidence interval, CI: 1.02-1.16), at least two previous live births (versus none; aPR: 1.22; 95% CI: 1.11-1.35) and a diagnosis of HIV infection during the first or second trimester (versus before pregnancy; aPR: 1.11; 95% CI: 1.03-1.20). The overall MTCT rate was 4.1% (95% CI: 3.4-4.9); 42% (49/116) of the transmissions were from the 8% (n = 238) of women without antenatal ART. Compared with AZTm, cART was associated with a 70% greater reduction in the risk of MTCT (adjusted odds ratio: 0.30; 95% CI: 0.16-0.56). Between 2008 and 2010, access to antenatal cART improved substantially in Ukraine, but implementation of the World Health Organization's Option-B policy was slow. For MTCT to be eliminated in Ukraine, improvements in the retention of women in HIV care and further roll-out of Option B are urgently needed.

Heart Mitochondrial TTP Synthesis and the Compartmentalization of TMP*

PubMed Central

Kamath, Vasudeva G.; Hsiung, Chia-Heng; Lizenby, Zachary J.; McKee, Edward E.

2015-01-01

The primary pathway of TTP synthesis in the heart requires thymidine salvage by mitochondrial thymidine kinase 2 (TK2). However, the compartmentalization of this pathway and the transport of thymidine nucleotides are not well understood. We investigated the metabolism of [3H]thymidine or [3H]TMP as precursors of [3H]TTP in isolated intact or broken mitochondria from the rat heart. The results demonstrated that [3H]thymidine was readily metabolized by the mitochondrial salvage enzymes to TTP in intact mitochondria. The equivalent addition of [3H]TMP produced far less [3H]TTP than the amount observed with [3H]thymidine as the precursor. Using zidovudine to inhibit TK2, the synthesis of [3H]TTP from [3H]TMP was effectively blocked, demonstrating that synthesis of [3H]TTP from [3H]TMP arose solely from the dephosphorysynthase pathway that includes deoxyuridine triphosphatelation of [3H]TMP to [3H]thymidine. To determine the role of the membrane in TMP metabolism, mitochondrial membranes were disrupted by freezing and thawing. In broken mitochondria, [3H]thymidine was readily converted to [3H]TMP, but further phosphorylation was prevented even though the energy charge was well maintained by addition of oligomycin A, phosphocreatine, and creatine phosphokinase. The failure to synthesize TTP in broken mitochondria was not related to a loss of membrane potential or inhibition of the electron transport chain, as confirmed by addition of carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone and potassium cyanide, respectively, in intact mitochondria. In summary, these data, taken together, suggest that the thymidine salvage pathway is compartmentalized so that TMP kinase prefers TMP synthesized by TK2 over medium TMP and that this is disrupted in broken mitochondria. PMID:25505243

New strategies for lowering the costs of antiretroviral treatment and care for people with HIV/AIDS in the United Kingdom

PubMed Central

Gazzard, Brian; Moecklinghoff, Christiane; Hill, Andrew

2012-01-01

In the UK, the annual cost of treatment and care for people with human immunodeficiency virus (HIV)/acquired immune deficiency virus (AIDS) rose by over 600% from £104 million in 1997 to £762 million in 2010; approximately two-thirds of the £762 million cost of treatment and care in 2010 was for the procurement of antiretrovirals and other related drugs. The number of people accessing care for HIV/AIDS rose from 22,000 in 2000 to 65,000 in 2009. Adoption of “test and treat” guidelines for treating all HIV-infected people with antiretrovirals would further increase the burden of costs. Given the current economic situation, there is now a new focus on strategies for treatment and care of people with HIV-1 infection which can maintain efficacy but at a lower cost. In this review, we propose three strategies which could potentially lower the costs of treatment and care, ie, stopping testing CD4 counts for patients with full HIV RNA suppression on antiretroviral treatment and recent CD4 counts above 350 cells/μL; more widespread use of generic antiretrovirals as replacements for patients currently taking patented versions; and use of darunavir-ritonavir monotherapy as a switch option for patients with full HIV RNA suppression on other antiretrovirals and no history of virological failure. However, it is important that high standards of clinical care are maintained despite cost-saving measures. Antiretrovirals with generic alternatives may have toxicity issues, eg, zidovudine and nevirapine. There could be ethical issues in starting patients on these drugs if they are currently tolerating other treatments. The use of darunavir-ritonavir monotherapy is not consistently recommended in international HIV treatment guidelines. PMID:22888265

Metabolic health across the BMI spectrum in HIV-infected and HIV-uninfected men.

PubMed

Lake, Jordan E; Li, Xiuhong; Palella, Frank J; Erlandson, Kristine M; Wiley, Dorothy; Kingsley, Lawrence; Jacobson, Lisa P; Brown, Todd T

2018-01-02

In the general population, metabolic health often declines as BMI increases. However, some obese individuals maintain metabolic health. HIV and antiretroviral therapy have been associated with metabolic disturbances. We hypothesized that HIV-infected (HIV) men on suppressive antiretroviral therapy experience less metabolic health than HIV-uninfected (HIV) men across all BMI categories. In a cross-sectional analysis of 1018 HIV and 1092 HIV men enrolled in the multicenter AIDS cohort study, Poisson regression with robust variance determined associations between HIV serostatus and metabolic health prevalence (defined as meeting ≤2 of 5 National Cholesterol Education Program Adult Treatment Panel III metabolic syndrome criteria), adjusting for age, race, BMI category, smoking, and hepatitis C virus infection status. HIV men were younger (54 vs. 59 years) and had lower median BMI (25 vs. 27 kg/m). Nonobese HIV men had lower metabolic health prevalence than HIV men (BMI ≤25 kg/m: 80 vs. 94%, P < 0.001; BMI 25-29 kg/m: 64 vs. 71%, P = 0.05), but metabolic health prevalence among obese men did not differ by HIV serostatus (BMI 30-34 kg/m: 35 vs. 39%, P = 0.48; BMI ≥35 kg/m: 27 vs. 25%, P = 0.79). In the adjusted model, nonobese HIV men were less likely to demonstrate metabolic health than nonobese HIV men. Among HIV men, per year darunavir, zidovudine, and stavudine use were associated with lower metabolic health likelihood. Metabolically healthy obesity prevalence does not differ by HIV serostatus. However, among nonobese men, HIV infection is associated with lower metabolic health prevalence, with associations between lack of metabolic health and darunavir and thymidine analog nucleoside reverse transcriptase inhibitor exposure observed.

Predictors of Persistent Anaemia in the First Year of Antiretroviral Therapy: A Retrospective Cohort Study from Goma, the Democratic Republic of Congo.

PubMed

Akilimali, Pierre Zalagile; Kashala-Abotnes, Espérance; Musumari, Patou Masika; Kayembe, Patrick Kalambayi; Tylleskar, Thorkild; Mapatano, Mala Ali

2015-01-01

Anaemia is associated with adverse outcomes including early death in the first year of antiretroviral therapy (ART). This study reports on the factors associated with persistent anaemia among HIV-infected patients initiating ART in the Democratic Republic of Congo (DR Congo). We conducted a retrospective cohort study and analyzed data from patients receiving HIV care between January 2004 and December 2012 at two major hospitals in Goma, DR Congo. Haemoglobin concentrations of all patients on ART regimen were obtained prior to and within one year of ART initiation. A logistic regression model was used to identify the predictors of persistent anaemia after 12 months of ART. Of 756 patients, 69% of patients were anaemic (IC95%: 65.7-72.3) at baseline. After 12 months of follow up, there was a 1.2 g/dl average increase of haemoglobin concentration (P < 0.001) with differences depending on the therapeutic regimen. Patients who received zidovudine (AZT) gained less than those who did not receive AZT (0.99 g/dl vs 1.33 g/dl; p< 0.001). Among 445 patient who had anaemia at the beginning, 33% (147/445) had the condition resolved. Among patients with anaemia at ART initiation, those who did not receive cotrimoxazole prophylaxis before starting ART(AOR 3.89; 95% CI 2.09-7.25; P < 0.001) and a AZT initial regimen (AOR 2.19; 95% CI 1.36-3.52; P < 0.001) were significantly at risk of persistent anaemia. More than two thirds of patients had anaemia at baseline. The AZT-containing regimen and absence of cotrimoxazole prophylaxis before starting ART were associated with persistent anaemia 12 months, after initiation of treatment. Considering the large proportion of patients with persistence of anaemia at 12 months, we suggest that it is necessary to conduct a large study to assess anaemia among HIV-infected patients in Goma.

Reassuring Birth Outcomes With Tenofovir/Emtricitabine/Efavirenz Used for Prevention of Mother-to-Child Transmission of HIV in Botswana.

PubMed

Zash, Rebecca; Souda, Sajini; Chen, Jennifer Y; Binda, Kelebogile; Dryden-Peterson, Scott; Lockman, Shahin; Mmalane, Mompati; Makhema, Joseph; Essex, Max; Shapiro, Roger

2016-04-01

Before introduction of tenofovir/emtricitabine/efavirenz (TDF/FTC/EFV), 3-drug antiretroviral therapy (ART) was associated with increased adverse birth outcomes when used for prevention of mother-to-child HIV transmission (PMTCT) in Botswana. We extracted obstetric records from all women at the 2 largest maternities in Botswana from 2009-2011 when Botswana National Guidelines recommended zidovudine (ZDV) from 28 weeks gestational age (GA) for CD4 ≥350 and ART for CD4 <350, and again in 2013-2014 after implementation of TDF/FTC/EFV for prevention of mother-to-child HIV transmission regardless of CD4 or GA. We compared the use of TDF/FTC/EFV in pregnancy with other 3-drug ART regimens, and with initiation of ZDV, among women with similar CD4 cell counts. Outcomes included small for gestational age (SGA), preterm delivery (PTD) (<37 weeks GA), and stillbirths (SB). Among 9445 HIV-infected women delivering during the study period, 170 were on TDF/FTC/EFV at conception and 1468 initiated TDF/FTC/EFV during pregnancy. Adverse birth outcomes were high overall (3% SB, 21% PTD, and 18% SGA) and among women receiving TDF/FTC/EFV (3% SB, 22% PTD, and 12% SGA). There was no difference in PTD or SB among women initiating TDF/FTC/EFV compared with ZDV or other 3-drug ART, but initiating TDF/FTC/EFV was associated with fewer SGA infants than other 3-drug ART (adjusted odds ratio: 0.4, 95% confidence interval: 0.2 to 0.7). Adverse birth outcomes remain high among HIV-infected women. TDF/FTC/EFV was at least as safe as other ART and associated with fewer SGA infants when initiated during pregnancy. Larger studies are needed to evaluate birth outcomes and congenital abnormalities among women on TDF/FTC/EFV at conception.

Raltegravir versus lopinavir/ritonavir for treatment of HIV-infected late-presenting pregnant women.

PubMed

Brites, Carlos; Nóbrega, Isabella; Luz, Estela; Travassos, Ana Gabriela; Lorenzo, Cynthia; Netto, Eduardo M

2018-06-01

Background Late-presenting pregnant women pose a challenge in the prevention of HIV-1 mother-to-child-transmission. We compared the safety and efficacy of raltegravir and lopinavir/ritonavir for this population. Methods We did a single-center, pilot, open-label, randomized trial in Brazil (N = 44). We randomly allocated late-presenting HIV-infected pregnant women (older than 18 years with a plasma HIV-1 RNA >1000 copies/mL) to receive raltegravir 400 mg twice a day or lopinavir/ritonavir 400/100 mg twice a day plus zidovudine and lamivudine (1:1). The primary endpoint was virological suppression at delivery (HIV-1 RNA <50 copies per mL), in all patients who received at least one dose of study drugs (modified intention-to-treat analysis). Missing information was treated as failure. We assessed safety in all patients. Results We enrolled and randomly assigned treatment to 33 patients (17 in raltegravir group) between June 2015 and June 2017. The study was interrupted by the IRB because a significant difference between arms was detected in an interim analysis. All patients completed follow up at delivery. At delivery, virological suppression was achieved by 13/17 (76.5%) of patients in raltegravir group, versus 4/16 (25.0%) in lopinavir/ritonavir group (RR 3.1, 95% CI: 1.3-7.4). Patients in raltegravir group had significantly higher proportion of virological suppression at 2, 4, and 6 weeks than lopinavir/ritonavir group. Adverse events were most of mild intensity, but patients in lopinavir/ritonavir group had significantly more gastrointestinal adverse events. There was neither discontinuation nor deaths in this trial. Conclusion Raltegravir might be a first-line option for treatment of HIV-infected late-presenting pregnant women.

Hollow mesoporous structured molecularly imprinted polymer as adsorbent in pipette-tip solid-phase extraction for the determination of antiretrovirals from plasma of HIV-infected patients.

PubMed

Simões, Nathália Soares; de Oliveira, Hanna Leijoto; da Silva, Ricky Cássio Santos; Teixeira, Leila Suleimara; Sales, Thaís Lorenna Souza; de Castro, Whocely Victor; de Paiva, Maria José Nunes; Sanches, Cristina; Borges, Keyller Bastos

2018-05-17

In this work a hollow mesoporous structured molecularly imprinted polymer was synthetized and used as adsorbent in pipette-tip solid-phase extraction for the determination of lamivudine (3TC), zidovudine (AZT) and efavirenz (EFZ) from plasma of human immunodeficiency virus (HIV) infected patients by high-performance liquid chromatography (HPLC). All parameters that influence the recovery of the pipette tip based on hollow mesoporous molecularly imprinted polymer solid-phase extraction (PT-HM-MIP-SPE) method were systematically studied and discussed in detail. The adsorbent material was prepared using methacrylic acid and 4-vinylpyridine as functional monomers, ethylene glycol dimethacrylate as crosslinker, acetonitrile as solvent, 4,4'-azobis(4-cyanovaleric acid) as radical initiator, benzalkonium chloride as surfactant), 3TC, and AZT as templates. The simultaneous separation of 3TC, AZT and EFZ by HPLC-UV was performed using a Gemini C18 Phenomenexࣨ column (250 mm × 4.6 mm, 5 μm) and mobile phase consisting of acetonitrile: water pH 3.2 (68:32, v/v), flow rate of 1.0 mL min -1 and λ = 260 nm. The method was linear over the concentration range from 0.25 to 10 μg mL -1 for 3TC and EFZ, and 0.05 to 2.0 μg mL -1 for AZT, with correlation coefficients larger than 0.99 for all analytes. Recovery ± relative standard deviations (RSDs %) were 41.99±2.38 %, 82.29±1.63 %, and 83.72±7.52 % for 3TC, AZT, and EFZ, respectively. The RSDs and relative errors (REs) were lower than 15 % for intra and interday assays. The method has been successfully applied for monitoring HIV-infected patients outside the therapeutic dosage.2 This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Long-term exposure of mice to nucleoside analogues disrupts mitochondrial DNA maintenance in cortical neurons.

PubMed

Zhang, Yulin; Song, Fengli; Gao, Ziyun; Ding, Wei; Qiao, Luxin; Yang, Sufang; Chen, Xi; Jin, Ronghua; Chen, Dexi

2014-01-01

Nucleoside analogue reverse transcriptase inhibitor (NRTI), an integral component of highly active antiretroviral therapy (HAART), was widely used to inhibit HIV replication. Long-term exposure to NRTIs can result in mitochondrial toxicity which manifests as lipoatrophy, lactic acidosis, cardiomyopathy and myopathy, as well as polyneuropathy. But the cerebral neurotoxicity of NRTIs is still not well known partly due to the restriction of blood-brain barrier (BBB) and the complex microenvironment of the central nervous system (CNS). In this study, the Balb/c mice were administered 50 mg/kg stavudine (D4T), 100 mg/kg zidovudine (AZT), 50 mg/kg lamivudine (3TC) or 50 mg/kg didanosine (DDI) per day by intraperitoneal injection, five days per week for one or four months, and primary cortical neurons were cultured and exposed to 25 µM D4T, 50 µM AZT, 25 µM 3TC or 25 µM DDI for seven days. Then, single neuron was captured from mouse cerebral cortical tissues by laser capture microdissection. Mitochondrial DNA (mtDNA) levels of the primary cultured cortical neurons, and captured neurons or glial cells, and the tissues of brains and livers and muscles were analyzed by relative quantitative real-time PCR. The data showed that mtDNA did not lose in both NRTIs exposed cultured neurons and one month NRTIs treated mouse brains. In four months NRTIs treated mice, brain mtDNA levels remained unchanged even if the mtDNA levels of liver (except for 3TC) and muscle significantly decreased. However, mtDNA deletion was significantly higher in the captured neurons from mtDNA unchanged brains. These results suggest that long-term exposure to NRTIs can result in mtDNA deletion in mouse cortical neurons.

Short-term in vivo modifications of platelet NADPH oxidase 2 (NOX2) and prostaglandin F2α in HIV-1 patients on abacavir-based therapies.

PubMed

Pastori, D; Esposito, A; Carnevale, R; Bartimoccia, S; Nocella, C; Fantauzzi, A; Pignatelli, P; Violi, F; Mezzaroma, I

2016-11-01

The aim of the study was to investigate the in vivo effect of abacavir (ABC) on platelet oxidative stress. We performed a randomized pilot study including 39 HIV-1-infected patients, 17 on zidovudine/lamivudine (ZDV/3TC) and 22 on tenofovir/emtricitabine (TDF/FTC). Ten patients on ZDV/3TC and eight patients on TDF/FTC were randomly allocated to switching the nucleoside backbone to ABC/3TC. At baseline and after 6 months, platelet oxidative stress was assessed by platelet NADPH oxidase 2 (NOX2)-derived peptide (sNOX2-dp), a marker of NOX2 activation, and platelet prostaglandin F 2α (8-iso-PGF 2α ). Platelet activation was measured by soluble CD40L (sCD40L). At baseline, no differences between ZDV/3TC or TDF/FTC recipients were found. After 6 months, patients switching from ZDV/3TC showed a decrease of sNOX2-dp (from 20.9±5.7 to 12.5±3.8 pg/ml, p=0.002) and 8-iso-PGF 2α (from 154.3±41.9 to 122.9±28.0 pmol/l, p=0.025). No effects on platelet oxidative stress biomarkers were observed in subjects from TDF/FTC, who showed a significant increase in blood glucose (p=0.043) and total cholesterol (p=0.027). ABC showed no effect on sCD40L levels in both groups. ABC reduced platelet sNOX2-dp and 8-iso-PGF 2α in HIV-1 subjects switching from ZDV/3TC but not in those from TDF/FTC after 6 months. No changes in platelet activation were found in both groups. © 2016 British HIV Association.

Short communication: initiation of an abacavir-containing regimen in HIV-infected adults is associated with a smaller decrease in inflammation and endothelial activation markers compared to non-abacavir-containing regimens.

PubMed

Hileman, Corrilynn O; Wohl, David A; Tisch, Daniel J; Debanne, Sara M; McComsey, Grace A

2012-12-01

Abacavir has been associated with myocardial infarction in several studies. This may be related to inflammation and endothelial cell activation. We compared changes in inflammation and endothelial activation markers between antiretroviral-naive adults initiating zidovudine, lamivudine, abacavir, and nonnucleoside reverse transcriptase inhibitor (NNRTI) or this regimen without abacavir. Changes in soluble tumor necrosis factor receptors-I, -II (sTNFR-I, -II), high sensitivity C-reactive protein, and soluble vascular cell adhesion molecule-1 (sVCAM-1) from baseline (pre-ART) to a second time point about 24 weeks after initiating antiretroviral therapy (ART) were compared between groups using multivariable linear regression. A total of 37 met eligibility criteria; 12 received abacavir. The median (interquartile range) age was 37 years (27-45). Most were men (32/37), African-American (15/37), or white (15/37). The median nadir CD4(+) and baseline HIV-1 RNA were 230 cells/mm(3) (180-301) and 82,642 copies/ml (34,400-204,703). In all, 15/30 smoked, 7/37 had hypertension, 1/37 had diabetes, and 1/37 had hyperlipidemia. None had coronary or renal disease. Changes in CD4(+) and HIV-1 RNA level and timing of stored samples with regard to ART initiation were not different between groups. In univariable analysis, log transformed percent change in sTNFR-I (p=0.05) and -II (p=0.04) showed significant between-group differences and trended toward significance for sVCAM-1 (p=0.08). These markers decreased less in the abacavir group. After adjustment for confounders, significantly less decrease for sTNFR-II and sVCAM-1 was seen for those receiving the abacavir-containing regimen. When taken with an NNRTI, abacavir induced a smaller decrease in inflammation biomarkers in this cohort, suggesting a possible proinflammatory effect of this nucleoside analogue.

Comparison of cardiovascular disease risk markers in HIV-infected patients receiving abacavir and tenofovir: the nucleoside inflammation, coagulation and endothelial function (NICE) study

PubMed Central

Wohl, David A; Arnoczy, Gretchen; Fichtenbaum, Carl J; Campbell, Thomas; Taiwo, Babafemi; Hicks, Charles; McComsey, Grace A; Koletar, Susan; Sax, Paul; Tebas, Pablo; Ha, Belinda; Massengale, Kelly; Walsh, Kendall; Stein, James H

2015-01-01

Background The association between abacavir (ABC) and cardiovascular disease (CVD) risk in HIV-infected individuals is unclear. Putative mechanisms for an effect of ABC on CVD risk including endothelial dysfunction have been proposed; however, a biological mechanism has not been established. Methods This was a cross-sectional study of HIV-infected subjects with HIV RNA levels <400 copies/ml, who were randomly assigned to ABC or tenofovir (TDF) as initial therapy during a prior clinical trial. A small cohort of subjects on zidovudine (AZT; not randomly assigned) were studied to explore long-term exposure to this agent. All underwent brachial artery ultrasound for flow-mediated dilation (FMD), and D-dimer, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and fasting lipids were measured. Between-arm differences were evaluated by multivariable linear or logistic regression modelling. Results There were 148 subjects (46 on ABC, 72 on TDF and 30 on AZT). Demographic characteristics were balanced across the groups except, as expected, AZT-treated participants were older, had higher CD4+ T-cell counts, and longer antiretroviral therapy duration. After adjusting for age, brachial artery diameter, and treatment duration, FMD was similar in those on ABC (3.9%) and TDF (5.4%; P=0.181). FMD was higher in those on AZT (6.1%; P<0.005). Levels of IL-6, hsCRP and detectable D-dimer were similar between groups. Conclusions Among individuals assigned to ABC or TDF in randomized clinical trials there were no significant differences in FMD or markers of inflammation and coagulation. Whether ABC contributes to risk of CVD remains unclear, but our results suggest that endothelial dysfunction, heightened inflammation, and altered coagulation are unlikely to be mechanisms by which the drug could increase CVD risk above that seen with TDF. PMID:23985706

Determinants of virological outcome and adverse events in African children treated with paediatric nevirapine fixed-dose-combination tablets

PubMed Central

BIENCZAK, Andrzej; DENTI, Paolo; Adrian, COOK; WIESNER, Lubbe; MULENGA, Veronica; KITYO, Cissy; KEKITIINWA, Addy; GIBB, Diana M.; BURGER, David; WALKER, A. Sarah; MCILLERON, Helen

2017-01-01

Background Nevirapine is the only non-nucleoside reverse transcriptase inhibitor currently available as a paediatric fixed-dose combination tablet and is widely used in African children. Nonetheless, the number of investigations into pharmacokinetic determinants of virological suppression in African children is limited and the predictive power of the current therapeutic range was never evaluated in this population, thereby limiting treatment optimisation. Methods We analysed data from 322 African children (aged 0.3–13 years) treated with nevirapine, lamivudine, and either abacavir, stavudine, or zidovudine, and followed up to 144 weeks. Nevirapine trough concentration (Cmin) and other factors were tested for associations with viral load (VL)>100 copies/mL and transaminase increases >grade 1 using proportional hazard and logistic models in 219 initially antiretroviral treatment(ART)-naïve children. Results Pre-ART VL, adherence, and nevirapine Cmin were associated with VL non-suppression (hazard-ratio [HR]=2.08 [95% CI: 1.50–2.90, p<0.001] for 10-fold higher pre-ART VL, HR=0.78 [95% CI: 0.68–0.90, p<0.001] for 10% improvement in adherence and HR=0.94 [95% CI: 0.90–0.99, p=0.014] for a 1mg/L increase in nevirapine Cmin). There were additional effects of pre-ART CD4% and clinical site. The risk of virological non-suppression decreased with increasing nevirapine Cmin and there was no clear Cmin threshold predictive of virological non-suppression. Transient transaminase elevations >grade 1 were associated with high Cmin (>12.4 mg/L), HR=5.18 (95%CI 1.95–13.80, p<0.001). Conclusions Treatment initiation at lower pre-ART VL and higher pre-ART CD4%, increased adherence, and maintaining average Cmin higher than current target could improve virological suppression of African children treated with nevirapine without increasing toxicity. PMID:28060017

Improved Neuropsychological and Neurological Functioning Across Three Antiretroviral Regimens in Diverse Resource-Limited Settings: AIDS Clinical Trials Group Study A5199, the International Neurological Study

PubMed Central

Robertson, K.; Jiang, H.; Kumwenda, J.; Supparatpinyo, K.; Evans, S.; Campbell, T. B.; Price, R.; Tripathy, S.; Kumarasamy, N.; La Rosa, A.; Santos, B.; Silva, M. T.; Montano, S.; Kanyama, C.; Faesen, S.; Murphy, R.; Hall, C.; Marra, C. M.; Marcus, C.; Berzins, B.; Allen, R.; Housseinipour, M.; Amod, F.; Sanne, I.; Hakim, J.; Walawander, A.; Nair, A.

2012-01-01

Background. AIDS Clinical Trials Group (ACTG) A5199 compared the neurological and neuropsychological (NP) effects of 3 antiretroviral regimens in participants infected with human immunodeficiency virus type 1 (HIV-1) in resource-limited settings. Methods. Participants from Brazil, India, Malawi, Peru, South Africa, Thailand, and Zimbabwe were randomized to 3 antiretroviral treatment arms: A (lamivudine-zidovudine plus efavirenz, n = 289), B (atazanavir, emtricitabine, and didanosine-EC, n = 293), and C (emtricitabine-tenofovir-disoproxil fumarate plus efavirenz, n = 278) as part of the ACTG PEARLS study (A5175). Standardized neurological and neuropsychological (NP) screening examinations (grooved pegboard, timed gait, semantic verbal fluency, and finger tapping) were administered every 24 weeks from February 2006 to May 2010. Associations with neurological and neuropsychological function were estimated from linear and logistic regression models using generalized estimating equations. Results. The median weeks on study was 168 (Q1 = 96, Q3 = 192) for the 860 participants. NP test scores improved (P < .05) with the exception of semantic verbal fluency. No differences in neurological and neuropsychological functioning between treatment regimens were detected (P > .10). Significant country effects were noted on all NP tests and neurological outcomes (P < .01). Conclusions. The study detected no significant differences in neuropsychological and neurological outcomes between randomized ART regimens. Significant improvement occurred in neurocognitive and neurological functioning over time after initiation of ARTs. The etiology of these improvements is likely multifactorial, reflecting reduced central nervous system HIV infection, better general health, and practice effects. This study suggests that treatment with either of the World Health Organization –recommended first-line antiretroviral regimens in resource-limited settings will improve

Unnecessary antiretroviral treatment switches and accumulation of HIV resistance mutations; two arguments for viral load monitoring in Africa.

PubMed

Sigaloff, Kim C E; Hamers, Raph L; Wallis, Carole L; Kityo, Cissy; Siwale, Margaret; Ive, Prudence; Botes, Mariette E; Mandaliya, Kishor; Wellington, Maureen; Osibogun, Akin; Stevens, Wendy S; van Vugt, Michèle; de Wit, Tobias F Rinke

2011-09-01

This study aimed to investigate the consequences of using clinicoimmunological criteria to detect antiretroviral treatment (ART) failure and guide regimen switches in HIV-infected adults in sub-Saharan Africa. Frequencies of unnecessary switches, patterns of HIV drug resistance, and risk factors for the accumulation of nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations were evaluated. Cross-sectional analysis of adults switching ART regimens at 13 clinical sites in 6 African countries was performed. Two types of failure identification were compared: diagnosis of clinicoimmunological failure without viral load testing (CIF only) or CIF with local targeted viral load testing (targeted VL). After study enrollment, reference HIV RNA and genotype were determined retrospectively. Logistic regression assessed factors associated with multiple thymidine analogue mutations (TAMs) and NRTI cross-resistance (≥2 TAMs or Q151M or K65R/K70E). Of 250 patients with CIF switching to second-line ART, targeted VL was performed in 186. Unnecessary switch at reference HIV RNA <1000 copies per milliliter occurred in 46.9% of CIF only patients versus 12.4% of patients with targeted VL (P < 0.001). NRTI cross-resistance was observed in 48.0% of 183 specimens available for genotypic analysis, comprising ≥2 TAMs (37.7%), K65R (7.1%), K70E (3.3%), or Q151M (3.3%). The presence of NRTI cross-resistance was associated with the duration of ART exposure and zidovudine use. Clinicoimmunological monitoring without viral load testing resulted in frequent unnecessary regimen switches. Prolonged treatment failure was indicated by extensive NRTI cross-resistance. Access to virological monitoring should be expanded to prevent inappropriate switches, enable early failure detection and preserve second-line treatment options in Africa.

Novel mutation in the human immunodeficiency virus type 1 reverse transcriptase gene that encodes cross-resistance to 2',3'-dideoxyinosine and 2',3'-dideoxycytidine.

PubMed Central

Gu, Z; Gao, Q; Li, X; Parniak, M A; Wainberg, M A

1992-01-01

We have used the technique of in vitro selection to generate variants of human immunodeficiency virus type 1 (HIV-1) that are resistant to 2',3'-dideoxyinosine (ddI) and cross-resistant to 2',3'-dideoxycytidine (ddC). The complete reverse transcriptase (RT)-coding regions, plus portions of flanking sequences, of viruses possessing a ddI-resistant phenotype were cloned and sequenced by polymerase chain reaction (PCR)-based methods. We observed that several of these viruses possessed mutations at amino acid sites 184 (Met-->Val; ATG-->GTG) and 294 (Pro-->Ser; CCA-->TCA). These mutations were introduced in the pol gene of infectious, cloned HXB2-D DNA by site-directed mutagenesis. Viral replication assays confirmed the importance of site 184 with regard to resistance to ddI. The recombinant viruses thus generated displayed more than fivefold-greater resistance to ddI than parental HXB2-D did. Moreover, more than fivefold-greater resistance to ddC was also documented; however, the recombinant viruses continued to be inhibited by zidovudine (AZT). No resistance to ddI, ddC, or AZT was introduced by inclusion of mutation site 294 in the pol gene of HXB2-D. PCR analysis performed on viral samples obtained from patients receiving long-term ddI therapy confirmed the presence of mutation site 184 in five of seven cases tested. In three of these five positive cases, the wild-type codon was also detected, indicating that mixtures of viral quasispecies were apparently present. Viruses possessing a ddI resistance phenotype were isolated from both subjects whose viruses contained only the mutated rather than wild-type codon at position 184 as well as from a third individual, whose viruses appeared to be mostly of the mutated variety. Images PMID:1279198

Effects of highly active antiretroviral therapy on the survival of HIV-infected adult patients in urban slums of Kenya

PubMed Central

Muhula, Samuel Opondo; Peter, Memiah; Sibhatu, Biadgilign; Meshack, Ndirangu; Lennie, Kyomuhangi

2015-01-01

Recent improvements in access to Anti-Retroviral Therapy (ART) have radically reduced hospitalizations and deaths associated with HIV infection in both developed countries and sub-Saharan Africa. Not much is known about survival of patients on ART in slums. The objective of this study was to identify factors associated with mortality among adult patients on ART in resource poor, urban, sub-Saharan African setting. A prospective open cohort study was conducted with adult patients on ART at a clinic in Kibera slums, Nairobi, Kenya. The patients’ enrollment to care was between March 2005 and November 2011. Descriptive statistics were computed and Kaplan-Meier (KM) methods used to estimate survival time while Cox's proportional hazards (CPH) model fitted to determine mortality predictors. A total of 2,011 adult patients were studied, 69% being female. Female gender (p = 0.0016), zidovudine-based regimen patients (p < 0.0001), CD4 count >351 patients (p < 0.0001), WHO stage I patients (p < 0.0001) and “Working” functional status patients recorded better survival probability on ART. In CPH analysis, the hazard of dying was higher in patients on Stavudine-based regimen(hazard ratio (HR) =1.8; 95% CI, 1.5-2.2; p < 0.0001),CD4 count <50 cells/µl (HR = 1.6; 95% CI, 1.5-1.7;p < 0.0001), WHO Stage IV at ART initiation (HR = 1.3; 95% CI, 1.1-1.6; p = 0.016) and bedridden patients (HR = 2.7; 95% CI, 1.7-4.4;p < 0.0001). There was increased mortality among the males, those with advanced Immunosuppression, late WHO stage and bedridden patients. The findings further justify the need to switch patients on Stavudine-based regimen as per the WHO recommendations. PMID:26090021

Naringin Ameliorates HIV-1 Nucleoside Reverse Transcriptase Inhibitors- Induced Mitochondrial Toxicity.

PubMed

Oluwafeyisetan, Adebiyi; Olubunmi, Adebiyi; Peter, Owira

2016-01-01

Mitochondrial reactive oxygen species (ROS) generation and defective oxidative phosphorylation (OXPHOS) have been proposed as possible mechanisms underlying the development of nucleoside reverse transcriptase inhibitors (NRTIs)-induced mitochondrial toxicities. Available options in managing these complications have, so far, produced controversial results, thus necessitating further research into newer agents with promise. Antioxidant and free-radical scavenging effects of naringin, a plant-derived flavonoid, have previously been demonstrated. This study was designed to investigate the effects of naringin on NRTIs-induced mitochondrial toxicity. Wistar rats were randomly divided into Zidovudine (AZT)-only (100 mg/kg body weight BW); AZT+Naringin (100+50 mg/kg BW); AZT+Vitamin E (100+100 mg/kg BW); Stavudine (d4T)- only (50 mg/kg BW); d4T+Naringin (50+50 mg/kg BW); d4T+Vitamin E (50+100 mg/kg BW) and Vehicle (3.0 mL/kg BW)-treated groups, respectively. After 56 days of oral daily dosing, rats were euthanized by halothane overdose, blood collected by cardiac puncture and livers promptly excised for further biochemical and ultrastructural analyses. </p> Results: AZT- or d4T-only caused significant mitochondrial dysfunction and mitochondrial ultrastructural damage compared to controls, while either naringin or vitamin E reversed indices of mitochondrial dysfunction evidenced by significantly reduced mitochondrial malondialdehyde (MDA) and blood lactate concentrations, increased liver manganese superoxide dismutase (MnSOD) activity and upregulate expression of mitochondrial-encoded subunit of electron transport chain (ETC) complex IV protein compared to AZT- or d4T-only treated rats. Furthermore, naringin or vitamin E, respectively, ameliorated mitochondrial damage observed in AZT- or d4T-only treated rats. Naringin ameliorated oxidative stress and NRTI-induced mitochondrial damage and might, therefore, be beneficial in managing toxicities and complications arising

Antiretrovirals, Methamphetamine, and HIV-1 Envelope Protein gp120 Compromise Neuronal Energy Homeostasis in Association with Various Degrees of Synaptic and Neuritic Damage.

PubMed

Sanchez, Ana B; Varano, Giuseppe P; de Rozieres, Cyrus M; Maung, Ricky; Catalan, Irene C; Dowling, Cari C; Sejbuk, Natalia E; Hoefer, Melanie M; Kaul, Marcus

2016-01-01

HIV-1 infection frequently causes HIV-associated neurocognitive disorders (HAND) despite combination antiretroviral therapy (cART). Evidence is accumulating that components of cART can themselves be neurotoxic upon long-term exposure. In addition, abuse of psychostimulants, such as methamphetamine, seems to aggravate HAND and compromise antiretroviral therapy. However, the combined effect of virus and recreational and therapeutic drugs on the brain is poorly understood. Therefore, we exposed mixed neuronal-glial cerebrocortical cells to antiretrovirals (ARVs) (zidovudine [AZT], nevirapine [NVP], saquinavir [SQV], and 118-D-24) of four different pharmacological categories and to methamphetamine and, in some experiments, the HIV-1 gp120 protein for 24 h and 7 days. Subsequently, we assessed neuronal injury by fluorescence microscopy, using specific markers for neuronal dendrites and presynaptic terminals. We also analyzed the disturbance of neuronal ATP levels and assessed the involvement of autophagy by using immunofluorescence and Western blotting. ARVs caused alterations of neurites and presynaptic terminals primarily during the 7-day incubation and depending on the specific compounds and their combinations with and without methamphetamine. Similarly, the loss of neuronal ATP was context specific for each of the drugs or combinations thereof, with and without methamphetamine or viral gp120. Loss of ATP was associated with activation of AMP-activated protein kinase (AMPK) and autophagy, which, however, failed to restore normal levels of neuronal ATP. In contrast, boosting autophagy with rapamycin prevented the long-term drop of ATP during exposure to cART in combination with methamphetamine or gp120. Our findings indicate that the overall positive effect of cART on HIV infection is accompanied by detectable neurotoxicity, which in turn may be aggravated by methamphetamine. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Decentralization Does Not Assure Optimal Delivery of PMTCT and HIV-Exposed Infant Services in a Low Prevalence Setting

PubMed Central

Edmonds, Andrew; Feinstein, Lydia; Okitolonda, Vitus; Thompson, Deidre; Kawende, Bienvenu; Behets, Frieda

2016-01-01

Background The consequences of decentralizing prevention of mother-to-child HIV transmission and HIV-exposed infant services to antenatal care (ANC)/labor and delivery (L&D) sites from dedicated HIV care and treatment (C&T) centers remain unknown, particularly in low prevalence settings. Methods In a cohort of mother–infant pairs, we compared delivery of routine services at ANC/L&D and C&T facilities in Kinshasa, Democratic Republic of Congo from 2010–2013, using methods accounting for competing risks (eg, death). Women could opt to receive interventions at 90 decentralized ANC/L&D sites, or 2 affiliated C&T centers. Additionally, we assessed decentralization’s population-level impacts by comparing proportions of women and infants receiving interventions before (2009–2010) and after (2011–2013) decentralization. Results Among newly HIV-diagnosed women (N = 1482), the 14-week cumulative incidence of receiving the package of CD4 testing and zidovudine or antiretroviral therapy was less at ANC/L&D [66%; 95% confidence interval (CI): 63% to 69%] than at C&T (88%; 95% CI: 83% to 92%) sites (subdistribution hazard ratio, 0.62; 95% CI: 0.55 to 0.69). Delivery of cotrimoxazole and DNA polymerase chain reaction testing to HIV-exposed infants (N = 1182) was inferior at ANC/L&D sites (subdistribution hazard ratio, 0.84; 95% CI: 0.76 to 0.92); the 10-month cumulative incidence of the package at ANC/L&D sites was 89% (95% CI: 82% to 93%) versus 97% (95% CI: 93% to 99%) at C&T centers. Receipt of the pregnancy (20% of 1518, to 64% of 1405) and infant (16%–31%) packages improved post decentralization. Conclusions Services were delivered less efficiently at ANC/L&D sites than C&T centers. Although access improved with decentralization, its potential cannot be realized without sufficient and sustained support. PMID:26262776

Absence of a Universal Mechanism of Mitochondrial Toxicity by Nucleoside Analogs▿

PubMed Central

Lund, Kaleb C.; Peterson, LaRae L.; Wallace, Kendall B.

2007-01-01

Nucleoside analogs are associated with various mitochondrial toxicities, and it is becoming increasingly difficult to accommodate these differences solely in the context of DNA polymerase gamma inhibition. Therefore, we examined the toxicities of zidovudine (AZT) (10 and 50 μM; 2.7 and 13.4 μg/ml), didanosine (ddI) (10 and 50 μM; 2.4 and 11.8 μg/ml), and zalcitabine (ddC) (1 and 5 μM; 0.21 and 1.1 μg/ml) in HepG2 and H9c2 cells without the presumption of mitochondrial DNA (mtDNA) depletion. Ethidium bromide (EtBr) (0.5 μg/ml; 1.3 μM) was used as a positive control. AZT treatment resulted in metabolic disruption (increased lactate and superoxide) and increased cell mortality with decreased proliferation, while mtDNA remained unchanged or increased (HepG2 cells; 50 μM AZT). ddC caused pronounced mtDNA depletion in HepG2 cells but not in H9c2 cells and increased mortality in HepG2 cells, but no significant metabolic disruption in either cell type. ddI caused a moderate depletion of mtDNA in both cell types but showed no other effects. EtBr exposure resulted in metabolic disruption, increased cell mortality with decreased cell proliferation, and mtDNA depletion in both cell types. We conclude that nucleoside analogs display unique toxicities within and between culture models, and therefore, care should be taken when generalizing about the mechanisms of nucleoside reverse transcriptase inhibitor toxicity. Additionally, mtDNA abundance does not necessarily correlate with metabolic disruption, especially in cell culture; careful discernment is recommended in this regard. PMID:17470651

Evaluation of Different Antiretroviral Drug Protocols on Naturally Infected Feline Immunodeficiency Virus (FIV) Cats in the late Phase of the Asymptomatic Stage of Infection

PubMed Central

Gómez, Nélida V.; Fontanals, Adriana; Castillo, Víctor; Gisbert, María A.; Suraniti, Adriana; Mira, Graciela; Pisano, Paola B.

2012-01-01

The aim of this study was to evaluate the efficacy of the antiretrovirals: Zidovudine (ZDV) alone; ZDV + Recombinant Human Interferon-α (rHuIFN-α); ZDV + Lamivudine (3TC) and ZDV + valproic acid (Valp) on naturally feline immunodeficiency virus (FIV)-infected cats, in the late phase of the asymptomatic stage of infection. The follow-up was performed over one year, through clinical evaluation and the determination of viral loads and CD4+/CD8+ ratios. Neurological signs were studied by visual and auditory evoked potentials (VEP, AEP) and the responses were abnormal in 80% of the FIV-infected cats. After one year, an improvement in VEP and AEP was observed in the ZDV + Valp group and a worsening in the group receiving ZDV + rHuIFN-α. The CD4+/CD8+ ratio showed a significant increase (both intra and inter-groups) only in ZDV and ZDV + 3TC, between their pre-treatment and one year values, as well as among the other groups. Viral load only showed a significant decrease in ZDV and ZDV + 3TC groups, when comparing the values at one year of treatment vs. pre-treatment values and when the different groups were compared. In addition, the viral load decrease was significantly more pronounced in the ZDV + 3TC vs. ZDV group. We conclude that ZDV and ZDV + 3TC produce significant reductions in viral load and stimulate a recovery of the CD4+/CD8+ ratio, compared with the other protocols. It is clear that the addition of 3TC resulted in a greater reduction in viral load than use of ZDV as a single drug. Therefore, the combination ZDV + 3TC could be more effective than the sole use of ZDV. PMID:22816032

Practical Management of HIV-Associated Anemia in Resource-Limited Settings: Prospective Observational Evaluation of a New Mozambican Guideline

PubMed Central

Silva, Wilson P.; Vermund, Sten H.; Valverde, Emilio; Buene, Manuel; Moon, Troy D.

2016-01-01

Abstract Mozambique's updated guideline for management of HIV-associated anemia prompts clinicians to consider opportunistic conditions, adverse drug reactions, and untreated immunosuppression in addition to iron deficiency, intestinal helminthes, and malaria. We prospectively evaluated this guideline in rural Zambézia Province. Likely cause(s) of anemia were determined through prespecified history, physical examination, and laboratory testing. Diagnoses were “etiologic” if laboratory confirmed (sputum microscopy, blood culture, Plasmodium falciparum malaria rapid test) or “syndromic” if not. To assess hemoglobin response, we used serial point-of-care measurements. We studied 324 ambulatory, anemic (hemoglobin <10 g/dl) HIV-infected adults. Study clinicians treated nearly all [315 (97.2%)] for suspected iron deficiency and/or helminthes; 56 (17.3%) had laboratory-confirmed malaria. Other assigned diagnoses included tuberculosis [30 (9.3%)], adverse drug reactions [26 (8.0%)], and bacteremia [13 (4.1%)]. Etiologic diagnosis was achieved in 79 (24.4%). Of 169 (52.2%) subjects who improved (hemoglobin increase of ≥1 g/dl without indications for hospitalization), only 65 (38.5%) received conventional management (iron supplementation, deworming, and/or antimalarials) alone. Thirty (9.3%) died and/or were hospitalized, and 125 (38.6%) were lost to follow-up. Multivariable linear and logistic regression models described better hemoglobin responses and/or outcomes in subjects with higher CD4+ T-lymphocyte counts, pre-enrollment antiretroviral therapy and/or co-trimoxazole prophylaxis, discontinuation of zidovudine for suspected adverse reaction, and smear-positive tuberculosis. Adverse outcomes were associated with fever, low body mass index, bacteremia, esophageal candidiasis, and low or missing CD4+ T cell counts. In this severely resource-limited setting, successful anemia management often required interventions other than conventional presumptive

Mutations of mtDNA polymerase-γ and hyperlactataemia in the HIV-infected Zulu population of South Africa.

PubMed

Ojwach, D B A; Aldous, C; Kochleff, P; Sartorius, B

2016-12-01

Mitochondrial toxicity, particularly symptomatic hyperlactataemia or lactic acidosis (SHL/LA), has been attributed to the use of nucleoside reverse transcriptase inhibitors (NRTIs), possibly because of their capacity to impede human mitochondrial DNA polymerase-γ (POLG), which is responsible for the replication of mitochondrial DNA. To determine whether known monogenic POLG1 polymorphisms could be linked with the unexpectedly high incidence of SHL/LA observed in HIV-infected Zulu-speaking patients exposed to the NRTIs stavudine or zidovudine in their antiretroviral therapy. One hundred and sixteen patients from Edendale Hospital, Pietermaritzburg, South Africa, participated in the study between March and August 2014. Fifty-nine symptomatic cases were compared with 57 non-symptomatic controls on stavudine for ≥24 months. Among the symptomatic patients, 13 had SHL with measured lactate between 3.0 and 4.99 mmol/L, and 46 had LA with a lactate level ≥5 mmol/L. Genomic DNA from 113 samples was used for subsequent allelic discrimination polymerase chain reaction screening for the R964C and E1143G single-nucleotide polymorphisms of POLG1. Sequencing was performed for 40/113 randomly selected samples for confirmation of the genotyping results. Neither of the two known POLG1 mutations was observed. The cases presented with SHL/LA between 4 and 18 months on stavudine. Females (70.4%) were significantly (p<0.001) more likely to be cases (adjusted odds ratio 24.24, 95% CI 5.14 - 114.25) compared with males. This study has shown that our sample of the Zulu-speaking population does not exhibit a genetic predisposition to SHL/LA associated with known monogenic POLG1 mutations, indicating another possible predisposing factor for increased risk of SHL/LA.

Establishment of new transmissible and drug-sensitive human immunodeficiency virus type 1 wild types due to transmission of nucleoside analogue-resistant virus.

PubMed

de Ronde, A; van Dooren, M; van Der Hoek, L; Bouwhuis, D; de Rooij, E; van Gemen, B; de Boer, R; Goudsmit, J

2001-01-01

Sequence analysis of human immunodeficiency virus type 1 (HIV-1) from 74 persons with acute infections identified eight strains with mutations in the reverse transcriptase (RT) gene at positions 41, 67, 68, 70, 215, and 219 associated with resistance to the nucleoside analogue zidovudine (AZT). Follow-up of the fate of these resistant HIV-1 strains in four newly infected individuals revealed that they were readily replaced by sensitive strains. The RT of the resistant viruses changed at amino acid 215 from tyrosine (Y) to aspartic acid (D) or serine (S), with asparagine (N) as a transient intermediate, indicating the establishment of new wild types. When we introduced these mutations and the original threonine (T)-containing wild type into infectious molecular clones and assessed their competitive advantage in vitro, the order of fitness was in accord with the in vivo observations: 215Y < 215D = 215S = 215T. As detected by real-time nucleic acid sequence-based amplification with two molecular beacons, the addition of AZT or stavudine (d4T) to the viral cultures favored the 215Y mutant in a dose-dependent manner. Our results illustrate that infection with nucleoside analogue-resistant HIV leads in newly infected individuals to mutants that are sensitive to nucleoside analogues, but only a single mutation removed from drug-resistant HIV. Such mutants were shown to be transmissible, stable, and prone to rapid selection for resistance to AZT or d4T as soon as antiretroviral therapy was administered. Monitoring of patients for the presence of new HIV-1 wild types with D, S, or N residues at position 215 may be warranted in order to estimate the threat to long-term efficacy of regimens including nucleoside analogues.

Change in Vitamin D Levels Occurs Early after Antiretroviral Therapy Initiation and Depends on Treatment Regimen in Resource-Limited Settings

PubMed Central

Havers, Fiona P.; Detrick, Barbara; Cardoso, Sandra W.; Berendes, Sima; Lama, Javier R.; Sugandhavesa, Patcharaphan; Mwelase, Noluthando H.; Campbell, Thomas B.; Gupta, Amita

2014-01-01

Study Background Vitamin D has wide-ranging effects on the immune system, and studies suggest that low serum vitamin D levels are associated with worse clinical outcomes in HIV. Recent studies have identified an interaction between antiretrovirals used to treat HIV and reduced serum vitamin D levels, but these studies have been done in North American and European populations. Methods Using a prospective cohort study design nested in a multinational clinical trial, we examined the effect of three combination antiretroviral (cART) regimens on serum vitamin D levels in 270 cART-naïve, HIV-infected adults in nine diverse countries, (Brazil, Haiti, Peru, Thailand, India, Malawi, South Africa, Zimbabwe and the United States). We evaluated the change between baseline serum vitamin D levels and vitamin D levels 24 and 48 weeks after cART initiation. Results Serum vitamin D levels decreased significantly from baseline to 24 weeks among those randomized to efavirenz/lamivudine/zidovudine (mean change: −7.94 [95% Confidence Interval (CI) −10.42, −5.54] ng/ml) and efavirenz/emtricitabine/tenofovir-DF (mean change: −6.66 [95% CI −9.40, −3.92] ng/ml) when compared to those randomized to atazanavir/emtricitabine/didanosine-EC (mean change: −2.29 [95% CI –4.83, 0.25] ng/ml). Vitamin D levels did not change significantly between week 24 and 48. Other factors that significantly affected serum vitamin D change included country (p<0.001), season (p<0.001) and baseline vitamin D level (p<0.001). Conclusion Efavirenz-containing cART regimens adversely affected vitamin D levels in patients from economically, geographically and racially diverse resource-limited settings. This effect was most pronounced early after cART initiation. Research is needed to define the role of Vitamin D supplementation in HIV care. PMID:24752177

AZT Impairs Immunological Recovery on First-line ART: Collaborative analysis of cohort studies in Southern Africa

PubMed Central

WANDELER, Gilles; GSPONER, Thomas; MULENGA, Lloyd; GARONE, Daniela; WOOD, Robin; MASKEW, Mhairi; PROZESKY, Hans; HOFFMANN, Christopher; EHMER, Jochen; DICKINSON, Diana; DAVIES, Mary-Ann; EGGER, Matthias; KEISER, Olivia

2013-01-01

Objectives Zidovudine (AZT) is recommended for first-line antiretroviral therapy (ART) in resource limited settings. AZT may, however, lead to anemia and impaired immunological response. We compared CD4 counts over 5 years between patients starting ART with and without AZT in Southern Africa. Design Cohort study Methods Patients aged ≥16 years who started first-line ART in South Africa, Botswana, Zambia or Lesotho were included. We used linear mixed-effect models to compare CD4 cell count trajectories between patients on AZT-containing regimens and patients on other regimens, censoring follow-up at first treatment change. Impaired immunological recovery, defined as a CD4 count below 100 cells/μl at 1 year, was assessed in logistic regression. Analyses were adjusted for baseline CD4 count and haemoglobin level, age, gender, type of regimen, viral load monitoring and calendar year. Results 72,597 patients starting ART, including 19,758 (27.2%) on AZT, were analysed. Patients on AZT had higher CD4 cell counts (150 vs.128 cells/μl) and haemoglobin level (12.0 vs. 11.0 g/dl) at baseline, and were less likely to be female than those on other regimens. Adjusted differences in CD4 counts between regimens containing and not containing AZT were −16 cells/μl (95% CI −18 to −14) at 1 year and −56 cells/μl (95% CI −59 to −52) at 5 years. Impaired immunological recovery was more likely with AZT compared to other regimens (odds ratio 1.40, 95% CI 1.22–1.61). Conclusions In Southern Africa AZT is associated with inferior immunological recovery compared to other backbones. Replacing AZT with another NRTI could avoid unnecessary switches to second-line ART. PMID:23660577

HIV-1 drug-resistance surveillance among treatment-experienced and -naïve patients after the implementation of antiretroviral therapy in Ghana.

PubMed

Nii-Trebi, Nicholas I; Ibe, Shiro; Barnor, Jacob S; Ishikawa, Koichi; Brandful, James A M; Ofori, Sampson B; Yamaoka, Shoji; Ampofo, William K; Sugiura, Wataru

2013-01-01

Limited HIV-1 drug-resistance surveillance has been carried out in Ghana since the implementation of antiretroviral therapy (ART). This study sought to provide data on the profile of HIV-1 drug resistance in ART-experienced and newly diagnosed individuals in Ghana. Samples were collected from 101 HIV-1-infected patients (32 ART-experienced cases with virological failure and 69 newly diagnosed ART-naïve cases, including 11 children), in Koforidua, Eastern region of Ghana, from February 2009 to January 2010. The pol gene sequences were analyzed by in-house HIV-1 drug-resistance testing. The most prevalent HIV-1 subtype was CRF02_AG (66.3%, 67/101) followed by unique recombinant forms (25.7%, 26/101). Among 31 ART-experienced adults, 22 (71.0%) possessed at least one drug-resistance mutation, and 14 (45.2%) had two-class-resistance to nucleoside and non-nucleoside reverse-transcriptase inhibitors used in their first ART regimen. Importantly, the number of accumulated mutations clearly correlated with the duration of ART. The most prevalent mutation was lamivudine-resistance M184V (n = 12, 38.7%) followed by efavirenz/nevirapine-resistance K103N (n = 9, 29.0%), and zidovudine/stavudine-resistance T215Y/F (n = 6, 19.4%). Within the viral protease, the major nelfinavir-resistance mutation L90M was found in one case. No transmitted HIV-1 drug-resistance mutation was found in 59 ART-naïve adults, but K103N and G190S mutations were observed in one ART-naïve child. Despite expanding accessibility to ART in Eastern Ghana, the prevalence of transmitted HIV-1 drug resistance presently appears to be low. As ART provision with limited options is scaled up nationwide in Ghana, careful monitoring of transmitted HIV-1 drug resistance is necessary.

Early antiretroviral treatment (eART) limits viral diversity over time in a long-term HIV viral suppressed perinatally infected child.

PubMed

Palma, Paolo; Zangari, Paola; Alteri, Claudia; Tchidjou, Hyppolite K; Manno, Emma Concetta; Liuzzi, Giuseppina; Perno, Carlo Federico; Rossi, Paolo; Bertoli, Ada; Bernardi, Stefania

2016-12-09

HIV genetic diversity implicates major challenges for the control of viral infection by the immune system and for the identification of an effective immunotherapeutic strategy. With the present case report we underline as HIV evolution could be effectively halted by early antiretroviral treatment (eART). Few cases supported this evidence due to the difficulty of performing amplification and sequencing analysis in long-term viral suppressed patients. Here, we reported the case of limited HIV-1 viral evolution over time in a successful early treated child. A perinatally HIV-1 infected infant was treated within 7 weeks of age with zidovudine, lamivudine, nevirapine and lopinavir/ritonavir. At antiretroviral treatment (ART) initiation HIV-1 viral load (VL) and CD4 percentage were >500,000 copies/ml and 35%, respectively. Plasma genotypic resistance test showed a wild-type virus. The child reached VL undetectability after 33 weeks of combination antiretroviral therapy (cART) since he maintained a stable VL <40copies/ml. After 116 weeks on ART we were able to perform amplification and sequencing assay on the plasma virus. At this time VL was <40 copies/ml and CD4 percentage was 40%. Again the genotypic resistance test revealed a wild-type virus. The phylogenetic analysis performed on the HIV-1 pol sequences of the mother and the child revealed that sequences clustered with C subtype reference strains and formed a monophyletic cluster distinct from the other C sequences included in the analysis (bootstrap value >90%). Any major evolutionary divergence was detected. eART limits the viral evolution avoiding the emergence of new viral variants. This result may have important implications in host immune control and may sustain the challenge search of new personalized immunotherapeutic approaches to achieve a prolonged viral remission.

Does short-term virologic failure translate to clinical events in antiretroviral-naïve patients initiating antiretroviral therapy in clinical practice?

PubMed

Mugavero, Michael J; May, Margaret; Harris, Ross; Saag, Michael S; Costagliola, Dominique; Egger, Matthias; Phillips, Andrew; Günthard, Huldrych F; Dabis, Francois; Hogg, Robert; de Wolf, Frank; Fatkenheuer, Gerd; Gill, M John; Justice, Amy; D'Arminio Monforte, Antonella; Lampe, Fiona; Miró, Jose M; Staszewski, Schlomo; Sterne, Jonathan A C

2008-11-30

To determine whether differences in short-term virologic failure among commonly used antiretroviral therapy (ART) regimens translate to differences in clinical events in antiretroviral-naïve patients initiating ART. Observational cohort study of patients initiating ART between January 2000 and December 2005. The Antiretroviral Therapy Cohort Collaboration (ART-CC) is a collaboration of 15 HIV cohort studies from Canada, Europe, and the United States. A total of 13 546 antiretroviral-naïve HIV-positive patients initiating ART with efavirenz, nevirapine, lopinavir/ritonavir, nelfinavir, or abacavir as third drugs in combination with a zidovudine and lamivudine nucleoside reverse transcriptase inhibitor backbone. Short-term (24-week) virologic failure (>500 copies/ml) and clinical events within 2 years of ART initiation (incident AIDS-defining event, death, and a composite measure of these two outcomes). Compared with efavirenz as initial third drug, short-term virologic failure was more common with all other third drugs evaluated; nevirapine (adjusted odds ratio = 1.87, 95% confidence interval (CI) = 1.58-2.22), lopinavir/ritonavir (1.32, 95% CI = 1.12-1.57), nelfinavir (3.20, 95% CI = 2.74-3.74), and abacavir (2.13, 95% CI = 1.82-2.50). However, the rate of clinical events within 2 years of ART initiation appeared higher only with nevirapine (adjusted hazard ratio for composite outcome measure 1.27, 95% CI = 1.04-1.56) and abacavir (1.22, 95% CI = 1.00-1.48). Among antiretroviral-naïve patients initiating therapy, between-ART regimen, differences in short-term virologic failure do not necessarily translate to differences in clinical outcomes. Our results should be interpreted with caution because of the possibility of residual confounding by indication.

Differential effects of efavirenz, lopinavir/r, and atazanavir/r on the initial viral decay rate in treatment naïve HIV-1-infected patients.

PubMed

Edén, Arvid; Andersson, Lars-Magnus; Andersson, Orjan; Flamholc, Leo; Josephson, Filip; Nilsson, Staffan; Ormaasen, Vidar; Svedhem, Veronica; Säll, Christer; Sönnerborg, Anders; Tunbäck, Petra; Gisslén, Magnus

2010-05-01

Initial viral decay rate may be useful when comparing the relative potency of antiretroviral regimens. Two hundred twenty-seven ART-naïve patients were randomized to receive efavirenz (EFV) (n = 74), lopinavir/ritonavir (LPV/r) (n = 77), or atazanavir/ritonavir (ATV/r) (n = 79) in combination with two NRTIs. The most frequently used NRTI combinations in the EFV and ATV/r groups were the nonthymidine analogues tenofovir and emtricitabine or lamivudine (70% and 68%, respectively) and, in the LPV/r group, lamivudine and the thymidine analogue zidovudine (89%). HIV-1 RNA was monitored during the first 28 days after treatment initiation. Phase 1 and 2 decay rate was estimated in a subset of 157 patients by RNA decrease from days 0 to 7, and days 14 to 28. One-way ANOVA and subsequent Tukey's post hoc tests were used for groupwise comparisons. Mean (95% CI) HIV-1 RNA reductions from days 0 to 28 were 2.59 (2.45-2.73), 2.42 (2.27-2.57), and 2.13 (2.01-2.25) log(10) copies/ml for the EFV-, LPV/r-, and ATV/r-based treatment groups, respectively, with a significantly larger decrease in the EFV-based group at all time points compared with ATV/r (p < 0.0001), and with LPV/r at days 7-21 (p < 0.0001-0.03). LPV/r gave a greater RNA decrease compared with ATV/r from day 14 (p = 0.02). Phase 1 decay rate was significantly higher in the EFV group compared with LPV/r (p = 0.003) or ATV/r (p < 0.0001). No difference was found in phase 2 decrease. EFV-based treatment gave a more rapid decline in HIV-1 RNA than did either of the boosted protease inhibitor-based regimens. The observed differences may reflect different inherent regimen potencies.

Timing of Initiation of Antiretroviral Therapy in Human Immunodeficiency Virus (HIV)–Associated Tuberculous Meningitis

PubMed Central

Török, M. Estee; Yen, Nguyen Thi Bich; Chau, Tran Thi Hong; Mai, Nguyen Thi Hoang; Phu, Nguyen Hoan; Mai, Pham Phuong; Dung, Nguyen Thi; Van Vinh Chau, Nguyen; Bang, Nguyen Duc; Tien, Nguyen Anh; Minh, N. H.; Hien, Nguyen Quang; Thai, Phan Vuong Khac; Dong, Doan The; Anh, Do Thi Tuong; Thoa, Nguyen Thi Cam; Hai, Nguyen Ngoc; Lan, Nguyen Ngoc; Lan, Nguyen Thi Ngoc; Quy, Hoang Thi; Dung, Nguyen Huy; Hien, Tran Tinh; Chinh, Nguyen Tran; Simmons, Cameron Paul; de Jong, Menno; Wolbers, Marcel; Farrar, Jeremy James

2015-01-01

Background The optimal time to initiate antiretroviral therapy (ART) in human immunodeficiency virus (HIV)–associated tuberculous meningitis is unknown. Methods We conducted a randomized, double-blind, placebo-controlled trial of immediate versus deferred ART in patients with HIV-associated tuberculous meningitis to determine whether immediate ART reduced the risk of death. Antiretroviral drugs (zidovudine, lamivudine, and efavirenz) were started either at study entry or 2 months after randomization. All patients were treated with standard antituberculosis treatment, adjunctive dexamethasone, and prophylactic co-trimoxazole and were followed up for 12 months. We conducted intention-to-treat, per-protocol, and prespecified subgroup analyses. Results A total of 253 patients were randomized, 127 in the immediate ART group and 126 in the deferred ART group; 76 and 70 patients died within 9 months in the immediate and deferred ART groups, respectively. Immediate ART was not significantly associated with 9-month mortality (hazard ratio [HR], 1.12; 95% confidence interval [CI], .81–1.55; P = .50) or the time to new AIDS events or death (HR, 1.16; 95% CI, .87–1.55; P = .31). The percentage of patients with severe (grade 3 or 4) adverse events was high in both arms (90% in the immediate ART group and 89% in the deferred ART group; P = .84), but there were significantly more grade 4 adverse events in the immediate ART arm (102 in the immediate ART group vs 87 in the deferred ART group; P = .04). Conclusions Immediate ART initiation does not improve outcome in patients presenting with HIV-associated tuberculous meningitis. There were significantly more grade 4 adverse events in the immediate ART arm, supporting delayed initiation of ART in HIV-associated tuberculous meningitis. Clinical Trials Registration ISRCTN63659091. PMID:21596680

Human Immunodeficiency Virus Type 1 (HIV-1) Integration: a Potential Target for Microbicides To Prevent Cell-Free or Cell-Associated HIV-1 Infection ▿

PubMed Central

Terrazas-Aranda, Katty; Van Herrewege, Yven; Hazuda, Daria; Lewi, Paul; Costi, Roberta; Di Santo, Roberto; Cara, Andrea; Vanham, Guido

2008-01-01

Conceptually, blocking human immunodeficiency virus type 1 (HIV-1) integration is the last possibility for preventing irreversible cellular infection. Using cocultures of monocyte-derived dendritic cells and CD4+ T cells, which represent primary targets in sexual transmission, we demonstrated that blocking integration with integrase strand transfer inhibitors (InSTIs), particularly L-870812, could consistently block cell-free and cell-associated HIV-1 infection. In a pretreatment setting in which the compound was present before and during infection and was afterwards gradually diluted during the culture period, the naphthyridine carboxamide L-870812 blocked infection with the cell-free and cell-associated HIV-1 Ba-L strain at concentrations of, respectively, 1,000 and 10,000 nM. The potency of L-870812 was similar to that of the nucleotide reverse transcriptase inhibitor R-9-(2-phosphonylmethoxypropyl) adenine (PMPA) but one or two orders of magnitude lower than those of the nonnucleoside reverse transcriptase inhibitors UC781 and TMC120. In contrast, the diketo acid RDS derivative InSTIs showed clear-cut but weaker antiviral activity than L-870812. Moreover, L-870812 completely blocked subtype C and CRFO2_AG primary isolates, which are prevalent in the African heterosexual epidemic. Furthermore, the addition of micromolar concentrations of L-870812 even 24 h after infection could still block both cell-free and cell-associated Ba-L, opening the prospect of postexposure prophylaxis. Finally, an evaluation of the combined activity of L-870812 with either T20, zidovudine, PMPA, UC781, or TMC120 against replication-deficient HIV-1 Ba-L (env) pseudovirus suggested synergistic activity for all combinations. Importantly, compounds selected for the study by using the coculture model were devoid of acute or delayed cytotoxic effects at HIV-blocking concentrations. Therefore, these findings provide evidence supporting consideration of HIV-1 integration as a target for

Antiretroviral drugs and acute pancreatitis in HIV/AIDS patients: is there any association? A literature review

PubMed Central

Oliveira, Natalia Mejias; Ferreira, Felipe Augusto Yamauti; Yonamine, Raquel Yumi; Chehter, Ethel Zimberg

2014-01-01

ABSTRACT In HIV-seropositive individuals, the incidence of acute pancreatitis may achieve 40% per year, higher than the 2% found in the general population. Since 1996, when combined antiretroviral therapy, known as HAART (highly active antiretroviral therapy), was introduced, a broad spectrum of harmful factors to the pancreas, such as opportunistic infections and drugs used for chemoprophylaxis, dropped considerably. Nucleotide analogues and metabolic abnormalities, hepatic steatosis and lactic acidosis have emerged as new conditions that can affect the pancreas. To evaluate the role of antiretroviral drugs to treat HIV/AIDS in a scenario of high incidence of acute pancreatitis in this population, a systematic review was performed, including original articles, case reports and case series studies, whose targets were HIV-seropositive patients that developed acute pancreatitis after exposure to any antiretroviral drugs. This association was confirmed after exclusion of other possible etiologies and/or a recurrent episode of acute pancreatitis after re-exposure to the suspected drug. Zidovudine, efavirenz, and protease inhibitors are thought to lead to acute pancreatitis secondary to hyperlipidemia. Nucleotide reverse transcriptase inhibitors, despite being powerful inhibitors of viral replication, induce a wide spectrum of side effects, including myelotoxicity and acute pancreatitis. Didanosine, zalcitabine and stavudine have been reported as causes of acute and chronic pancreatitis. They pose a high risk with cumulative doses. Didanosine with hydroxyurea, alcohol or pentamidine are additional risk factors, leading to lethal pancreatitis, which is not a frequent event. In addition, other drugs used for prophylaxis of AIDS-related opportunistic diseases, such as sulfamethoxazole-trimethoprim and pentamidine, can produce necrotizing pancreatitis. Despite comorbidities that can lead to pancreatic involvement in the HIV/AIDS population, antiretroviral drug

Renal and Metabolic Toxicities Following Initiation of HIV-1 Treatment Regimen in a Diverse, Multinational Setting: A Focused Safety Analysis of ACTG PEARLS (A5175)

PubMed Central

Romo, F. Touzard; Smeaton, L.M.; Campbell, T.B.; Riviere, C.; Mngqibisa, R.; Nyirenda, M.; Supparatpinyo, K.; Kumarasamy, N.; Hakim, J.G.; Flanigan, T.P.

2015-01-01

Background Convenient dosing, potency, and low toxicity support use of tenofovir disoproxil fumarate (TDF) as preferred nucleotide reverse transcriptase inhibitor (NRTI) for HIV-1 treatment. However, renal and metabolic safety of TDF compared to other NRTIs has not been well described in resource-limited settings. Methods This was a secondary analysis examining the occurrence of renal abnormalities (RAs) and renal and metabolic serious non-AIDS-defining events (SNADEs) through study follow-up between participants randomized to zidovudine (ZDV)/lamivudine/efavirenz and TDF/emtricitabine/efavirenz treatment arms within A5175/PEARLS trial. Exact logistic regression explored associations between baseline covariates and RAs. Response profile longitudinal analysis compared creatinine clearance (CrCl) over time between NRTI groups. Results Twenty-one of 1,045 participants developed RAs through 192 weeks follow-up; there were 15 out of 21 in the TDF arm (P = .08). Age 41 years or older (odds ratio [OR], 3.35; 95% CI, 1.1–13.1), history of diabetes (OR, 10.7; 95% CI, 2.1–55), and lower baseline CrCl (OR, 3.1 per 25 mL/min decline; 95% CI, 1.7–5.8) were associated with development of RAs. Renal SNADEs occurred in 42 participants; 33 were urinary tract infections and 4 were renal failure/insufficiency; one event was attributed to TDF. Significantly lower CrCl values were maintained among patients receiving TDF compared to ZDV (repeated measures analysis P = .05), however worsening CrCl from baseline was not observed with TDF exposure over time. Metabolic SNADEs were rare, but were higher in the ZDV arm (20 vs 3; P < .001). Conclusions TDF is associated with lower serious metabolic toxicities but not higher risk of RAs, serious renal events, or worsening CrCl over time compared to ZDV in this randomized multinational study. PMID:25433664

Mothers on the margins: implications for eradicating perinatal HIV.

PubMed

Lindau, Stacy Tessler; Jerome, Jessica; Miller, Kate; Monk, Elizabeth; Garcia, Patricia; Cohen, Mardge

2006-01-01

Tactics aimed at reducing perinatal transmission of HIV are proving ineffective at accomplishing complete eradication: a group of women with HIV remain at very high risk for transmitting the virus to their newborns. This study engaged a uniquely high-risk group of HIV-infected mothers as expert informants on childbearing with HIV to inform strategies to eradicate perinatal HIV transmission. The sample draws from an Illinois Department of Children and Family Services (DCFS) database of 1104 HIV-seropositive women with children in protective services between 1989 and 2001. Of these, 32 women knew their HIV-positive status and gave birth to at least two children after 1997 (zidovudine widely implemented as standard of care). Twelve were accessible and consented to participate. Three others, currently pregnant, also participated. Fifteen interviews were completed. The 15 women had given birth to 78 children (9 HIV-infected), fathered by 62 men. Respondents were severely socioeconomically marginalized. They were aware of their HIV status and the benefits of prophylaxis, most desired healthy babies to parent, and most delivered their babies in hospitals equipped to provide adequate prophylaxis. Yet most received inadequate or no prenatal care and did not disclose their HIV status at delivery. Women indicated that denial and substance use were the primary intrinsic barriers and disrespectful treatment was the primary extrinsic barrier to disclosure and care. Women's recommendations about eradication of perinatal HIV transmission emphasized the problem of substance use, the need for private and thorough communication with medical and DCFS personnel, and the need for positive social relationships to enable HIV positive mothers to engage in care. Attention to potent social and institutional barriers that impair the ability of the most marginalized women to disclose their HIV status and accept care is essential to realize eradication of perinatal transmission.

Kericho CLinic-based ART Diagnostic Evaluation (CLADE): design, accrual, and baseline characteristics of a randomized controlled trial conducted in predominately rural, district-level, HIV clinics of Kenya.

PubMed

Sawe, Fredrick K; Obiero, Eunice; Yegon, Peter; Langat, Rither C; Aoko, Appolonia; Tarus, Jemutai; Kiptoo, Ignatius; Langat, Raphael K; Maswai, Jonah; Bii, Margaret; Khamadi, Samoel; Shikuku, Kibet P; Close, Nicole; Sinei, Samuel; Shaffer, Douglas N

2015-01-01

Prospective clinical trial data regarding routine HIV-1 viral load (VL) monitoring of antiretroviral therapy (ART) in non-research clinics of Sub-Saharan Africa are needed for policy makers. CLinic-based ART Diagnostic Evaluation (CLADE) is a randomized, controlled trial (RCT) evaluating feasibility, superiority, and cost-effectiveness of routine VL vs. standard of care (clinical and immunological) monitoring in adults initiating dual nucleoside reverse transcriptase inhibitor (NRTI)+non-NRTI ART. Participants were randomized (1:1) at 7 predominately rural, non-research, district-level clinics of western Kenya. Descriptive statistics present accrual patterns and baseline cohort characteristics. Over 15 months, 820 adults enrolled at 7 sites with 86-152 enrolled per site. Monthly site enrollment ranged from 2-92 participants. Full (100%) informed consent compliance was independently documented. Half (49.9%) had HIV diagnosed through voluntary counseling and testing. Study arms were similar: mostly females (57.6%) aged 37.6 (SD = 9.0) years with low CD4 (166 [SD = 106]) cells/m3). Notable proportions had WHO Stage III or IV disease (28.7%), BMI <18.5 kg/m2 (23.1%), and a history of tuberculosis (5.6%) or were receiving tuberculosis treatment (8.2%) at ART initiation. In the routine VL arm, 407/409 (99.5%) received baseline VL (234,577 SD = 151,055 copies/ml). All participants received lamivudine; 49.8% started zidovudine followed by 38.4% stavudine and 11.8% tenofovir; and, 64.4% received nevirapine as nNRTI (35.6% efavirenz). A RCT can be enrolled successfully in rural, non-research, resource limited, district-level clinics in western Kenya. Many adults presenting for ART have advanced HIV/AIDS, emphasizing the importance of universal HIV testing and linkage-to-care campaigns. ClinicalTrials.gov NCT01791556.

Tenofovir-based regimens associated with less drug resistance in HIV-1-infected Nigerians failing first-line antiretroviral therapy.

PubMed

Etiebet, Mary-Ann A; Shepherd, James; Nowak, Rebecca G; Charurat, Man; Chang, Harry; Ajayi, Samuel; Elegba, Olufunmilayo; Ndembi, Nicaise; Abimiku, Alashle; Carr, Jean K; Eyzaguirre, Lindsay M; Blattner, William A

2013-02-20

In resource-limited settings, HIV-1 drug resistance testing to guide antiretroviral therapy (ART) selection is unavailable. We retrospectively conducted genotypic analysis on archived samples from Nigerian patients who received targeted viral load testing to confirm treatment failure and report their drug resistance mutation patterns. Stored plasma from 349 adult patients on non-nucleoside reverse transcriptase inhibitor (NNRTI) regimens was assayed for HIV-1 RNA viral load, and samples with more than 1000 copies/ml were sequenced in the pol gene. Analysis for resistance mutations utilized the IAS-US 2011 Drug Resistance Mutation list. One hundred and seventy-five samples were genotyped; the majority of the subtypes were G (42.9%) and CRF02_AG (33.7%). Patients were on ART for a median of 27 months. 90% had the M184V/I mutation, 62% had at least one thymidine analog mutation, and 14% had the K65R mutation. 97% had an NNRTI resistance mutation and 47% had at least two etravirine-associated mutations. In multivariate analysis tenofovir-based regimens were less likely to have at least three nucleoside reverse transcriptase inhibitor (NRTI) mutations after adjusting for subtype, previous ART, CD4, and HIV viral load [P < 0.001, odds ratio (OR) 0.04]. 70% of patients on tenofovir-based regimens had at least two susceptible NRTIs to include in a second-line regimen compared with 40% on zidovudine-based regimens (P = 0.04, OR = 3.4). At recognition of treatment failure, patients on tenofovir-based first-line regimens had fewer NRTI drug-resistant mutations and more active NRTI drugs available for second-line regimens. These findings can inform strategies for ART regimen sequencing to optimize long-term HIV treatment outcomes in low-resource settings.

Antiretroviral drug susceptibility among drug-naive adults with recent HIV infection in Rakai, Uganda

PubMed Central

Eshleman, Susan H.; Laeyendecker, Oliver; Parkin, Neil; Huang, Wei; Chappey, Colombe; Paquet, Agnes C.; Serwadda, David; Reynolds, Steven J.; Kiwanuka, Noah; Quinn, Thomas C.; Gray, Ronald; Wawer, Maria

2009-01-01

Objective To analyze antiretroviral drug susceptibility in HIV from recently infected adults in Rakai, Uganda, prior to the availability of antiretroviral drug treatment. Methods Samples obtained at the time of HIV seroconversion (1998–2003) were analyzed using the GeneSeq HIV and PhenoSense HIV assays (Monogram Biosciences, Inc., South San Francisco, California, USA). Results Test results were obtained for 104 samples (subtypes: 26A, 1C, 66D, 9A/D, 1C/D, 1 intersubtype recombinant). Mutations used for genotypic surveillance of transmitted antiretroviral drug resistance were identified in six samples: three had nucleoside reverse transcriptase inhibitor (NRTI) surveillance mutations (two had M41L, one had K219R), and three had protease inhibitor surveillance mutations (I47V, F53L, N88D); none had nonnucleoside reverse transcriptase inhibitor (NNRTI) surveillance mutations. Other resistance-associated mutations were identified in some samples. However, none of the samples had a sufficient number of mutations to predict reduced antiretroviral drug susceptibility. Ten (9.6%) of the samples had reduced phenotypic susceptibility to at least one drug (one had partial susceptibility to didanosine, one had nevirapine resistance, and eight had resistance or partial susceptibility to at least one protease inhibitor). Fifty-three (51%) of the samples had hypersusceptibility to at least one drug (seven had zidovudine hypersusceptibility, 28 had NNRTI hypersusceptibility, 34 had protease inhibitor hypersusceptibility). Delavirdine hyper-susceptibility was more frequent in subtype A than D. In subtype D, efavirenz hypersusceptibility was associated with substitutions at codon 11 in HIV-reverse transcriptase. Conclusion Phenotyping detected reduced antiretroviral drug susceptibility and hypersusceptibility in HIV from some antiretroviral-naive Ugandan adults that was not predicted by genotyping. Phenotyping may complement genotyping for analysis of antiretroviral drug

Antiretroviral drug susceptibility among drug-naive adults with recent HIV infection in Rakai, Uganda.

PubMed

Eshleman, Susan H; Laeyendecker, Oliver; Parkin, Neil; Huang, Wei; Chappey, Colombe; Paquet, Agnes C; Serwadda, David; Reynolds, Steven J; Kiwanuka, Noah; Quinn, Thomas C; Gray, Ronald; Wawer, Maria

2009-04-27

To analyze antiretroviral drug susceptibility in HIV from recently infected adults in Rakai, Uganda, prior to the availability of antiretroviral drug treatment. Samples obtained at the time of HIV seroconversion (1998-2003) were analyzed using the GeneSeq HIV and PhenoSense HIV assays (Monogram Biosciences, Inc., South San Francisco, California, USA). Test results were obtained for 104 samples (subtypes: 26A, 1C, 66D, 9A/D, 1C/D, 1 intersubtype recombinant). Mutations used for genotypic surveillance of transmitted antiretroviral drug resistance were identified in six samples: three had nucleoside reverse transcriptase inhibitor (NRTI) surveillance mutations (two had M41L, one had K219R), and three had protease inhibitor surveillance mutations (I47V, F53L, N88D); none had nonnucleoside reverse transcriptase inhibitor (NNRTI) surveillance mutations. Other resistance-associated mutations were identified in some samples. However, none of the samples had a sufficient number of mutations to predict reduced antiretroviral drug susceptibility. Ten (9.6%) of the samples had reduced phenotypic susceptibility to at least one drug (one had partial susceptibility to didanosine, one had nevirapine resistance, and eight had resistance or partial susceptibility to at least one protease inhibitor). Fifty-three (51%) of the samples had hypersusceptibility to at least one drug (seven had zidovudine hypersusceptibility, 28 had NNRTI hypersusceptibility, 34 had protease inhibitor hypersusceptibility). Delavirdine hypersusceptibility was more frequent in subtype A than D. In subtype D, efavirenz hypersusceptibility was associated with substitutions at codon 11 in HIV-reverse transcriptase. Phenotyping detected reduced antiretroviral drug susceptibility and hypersusceptibility in HIV from some antiretroviral-naive Ugandan adults that was not predicted by genotyping. Phenotyping may complement genotyping for analysis of antiretroviral drug susceptibility in populations with nonsubtype B

Long-term viral suppression and immune recovery during first-line antiretroviral therapy: a study of an HIV-infected adult cohort in Hanoi, Vietnam.

PubMed

Tanuma, Junko; Matsumoto, Shoko; Haneuse, Sebastien; Cuong, Do Duy; Vu, Tuong Van; Thuy, Pham Thi Thanh; Dung, Nguyen Thi; Dung, Nguyen Thi Hoai; Trung, Nguyen Vu; Kinh, Nguyen Van; Oka, Shinichi

2017-12-01

Achieving viral suppression is key in the global strategy to end the HIV epidemic. However, the levels of viral suppression have yet to be described in many resource-limited settings. We investigated the time to virologic failure (VF; defined as a viral load of ≥1000 copies/ml) and changes in CD4 counts since starting antiretroviral therapy (ART) in a cohort of HIV-infected adults in Hanoi, Vietnam. Factors related to the time to VF and impaired early immune recovery (defined as not attaining an increase in 100 cells/mm 3 in CD4 counts at 24 months) were further analysed. From 1806 participants, 225 were identified as having VF at a median of 50 months of first-line ART. The viral suppression rate at 12 months was 95.5% and survival without VF was maintained above 90% until 42 months. An increase in CD4 counts from the baseline was greater in groups with lower baseline CD4 counts. A younger age (multivariate hazard ratio (HR) 0.75, vs. <30), hepatitis C (HCV)-antibody positivity (HR 1.43), and stavudine (d4T)-containing regimens (HR 1.4, vs. zidovudine (AZT)) were associated with earlier VF. Factors associated with impaired early immune recovery included the male sex (odds ratio (OR) 1.78), HCV-antibody positivity (OR 1.72), d4T-based regimens (OR 0.51, vs. AZT), and nevirapine-based regimens (OR 0.53, vs. efavirenz) after controlling for baseline CD4 counts. Durable high-rate viral suppression was observed in the cohort of patients on first-line ART in Vietnam. Our results highlight the need to increase adherence support among injection drug users and HCV co-infected patients. © 2017 The Authors. Journal of the International AIDS Society published by John Wiley & sons Ltd on behalf of the International AIDS Society.

Serum lactate levels in infants exposed peripartum to antiretroviral agents to prevent mother-to-child transmission of HIV: Agence Nationale de Recherches Sur le SIDA et les Hépatites Virales 1209 study, Abidjan, Ivory Coast

PubMed Central

Ekouevi, Didier Koumavi; Touré, Ramata; Becquet, Renaud; Viho, Ida; Sakarovitch, Charlotte; Rouet, François; Towne-Gold, Besigin; Fassinou, Patricia; Leroy, Valériane; Blanche, Stéphane; Dabis, François

2006-01-01

Background Mitochondrial toxicity was described in infants exposed to long-term antiretroviral regimens (ARVs) containing nucleoside analogues for the prevention of mother-to-child transmission of HIV (PMTCT). We measured the serum lactate levels in children born to HIV-1 infected (HIV+) African women receiving short-term ARV PMTCT regimens. Methods A prospective study was conducted in women-child pairs from the third trimester of pregnancy to three months of life. The exposed group was formed by children exposed in utero to nucleoside analogue ARVs, zidovudine (ZDV) or ZDV + lamivudine (3TC) from 32–36 weeks of amenorrhea until delivery. All these women received nevirapine single-dose (NVPsd) at the beginning of labor. The children received ZDV during the first 7 days of life and a NVPsd at day 3. The control group was formed by infants born to HIV+ women who had received NVPsd only and not exposed to nucleoside analogue ARVs. Serum lactate levels were measured at 4, 6 and 12 weeks of life by Cobas Integra 400™. Results A total of 836 blood samples from 338 infants were collected (262 exposed and 76 controls). Median lactacidemia was 1.8 mmol/l, Interquartile Range [1.2–2.7 mmol/l]). Overall serum lactate levels ≥2.5 mmol/l, defining hyperlactatemia were observed in 39 of the 292 infants who had at least two serum lactate measurements, 13.4%, 95% confidence Interval [9.6–17.8%]. The three-month period prevalence of hyperlactatemia did not differ between the exposed group (13.1%) and the control group (14.3%) (p=0.84). All serum lactate levels returned to normal values in all subsequent samples No case of symptomatic hyperlactatemia was detected during the study period. Conclusion Increased lactate levels were identified equally in infants whose mother received a short-term of nucleoside analogues or NVPsd for PMTCT. Although not rare, hyperlactatemia was not related to short-term exposure to nucleoside analogue ARVs PMID:16950945

Predictors of 25-hydroxyvitamin D Levels in HIV-infected Patients in Hawai‘i

PubMed Central

Chow, Dominic C; Liang, Chin-Yuan; Nakamoto, Beau K; Umaki, Tracie M; Kallianpur, Kalpana J; Shikuma, Cecilia M

2013-01-01

HIV-infected individuals are at increased risk for several metabolic diseases, including low 25-hydroxyvitamin D [25(OH)D]. Data on the prevalence and risk factors for low 25(OH)D in HIV patients living in the tropics is scarce. Patients ≥ 40 years old on stable antiretroviral therapy were enrolled from March 2009 to July 2011 in Hawai‘i (latitude 21° North). Chemiluminescent immunoassay (DiaSorin) was used to determine plasma 25(OH)D levels. Patients were grouped by whether 25(OH)D was collected in summer (May 1 – September 30) or winter (October 1 – April 30). Of 158 patients enrolled, 88 (56%) and 70 (44%) were enrolled in winter and summer, respectively. There were 57.6% Caucasians and 88% men. Over-all median (quartile1, quartile3) age was 51 (46, 57) years and median 25(OH)D was 32.4 (24.0, 41.0) ng/ml. Forty-three percent (n=68) had 25(OH)D<30.0 ng/ml. Median 25(OH)D levels were 29.6 (22.0, 38.0) ng/ml in winter and 36.9 (25.0, 44.5) ng/ml in summer (P = .01). Median body mass index (BMI) of winter patients was significantly higher (P = .03). By simple linear regression, log-transformed 25(OH)D was significantly associated with winter visit (β = −.0737, P = .01), ethnicity (Caucasian versus non-Caucasian, β = .1194, P < .01), BMI (β = −.0111, P < .01) and current use of zidovudine (β = −.1233, P = .03). In multiple linear regression, only Caucasian ethnicity (β = .1004, P < .01) and BMI (β = −.0078, P = .02) retained statistical significance. Seasonal variation in 25(OH)D was observed but the significance of winter visit was not preserved in the final multivariate model. Ethnicity and BMI were better predictors of 25(OH)D levels than season in the tropics. PMID:23795329

Predictors of unstructured antiretroviral treatment interruption and resumption among HIV-positive individuals in Canada.

PubMed

Samji, H; Taha, T E; Moore, D; Burchell, A N; Cescon, A; Cooper, C; Raboud, J M; Klein, M B; Loutfy, M R; Machouf, N; Tsoukas, C M; Montaner, J S G; Hogg, R S

2015-02-01

Sustained optimal use of combination antiretroviral therapy (cART) has been shown to decrease morbidity, mortality and HIV transmission. However, incomplete adherence and treatment interruption (TI) remain challenges to the full realization of the promise of cART. We estimated trends and predictors of treatment interruption and resumption among individuals in the Canadian Observational Cohort (CANOC) collaboration. cART-naïve individuals ≥ 18 years of age who initiated cART between 2000 and 2011 were included in the study. We defined TIs as ≥ 90 consecutive days off cART. We used descriptive analyses to study TI trends over time and Cox regression to identify factors predicting time to first TI and time to treatment resumption after a first TI. A total of 7633 participants were eligible for inclusion in the study, of whom 1860 (24.5%) experienced a TI. The prevalence of TI in the first calendar year of cART decreased by half over the study period. Our analyses highlighted a higher risk of TI among women [adjusted hazard ratio (aHR) 1.59; 95% confidence interval (CI) 1.33-1.92], younger individuals (aHR 1.27; 95% CI 1.15-1.37 per decade increase), earlier treatment initiators (CD4 count ≥ 350 vs. <200 cells/μL: aHR 1.46; 95% CI 1.17-1.81), Aboriginal participants (aHR 1.67; 95% CI 1.27-2.20), injecting drug users (aHR 1.43; 95% CI 1.09-1.89) and users of zidovudine vs. tenofovir in the initial cART regimen (aHR 2.47; 95% CI 1.92-3.20). Conversely, factors predicting treatment resumption were male sex, older age, and a CD4 cell count <200 cells/μL at cART initiation. Despite significant improvements in cART since its advent, our results demonstrate that TIs remain relatively prevalent. Strategies to support continuous HIV treatment are needed to maximize the benefits of cART. © 2014 British HIV Association.

Late Antiretroviral Therapy (ART) Initiation Is Associated with Long-Term Persistence of Systemic Inflammation and Metabolic Abnormalities

PubMed Central

Ghislain, Mathilde; Bastard, Jean-Philippe; Meyer, Laurence; Capeau, Jacqueline; Fellahi, Soraya; Gérard, Laurence; May, Thierry; Simon, Anne; Vigouroux, Corinne; Goujard, Cécile

2015-01-01

Objectives HIV-induced immunodeficiency is associated with metabolic abnormalities and systemic inflammation. We investigated the effect of antiretroviral therapy (ART) on restoration of insulin sensitivity, markers of immune activation and inflammation. Methods Immunological, metabolic and inflammatory status was assessed at antiretroviral therapy initiation and three years later in 208 patients from the ANRS-COPANA cohort. Patients were compared according to their pre-ART CD4+ cell count (group 1: ≤ 200/mm3, n = 66 vs. group 2: > 200/mm3, n = 142). Results Median CD4+ cell count increased in both groups after 3 years of successful ART but remained significantly lower in group 1 than in group 2 (404 vs 572 cells/mm3). Triglyceride and insulin levels were higher or tended to be higher in group 1 than in group 2 at ART initiation (median: 1.32 vs 0.97 mmol/l, p = 0.04 and 7.6 vs 6.8 IU, p = 0.09, respectively) and remained higher after three years of ART (1.42 vs 1.16 mmol/L, p = 0.0009 and 8.9 vs 7.2 IU, p = 0.01). After adjustment for individual characteristics and antiretroviral therapy regimens (protease inhibitor (PI), zidovudine), insulin levels remained significantly higher in patients with low baseline CD4+ cell count. Baseline IL-6, sCD14 and sTNFR2 levels were higher in group 1 than in group 2. Most biomarkers of immune activation/inflammation declined during ART, but IL-6 and hsCRP levels remained higher in patients with low baseline CD4+ cell count than in the other patients (median are respectively 1.4 vs 1.1 pg/ml, p = 0.03 and 2.1 vs 1.3 mg/ml, p = 0.07). Conclusion After three years of successful ART, low pretreatment CD4+ T cell count remained associated with elevated insulin, triglyceride, IL-6 and hsCRP levels. These persistent metabolic and inflammatory abnormalities could contribute to an increased risk of cardiovascular and metabolic disease. PMID:26636578

Birth outcome in HIV vertically-exposed children in two Romanian centers

PubMed Central

Tudor, Ana Maria; Mărdărescu, Mariana; Petre, Cristina; Neagu Drăghicenoiu, Ruxandra; Ungurianu, Rodica; Tilişcan, Cătălin; Oţelea, Dan; Cambrea, Simona Claudia; Tănase, Doina Eugenia; Schweitzer, Ana Maria; Ruţă, Simona

2015-01-01

Background The Romanian HIV epidemic is characterized by a high prevalence among children born in the late ’80s, perinatally infected. The impact of long-term treatment on their offspring is unknown. We evaluated the influence of prenatal care on the rate of premature birth among the HIV-exposed children of heavily treated HIV-infected mothers in two Romanian centers. Methods We retrospectively analyzed data on all patients born by HIV-infected mothers between 2006 and 2012 followed up in two main regional centers. We compared the rate of premature birth and the differences between the sites regarding children and maternal demographic characteristics and antiretroviral exposure in pregnant women. Results A total of 358 children born to 315 women were enrolled between 2006-2012, 262 children from the National Institute for Infectious Diseases “Prof. Dr. Matei Balş” Bucharest (NIID) and 96 children from the Clinical Infectious Diseases Hospital Constanţa (IDHC). Gender rate in newborns and mean age in mothers were similar. We recorded statistically significant differences between centers in the rate of HIV vertical transmission (16.8% vs. 6.2%, p=0.002) and prematurity (25.2 vs. 14.6%, p=0.023). The most used antiretroviral combination during pregnancy in IDHC was boosted lopinavir and fixed dose zidovudine-lamivudine (66% of cases), while in NIID a greater diversity of antiretrovirals were used. Women from IDHC were more frequently treated during pregnancy (83.3% vs. 68.6%, p=0.004). HCV coinfection and illegal drug use were associated with prematurity in the NIID cohort (p=0.037, p=0.024). Conclusion We found a higher rate of premature birth and HIV infection in NIID. In IDHC we found a higher rate of low birth weight in children and a higher rate of heavily treated women. Prematurity was associated with hepatitis C infection and illegal drug use in the NIID cohort. PMID:26716100

Endothelial Function in HIV-Infected Antiretroviral Naïve Subjects Before and After Starting Potent Antiretroviral Therapy: AIDS Clinical Trials Group Study 5152s

PubMed Central

Torriani, Francesca J.; Komarow, Lauren; Parker, Robert A.; Cotter, Bruno R.; Currier, Judith S.; Dubé, Michael P.; Fichtenbaum, Carl J.; Gerschenson, Mariana; Mitchell, Carol K.C.; Murphy, Robert L.; Squires, Kathleen; Stein, James H.

2008-01-01

Objectives This study evaluated the effects of three class-sparing antiretroviral therapy (ART) regimens on endothelial function in HIV-infected subjects participating in a randomized trial. Background Endothelial dysfunction has been observed in patients receiving ART for human immunodeficiency virus (HIV) infection. Methods This was a prospective, multicenter study of treatment-naïve subjects who were randomly assigned to receive a protease inhibitor-sparing regimen of nucleoside reverse transcriptase inhibitors (NRTIs) + efavirenz, a non-nucleoside reverse transcriptase inhibitor-sparing regimen of NRTIs + lopinavir/ritonavir, or a NRTI-sparing regimen of efavirenz + lopinavir/ritonavir. NRTIs were lamivudine + stavudine, zidovudine, or tenofovir. Brachial artery flow-mediated dilation (FMD) was determined by B-mode ultrasound before starting on ART, then after 4 and 24 weeks. Results There were 82 subjects (median age 35 years, 91% men, 54% white). Baseline CD4 cell counts and plasma HIV RNA values were 245 cells/mm3 and 4.8 log10 copies/ml, respectively. At baseline, FMD was 3.68% (interquartile range 1.98 – 5.51%). After 4 and 24 weeks of ART, plasma HIV RNA decreased by 2.1 and 3.0 log10 copies/mL, respectively. FMD increased by 0.74% (−0.62 – +2.74, p=0.003) and 1.48% (−0.20 – +4.30%, p< 0.001), respectively, with similar changes in each arm (pKW>0.600). The decrease in plasma HIV RNA at 24 weeks was associated with greater FMD (rs=− 0.30, p=0.017). Conclusions Among treatment-naïve individuals with HIV, three different ART regimens rapidly improved endothelial function. Benefits were similar for all ART regimens, appeared quickly, and persisted at 24 weeks. Condensed Abstract Among 82 treatment-naïve HIV-infected subjects participating in a prospective, multicenter study of three class-sparing antiretroviral therapy regimens, flow-mediated dilation of the brachial artery improved after 4 (+0.74%, p=0.003) and 24 weeks (+1.48%, p< 0

Thai national guidelines for the prevention of mother-to-child transmission of human immunodeficiency virus 2017

PubMed Central

Lolekha, Rangsima; Chokephaibulkit, Kulkanya; Phanuphak, Nittaya; Chaithongwongwatthana, Surasith; Kiertiburanakul, Sasisopin; Chetchotisakd, Pleonchan; Boonsuk, Sarawut

2018-01-01

Background Thailand has made progress in reducing perinatal HIV transmission rates to levels that meet the World Health Organization targets for so-called “elimination” (<2%) of mother-to-child transmission (MTCT). Objectives To highlight the Thailand National Guidelines on HIV/AIDS Treatment Prevention Working Group issued a new version of its National Prevention of MTCT guidelines in March 2017 aimed to reduce MTCT rate to <1% by 2020. Discussion of guidelines The guidelines include recommending initiation of antepartum antiretroviral therapy (ART) containing tenofovir disoproxil fumarate (TDF) plus lamivudine (3TC)/emtricitabine (FTC) plus efavirenz regardless of CD4 cell count as soon as HIV is diagnosed for ART naïve HIV-infected pregnant women. An alternative regimen is TDF or zidovudine (AZT) plus 3TC/FTC plus lopinavir/ritonavir (LPV/r) for HIV-infected pregnant women suspected resistant to non-nucleoside reverse transcriptase inhibitors. Treatment should be started immediately irrespective of gestational age and continued after delivery for life. Raltegravir is recommended in addition to the ART regimen for HIV-infected pregnant women who present late (gestational age (GA) ≥32 weeks) or those who have a viral load (VL) >1000 copies/mL at GA ≥32 weeks. HIV-infected pregnant women who conceive while receiving ART should continue their treatment regimen during pregnancy. HIV-infected pregnant women who present in labor and are not receiving ART should receive single-dose nevirapine immediately along with oral AZT, and continue ART for life. Infants born to HIV-infected mothers are categorized as high or standard risk for MTCT. High MTCT risk is defined as an infant whose mother has a viral load (VL) > 50 copies/mL at GA > 36 weeks or has received ART <12 weeks before delivery, or has poor ART adherence. These infants should be started on AZT plus 3TC plus NVP for 6 weeks after delivery. Infants with standard MTCT risk should receive AZT for 4 weeks

Cross Sectional Characterization of Factors Associated with Pediatric HIV Status Disclosure in Southern Ethiopia.

PubMed

Tadesse, Birkneh Tilahun; Foster, Byron Alexander; Berhan, Yifru

2015-01-01

Disclosure of HIV positive status to children and adolescents is a complex process. However, disclosure has been found to be associated with improved outcomes. The objective of the current study was to identify the predictors that facilitate disclosure of HIV status to children and adolescents and to study the reasons for non-disclosure. Interviews of caregivers and reviews of records were done to collect data on caregiver and child information and details regarding the disclosure status of children. Bivariate analysis was done to test the association between HIV status disclosure and different caregiver and child factors. To identify the independent predictors of disclosure, we did multivariable logistic regression. A total of 177 children attending an HIV clinic were included. The mean age of the participants was 10.1 years (SD = 2.8), and about half (50.8%) were female. Most caregivers, 137 (77.8%) stated that disclosure of HIV status to children is important and should be done. However, disclosure had only been made to 59 (33.3%) of the participants. Child age more than 10 years [AOR = 6.7; 95%CI: 1.73-26.01], duration of HIV diagnosis of 5 years or more [AOR = 4.4; 95%CI: 1.26-15.06] and taking a zidovudin (AZT) based regimen [AOR = 3.5; 95%CI: 1.31-9.53] predicted HIV positive status disclosure. Additionally, length of treatment of caregivers of more than 14 years [AOR = 3.9; 95%CI: 1.07-14.61], disclosure of caregiver's HIV status to children and/or others [AOR = 4.7; 95%CI: 1.19-18.74], and the child's inquiry about their condition [AOR = 4.5; 95%CI: 1.16-17.43] increased the odds of disclosure. The rate of disclosure among HIV infected children in southern Ethiopia is low. Primarily time-based factors were associated with the probability of HIV positive status disclosure and a specific regimen which has not been found previously. Further qualitative research may elucidate more on these factors; educational strategies may address some of these determinants.

Risk factors for mortality in a south Indian population on generic antiretroviral therapy.

PubMed

Rupali, Priscilla; Mannam, Sam; Bella, Annie; John, Lydia; Rajkumar, S; Clarence, Peace; Pulimood, Susanne A; Samuel, Prasanna; Karthik, Rajiv; Abraham, Ooriapadickal Cherian; Mathai, Dilip

2012-12-01

Antiretroviral treatment (ART) programs from low-income countries utilizing standardized ART regimens, simplified approaches to clinical decision making and basic lab monitoring have reported high mortality rates. We determined the risk factors for mortality among HIV-infected adults following the initiation of ART from a single center in south India. ART-naive HIV-infected south Indian adults attending the Infectious Diseases clinic in a 2000-bed academic medical center in south India who were initiated on ART (generic, fixed-dose combinations) as per the national guidelines were followed up. Cases (32 patients who died) were compared with age and sex matched controls. Eight-hundred and twenty-two patients were started on ART from January 1, 2000 to December 31, 2008. The cumulative mortality was 6.8% (56/822). Among the cases mean age was 44 years, 18% were women and mean CD4 counts was 107 cells/microl. Among the controls mean age was 41 years, 18% were women and mean CD4 counts were 113 cells/microl. Stavudine based ART was predominant 62.5% in the cases vs 37.5% in the controls, followed by zidovudine based therapy in 31.2% of cases and 43.7% in the controls. Tenofovir based therapy was used in 6.2% of cases vs 18.7% in the controls. The commonest causes of death were drug toxicity 19%, advanced Acquired Immunodeficiency Syndrome (AIDS) in 37%, Immune Reconstitution Inflammatory Syndrome (IRIS) in 16%, non AIDS related deaths in 22% and malignancies 6%. In a univariate analysis, absolute lymphocyte count <1200 cells/cmm (p=0.03), development of immune reconstitution inflammatory syndrome (IRIS) (p=0.000) and mean CD4 cell count increase <75 cells/microl after 1 year of ART (p=0.001) were significantly associated with mortality. The mortality among our patients was comparable to that reported from other low-income countries. Earlier initiation of ART may reduce the high mortality rates observed.

Molecular mechanisms of serotonergic action of the HIV-1 antiretroviral efavirenz.

PubMed

Dalwadi, Dhwanil A; Kim, Seongcheol; Amdani, Shahnawaz M; Chen, Zhenglan; Huang, Ren-Qi; Schetz, John A

2016-08-01

Efavirenz is highly effective at suppressing HIV-1, and the WHO guidelines list it as a component of the first-line antiretroviral (ARV) therapies for treatment-naïve patients. Though the pharmacological basis is unclear, efavirenz is commonly associated with a risk for neuropsychiatric adverse events (NPAEs) when taken at the prescribed dose. In many patients these NPAEs appear to subside after several weeks of treatment, though long-term studies show that in some patients the NPAEs persist. In a recent study focusing on the abuse potential of efavirenz, its receptor psychopharmacology was reported to include interactions with a number of established molecular targets for known drugs of abuse, and it displayed a prevailing behavioral profile in rodents resembling an LSD-like activity. In this report, we discovered interactions with additional serotonergic targets that may be associated with efavirenz-induced NPAEs. The most robust interactions were with 5-HT3A and 5-HT6 receptors, with more modest interactions noted for the 5-HT2B receptor and monoamine oxidase A. From a molecular mechanistic perspective, efavirenz acts as a 5-HT6 receptor inverse agonist of Gs-signaling, 5-HT2A and 5-HT2C antagonist of Gq-signaling, and a blocker of the 5-HT3A receptor currents. Efavirenz also completely or partially blocks agonist stimulation of the M1 and M3 muscarinic receptors, respectively. Schild analysis suggests that efavirenz competes for the same site on the 5-HT2A receptor as two known hallucinogenic partial agonists (±)-DOI and LSD. Prolonged exposure to efavirenz reduces 5-HT2A receptor density and responsiveness to 5-HT. Other ARVs such as zidovudine, nevirapine and emtricitabine did not share the same complex pharmacological profile as efavirenz, though some of them weakly interact with the 5-HT6 receptor or modestly block GABAA currents. Published by Elsevier Ltd.

Use of antiretroviral therapy in resource-limited countries in 2006: distribution and uptake of first- and second-line regimens.

PubMed

Renaud-Théry, Françoise; Nguimfack, Boniface Dongmo; Vitoria, Marco; Lee, Evan; Graaff, Peter; Samb, Badara; Perriëns, Joseph

2007-07-01

To address the information gap on current use of antiretroviral drugs (ARTs) in developing countries. The AIDS Medicines and Diagnostics Service of the World Health Organization (WHO) carried out a multi-country survey in early 2006. Questionnaires covered the use of first- and second-line regimens in adults and children, and the rates of switching from first-line to second-line regimen. Weighted percentages of use of ARTs across the cohort of adults and children were calculated and correlated with 2006 WHO guidelines. A second analysis compared demand for ARTs with rates of production of active pharmaceutical ingredients. Twenty-three countries (96%) returned the questionnaires, representing 53% of relevant patients in developing countries as of June 2006, and comprising 92% adults and 8% children receiving ARTs. Response rates were highest for questions regarding first-line use and lowest for those regarding pediatric regimens. The distribution of first-line: second-line use was 96%: 4% among adults and 99%: 1% among children. For adults, 95% of those receiving first-line treatment, but only 25% of those receiving second-line treatment, were on regimens consistent with those preferred by the WHO. Among first-line users, the most common regimen (61%) was stavudine+lamivudine+nevirapine. Among second-line users, abacavir+didanosine+lopinavir/ritonavir was the most common regimen (24%). Among children, compliance with WHO guidelines was high among the respondents, with zidovudine+lamivudine+nevirapine reported as the main option. Estimates of first-year switching rate were highly variable, ranging from 1% to 15%, with only ten responses. Comparison of supply and demand showed that the stated production capacity for active pharmaceutical ingredients is sufficient to meet current demands for ARTs. This survey has provided valuable information on the uptake of ARTs in developing countries and will help forecast future demand. Reporting for second-line and pediatric

Impact of drug stock-outs on death and retention to care among HIV-infected patients on combination antiretroviral therapy in Abidjan, Côte d'Ivoire.

PubMed

Pasquet, Armelle; Messou, Eugène; Gabillard, Delphine; Minga, Albert; Depoulosky, Ayeby; Deuffic-Burban, Sylvie; Losina, Elena; Freedberg, Kenneth A; Danel, Christine; Anglaret, Xavier; Yazdanpanah, Yazdan

2010-10-15

To evaluate the type and frequency of antiretroviral drug stock-outs, and their impact on death and interruption in care among HIV-infected patients in Abidjan, Côte d'Ivoire. We conducted a cohort study of patients who initiated combination antiretroviral therapy (cART) in three adult HIV clinics between February 1, 2006 and June 1, 2007. Follow-up ended on February 1, 2008. The primary outcome was cART regimen modification, defined as at least one drug substitution, or discontinuation for at least one month due to drug stock-outs at the clinic pharmacy. The secondary outcome for patients who were on cART for at least six months was interruption in care, or death. A Cox regression model with time-dependent variables was used to assess the impact of antiretroviral drug stock-outs on interruption in care or death. Overall, 1,554 adults initiated cART and were followed for a mean of 13.2 months. During this time, 72 patients discontinued treatment and 98 modified their regimen because of drug stock-outs. Stock-outs involved nevirapine and fixed-dose combination zidovudine/lamivudine in 27% and 51% of cases. Of 1,554 patients, 839 (54%) initiated cART with fixed-dose stavudine/lamivudine/nevirapine and did not face stock-outs during the study period. Among the 975 patients who were on cART for at least six months, stock-out-related cART discontinuations increased the risk of interruption in care or death (adjusted hazard ratio [HR], 2.83; 95%CI, 1.25-6.44) but cART modifications did not (adjusted HR, 1.21; 95%CI, 0.46-3.16). cART stock-outs affected at least 11% of population on treatment. Treatment discontinuations due to stock-outs were frequent and doubled the risk of interruption in care or death. These stock-outs did not involve the most common first-line regimen. As access to cART continues to increase in sub-Saharan Africa, first-line regimens should be standardized to decrease the probability of drug stock-outs.

Inaccuracy of haemoglobin A1c among HIV-infected men: effects of CD4 cell count, antiretroviral therapies and haematological parameters

PubMed Central

Slama, Laurence; Palella, Frank J.; Abraham, Alison G.; Li, Xiuhong; Vigouroux, Corinne; Pialoux, Gilles; Kingsley, Lawrence; Lake, Jordan E.; Brown, Todd T.; Margolick, Joseph B.; Crain, Barbara; Dobs, Adrian; Farzadegan, Homayoon; Gallant, Joel; Johnson-Hill, Lisette; Plankey, Michael; Sacktor, Ned; Selnes, Ola; Shepard, James; Thio, Chloe; Wolinsky, Steven M.; Phair, John P.; Badri, Sheila; O'Gorman, Maurice; Ostrow, David; Palella, Frank; Ragin, Ann; Detels, Roger; Martínez-Maza, Otoniel; Aronow, Aaron; Bolan, Robert; Breen, Elizabeth; Butch, Anthony; Jamieson, Beth; Miller, Eric N.; Oishi, John; Vinters, Harry; Wiley, Dorothy; Witt, Mallory; Yang, Otto; Young, Stephen; Zhang, Zuo Feng; Rinaldo, Charles R.; Kingsley, Lawrence A.; Becker, James T.; Cranston, Ross D.; Martinson, Jeremy J.; Mellors, John W.; Silvestre, Anthony J.; Stall, Ronald D.; Jacobson, Lisa P.; Munoz, Alvaro; Abraham, Alison; Althoff, Keri; Cox, Christopher; D'Souza, Gypsyamber; Golub, Elizabeth; Schollenberger, Janet; Seaberg, Eric C.; Su, Sol; Huebner, Robin E.; Dominguez, Geraldina

2014-01-01

Background There is limited evidence that among HIV-infected patients haemoglobin A1c (HbA1c) values may not accurately reflect glycaemia. We assessed HbA1c discordance (observed HbA1c − expected HbA1c) and associated factors among HIV-infected participants in the Multicenter AIDS Cohort Study (MACS). Methods Fasting glucose (FG) and HbA1c were measured at each semi-annual MACS visit since 1999. All HIV-infected and HIV-uninfected men for whom at least one FG and HbA1c pair measurement was available were evaluated. Univariate median regression determined the association between HbA1c and FG by HIV serostatus. The relationship between HbA1c and FG in HIV-uninfected men was used to determine the expected HbA1c. Generalized estimating equations determined factors associated with the Hb1Ac discordance among HIV-infected men. Clinically significant discordance was defined as observed HbA1c − expected HbA1c ≤−0.5%. Results Over 13 years, 1500 HIV-uninfected and 1357 HIV-infected men were included, with a median of 11 visits for each participant. At an FG of 125 mg/dL, the median HbA1c among HIV-infected men was 0.21% lower than among HIV-uninfected men and the magnitude of this effect increased with FG >126 mg/dL. Sixty-three percent of HIV-infected men had at least one visit with clinically significant HbA1c discordance, which was independently associated with: low CD4 cell count (<500 cells/mm3); a regimen containing a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor or zidovudine; high mean corpuscular volume; and abnormal corpuscular haemoglobin. Conclusion HbA1c underestimates glycaemia in HIV-infected patients and its use in patients with risk factors for HbA1c discordance may lead to under-diagnosis and to under-treatment of established diabetes mellitus. PMID:25096078

Nucleoside Reverse Transcriptase Inhibitors Suppress Laser-Induced Choroidal Neovascularization in Mice

PubMed Central

Mizutani, Takeshi; Fowler, Benjamin J.; Kim, Younghee; Yasuma, Reo; Krueger, Laura A.; Gelfand, Bradley D.; Ambati, Jayakrishna

2015-01-01

Purpose To evaluate the efficacy of nucleoside reverse transcriptase inhibitors (NRTIs) in the laser-induced mouse model of choroidal neovascularization (CNV). Methods We evaluated the NRTIs lamivudine (3TC), zidovudine (AZT), and abacavir (ABC) and the P2X7 antagonist A438079. Choroidal neovascularization was induced by laser injury in C57BL/6J wild-type, Nlrp3−/−, and P2rx7−/− mice, and CNV volume was measured after 7 days by confocal microscopy. Drugs were administered by intravitreous injection immediately after the laser injury. Vascular endothelial growth factor-A in RPE-choroid lysates was measured 3 days after laser injury by ELISA. HEK293 cells expressing human and mouse P2X7 were exposed to the selective P2X7 receptor agonist 2′, 3′-(benzoyl-4-benzoyl)-ATP (Bz-ATP) with or without 3TC, and VEGF-A levels in media were measured by ELISA. Results Intravitreous injection of 3TC, AZT, and ABC significantly suppressed laser-induced CNV in C57BL/6J wild-type and Nlrp3−/− mice (P < 0.05) but not in P2rx7−/− mice. Intravitreous injection of A438079 also suppressed the laser-induced CNV (P < 0.05). The NRTIs 3TC, AZT, and ABC blocked VEGF-A levels in the RPE/choroid after laser injury in wild-type (P < 0.05) but not P2rx7−/− mice. Moreover, there was no additive effect of 3TC on CNV inhibition when coadministered with a neutralizing VEGF-A antibody. Stimulation of human and mouse P2X7-expressing HEK293 cells with Bz-ATP increased VEGF secretion (P < 0.001), which was abrogated by 3TC (P < 0.001). Stimulation of primary human RPE cells with Bz-ATP increased VEGFA and IL6 mRNA levels, which were abrogated by 3TC. Conclusions Multiple clinically relevant NRTIs suppressed laser-induced CNV and downregulated VEGF-A, via P2X7. PMID:26529046

Facteurs influençant l'initiation au traitement antirétroviral des personnes vivant avec le VIH dans les Centres de Traitement Agréés de Bamenda et de Bertoua au Cameroun

PubMed Central

Mbopi-Keou, Francois-Xavier; Voundi, Esther Voundi; Kalla, Ginette Claude Mireille; Emah, Irène; Angwafo, Fru; Muna, Walinjom

2014-01-01

Introduction L'objectif de ce travail était de déterminer les facteurs influençant l'initiation au traitement antirétroviral des personnes vivant avec le VIH (PVVIH) dans les centres de traitements agrées (CTA) de Bamenda et de Bertoua au Cameroun. Méthodes Il s'agissait d'une étude transversale, analytique réalisée de Janvier à Avril 2011, dans les CTA de Bamenda et de Bertoua. Pour cette étude, nous avons obtenu une clairance éthique. Résultats Nous avons étudiés 460 dossiers de patients séropositifs en phase d'initiation au traitement antirétroviral dans les CTA de Bamenda et de Bertoua, 53,9% et 46,1% respectivement. L ‘âge médian était de 36 ans. La plupart des séropositifs à Bertoua (41) avaient fait un dépistage volontaire du VIH par rapport à ceux de Bamenda (22) (p= 0.008). Il y ‘avait plus de VIH de type 1 et 2 dans le CTA de Bamenda (15) par rapport à Bertoua (3) (p= 0.011). La majorité des patients était classé au stade clinique II à Bamenda (54,0%) tandis qu ‘à Bertoua le stade clinique III était prédominant (52,4%) (p = 0,000). Le taux médian de CD4 était de 133 cellules/mm3 dans le CTA de Bamenda et de 175 cellules/mm3 à Bertoua (p = 0,008). La Zidovudine était plus prescrit à Bamenda et le Ténofovir à Bertoua (p = 0,000). L ‘Efavirenz était plus prescrit à Bertoua tandis que la Névirapine l ‘était plus à Bamenda (p = 0,000). Le Lopinavir/r était plus prescrit à Bamenda qu ‘à Bertoua (p = 0,017). Conclusion Il apparait urgent de standardiser la prise en charge des PVVIH dans les CTA du Cameroun. PMID:25184023

Reduced Antituberculosis Drug Concentrations in HIV-Infected Patients Who Are Men or Have Low Weight: Implications for International Dosing Guidelines

PubMed Central

Rustomjee, Roxana; Vahedi, Mahnaz; Mthiyane, Thuli; Denti, Paolo; Connolly, Catherine; Rida, Wasima; Pym, Alexander; Smith, Peter J.; Onyebujoh, Philip C.

2012-01-01

Reduced antituberculosis drug concentrations may contribute to unfavorable treatment outcomes among HIV-infected patients with more advanced immune suppression, and few studies have evaluated pharmacokinetics of the first-line antituberculosis drugs in such patients given fixed-dose combination tablets according to international guidelines using weight bands. In this study, pharmacokinetics were evaluated in 60 patients on 4 occasions during the first month of antituberculosis therapy. Multilevel linear mixed-effects regression analysis was used to examine the effects of age, sex, weight, drug dose/kilogram, CD4+ lymphocyte count, treatment schedule (5 versus 7 days/week), and concurrent antiretrovirals (efavirenz plus lamivudine plus zidovudine) on the area under the concentration-time curve from 0 to 12 h (AUC0-12) of the respective antituberculosis drugs and to compare AUC0-12s at day 8, day 15, and day 29 with the day 1 AUC0-12. Median (range) age, weight, and CD4+ lymphocyte count were 32 (18 to 47) years, 55.2 (34.4 to 98.7) kg, and 252 (12 to 500)/μl. For every 10-kg increase in body weight, the predicted day 29 AUC0-12 increased by 14.1% (95% confidence interval [CI], 7.5, 20.8), 14.1% (95% CI, −0.7, 31.1), 6.1% (95% CI, 2.7, 9.6) and 6.0% (95% CI, 0.8, 11.3) for rifampin, isoniazid, pyrazinamide, and ethambutol, respectively. Males had day 29 AUC0-12s 19.3% (95% CI, 3.6, 35.1) and 14.0% (95% CI, 5.6, 22.4) lower than females for rifampin and pyrazinamide, respectively. Level of immune suppression and concomitant antiretrovirals had little effect on the concentrations of the antituberculosis agents. As they had reduced drug concentrations, it is important to review treatment responses in patients in the lower weight bands and males to inform future treatment guidelines, and revision of doses in these patients should be considered. PMID:22411614

Reduced antituberculosis drug concentrations in HIV-infected patients who are men or have low weight: implications for international dosing guidelines.

PubMed

McIlleron, Helen; Rustomjee, Roxana; Vahedi, Mahnaz; Mthiyane, Thuli; Denti, Paolo; Connolly, Catherine; Rida, Wasima; Pym, Alexander; Smith, Peter J; Onyebujoh, Philip C

2012-06-01

Reduced antituberculosis drug concentrations may contribute to unfavorable treatment outcomes among HIV-infected patients with more advanced immune suppression, and few studies have evaluated pharmacokinetics of the first-line antituberculosis drugs in such patients given fixed-dose combination tablets according to international guidelines using weight bands. In this study, pharmacokinetics were evaluated in 60 patients on 4 occasions during the first month of antituberculosis therapy. Multilevel linear mixed-effects regression analysis was used to examine the effects of age, sex, weight, drug dose/kilogram, CD4(+) lymphocyte count, treatment schedule (5 versus 7 days/week), and concurrent antiretrovirals (efavirenz plus lamivudine plus zidovudine) on the area under the concentration-time curve from 0 to 12 h (AUC(0-12)) of the respective antituberculosis drugs and to compare AUC(0-12)s at day 8, day 15, and day 29 with the day 1 AUC(0-12). Median (range) age, weight, and CD4(+) lymphocyte count were 32 (18 to 47) years, 55.2 (34.4 to 98.7) kg, and 252 (12 to 500)/μl. For every 10-kg increase in body weight, the predicted day 29 AUC(0-12) increased by 14.1% (95% confidence interval [CI], 7.5, 20.8), 14.1% (95% CI, -0.7, 31.1), 6.1% (95% CI, 2.7, 9.6) and 6.0% (95% CI, 0.8, 11.3) for rifampin, isoniazid, pyrazinamide, and ethambutol, respectively. Males had day 29 AUC(0-12)s 19.3% (95% CI, 3.6, 35.1) and 14.0% (95% CI, 5.6, 22.4) lower than females for rifampin and pyrazinamide, respectively. Level of immune suppression and concomitant antiretrovirals had little effect on the concentrations of the antituberculosis agents. As they had reduced drug concentrations, it is important to review treatment responses in patients in the lower weight bands and males to inform future treatment guidelines, and revision of doses in these patients should be considered.

Occurrence, fate and removal of pharmaceuticals, personal care products and pesticides in wastewater stabilization ponds and receiving rivers in the Nzoia Basin, Kenya.

PubMed

K'oreje, Kenneth Otieno; Kandie, Faith Jebiwot; Vergeynst, Leendert; Abira, Margaret Akinyi; Van Langenhove, Herman; Okoth, Maurice; Demeestere, Kristof

2018-05-08

Although there is increased global environmental concern about emerging organic micropollutants (EOMPs) such as pharmaceuticals, personal care products (PPCPs) and polar pesticides, limited information is available on their occurrence in Africa. This study presents unique data on concentrations and loads of 31 PPCPs and 10 pesticides in four wastewater stabilization ponds (WSPs) and receiving rivers (flowing through urban centres) in Kenya. The WSPs indicate a high potential to remove pharmaceutically active compounds (PhACs) with removals by up to >4 orders of magnitude (>99.99% removal), mainly occurring at the facultative stage. However, there are large differences in removal among the different classes, and a shift in the relative PhACs occurrence is observed during wastewater treatment. Whereas the influent is dominated by high-consumption PhACs like anti-inflammatory drugs (e.g. paracetamol and ibuprofen, up to 1000 μg L -1 ), the most recalcitrant PhACs including mainly antibiotics (e.g. sulfadoxin and sulfamethoxazole) and antiretrovirals (e.g. lamivudine and nevirapine) are largely abundant (up to 100 μg L -1 ) in treated effluent. Overall, concentrations of EOMPs in the Nzoia Basin rivers are the highest in dry season (except pesticides) and in small tributaries. They are of the same order of magnitude as those measured in the western world, but clearly lower than what we recently measured in the Ngong River, Nairobi region. Based on the specific consumption patterns and recalcitrant behavior, high concentrations (>1000 ng L -1 ) are observed in the rivers for PPCPs like lamivudine, zidovudine, sulfamethoxazole and methylparaben. Concentration levels of pesticides are in general one order of magnitude lower (<250 ng L -1 ). Our data suggest a continuous input of EOMPs to the rivers from both point (WSPs) and diffuse (urban centres) sources. To better understand and manage the impact of both sources, EOMP removal mechanisms in WSPs and

Antiretroviral treatment, viral load of mothers & perinatal HIV transmission in Mumbai, India

PubMed Central

Ahir, Swati P.; Chavan, V.; Kerkar, S.; Samant-Mavani, P.; Nanavati, R.; Mehta, P.R.; Mania-Pramanik, J.

2013-01-01

Background & objectives: Mother-to-child transmission (MTCT) is the most significant route of HIV transmission in children below the age of 15 yr. In India, perinatal HIV transmission, even after treatment, accounts for 5.4 per cent of HIV cases. The present study was conducted to evaluate the efficacy of anti-retro viral therapy (ART) or prophylactic treatment (PT) to control maternal viral load in HIV positive women, and its effect on vertical HIV transmission to their infants. Methods: A total of 58 HIV positive women were enrolled at the time of delivery and their plasma samples were obtained within 24 h of delivery for estimation of viral load. Viral load analysis was completed in 38 women. Infants received single dose nevirapine within 2 h of birth and zidovudine for 6 wk. At the end of 18 month follow up, HIV positive or negative status was available in 28 infants. Results: Results revealed undetectable levels of viral load in 58.3 per cent of women with ART compared to 30.7 per cent of women with PT. No women on ART had viral load more than 10,000 copies/ml, whereas seven (26.9%, P=0.07) women receiving PT had this viral load. Median CD4 count of women on PT (483 cells/μl) was high compared to the women on ART (289 cells/ μl). At the end of 18 months follow up, only two children were HIV positive, whose mothers were on PT. One had in utero transmission; infection detected within 48 h of delivery, while the other child was infected post partum as HIV was detected at six months follow up. Interpretation & conclusions: Women who received a single dose of nevirapine during delivery had higher levels of viral load than women on ART. Combination drug therapy for pregnant women is now a standard of care in most of the western countries; use of nevirapine monotherapy at the time of delivery in our settings is not effective in controlling viral load. This highlights initiation of ART in pregnant women to control their viral load and thus to inhibit mother to child

Adult HIV care resources, management practices and patient characteristics in the Phase 1 IeDEA Central Africa cohort

PubMed Central

Divaris, Kimon; Newman, Jamie; Hemingway-Foday, Jennifer; Akam, Wilfred; Balimba, Ashu; Dusengamungu, Cyrille; Kalenga, Lucien; Mbaya, Marcel; Molu, Brigitte Mfangam; Mugisha, Veronicah; Mukumbi, Henri; Mushingantahe, Jules; Nash, Denis; Niyongabo, Théodore; Atibu, Joseph; Azinyue, Innocent; Kiumbu, Modeste; Woelk, Godfrey

2012-01-01

Introduction Despite recent advances in the management of HIV infection and increased access to treatment, prevention, care and support, the HIV/AIDS epidemic continues to be a major global health problem, with sub-Saharan Africa suffering by far the greatest humanitarian, demographic and socio-economic burden of the epidemic. Information on HIV/AIDS clinical care and established cohorts’ characteristics in the Central Africa region are sparse. Methods A survey of clinical care resources, management practices and patient characteristics was undertaken among 12 adult HIV care sites in four countries of the International Epidemiologic Databases to Evaluate AIDS Central Africa (IeDEA-CA) Phase 1 regional network in October 2009. These facilities served predominantly urban populations and offered primary care in the Democratic Republic of Congo (DRC; six sites), secondary care in Rwanda (two sites) and tertiary care in Cameroon (three sites) and Burundi (one site). Results Despite some variation in facility characteristics, sites reported high levels of monitoring resources, including electronic databases, as well as linkages to prevention of mother-to-child HIV transmission programs. At the time of the survey, there were 21,599 HIV-positive adults (median age=37 years) enrolled in the clinical cohort. Though two-thirds were women, few adults (6.5%) entered HIV care through prevention of mother-to-child transmission services, whereas 55% of the cohort entered care through voluntary counselling and testing. Two-thirds of patients at sites in Cameroon and DRC were in WHO Stage III and IV at baseline, whereas nearly all patients in the Rwanda facilities with clinical stage information available were in Stage I and II. WHO criteria were used for antiretroviral therapy initiation. The most common treatment regimen was stavudine/lamivudine/nevirapine (64%), followed by zidovudine/lamivudine/nevirapine (19%). Conclusions Our findings demonstrate the feasibility of

An assessment of mother-to-child HIV transmission prevention in 16 pilot antenatal clinics in Jamaica.

PubMed

Harvey, K M; Figueroa, J P; Tomlinson, J; Gebre, Y; Forbes, S; Toyloy, T; Thompson, T; Thompson, K

2004-10-01

This study aims to determine the number and age distribution of pregnant women testing positive for HIV at 16 selected clinics in Jamaica between 2001 and 2002; the utilization of therapeutic interventions to minimize the risk of mother-to-child transmission (MTCT) and the current status of the HIV-exposed infants and, finally, the number of children who received testing for detection of HIV and to calculate the incidence of MTCT in these children. A retrospective study was carried out at sixteen pilot clinic sites by examining the patient records for all confirmed HIV-positive pregnant mothers and the resultant infants at these facilities for the period January 2001 to December 2002. One hundred and twenty-three of 8116 pregnant women newly tested positive during the period January 2001 to December 2002; however, 176 HIV+ women delivered. Fifty-three (30%) knew their HIV status prior to participating in the programme. Sixty-two (1.4%) and 61 (1.6%) tested positive in 2001 and 2002, respectively. One hundred and ten (77%) and 113 (83%) mothers and infants, respectively, received ARV therapy, (92% - nevirapine, 8% - zidovudine). Twenty-three per cent of pregnant women received no ARV Forty-four (25.0%) of the 176 infants had a documented ELISA HIV test before eighteen months of age, none had a PCR test. The health status of 40 (23%) of these children was known: 30 (75%) were alive and well, five of whom did not receive any ARV, one (2.5%) was alive and ill and nine (22.5%) were reported dead, five of whom received ARV; 28.6% of infants who did not receive ARV were reported as either dead or ill compared to 13.8% of those receiving ARV CONCLUSION: Though the majority of pregnant women discovered their HIV status during pregnancy, a significant number got pregnant knowing that they were HIV+. The majority of mothers and infants received ARV but the follow-up and testing of infants was limited. Nevirapine is clearly protective in the prevention of MTCT of HIV and

Effectiveness of community-based support for pregnant women living with HIV: a cohort study in South Africa.

PubMed

Fatti, Geoffrey; Shaikh, Najma; Eley, Brian; Grimwood, Ashraf

2016-01-01

Antiretroviral treatment (ART) initiation in HIV-infected pregnant women in sub-Saharan Africa (SSA) remains inadequate, and there is a severe shortage of professional healthcare workers in the region. The effectiveness of community support programmes for HIV-infected pregnant women and their infants in SSA is unclear. This study compared initiation of maternal antiretrovirals and infant outcomes amongst HIV-infected pregnant women and their infants who received and did not receive community-based support (CBS) in a high HIV-prevalence setting in South Africa. A cohort study, including HIV-infected pregnant women and their infants, was conducted at three sentinel surveillance facilities between January 2009 and June 2012, utilising enhanced routine clinical data. Through home visits, CBS workers encouraged uptake of interventions in the ART cascade, provided HIV-related education, ART initiation counselling and psychosocial support. Outcomes were compared using Kaplan-Meier analyses and multivariable Cox and log-binomial regression. Amongst 1105 mother-infant pairs included, 264 (23.9%) received CBS. Amongst women eligible to start ART antenatally, women who received CBS had a reduced risk of not initiating antenatal ART, 5.4% vs. 30.3%; adjusted risk ratio (aRR) = 0.18 (95% CI: 0.08-0.44; P < .0001). Women who received CBS initiated antenatal ART with less delay after the first antenatal visit, median 26 days vs. 39 days; adjusted hazard ratio (aHR) = 1.57 (95% CI: 1.15-2.14; P = .004). Amongst women who initiated antenatal zidovudine (ZDV) to prevent vertical transmission, women who received CBS initiated ZDV with less delay, aHR = 1.52 (95% CI: 1.18-2.01; P = .001). Women who received CBS had a lower risk of stillbirth, 1.5% vs. 5.4%; aRR = 0.24 (95% CI: 0.07-1.00; P = .050). Pregnant women living with HIV who received CBS had improved antenatal triple ART initiation in eligible women, women initiated ART and ZDV with shorter

Limited-sampling strategies for anti-infective agents: systematic review.

PubMed

Sprague, Denise A; Ensom, Mary H H

2009-09-01

Area under the concentration-time curve (AUC) is a pharmacokinetic parameter that represents overall exposure to a drug. For selected anti-infective agents, pharmacokinetic-pharmacodynamic parameters, such as AUC/MIC (where MIC is the minimal inhibitory concentration), have been correlated with outcome in a few studies. A limited-sampling strategy may be used to estimate pharmacokinetic parameters such as AUC, without the frequent, costly, and inconvenient blood sampling that would be required to directly calculate the AUC. To discuss, by means of a systematic review, the strengths, limitations, and clinical implications of published studies involving a limited-sampling strategy for anti-infective agents and to propose improvements in methodology for future studies. The PubMed and EMBASE databases were searched using the terms "anti-infective agents", "limited sampling", "optimal sampling", "sparse sampling", "AUC monitoring", "abbreviated AUC", "abbreviated sampling", and "Bayesian". The reference lists of retrieved articles were searched manually. Included studies were classified according to modified criteria from the US Preventive Services Task Force. Twenty studies met the inclusion criteria. Six of the studies (involving didanosine, zidovudine, nevirapine, ciprofloxacin, efavirenz, and nelfinavir) were classified as providing level I evidence, 4 studies (involving vancomycin, didanosine, lamivudine, and lopinavir-ritonavir) provided level II-1 evidence, 2 studies (involving saquinavir and ceftazidime) provided level II-2 evidence, and 8 studies (involving ciprofloxacin, nelfinavir, vancomycin, ceftazidime, ganciclovir, pyrazinamide, meropenem, and alpha interferon) provided level III evidence. All of the studies providing level I evidence used prospectively collected data and proper validation procedures with separate, randomly selected index and validation groups. However, most of the included studies did not provide an adequate description of the methods or

Indian Adolescent Living with HIV-AIDS: Current Clinical Scenario.

PubMed

Joshi, Kavita S; Bhaware, Bhushan D; Pazare, Amar R

2017-07-01

Statistics suggest that, HIV has now largely become the disease of young patients. Hence, the adolescent HIV/AIDS needs to be handled and managed separately from adult HIV. Relatively fewer Indian data exist to characterize the associations in adolescents and young adults infected with HIV disease. The present study explores the current challenges in the management of HIV infected adolescents. The study was aimed at evaluating, relationship between CD4 count and duration of antiretroviral therapy (ART), effects of ART on body mass index and the adverse effects of antiretroviral drugs in adolescent HIV positive patients. This was a cross-sectional study involving 60 HIV positive adolescent patients attending tertiary care Institute KEM Hospital, Parel over duration of one year conducted at Mumbai. Patients on ART between age group 12 to 19 years. ART naïve patients were excluded from the study. 60 adolescent HIV positive patients attended our OPD including 37 males (61.67%) and 23 females (38.33%).The most common mode of transmission was vertical (80%). Education level was: school dropouts - 15%, primary education - 30%, Completed SSC - 31.7%, higher secondary - 23%. Among ADRs were 12 (63.15%) cases of anaemia due to Zidovudine, 4 (21.05%) hepatitis due to Nevirapine, 2 (10.52%) Tenofovir induced AKI and 1 (5.26%) Nevirapine rash. Wilcoxon matched pairs test showed a highly significant increase in the BMI (p <0.0001) post therapy. The mean CD4 of the patients at baseline and current presentation was 295.57 ± 109.81 and 630.93 ± 188.70 cells/mm3 respectively. The CD4 count was seen to be increasing with the increase in the duration of HAART treatment. High efficacy of HAART and availability of free ART under government programme has increased the duration of survival of the adolescent population with HIV. Treatment with HAART showed a favourable response with a statistical significant increase in CD4 count. Longer the duration of HAART, higher was the gain in CD4

Drug-Based Lead Discovery: The Novel Ablative Antiretroviral Profile of Deferiprone in HIV-1-Infected Cells and in HIV-Infected Treatment-Naive Subjects of a Double-Blind, Placebo-Controlled, Randomized Exploratory Trial

PubMed Central

Saxena, Deepti; Spino, Michael; Tricta, Fernando; Connelly, John; Cracchiolo, Bernadette M.; Hanauske, Axel-Rainer; D’Alliessi Gandolfi, Darlene; Mathews, Michael B.; Karn, Jonathan; Holland, Bart; Park, Myung Hee; Pe’ery, Tsafi; Palumbo, Paul E.; Hanauske-Abel, Hartmut M.

2016-01-01

Antiretrovirals suppress HIV-1 production yet spare the sites of HIV-1 production, the HIV-1 DNA-harboring cells that evade immune detection and enable viral resistance on-drug and viral rebound off-drug. Therapeutic ablation of pathogenic cells markedly improves the outcome of many diseases. We extend this strategy to HIV-1 infection. Using drug-based lead discovery, we report the concentration threshold-dependent antiretroviral action of the medicinal chelator deferiprone and validate preclinical findings by a proof-of-concept double-blind trial. In isolate-infected primary cultures, supra-threshold concentrations during deferiprone monotherapy caused decline of HIV-1 RNA and HIV-1 DNA; did not allow viral breakthrough for up to 35 days on-drug, indicating resiliency against viral resistance; and prevented, for at least 87 days off-drug, viral rebound. Displaying a steep dose-effect curve, deferiprone produced infection-independent deficiency of hydroxylated hypusyl-eIF5A. However, unhydroxylated deoxyhypusyl-eIF5A accumulated particularly in HIV-infected cells; they preferentially underwent apoptotic DNA fragmentation. Since the threshold, ascertained at about 150 μM, is achievable in deferiprone-treated patients, we proceeded from cell culture directly to an exploratory trial. HIV-1 RNA was measured after 7 days on-drug and after 28 and 56 days off-drug. Subjects who attained supra-threshold concentrations in serum and completed the protocol of 17 oral doses, experienced a zidovudine-like decline of HIV-1 RNA on-drug that was maintained off-drug without statistically significant rebound for 8 weeks, over 670 times the drug’s half-life and thus clearance from circulation. The uniform deferiprone threshold is in agreement with mapping of, and crystallographic 3D-data on, the active site of deoxyhypusyl hydroxylase (DOHH), the eIF5A-hydroxylating enzyme. We propose that deficiency of hypusine-containing eIF5A impedes the translation of mRNAs encoding proline

A Comparison of the Diabetes Risk Score in HIV/AIDS Patients on Highly Active Antiretroviral Therapy (HAART) and HAART-Naïve Patients at the Limbe Regional Hospital, Cameroon.

PubMed

Dimala, Christian Akem; Atashili, Julius; Mbuagbaw, Josephine C; Wilfred, Akam; Monekosso, Gottlieb L

2016-01-01

Highly active antiretroviral therapy (HAART) has been associated with dysglycaemia. However, there is scarce data on the risk of developing diabetes mellitus (DM) in HIV/AIDS patients in Africa. Primarily to quantify and compare the risk of having diabetes mellitus in HIV/AIDS patients on HAART and HAART-naïve patients in Limbe, Cameroon; and secondarily to determine if there is an association between HAART and increased DM risk. A cross-sectional study was conducted at the Limbe Regional Hospital HIV treatment center between April and June 2013, involving 200 HIV/AIDS patients (100 on first-line HAART regimens for at least 12 months matched by age and gender to 100 HAART-naïve patients). The Diabetes Risk Score (DRS) was calculated using a clinically validated model based on routinely recorded primary care parameters. A DRS ≥ 7% was considered as indicative of an increased risk of developing DM. The median DRS was significantly higher in patients on HAART (2.30%) than in HAART-naïve patients (1.62%), p = 0.002. The prevalence of the increased DM risk (DRS ≥ 7%) was significantly higher in patients on HAART, 31% (95% CI: 22.13-41.03) than in HAART-naïve patients, 17% (95% CI: 10.23-25.82), p = 0.020. HAART was significantly associated with an increased DM risk, the odds ratio of the HAART group compared to the HAART-naïve group was 2.19 (95% CI: 1.12-4.30, p = 0.020). However, no association was found after adjusting for BMI-defined overweight, hypertension, age, sex, family history of DM and smoking (Odds ratio = 1.22, 95% CI: 0.42-3.59, p = 0.708). Higher BMI and hypertension accounted for the increased risk of DM in patients on HAART. Also, more than 82% of the participants were receiving or had ever used Zidovudine based HAART regimens. HIV/AIDS patients on HAART could be at a greater risk of having DM than HAART-naïve patients as a result of the effect of HAART on risk factors of DM such as BMI and blood pressure.

HIV-1 Drug Resistance and Second-Line Treatment in Children Randomized to Switch at Low Versus Higher RNA Thresholds.

PubMed

Harrison, Linda; Melvin, Ann; Fiscus, Susan; Saidi, Yacine; Nastouli, Eleni; Harper, Lynda; Compagnucci, Alexandra; Babiker, Abdel; McKinney, Ross; Gibb, Diana; Tudor-Williams, Gareth

2015-09-01

The PENPACT-1 trial compared virologic thresholds to determine when to switch to second-line antiretroviral therapy (ART). Using PENPACT-1 data, we aimed to describe HIV-1 drug resistance accumulation on first-line ART by virologic threshold. PENPACT-1 had a 2 × 2 factorial design, randomizing HIV-infected children to start protease inhibitor (PI) versus nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART, and switch at a 1000 copies/mL versus 30,000 copies/mL threshold. Switch criteria were not achieving the threshold by week 24, confirmed rebound above the threshold thereafter, or Center for Disease Control and Prevention stage C event. Resistance tests were performed on samples ≥1000 copies/mL before switch, resuppression, and at 4-years/trial end. Sixty-seven children started PI-based ART and were randomized to switch at 1000 copies/mL (PI-1000), 64 PIs and 30,000 copies/mL (PI-30,000), 67 NNRTIs and 1000 copies/mL (NNRTI-1000), and 65 NNRTI and 30,000 copies/mL (NNRTI-30,000). Ninety-four (36%) children reached the 1000 copies/mL switch criteria during 5-year follow-up. In 30,000 copies/mL threshold arms, median time from 1000 to 30,000 copies/mL switch criteria was 58 (PI) versus 80 (NNRTI) weeks (P = 0.81). In NNRTI-30,000, more nucleoside reverse transcriptase inhibitor (NRTI) resistance mutations accumulated than other groups. NNRTI mutations were selected before switching at 1000 copies/mL (23% NNRTI-1000, 27% NNRTI-30,000). Sixty-two children started abacavir + lamivudine, 166 lamivudine + zidovudine or stavudine, and 35 other NRTIs. The abacavir + lamivudine group acquired fewest NRTI mutations. Of 60 switched to second-line, 79% PI-1000, 63% PI-30,000, 64% NNRTI-1000, and 100% NNRTI-30,000 were <400 copies/mL 24 weeks later. Children on first-line NNRTI-based ART who were randomized to switch at a higher virologic threshold developed the most resistance, yet resuppressed on second-line. An abacavir + lamivudine NRTI combination seemed

Marginal Structural Models with Counterfactual Effect Modifiers.

PubMed

Zheng, Wenjing; Luo, Zhehui; van der Laan, Mark J

2018-06-08

In health and social sciences, research questions often involve systematic assessment of the modification of treatment causal effect by patient characteristics. In longitudinal settings, time-varying or post-intervention effect modifiers are also of interest. In this work, we investigate the robust and efficient estimation of the Counterfactual-History-Adjusted Marginal Structural Model (van der Laan MJ, Petersen M. Statistical learning of origin-specific statically optimal individualized treatment rules. Int J Biostat. 2007;3), which models the conditional intervention-specific mean outcome given a counterfactual modifier history in an ideal experiment. We establish the semiparametric efficiency theory for these models, and present a substitution-based, semiparametric efficient and doubly robust estimator using the targeted maximum likelihood estimation methodology (TMLE, e.g. van der Laan MJ, Rubin DB. Targeted maximum likelihood learning. Int J Biostat. 2006;2, van der Laan MJ, Rose S. Targeted learning: causal inference for observational and experimental data, 1st ed. Springer Series in Statistics. Springer, 2011). To facilitate implementation in applications where the effect modifier is high dimensional, our third contribution is a projected influence function (and the corresponding projected TMLE estimator), which retains most of the robustness of its efficient peer and can be easily implemented in applications where the use of the efficient influence function becomes taxing. We compare the projected TMLE estimator with an Inverse Probability of Treatment Weighted estimator (e.g. Robins JM. Marginal structural models. In: Proceedings of the American Statistical Association. Section on Bayesian Statistical Science, 1-10. 1997a, Hernan MA, Brumback B, Robins JM. Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men. 2000;11:561-570), and a non-targeted G-computation estimator (Robins JM. A new approach to

Association Between the Occurrence of Adverse Drug Events and Modification of First-Line Highly Active Antiretroviral Therapy in Ghanaian HIV Patients.

PubMed

Tetteh, Raymond A; Nartey, Edmund T; Lartey, Margaret; Mantel-Teeuwisse, Aukje K; Leufkens, Hubert G M; Yankey, Barbara A; Dodoo, Alexander N O

2016-11-01

Patients initiated on highly active antiretroviral therapy (HAART) generally remain on medication indefinitely. A modification in the HAART regimen may become necessary because of possible acute or chronic toxicities, concomitant clinical conditions, development of virological failure or the advent of adverse drug events. The study documents adverse drug events of HIV-positive Ghanaian patients with HAART modifications. It also investigates the association between documented adverse drug events and HAART modification using an unmatched case-control study design. The study was conducted in the Fevers Unit of the Korle Bu Teaching Hospital and involved patients who attended the HIV Care Clinic between January 2004 and December 2009. Data from 298 modified therapy patients (cases) were compared with 298 continuing therapy patients (controls) who had been on treatment for at least 1 month before the end of study. Controls were sampled from the same database of a cohort of HIV-positive patients on HAART, at the time a case occurred, in terms of treatment initiation ±1 month. Data were obtained from patients' clinical folders and the HIV clinic database linked to the pharmacy database. The nature of the documented adverse drug events of the cases was described and the association between the documented adverse drug events and HAART modification was determined by logistic regression with reported odds ratios (ORs) and their 95 % confidence interval (CI). Among the 298 modified therapy patients sampled in this study, 52.7 % of them had at least one documented adverse drug event. The most documented adverse drug event was anaemia, recorded in 18.5 % of modified therapy patients, all of whom were on a zidovudine-based regimen. The presence of documented adverse drug events was significantly associated with HAART modification [adjusted OR = 2.71 (95 % CI 2.11-3.48), p < 0.001]. Among HIV patients on HAART, adverse drug events play a major role in treatment

Switch from unboosted protease inhibitor to a single-tablet regimen containing rilpivirine improves cholesterol and triglycerides.

PubMed

Di Biagio, Antonio; Riccardi, Niccolò; Taramasso, Lucia; Capetti, Amedeo; Cenderello, Giovanni; Signori, Alessio; Vitiello, Paola; Guerra, Michele; de Socio, Giuseppe Vittorio; Cassola, Giovanni; Quirino, Tiziano; Viscoli, Claudio

2016-11-01

This study aimed to evaluate the efficacy, tolerability and potential savings of combined antiretroviral therapy (cART) simplification from an unboosted protease inhibitor (PI) regimen with atazanavir or fosamprenavir to a single-tablet regimen (STR) based on rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) among HIV-1-infected patients with HIV-1 RNA <50 copies/mL. This was a retrospective, multicentre, open-label, 12-week trial. Plasma HIV-1-RNA levels, CD4+ cell counts, cholesterol, triglycerides, bilirubin, glycaemia, creatinine and physical examination were performed at baseline and at scheduled follow-up. All patient costs were calculated and were estimated for 52 weeks of therapy. Fifty-one patients were enrolled [28 male (54.9%)]. At baseline, 30 patients (58.8%) were treated with FTC/TDF, 20 (39.2%) with abacavir/lamivudine and 1 (2.0%) with lamivudine/zidovudine. Thirty-three patients (64.7%) received atazanavir. All patients maintained HIV-RNA <50 copies/mL; the median CD4+ cell count remained stable. Mean triglycerides decreased from 124 mg/dL (range, 39-625) at enrolment to 108.7 mg/dL (range, 39-561) at study end (P = 0.25). At baseline, mean cholesterol was 172.8 ± 38.1 mg/dL and decreased to 161.9 ± 38.6 mg/dL (P = 0.038); likewise, median total bilirubin decreased from 1.07 mg/dL (range, 0.2-4.7) to 0.6 mg/dL (range, 0.13-3.1) (P <0.001). cART-related annual cost reduction with a STR was €3155.47 per patient (-24%). Non-cART patient management expenses were €402.68 vs. €299.10 for atazanavir or fosamprenavir and STR regimens, respectively. Switching to RPV/FTC/TDF from an unboosted PI in virologically suppressed HIV-infected patients is safe and is associated with a reduction in triglycerides, cholesterol and cART-related costs. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Structural Insights into HIV Reverse Transcriptase Mutations Q151M and Q151M Complex That Confer Multinucleoside Drug Resistance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Das, Kalyan; Martinez, Sergio E.; Arnold, Eddy

HIV-1 reverse transcriptase (RT) is targeted by multiple drugs. RT mutations that confer resistance to nucleoside RT inhibitors (NRTIs) emerge during clinical use. Q151M and four associated mutations, A62V, V75I, F77L, and F116Y, were detected in patients failing therapies with dideoxynucleosides (didanosine [ddI], zalcitabine [ddC]) and/or zidovudine (AZT). The cluster of the five mutations is referred to as the Q151M complex (Q151Mc), and an RT or virus containing Q151Mc exhibits resistance to multiple NRTIs. To understand the structural basis for Q151M and Q151Mc resistance, we systematically determined the crystal structures of the wild-type RT/double-stranded DNA (dsDNA)/dATP (complex I), wild-type RT/dsDNA/ddATPmore » (complex II), Q151M RT/dsDNA/dATP (complex III), Q151Mc RT/dsDNA/dATP (complex IV), and Q151Mc RT/dsDNA/ddATP (complex V) ternary complexes. The structures revealed that the deoxyribose rings of dATP and ddATP have 3'-endo and 3'-exo conformations, respectively. The single mutation Q151M introduces conformational perturbation at the deoxynucleoside triphosphate (dNTP)-binding pocket, and the mutated pocket may exist in multiple conformations. The compensatory set of mutations in Q151Mc, particularly F116Y, restricts the side chain flexibility of M151 and helps restore the DNA polymerization efficiency of the enzyme. The altered dNTP-binding pocket in Q151Mc RT has the Q151-R72 hydrogen bond removed and has a switched conformation for the key conserved residue R72 compared to that in wild-type RT. On the basis of a modeled structure of hepatitis B virus (HBV) polymerase, the residues R72, Y116, M151, and M184 in Q151Mc HIV-1 RT are conserved in wild-type HBV polymerase as residues R41, Y89, M171, and M204, respectively; functionally, both Q151Mc HIV-1 and wild-type HBV are resistant to dideoxynucleoside analogs.« less

Adverse drug reactions to antiretroviral therapy (ARVs): incidence, type and risk factors in Nigeria

PubMed Central

2012-01-01

Background Data on adverse drug reactions (ADRs) related to antiretroviral (ARV) use in public health practice are few indicating the need for ART safety surveillance in clinical care. Objectives To evaluate the incidence, type and risk factors associated with adverse drug reactions (ADRs) among patients on antiretroviral drugs (ARV). Methods Patients initiated on ARVs between May 2006 and May 2009 were evaluated in a retrospective cohort analysis in three health facilities in Nigeria. Regimens prescribed include nucleoside backbone of zidovudine (AZT)/lamivudine (3TC), stavudine (d4T)/3TC, or tenofovir (TDF)/3TC in combination with either nevirapine (NVP) or efavirenz (EFV). Generalized Estimating Equation (GEE) model was used to identify risk factors associated with occurrence of ADR. Results 2650 patients were followed-up for 2456 person-years and reported 114 ADRs (incidence rate = 4.6/100 person-years).There were more females 1706(64%) and 73(64%) of the ADRs were reported by women. Overall, 61(54%) of ADRs were reported by patients on AZT with 54(47%) of these occurring in patients on AZT/NVP. The commonest ADRs reported were pain 25(30%) and skinrash 10(18%). Most ADRs were grade 1(39%) with only 1% being life threatening (grade 4). Adjusted GEE analysis showed that ADR was less likely to occur in patients on longer duration of ART compared to the first six months on treatment; 6-12 months AOR 0.38(95% CI:0.16-0.91) and 12-24 months AOR 0.34(95% CI:0.16-0.73) respectively. Compared to patients on TDF, ADR was less likely to occur in patients on d4T and AZT AOR 0.18(95% CI 0.05-0.64) and AOR 0.24(95% CI:0.7-0.9) respectively. Age, gender and CD4 count were not significantly associated with ADRs. Conclusion ADRs are more likely to occur within the first six months on treatment. Close monitoring within this period is required to prevent occurrence of severe ADR and improve ART adherence. Further research on the tolerability of tenofovir in this environment is

Immune restoration does not invariably occur following long-term HIV-1 suppression during antiretroviral therapy. INCAS Study Group.

PubMed

Pakker, N G; Kroon, E D; Roos, M T; Otto, S A; Hall, D; Wit, F W; Hamann, D; van der Ende, M E; Claessen, F A; Kauffmann, R H; Koopmans, P P; Kroon, F P; ten Napel, C H; Sprenger, H G; Weigel, H M; Montaner, J S; Lange, J M; Reiss, P; Schellekens, P T; Miedema, F

1999-02-04

Current antiretroviral treatment can induce significant and sustained virological and immunological responses in HIV-1-infected persons over at least the short- to mid-term. In this study, long-term immune reconstitution was investigated during highly active antiretroviral therapy. Patients enrolled in the INCAS study in The Netherlands were treated for 102 weeks (range 52-144 weeks) with nevirapine (NVP) + zidovudine (ZDV) (n = 9), didanosine (ddl) + ZDV (n = 10), or NVP + ddl + ZDV (n = 10). Memory and naïve CD4+ and CD8+ T cells were measured using CD45RA and CD27 monoclonal antibodies (mAb), T-cell function was assayed by CD3 + CD28 mAb stimulation, and plasma HIV-1 RNA load was measured by ultra-direct assay (cut-off < 20 copies/ml). Compared to both double combination regimens the triple combination regimen resulted in the most sustained increase in CD4+ T cells (change in CD4+, + 253 x 10(6) cells/l; standard error, 79 x 10(6) cells/l) and reduction of plasma HIV-1 RNA. In nine patients (31%) (ddl + ZDV, n = 2; NVP + ddl + ZDV, n = 7) plasma HIV-1 RNA levels remained below cut-off for at least 2 years. On average, these long-term virological responders demonstrated a significantly higher increase of naïve and memory CD4+ T cells (P = 0.01 and 0.02, respectively) as compared with patients with a virological failure, and showed improved T-cell function and normalization of the naïve; memory CD8+ T-cell ratio. However, individual virological success or failure did not predict the degree of immunological response. T-cell patterns were independent of baseline CD4+ T-cell count, T-cell function, HIV-1 RNA load or age. Low numbers of naïve CD4+ T cells at baseline resulted in modest long-term naïve T-cell recovery. Patients with prolonged undetectable plasma HIV-1 RNA levels during antiretroviral therapy do not invariably show immune restoration. Naïve T-cell recovery in the setting of complete viral suppression is a gradual process, similar to that reported

Anaemia during pregnancy in Burkina Faso, west Africa, 1995-96: prevalence and associated factors. DITRAME Study Group.

PubMed Central

Meda, N.; Mandelbrot, L.; Cartoux, M.; Dao, B.; Ouangré, A.; Dabis, F.

1999-01-01

We report the results of a cross-sectional study carried out in 1995-96 on anaemia in pregnant women who were attending two antenatal clinics in Bobo-Dioulasso, Burkina Faso, as part of a research programme including a clinical trial of zidovudine (ZDV) in pregnancy (ANRS 049 Clinical Trial). For women infected with human immunodeficiency virus (HIV) in Africa, anaemia is of particular concern when considering the use of ZDV to decrease mother-to-child transmission of HIV. The objectives were to determine the prevalence of and risk factors for maternal anaemia in the study population, and the effect of HIV infection on the severity of maternal anaemia. HIV counselling and testing were offered to all women, and haemograms were determined for those women who consented to serological testing. Haemoglobin (Hb) levels were available for 2308 of the 2667 women who accepted HIV testing. The prevalence of HIV infection was 9.7% (95% confidence interval (CI): 8.6-10.8%). The overall prevalence of anaemia during pregnancy (Hb level < 11 g/dl) was 66% (95% CI: 64-68%). The prevalence of mild (10 g/dl < or = Hb < 11 g/dl), moderate (7 g/dl < or = Hb < 10 g/dl) and severe (Hb < 7 g/dl) anaemia was 30.8%, 33.5% and 1.7%, respectively. The prevalence of anaemia was 78.4% in HIV-infected women versus 64.7% in HIV-seronegative women (P < 0.001). Although the relative risk of HIV-seropositivity increased with the severity of anaemia, no significant association was found between degree of anaemia and HIV serostatus among the study women with anaemia. Logistic regression analysis showed that anaemia was significantly and independently related to HIV infection, advanced gestational age, and low socioeconomic status. This study confirms the high prevalence of anaemia during pregnancy in Burkina Faso. Antenatal care in this population must include iron supplementation. Although HIV-infected women had a higher prevalence of anaemia, severe anaemia was infrequent, possibly because few

Maternal CD4+ cell count decline after interruption of antiretroviral prophylaxis for the prevention of mother-to-child transmission of HIV.

PubMed

Ekouevi, Didier; Abrams, Elaine J; Schlesinger, Malka; Myer, Landon; Phanuphak, Nittaya; Carter, Rosalind J

2012-01-01

We evaluated maternal CD4+ cell count (CD4+) decline after PMTCT prophylaxis in a multi-country HIV care program. Analysis was restricted to antiretroviral therapy (ART)-naive, HIV-infected pregnant women with CD4+ ≥250 cells/mm(3) at enrollment. Single-dose nevirapine (sd-NVP) or short-course antiretroviral prophylaxis (sc-ARVp) with zidovudine (AZT) or AZT + lamivudine (3TC) was initiated in 11 programs while 2 programs offered triple-drug antiretroviral prophylaxis (tARVp) (AZT+3TC+ NVP or nelfinavir). All regimens were stopped at delivery. CD4+ decline was defined as proportion of women who declined to CD4+ <350 cells/mm(3) or <200 cells/mm(3) at 24 months. Weibull regression was used for multivariable analysis. A total of 1,393 women with enrollment CD4+ ≥250 cells/mm(3) initiated tARVp (172; 12%) or sc-ARVp (532; 38%) during pregnancy or received intrapartum sd-NVP (689; 50%). At enrollment, maternal median age was 27 years (interquartile range (IQR) 23-30), median CD4+ was 469 cells/mm(3) (IQR: 363-613). At 24 months post-delivery, the cumulative probability of CD4+ decline to <200 cells/mm(3) was 12% (95% CI: 10-14). Among a subgroup of 903 women with CD4+ ≥400 cells at enrollment, the 24 month cumulative probability of decline to CD4+ <350 cells/mm(3) was 28%; (95% CI: 25-32). Lower antepartum CD4+ was associated with higher probability of CD4+ decline to <350 cells/mm(3): 46% (CD4+400-499 cells/mm(3)) vs. 19% (CD4+ ≥500 cells/mm(3)). After adjusting for age, enrollment CD4+ and WHO stage, women who received tARVp or sd-NVP were twice as likely to experience CD4+ decline to <350 cells/mm(3) within 24 months than women receiving sc-ARVp (adjusted hazard ratio: 2.2; 95% CI: 1.5-3.2, p<0.0001). Decline in CD4+ cell count to ART eligibility thresholds by 24 months postpartum was common among women receiving PMTCT prophylaxis during pregnancy and/or delivery.

Trends in first-line antiretroviral therapy in Asia: results from the TREAT Asia HIV observational database.

PubMed

Boettiger, David Charles; Kerr, Stephen; Ditangco, Rossana; Merati, Tuti Parwati; Pham, Thuy Thi Thanh; Chaiwarith, Romanee; Kiertiburanakul, Sasisopin; Li, Chung Ki Patrick; Kumarasamy, Nagalingeswaran; Vonthanak, Saphonn; Lee, Christopher; Van Kinh, Nguyen; Pujari, Sanjay; Wong, Wing Wai; Kamarulzaman, Adeeba; Zhang, Fujie; Yunihastuti, Evy; Choi, Jun Yong; Oka, Shinichi; Ng, Oon Tek; Kantipong, Pacharee; Mustafa, Mahiran; Ratanasuwan, Winai; Sohn, Annette; Law, Matthew

2014-01-01

Antiretroviral therapy (ART) has evolved rapidly since its beginnings. This analysis describes trends in first-line ART use in Asia and their impact on treatment outcomes. Patients in the TREAT Asia HIV Observational Database receiving first-line ART for ≥ 6 months were included. Predictors of treatment failure and treatment modification were assessed. Data from 4662 eligible patients was analysed. Patients started ART in 2003-2006 (n = 1419), 2007-2010 (n = 2690) and 2011-2013 (n = 553). During the observation period, tenofovir, zidovudine and abacavir use largely replaced stavudine. Stavudine was prescribed to 5.8% of ART starters in 2012/13. Efavirenz use increased at the expense of nevirapine, although both continue to be used extensively (47.5% and 34.5% of patients in 2012/13, respectively). Protease inhibitor use dropped after 2004. The rate of treatment failure or modification declined over time (22.1 [95%CI 20.7-23.5] events per 100 patient/years in 2003-2006, 15.8 [14.9-16.8] in 2007-2010, and 11.6 [9.4-14.2] in 2011-2013). Adjustment for ART regimen had little impact on the temporal decline in treatment failure rates but substantially attenuated the temporal decline in rates of modification due to adverse event. In the final multivariate model, treatment modification due to adverse event was significantly predicted by earlier period of ART initiation (hazard ratio 0.52 [95%CI 0.33-0.81], p = 0.004 for 2011-2013 versus 2003-2006), older age (1.56 [1.19-2.04], p = 0.001 for ≥ 50 years versus <30 years), female sex (1.29 [1.11-1.50], p = 0.001 versus male), positive hepatitis C status (1.33 [1.06-1.66], p = 0.013 versus negative), and ART regimen (11.36 [6.28-20.54], p<0.001 for stavudine-based regimens versus tenofovir-based). The observed trends in first-line ART use in Asia reflect changes in drug availability, global treatment recommendations and prescriber preferences over the past decade. These changes have contributed to a declining rate of

High rates of virological failure and drug resistance in perinatally HIV-1-infected children and adolescents receiving lifelong antiretroviral therapy in routine clinics in Togo

PubMed Central

Salou, Mounerou; Dagnra, Anoumou Y; Butel, Christelle; Vidal, Nicole; Serrano, Laetitia; Takassi, Elom; Konou, Abla A; Houndenou, Spero; Dapam, Nina; Singo-Tokofaï, Assetina; Pitche, Palokinam; Atakouma, Yao; Prince-David, Mireille; Delaporte, Eric; Peeters, Martine

2016-01-01

Introduction Antiretroviral treatment (ART) has been scaled up over the last decade but compared to adults, children living with HIV are less likely to receive ART. Moreover, children and adolescents are more vulnerable than adults to virological failure (VF) and emergence of drug resistance. In this study we determined virological outcome in perinatally HIV-1-infected children and adolescents receiving ART in Togo. Methods HIV viral load (VL) testing was consecutively proposed to all children and adolescents who were on ART for at least 12 months when attending HIV healthcare services for their routine follow-up visit (June to September 2014). Plasma HIV-1 VL was measured using the m2000 RealTime HIV-1 assay (Abbott Molecular, Des Plaines, IL, USA). Genotypic drug resistance was done for all samples with VL>1000 copies/ml. Results and discussion Among 283 perinatally HIV-1-infected children and adolescents included, 167 (59%) were adolescents and 116 (41%) were children. The median duration on ART was 48 months (interquartile range: 28 to 68 months). For 228 (80.6%), the current ART combination consisted of two nucleoside reverse transcriptase inhibitors (NRTIs) (zidovudine and lamivudine) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) (nevirapine or efavirenz). Only 28 (9.9%) were on a protease inhibitor (PI)-based regimen. VL was below the detection limit (i.e. 40 copies/ml) for 102 (36%), between 40 and 1000 copies/ml for 35 (12.4%) and above 1000 copies/ml for 146 (51.6%). Genotypic drug-resistance testing was successful for 125/146 (85.6%); 110/125 (88.0%) were resistant to both NRTIs and NNRTIs, 1/125 (0.8%) to NRTIs only, 4/125 (3.2%) to NNRTIs only and three harboured viruses resistant to reverse transcriptase and PIs. Overall, 86% (108/125) of children and adolescents experiencing VF and successfully genotyped, corresponding thus to at least 38% of the study population, had either no effective ART or had only a single effective drug in

18-Month Effectiveness of Short-Course Antiretroviral Regimens Combined with Alternatives to Breastfeeding to Prevent HIV Mother-to-Child Transmission

PubMed Central

Leroy, Valériane; Ekouevi, Didier K.; Becquet, Renaud; Viho, Ida; Dequae-Merchadou, Laurence; Tonwe-Gold, Besigin; Rouet, François; Sakarovitch, Charlotte; Horo, Appolinaire; Timité-Konan, Marguerite; Rouzioux, Christine; Dabis, François

2008-01-01

Objective We assessed the 18-month effectiveness of short-course (sc) antiretroviral peripartum regimens combined with alternatives to prolonged breastfeeding to prevent mother-to-child transmission (MTCT) of HIV-1 in Abidjan, Côte d'Ivoire. Methodology HIV-1 infected pregnant women received from ≥32–36 weeks of gestation scZidovudine (ZDV)+/−Lamivudine (3TC)+single-dose Nevirapine (sdNVP) at delivery within the ANRS 1201/1202 DITRAME-Plus cohort (2001–2003). Neonates received a sdNVP+7-day ZDV prophylaxis. Two infant-feeding interventions were systematically offered free of charge: formula-feeding or exclusive shortened breastfeeding with early cessation from four months. The reference group was the ANRS 049a DITRAME cohort (1994–2000) exposed to scZDV from 36 weeks, then to prolonged breastfeeding. Pediatric HIV infection was defined by a positive plasma HIV-1 RNA at any age, or if aged ≥18 months, a positive HIV-1 serology. Turnbull estimates of cumulative transmission risks (CTR) and effectiveness (HIV-free survival) were compared by exposure group using a Cox model. Findings Among 926 live-born children enrolled, 107 (11.6%) were HIV-infected at 18 months. CTRs were 22.3% (95% confidence interval[CI]:16–30%) in the 238 ZDV long-term breastfed reference group, 15.9% (CI:10–27%) in the 169 ZDV+sdNVP shortened breastfed group; 9.4% (CI:6–14%) in the 195 ZDV+sdNVP formula-fed group; 6.8% (CI:4–11%) in the 198 ZDV+3TC+sdNVP shortened breastfed group, and 5.6% (CI:2–10%) in the 126 ZDV+3TC+sdNVP formula-fed group. Each combination had a significantly higher effectiveness than the ZDV long-term breastfed group except for ZDV+sdNVP shortened breastfed children, ranging from 51% (CI:20–70%) for ZDV+sdNVP formula fed children to 63% (CI:40–80%) for ZDV+3TC+NVPsd shortened breastfed children, after adjustment for maternal eligibility for antiretroviral therapy (ART), home delivery and low birth-weight. Substantial MTCT risk reductions are

Critical race theory as a tool for understanding poor engagement along the HIV care continuum among African American/Black and Hispanic persons living with HIV in the United States: a qualitative exploration.

PubMed

Freeman, Robert; Gwadz, Marya Viorst; Silverman, Elizabeth; Kutnick, Alexandra; Leonard, Noelle R; Ritchie, Amanda S; Reed, Jennifer; Martinez, Belkis Y

2017-03-24

African American/Black and Hispanic persons living with HIV (AABH-PLWH) in the U.S. evidence insufficient engagement in HIV care and low uptake of HIV antiretroviral therapy, leading to suboptimal clinical outcomes. The present qualitative study used critical race theory, and incorporated intersectionality theory, to understand AABH-PLWH's perspectives on the mechanisms by which structural racism; that is, the macro-level systems that reinforce inequities among racial/ethnic groups, influence health decisions and behaviors. Participants were adult AABH-PLWH in New York City who were not taking antiretroviral therapy nor well engaged in HIV care (N = 37). Participants were purposively sampled for maximum variation from a larger study, and engaged in semi-structured in-depth interviews that were audio-recorded and professionally transcribed verbatim. Data were analyzed using a systematic content analysis approach. We found AABH-PLWH experienced HIV care and medication decisions through a historical and cultural lens incorporating knowledge of past and present structural racism. This contextual knowledge included awareness of past maltreatment of people of color in medical research. Further, these understandings were linked to the history of HIV antiretroviral therapy itself, including awareness of the first HIV antiretroviral regimen; namely, AZT (zidovudine) mono-therapy, which was initially prescribed in unacceptably high doses, causing serious side effects, but with only modest efficacy. In this historical/cultural context, aspects of structural racism negatively influenced health care decisions and behavior in four main ways: 1) via the extent to which healthcare settings were experienced as overly institutionalized and, therefore, dehumanizing; 2) distrust of medical institutions and healthcare providers, which led AABH-PLWH to feel pressured to take HIV antiretroviral therapy when it was offered; 3) perceptions that patients are excluded from the health

Intervening in global markets to improve access to HIV/AIDS treatment: an analysis of international policies and the dynamics of global antiretroviral medicines markets

PubMed Central

2010-01-01

Background Universal access to antiretroviral therapy (ART) in low- and middle-income countries faces numerous challenges: increasing numbers of people needing ART, new guidelines recommending more expensive antiretroviral (ARV) medicines, limited financing, and few fixed-dose combination (FDC) products. Global initiatives aim to promote efficient global ARV markets, yet little is known about market dynamics and the impact of global policy interventions. Methods We utilize several data sources, including 12,958 donor-funded, adult first-line ARV purchase transactions, to describe the market from 2002-2008. We examine relationships between market trends and: World Health Organization (WHO) HIV/AIDS treatment guidelines; WHO Prequalification Programme (WHO Prequal) and United States (US) Food and Drug Administration (FDA) approvals; and procurement policies of the Global Fund to Fight AIDS, Tuberculosis, and Malaria (GFATM), US President's Emergency Plan for AIDS Relief (PEPFAR) and UNITAID. Results WHO recommended 7, 4, 24, and 6 first-line regimens in 2002, 2003, 2006 and 2009 guidelines, respectively. 2009 guidelines replaced a stavudine-based regimen ($88/person/year) with more expensive zidovudine- ($154-260/person/year) or tenofovir-based ($244-465/person/year) regimens. Purchase volumes for ARVs newly-recommended in 2006 (emtricitabine, tenofovir) increased >15-fold from 2006 to 2008. Twenty-four generic FDCs were quality-approved for older regimens but only four for newer regimens. Generic FDCs were available to GFATM recipients in 2004 but to PEPFAR recipients only after FDA approval in 2006. Price trends for single-component generic medicines mirrored generic FDC prices. Two large-scale purchasers, PEPFAR and UNITAID, together accounted for 53%, 84%, and 77% of market volume for abacavir, emtricitabine, and tenofovir, respectively, in 2008. PEPFAR and UNITAID purchases were often split across two manufacturers. Conclusions Global initiatives facilitated the

Weight-based dosing in medication use: what should we know?

PubMed Central

Pan, Sheng-dong; Zhu, Ling-ling; Chen, Meng; Xia, Ping; Zhou, Quan

2016-01-01

Background Weight-based dosing strategy is still challenging due to poor awareness and adherence. It is necessary to let clinicians know of the latest developments in this respect and the correct circumstances in which weight-based dosing is of clinical relevance. Methods A literature search was conducted using PubMed. Results Clinical indications, physiological factors, and types of medication may determine the applicability of weight-based dosing. In some cases, the weight effect may be minimal or the proper dosage can only be determined when weight is combined with other factors. Medications within similar therapeutic or structural class (eg, anticoagulants, antitumor necrosis factor medications, P2Y12-receptor antagonists, and anti-epidermal growth factor receptor antibodies) may exhibit differences in requirements on weight-based dosing. In some cases, weight-based dosing is superior to currently recommended fixed-dose regimen in adult patients (eg, hydrocortisone, vancomycin, linezolid, and aprotinin). On the contrary, fixed dosing is noninferior to or even better than currently recommended weight-based regimen in adult patients in some cases (eg, cyclosporine microemulsion, recombinant activated Factor VII, and epoetin α). Ideal body-weight-based dosing may be superior to the currently recommended total body-weight-based regimen (eg, atracurium and rocuronium). For dosing in pediatrics, whether weight-based dosing is better than body surface-area-based dosing is dependent on the particular medication (eg, methotrexate, prednisone, prednisolone, zidovudine, didanosine, growth hormone, and 13-cis-retinoic acid). Age-based dosing strategy is better than weight-based dosing in some cases (eg, intravenous busulfan and dalteparin). Dosing guided by pharmacogenetic testing did not show pharmacoeconomic advantage over weight-adjusted dosing of 6-mercaptopurine. The common viewpoint (ie, pediatric patients should be dosed on the basis of body weight) is not always

The burden of hypertension, diabetes mellitus, and cardiovascular risk factors among adult Malawians in HIV care: consequences for integrated services.

PubMed

Divala, Oscar H; Amberbir, Alemayehu; Ismail, Zahra; Beyene, Teferi; Garone, Daniela; Pfaff, Colin; Singano, Victor; Akello, Harriet; Joshua, Martias; Nyirenda, Moffat J; Matengeni, Alfred; Berman, Josh; Mallewa, Jane; Chinomba, Gift S; Kayange, Noel; Allain, Theresa J; Chan, Adrienne K; Sodhi, Sumeet K; van Oosterhout, Joep J

2016-12-12

Hypertension and diabetes prevalence is high in Africans. Data from HIV infected populations are limited, especially from Malawi. Integrating care for chronic non-communicable co-morbidities in well-established HIV services may provide benefit for patients by preventing multiple hospital visits but will increase the burden of care for busy HIV clinics. Cross-sectional study of adults (≥18 years) at an urban and a rural HIV clinic in Zomba district, Malawi, during 2014. Hypertension and diabetes were diagnosed according to stringent criteria. Proteinuria, non-fasting lipids and cardio/cerebro-vascular disease (CVD) risk scores (Framingham and World Health Organization/International Society for Hypertension) were determined. The association of patient characteristics with diagnoses of hypertension and diabetes was studied using multivariable analyses. We explored the additional burden of care for integrated drug treatment of hypertension and diabetes in HIV clinics. We defined that burden as patients with diabetes and/or stage II and III hypertension, but not with stage I hypertension unless they had proteinuria, previous stroke or high Framingham CVD risk. Nine hundred fifty-two patients were enrolled, 71.7% female, median age 43.0 years, 95.9% on antiretroviral therapy (ART), median duration 47.7 months. Rural and urban patients' characteristics differed substantially. Hypertension prevalence was 23.7% (95%-confidence interval 21.1-26.6; rural 21.0% vs. urban 26.5%; p = 0.047), of whom 59.9% had stage I (mild) hypertension. Diabetes prevalence was 4.1% (95%-confidence interval 3.0-5.6) without significant difference between rural and urban settings. Prevalence of proteinuria, elevated total/high-density lipoprotein-cholesterol ratio and high CVD risk score was low. Hypertension diagnosis was associated with increasing age, higher body mass index, presence of proteinuria, being on regimen zidovudine/lamivudine/nevirapine and inversely with World Health

Predicting the extent of metabolism using in vitro permeability rate measurements and in silico permeability rate predictions

PubMed Central

Hosey, Chelsea M; Benet, Leslie Z

2015-01-01

The Biopharmaceutics Drug Disposition Classification System (BDDCS) can be utilized to predict drug disposition, including interactions with other drugs and transporter or metabolizing enzyme effects based on the extent of metabolism and solubility of a drug. However, defining the extent of metabolism relies upon clinical data. Drugs exhibiting high passive intestinal permeability rates are extensively metabolized. Therefore, we aimed to determine if in vitro measures of permeability rate or in silico permeability rate predictions could predict the extent of metabolism, to determine a reference compound representing the permeability rate above which compounds would be expected to be extensively metabolized, and to predict the major route of elimination of compounds in a two-tier approach utilizing permeability rate and a previously published model predicting the major route of elimination of parent drug. Twenty-two in vitro permeability rate measurement data sets in Caco-2 and MDCK cell lines and PAMPA were collected from the literature, while in silico permeability rate predictions were calculated using ADMET Predictor™ or VolSurf+. The potential for permeability rate to differentiate between extensively and poorly metabolized compounds was analyzed with receiver operating characteristic curves. Compounds that yielded the highest sensitivity-specificity average were selected as permeability rate reference standards. The major route of elimination of poorly permeable drugs was predicted by our previously published model and the accuracies and predictive values were calculated. The areas under the receiver operating curves were >0.90 for in vitro measures of permeability rate and >0.80 for the VolSurf+ model of permeability rate, indicating they were able to predict the extent of metabolism of compounds. Labetalol and zidovudine predicted greater than 80% of extensively metabolized drugs correctly and greater than 80% of poorly metabolized drugs correctly in Caco

Integrase inhibitors in late pregnancy and rapid HIV viral load reduction.

PubMed

Rahangdale, Lisa; Cates, Jordan; Potter, JoNell; Badell, Martina L; Seidman, Dominika; Miller, Emilly S; Coleman, Jenell S; Lazenby, Gweneth B; Levison, Judy; Short, William R; Yawetz, Sigal; Ciaranello, Andrea; Livingston, Elizabeth; Duthely, Lunthita; Rimawi, Bassam H; Anderson, Jean R; Stringer, Elizabeth M

2016-03-01

Minimizing time to HIV viral suppression is critical in pregnancy. Integrase strand transfer inhibitors (INSTIs), like raltegravir, are known to rapidly suppress plasma HIV RNA in nonpregnant adults. There are limited data in pregnant women. We describe time to clinically relevant reduction in HIV RNA in pregnant women using INSTI-containing and non-INSTI-containing antiretroviral therapy (ART) options. We conducted a retrospective cohort study of pregnant HIV-infected women in the United States from 2009 through 2015. We included women who initiated ART, intensified their regimen, or switched to a new regimen due to detectable viremia (HIV RNA >40 copies/mL) at ≥20 weeks gestation. Among women with a baseline HIV RNA permitting 1-log reduction, we estimated time to 1-log RNA reduction using the Kaplan-Meier estimator comparing women starting/adding an INSTI in their regimen vs other ART. To compare groups with similar follow-up time, we also conducted a subgroup analysis limited to women with ≤14 days between baseline and follow-up RNA data. This study describes 101 HIV-infected pregnant women from 11 US clinics. In all, 75% (76/101) of women were not taking ART at baseline; 24 were taking non-INSTI containing ART, and 1 received zidovudine monotherapy. In all, 39% (39/101) of women started an INSTI-containing regimen or added an INSTI to their ART regimen. Among 90 women with a baseline HIV RNA permitting 1-log reduction, the median time to 1-log RNA reduction was 8 days (interquartile range [IQR], 7-14) in the INSTI group vs 35 days (IQR, 20-53) in the non-INSTI ART group (P < .01). In a subgroup of 39 women with first and last RNA measurements ≤14 days apart, median time to 1-log reduction was 7 days (IQR, 6-10) in the INSTI group vs 11 days (IQR, 10-14) in the non-INSTI group (P < .01). ART that includes INSTIs appears to induce more rapid viral suppression than other ART regimens in pregnancy. Inclusion of an INSTI may play a role in optimal reduction

Trends in First-Line Antiretroviral Therapy in Asia: Results from the TREAT Asia HIV Observational Database

PubMed Central

Boettiger, David Charles; Kerr, Stephen; Ditangco, Rossana; Merati, Tuti Parwati; Pham, Thuy Thi Thanh; Chaiwarith, Romanee; Kiertiburanakul, Sasisopin; Li, Chung Ki Patrick; Kumarasamy, Nagalingeswaran; Vonthanak, Saphonn; Lee, Christopher; Van Kinh, Nguyen; Pujari, Sanjay; Wong, Wing Wai; Kamarulzaman, Adeeba; Zhang, Fujie; Yunihastuti, Evy; Choi, Jun Yong; Oka, Shinichi; Ng, Oon Tek; Kantipong, Pacharee; Mustafa, Mahiran; Ratanasuwan, Winai; Sohn, Annette; Law, Matthew

2014-01-01

Background Antiretroviral therapy (ART) has evolved rapidly since its beginnings. This analysis describes trends in first-line ART use in Asia and their impact on treatment outcomes. Methods Patients in the TREAT Asia HIV Observational Database receiving first-line ART for ≥6 months were included. Predictors of treatment failure and treatment modification were assessed. Results Data from 4662 eligible patients was analysed. Patients started ART in 2003–2006 (n = 1419), 2007–2010 (n = 2690) and 2011–2013 (n = 553). During the observation period, tenofovir, zidovudine and abacavir use largely replaced stavudine. Stavudine was prescribed to 5.8% of ART starters in 2012/13. Efavirenz use increased at the expense of nevirapine, although both continue to be used extensively (47.5% and 34.5% of patients in 2012/13, respectively). Protease inhibitor use dropped after 2004. The rate of treatment failure or modification declined over time (22.1 [95%CI 20.7–23.5] events per 100 patient/years in 2003–2006, 15.8 [14.9–16.8] in 2007–2010, and 11.6 [9.4–14.2] in 2011–2013). Adjustment for ART regimen had little impact on the temporal decline in treatment failure rates but substantially attenuated the temporal decline in rates of modification due to adverse event. In the final multivariate model, treatment modification due to adverse event was significantly predicted by earlier period of ART initiation (hazard ratio 0.52 [95%CI 0.33–0.81], p = 0.004 for 2011–2013 versus 2003–2006), older age (1.56 [1.19–2.04], p = 0.001 for ≥50 years versus <30years), female sex (1.29 [1.11–1.50], p = 0.001 versus male), positive hepatitis C status (1.33 [1.06–1.66], p = 0.013 versus negative), and ART regimen (11.36 [6.28–20.54], p<0.001 for stavudine-based regimens versus tenofovir-based). Conclusions The observed trends in first-line ART use in Asia reflect changes in drug availability, global treatment recommendations and

Early limited antiretroviral therapy is superior to deferred therapy in HIV-infected South African infants: results from the CHER (Children with HIV Early antiRetroviral) Randomized Trial

PubMed Central

Cotton, Mark F; Violari, Avy; Otwombe, Kennedy; Panchia, Ravindre; Dobbels, Els; Rabie, Helena; Josipovic, Deirdre; Liberty, Afaff; Lazarus, Erica; Innes, Steve; van Rensburg, Anita Janse; Pelser, Wilma; Truter, Handre; Madhi, Shabir A; Handelsman, Edward; Jean-Philippe, Patrick; McIntyre, James A; Gibb, Diana M; Babiker, Abdel G

2014-01-01

Background Interim results from the CHER trial showed that early antiretroviral therapy (ART) was life-saving for HIV-infected infants. Given limited options and potential for toxicity with life-long ART, CHER compared early limited ART with deferred ART. Methods CHER was an open 3-arm trial in HIV-infected asymptomatic infants aged <12 weeks with CD4% ≥25%. Infants were randomized to deferred (ART-Def) or immediate ART for 40weeks (ART-40W) or 96weeks (ART-96W), followed by interruption. Criteria for ART initiation in ART-Def and re-initiation after interruption were CD4% <25% in infancy; otherwise <20% or CDC severe stage B or stage C disease. Lopinavir-ritonavir, zidovudine, lamivudine was the first-line regimen at ART initiation and re-initiation. The primary endpoint was time-to-failure of first-line ART (immunological/clinical/virological) or death. Comparisons were by intent-to-treat, using time-to-event methods. Findings 377 infants were enrolled: median age 7.4weeks; CD4% 35% and HIV RNA log 5.7copies/ml. Median follow-up was 4.8 years; 34 (9%) were lost-to-follow-up. Median time to ART initiation in ART-Def was 20 (IQR 16–25) weeks. Time to restarting ART after interruption was 33 (26–45) weeks in ART-40W and 70 (35–109) weeks in ART-96W; at trial end 19% and 32% respectively, remained off ART. Proportions of follow-up time spent on ART were 81%, 70% and 69% in ART-Def, ART-40W and ART-96W arms. 48/125(38%), 32/126(25%) and 26/126(21%) children reached the primary endpoint; hazard ratio (95%CI), relative to ART-Def, was 0.59(0.38-0.93, p=0.02) for ART-40W and 0.47(0.27-0.76, p=0.002) for ART-96W. Seven children (3 ART-Def, 3 ART-40W, 1 ART-96W) switched to second-line ART. Interpretation Early limited ART had superior clinical/immunological outcome with no evidence of excess disease progression during subsequent interruption and less overall ART exposure than deferred ART. Longer time on primary ART permits longer subsequent interruption with

The management of HIV in pregnancy: A 10-year experience.

PubMed

Raffe, Sonia F; Savage, Charlotte; Perry, Louisa A; Patel, Amie; Keith, Tricia; Howell, Richard; Bradley, Robert; Bomont, Rob; Fidler, Katy; Gilleece, Yvonne

2017-03-01

The package of care to reduce HIV mother to child transmission (MTCT) has evolved significantly since trials of ante and intrapartum antiretroviral therapy (ART) in 1994. In the UK MTCT rate has fallen from 25.6% in the 1990s to 0.46%. We review the management of HIV in pregnancy in Brighton in the context of evolving guidelines. HIV, obstetric and neonatal notes of all HIV positive women, pregnant between 2003 and 2014, were reviewed. 97 pregnancies in 75 women were identified, resulting in 79 live births. Antenatal HIV diagnosis was made in 22 (28%). The proportion of pregnancies in those with known HIV at conception increased over the time period. At conception 58 (60%) were on ART, 33 (57%) of who continued on their original regimen. 34 (35%) initiated ART following conception: 14 known to be HIV positive, 20 diagnosed during pregnancy. Two did not start ART (1 due to miscarriage, 1 as diagnosed post-delivery) and in three cases ART history was unavailable due to transfer to alternative centres. ART was initiated on average at 22 weeks gestation (range 6-34). 4(5%) received Zidovudine (AZT) monotherapy, all before 2006. Choice of combination ART (cART) varied with time reflecting changing guidelines. Prior to 2008 an AZT containing regimen was used in 83% versus 8% after. Planned mode of delivery was documented in 73: 30(41%) planned a normal vaginal delivery (NVD), 43(59%) a caesarean section (CS). The viral load (VL) was <50copies/mL in 58(76%) at 36 weeks and 64(84%) at delivery. 90% with a detectable VL at 36 weeks delivered via CS. 100% received neonatal post-exposure prophylaxis (PEP): 68(88%) AZT monotherapy, 9(12%) cART. 84% initiated PEP within four hours. 90% completed 28days. 8(10%) babies experienced side effects. In the 10-year review period, one infant (1.3%) was diagnosed HIV positive. Both mother and infant received care in accordance with guidelines, including neonatal PEP within 4hours. Care of the HIV positive pregnant woman in Brighton has

Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings

PubMed Central

Campbell, Thomas B.; Smeaton, Laura M.; Kumarasamy, N.; Flanigan, Timothy; Klingman, Karin L.; Firnhaber, Cynthia; Grinsztejn, Beatriz; Hosseinipour, Mina C.; Kumwenda, Johnstone; Lalloo, Umesh; Riviere, Cynthia; Sanchez, Jorge; Melo, Marineide; Supparatpinyo, Khuanchai; Tripathy, Srikanth; Martinez, Ana I.; Nair, Apsara; Walawander, Ann; Moran, Laura; Chen, Yun; Snowden, Wendy; Rooney, James F.; Uy, Jonathan; Schooley, Robert T.; De Gruttola, Victor; Hakim, James Gita; Swann, Edith; Barnett, Ronald L.; Brizz, Barbara; Delph, Yvette; Gettinger, Nikki; Mitsuyasu, Ronald T.; Eshleman, Susan; Safren, Steven; Fiscus, Susan A.; Andrade, Adriana; Haas, David W.; Amod, Farida; Berthaud, Vladimir; Bollinger, Robert C.; Bryson, Yvonne; Celentano, David; Chilongozi, David; Cohen, Myron; Collier, Ann C.; Currier, Judith Silverstein; Cu-Uvin, Susan; Eron, Joseph; Flexner, Charles; Gallant, Joel E.; Gulick, Roy M.; Hammer, Scott M.; Hoffman, Irving; Kazembe, Peter; Kumwenda, Newton; Lama, Javier R.; Lawrence, Jody; Maponga, Chiedza; Martinson, Francis; Mayer, Kenneth; Nielsen, Karin; Pendame, Richard B.; Ramratnam, Bharat; Sanne, Ian; Severe, Patrice; Sirisanthana, Thira; Solomon, Suniti; Tabet, Steve; Taha, Taha; van der Horst, Charles; Wanke, Christine; Gormley, Joan; Marcus, Cheryl J.; Putnam, Beverly; Loeliger, Edde; Pappa, Keith A.; Webb, Nancy; Shugarts, David L.; Winters, Mark A.; Descallar, Renard S.; Steele, Joseph; Wulfsohn, Michael; Said, Farideh; Chen, Yue; Martin, John C; Bischofberger, Norbert; Cheng, Andrew; Jaffe, Howard; Sharma, Jabin; Poongulali, S.; Cardoso, Sandra Wagner; Faria, Deise Lucia; Berendes, Sima; Burke, Kelly; Mngqibisa, Rosie; Kanyama, Cecelia; Kayoyo, Virginia; Samaneka, Wadzanai P.; Chisada, Anthony; Faesen, Sharla; Chariyalertsak, Suwat; Santos, Breno; Lira, Rita Alves; Joglekar, Anjali A.; Rosa, Alberto La; Infante, Rosa; Jain, Mamta; Petersen, Tianna; Godbole, Sheela; Dhayarkar, Sampada; Feinberg, Judith; Baer, Jenifer; Pollard, Richard B.; Asmuth, David; Gangakhedkar, Raman R; Gaikwad, Asmita; Ray, M. Graham; Basler, Cathi; Para, Michael F.; Watson, Kathy J.; Taiwo, Babafemi; McGregor, Donna; Balfour, Henry H.; Mullan, Beth; Kim, Ge-Youl; Klebert, Michael K.; Cox, Gary Matthew; Silberman, Martha; Mildvan, Donna; Revuelta, Manuel; Tashima, Karen T.; Patterson, Helen; Geiseler, P. Jan; Santos, Bartolo; Daar, Eric S; Lopez, Ruben; Frarey, Laurie; Currin, David; Haas, David H.; Bailey, Vicki L.; Tebas, Pablo; Zifchak, Larisa; Noel-Connor, Jolene; Torres, Madeline; Sha, Beverly E.; Fritsche, Janice M.; Cespedes, Michelle; Forcht, Janet; O'Brien, William A.; Mogridge, Cheryl; Hurley, Christine; Corales, Roberto; Palmer, Maria; Adams, Mary; Luque, Amneris; Lopez-Detres, Luis; Stroberg, Todd

2012-01-01

Background Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world. Methods and Findings 1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure. An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72–1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54–0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39–0.64 for women; HR 0.79, CI 0.62–1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12–2.04; p = 0.007). Conclusion EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected

Safety and Effectiveness of Highly Active Antiretroviral Therapy in Treatment-Naïve HIV Patients: Preliminary Findings of a Cohort Event Monitoring Study in Belarus.

PubMed

Setkina, Svetlana; Dotsenko, Marina; Bondar, Sviatlana; Charnysh, Iryna; Kuchko, Alla; Kaznacheeva, Alena; Kozorez, Elena; Dodaleva, Alena; Rossa, Natalia

2015-04-01

neurotoxic adverse reactions. In several cases, some types of toxicities, associated with zidovudine, efavirenz, and nevirapine, had a high level of severity, necessitating hospitalization and drug regimen or single-agent substitution. Severe cases of hematological, hepatobiliary, and psychiatric toxicities were associated with pre-existing risk factors. CEM is an effective tool for safety and effectiveness monitoring and could be successfully implemented for intensive study of important safety issues and for overcoming knowledge gaps regarding safety. In order to achieve a favorable benefit-risk ratio for HAART in the specific sections of the population with pre-existing risk factors for development of ART toxicities, more vigilant consideration and careful assessment before therapy is commenced and further regular monitoring of key laboratory parameters is required.

Predicted savings to the UK National Health Service from switching to generic antiretrovirals, 2014-2018.

PubMed

Hill, Andrew; Hill, Teresa; Jose, Sophie; Pozniak, Anton

2014-01-01

In other disease areas, generic drugs are normally used after patent expiry. Patents on zidovudine, lamivudine, nevirapine and efavirenz have already expired. Patents will expire for abacavir in late 2014, lopinavir/r in 2016, and tenofovir, darunavir and atazanavir in 2017. However, patents on single-tablet regimens do not expire until after 2026. The number of people taking each antiretroviral in the UK was estimated from 23,655 individuals in the UK CHIC cohort (2012 database). Costs of patented drugs were taken from the British National Formulary database, assuming a 30% discount. Costs of generic antiretrovirals were estimated using an 80% discount from patented prices, or actual costs where available. Two options were analysed: 1 - all patients use single-tablet regimens and patented versions of drugs; prices remain stable over time; 2 - all people switch from patented to generic drugs when available, after patent expiry (dates shown above). There were an estimated 67,000 people taking antiretrovirals in the UK in 2014, estimated to rise by 8% per year until 2018 (in line with previous rises). The most widely used antiretrovirals in the CHIC cohort were tenofovir (TDF) (75%), emtricitabine (FTC) (69%), efavirenz (EFV) (39%), lamivudine (3TC) (23%), abacavir (ABC) (18%), darunavir (DRV) (21%) and atazanavir (ATV) (16%). The predicted annual UK cost of generic ABC/3TC/EFV (three generic tablets once daily) was £1018 per person-year. Costs of patented single-tablet regimens ranged from £5000 to £7500 per person-year. Assuming continued use of patented antiretrovirals in the UK, the predicted total national costs of antiretroviral treatment were predicted to rise from £425 million in 2014 to £459 m in 2015, £495 m in 2016, £536 m in 2017 and £578 m in 2018. With a 100% switch to generics, total predicted costs were £337 m in 2014, £364 m in 2015, £382 m in 2016, £144 m in 2017 and £169 m in 2018. The total predicted saving over five years from a

Longitudinal Analysis of Adherence to First-Line Antiretroviral Therapy: Evidence of Treatment Sustainability from an Indian HIV Cohort.

PubMed

Shet, Anita; Kumarasamy, N; Poongulali, Selvamuthu; Shastri, Suresh; Kumar, Dodderi Sunil; Rewari, Bharath B; Arumugam, Karthika; Antony, Jimmy; De Costa, Ayesha; D'Souza, George

2016-01-01

Given the chronic nature of HIV infection and the need for life-long antiretroviral therapy (ART), maintaining long-term optimal adherence is an important strategy for maximizing treatment success. In order to understand better the dynamic nature of adherence behaviors in India where complex cultural and logistic features prevail, we assessed the patterns, trajectories and time-dependent predictors of adherence levels in relation to virological failure among individuals initiating first-line ART in India. Between July 2010 and August 2013, eligible ART-naïve HIV-infected individuals newly initiating first-line ART within the national program at three sites in southern India were enrolled and monitored for two years. ART included zidovudine/stavudine/tenofovir plus lamivudine plus nevirapine/efavirenz. Patients were assessed using clinical, laboratory and adherence parameters. Every three months, medication adherence was measured using pill count, and a structured questionnaire on adherence barriers was administered. Optimal adherence was defined as mean adherence ≥95%. Statistical analysis was performed using a bivariate and a multivariate model of all identified covariates. Adherence trends and determinants were modeled as rate ratios using generalized estimating equation analysis in a Poisson distribution. A total of 599 eligible ART-naïve patients participated in the study, and contributed a total of 921 person-years of observation time. Women constituted 43% and mean CD4 count prior to initiating ART was 192 cells/mm3. Overall mean adherence among all patients was 95.4%. The proportion of patients optimally adherent was 75.6%. Predictors of optimal adherence included older age (≥40 years), high school-level education and beyond, lower drug toxicity-related ART interruption, full disclosure, sense of satisfaction with one's own health and patient's perception of having good access to health-care services. Adherence was inversely proportional to virological

Early infant diagnosis of HIV infection using DNA-PCR at a referral center: an 8 years retrospective analysis.

PubMed

Olana, Tolessa; Bacha, Tigist; Worku, Walelign; Tadesse, Birkneh Tilahun

2016-01-01

Over the last decade, Ethiopia adopted different strategies of prevention of mother to child transmission of HIV (PMTCT). Prior to implementation of Option A in 2011, there was no provision of prophylaxis for PMTCT. With 'Option A', PMTCT interventions relied on maternal CD4 count. In early 2013, ''Option B+'' has been started; with this option, antiretroviral therapy is started and continued for life to any HIV positive pregnant mother irrespective of CD4 count with an enhanced treatment for the baby. Though there are a number of studies which evaluated the effectiveness of PMTCT interventions, the current study assessed the real-world effectiveness of PMTCT options in a setting where there is limitation of resources. This study tried to address three questions: what proportion of babies tested by DNA-PCR are HIV infected in the first 2 months of life? How does the type of PMTCT intervention affect presence of HIV infection at this age? What are the factors affecting HIV transmission, after controlling for type of PMCT-HIV intervention? We assessed records of 624 registered HIV exposed infants and 412 mothers who were delivered at Bishoftu Hospital from May 2006 to August 2014. Presence of HIV infection at 6-8 weeks of age was assessed from the records. Maternal and infant risk factors for infection at this age were analyzed. Data were collected using standard data abstraction format and were analyzed using SPSS version 20. Among all the infants who were delivered at the hospital during the study period, 624/936 (66.7 %) had undergone early infant diagnosis at 6-8 weeks. Twenty-seven (4.3 %) were positive for HIV DNA PCR at the age of 6-8 weeks. None of the infants who received ''Option B+'' had a positive HIV DNA PCR result. HIV infection rate was highest among those who took either no prophylaxis or single dose Nevirapine (11.5 and 11.1 % respectively). Those who took single dose Nevirapine and Zidovudine had HIV positivity rate of 3.9 %. Many of the

Efficacy and safety of three antiretroviral regimens for initial treatment of HIV-1: a randomized clinical trial in diverse multinational settings.

PubMed

Campbell, Thomas B; Smeaton, Laura M; Kumarasamy, N; Flanigan, Timothy; Klingman, Karin L; Firnhaber, Cynthia; Grinsztejn, Beatriz; Hosseinipour, Mina C; Kumwenda, Johnstone; Lalloo, Umesh; Riviere, Cynthia; Sanchez, Jorge; Melo, Marineide; Supparatpinyo, Khuanchai; Tripathy, Srikanth; Martinez, Ana I; Nair, Apsara; Walawander, Ann; Moran, Laura; Chen, Yun; Snowden, Wendy; Rooney, James F; Uy, Jonathan; Schooley, Robert T; De Gruttola, Victor; Hakim, James Gita

2012-01-01

Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world. 1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure. An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54-0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39-0.64 for women; HR 0.79, CI 0.62-1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12-2.04; p = 0.007). EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are

Evaluation of treatment outcomes for patients on first-line regimens in US President's Emergency Plan for AIDS Relief (PEPFAR) clinics in Uganda: predictors of virological and immunological response from RV288 analyses.

PubMed

Crawford, K W; Wakabi, S; Magala, F; Kibuuka, H; Liu, M; Hamm, T E

2015-02-01

Viral load (VL) monitoring is recommended, but seldom performed, in resource-constrained countries. RV288 is a US President's Emergency Plan for AIDS Relief (PEPFAR) basic programme evaluation to determine the proportion of patients on treatment who are virologically suppressed and to identify predictors of virological suppression and recovery of CD4 cell count. Analyses from Uganda are presented here. In this cross-sectional, observational study, patients on first-line antiretroviral therapy (ART) (efavirenz or nevirapine+zidovudine/lamivudine) from Kayunga District Hospital and Kagulamira Health Center were randomly selected for a study visit that included determination of viral load (HIV-1 RNA), CD4 cell count and clinical chemistry tests. Subjects were recruited by time on treatment: 6-12, 13-24 or >24 months. Logistic regression modelling identified predictors of virological suppression. Linear regression modelling identified predictors of CD4 cell count recovery on ART. We found that 85.2% of 325 subjects were virologically suppressed (viral load<47 HIV-1 RNA copies/ml). There was no difference in the proportion of virologically suppressed subjects by time on treatment, yet CD4 counts were higher in each successive stratum. Women had higher median CD4 counts than men overall (406 vs. 294 cells/μL, respectively; P<0.0001) and in each time-on-treatment stratum. In a multivariate logistic regression model, predictors of virological suppression included efavirenz use [odds ratio (OR) 0.47; 95% confidence interval (CI) 0.22-1.02; P=0.057], lower cost of clinic visits (OR 0.815; 95% CI 0.66-1.00; P=0.05), improvement in CD4 percentage (OR 1.06; 95% CI 1.014-1.107; P=0.009), and care at Kayunga vs. Kangulamira (OR 0.47; 95% CI 0.23-0.92; P=0.035). In a multivariate linear regression model of covariates associated with CD4 count recovery, time on highly active antiretroviral therapy (ART) (P<0.0001), patient satisfaction with care (P=0.038), improvements in total

HIV-1 virological remission lasting more than 12 years after interruption of early antiretroviral therapy in a perinatally infected teenager enrolled in the French ANRS EPF-CO10 paediatric cohort: a case report.

PubMed

Frange, Pierre; Faye, Albert; Avettand-Fenoël, Véronique; Bellaton, Erianna; Descamps, Diane; Angin, Mathieu; David, Annie; Caillat-Zucman, Sophie; Peytavin, Gilles; Dollfus, Catherine; Le Chenadec, Jerome; Warszawski, Josiane; Rouzioux, Christine; Sáez-Cirión, Asier

2016-01-01

Durable HIV-1 remission after interruption of combined antiretroviral therapy (ART) has been reported in some adults who started treatment during primary infection; however, whether long-term remission in vertically infected children is possible was unknown. We report a case of a young adult perinatally infected with HIV-1 with viral remission despite long-term treatment interruption. The patient was identified in the ANRS EPF-CO10 paediatric cohort among 100 children infected with HIV perinatally who started ART before 6 months of age. HIV RNA viral load and CD4 cell counts were monitored from birth. Ultrasensitive HIV RNA, peripheral blood mononuclear cell (PBMC)-associated HIV DNA, HIV-specific T-cell responses (ie, production of cytokines and capacity to suppress HIV infection), reactivation of the CD4 cell reservoir (measured by p24 ELISA and HIV RNA in supernatants upon phytohaemagglutinin activation of purified CD4 cells), and plasma concentrations of antiretroviral drugs were assessed after 10 years of documented control off therapy. The infant was born in 1996 to a woman with uncontrolled HIV-1 viraemia and received zidovudine-based prophylaxis for 6 weeks. HIV RNA and DNA were not detected 3 days and 14 days after birth. HIV DNA was detected at 4 weeks of age. HIV RNA reached 2·17× 10(6) copies per mL at 3 months of age and ART was started. HIV RNA was undetectable 1 month later. ART was discontinued by the family at some point between 5·8 and 6·8 years of age. HIV RNA was undetectable at 6·8 years of age and ART was not resumed. HIV RNA has remained below 50 copies per mL and CD4 cell counts stable through to 18·6 years of age. After 11·5 years of control off treatment, HIV RNA was below 4 copies per mL and HIV DNA was 2·2 log10 copies per 10(6) PBMCs. The HLA genotype showed homozygosity at several loci (A*2301-, B*1503/4101, C*0210/0802, DRB1*1101-, and DQB1*0602-). HIV-specific CD8 T-cell responses and T-cell activation were weak. Findings

The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic.

PubMed

Broder, Samuel

2010-01-01

In the last 25 years, HIV-1, the retrovirus responsible for the acquired immunodeficiency syndrome (AIDS), has gone from being an "inherently untreatable" infectious agent to one eminently susceptible to a range of approved therapies. During a five-year period, starting in the mid-1980s, my group at the National Cancer Institute played a role in the discovery and development of the first generation of antiretroviral agents, starting in 1985 with Retrovir (zidovudine, AZT) in a collaboration with scientists at the Burroughs-Wellcome Company (now GlaxoSmithKline). We focused on AZT and related congeners in the dideoxynucleoside family of nucleoside reverse transcriptase inhibitors (NRTIs), taking them from the laboratory to the clinic in response to the pandemic of AIDS, then a terrifying and lethal disease. These drugs proved, above all else, that HIV-1 infection is treatable, and such proof provided momentum for new therapies from many sources, directed at a range of viral targets, at a pace that has rarely if ever been matched in modern drug development. Antiretroviral therapy has brought about a substantial decrease in the death rate due to HIV-1 infection, changing it from a rapidly lethal disease into a chronic manageable condition, compatible with very long survival. This has special implications within the classic boundaries of public health around the world, but at the same time in certain regions may also affect a cycle of economic and civil instability in which HIV-1/AIDS is both cause and consequence. Many challenges remain, including (1) the life-long duration of therapy; (2) the ultimate role of pre-exposure prophylaxis (PrEP); (3) the cardiometabolic side-effects or other toxicities of long-term therapy; (4) the emergence of drug-resistance and viral genetic diversity (non-B subtypes); (5) the specter of new cross-species transmissions from established retroviral reservoirs in apes and Old World monkeys; and (6) the continued pace of new HIV-1

The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic

PubMed Central

Broder, Samuel

2010-01-01

In the last 25 years, HIV-1, the retrovirus responsible for the Acquired Immunodeficiency Syndrome (AIDS), has gone from being an “inherently untreatable” infectious agent to one eminently susceptible to a range of approved therapies. During a five-year period, starting in the mid-1980s, my group at the National Cancer Institute played a role in the discovery and development of the first generation of antiretroviral agents, starting in 1985 with Retrovir® (zidovudine, AZT) in a collaboration with scientists at the Burroughs-Wellcome Company (now GlaxoSmithKline). We focused on AZT and related congeners in the dideoxynucleoside family of nucleoside reverse transcriptase inhibitors (NRTIs), taking them from the laboratory to the clinic in response to the pandemic of AIDS, then a terrifying and lethal disease. These drugs proved, above all else, that HIV-1 infection is treatable, and such proof provided momentum for new therapies from many sources, directed at a range of viral targets, at a pace that has rarely if ever been matched in modern drug development. Antiretroviral therapy has brought about a substantial decrease in the death rate due to HIV-1 infection, changing it from a rapidly lethal disease into a chronic manageable condition, compatible with very long survival. This has special implications within the classic boundaries of public health around the world, but at the same time in certain regions may also affect a cycle of economic and civil instability in which HIV-1/AIDS is both cause and consequence. Many challenges remain, including 1.) the life-long duration of therapy; 2.) the ultimate role of pre-exposure prophylaxis (PrEP); 3.) the cardiometabolic side effects or other toxicities of long-term therapy; 4.) the emergence of drug-resistance and viral genetic diversity (non-B subtypes); 5.) the specter of new cross-species transmissions from established retroviral reservoirs in apes and Old World monkeys; and 6.) the continued pace of new HIV-1

Pulmonary aspergillosis in patients with AIDS. Clinical and radiographic correlations.

PubMed

Miller, W T; Sais, G J; Frank, I; Gefter, W B; Aronchick, J M; Miller, W T

1994-01-01

To evaluate the clinical and radiographic features of pulmonary aspergillosis as they present in AIDS patients; in particular, to determine similarities and differences between Aspergillus infection in patients with AIDS vs those without AIDS. Six new cases of confirmed or probable pulmonary aspergillosis were discovered during a search of hospital records. These are reviewed with 30 previously reported cases with special attention to radiographic appearance of disease and how radiographic appearance influences clinical outcome. Symptoms of pulmonary aspergillosis in AIDS were nonspecific, most often including fever, cough, and dyspnea, and less commonly, chest pain or hemoptysis. Major risk factors for the development of pulmonary aspergillosis in patients with AIDS were steroid administration and neutropenia. Neutropenia was often a complication of therapies for AIDS, in particular, ganciclovir and zidovudine. Radiographic appearance of disease could be divided into three general categories. One third of the patients (13/36) presented with cavitary upper lobe disease resembling noninvasive or chronic necrotizing aspergillosis. Fatal hemoptysis occurred in 42 percent of patients with this form of disease. Twenty-two percent (8/36) of the cases presented as a nondescript focal alveolar opacity similar to invasive aspergillosis. In several patients, the focal infiltrate remained stable for several months, a feature that is unusual for aspergillosis in non-AIDS patients. The air crescent sign was present in none of the 36 reported cases. Patients with only focal disease had the best prognosis of patients with pulmonary aspergillosis. Bilateral alveolar or interstitial disease similar to invasive aspergillosis was present in 23 percent (9/36) of the patients. Bilateral disease appears to be a marker for disseminated infection and was associated with a high mortality due to aspergillosis. Two new forms of bronchial aspergillosis (5/36 cases) have been described

A survey of the syntheses of active pharmaceutical ingredients for antiretroviral drug combinations critical to access in emerging nations.

PubMed

Pinheiro, Eloan Dos Santos; Antunes, Octavio Augusto Ceva; Fortunak, Joseph M D

2008-09-01

It has been roughly 25 years since the threat posed by human immunodeficiency virus type 1 (HIV-1) became widely known. The cumulative death toll from HIV/AIDS is now greater than 25 million. There are approximately 33 million people living worldwide with this disease, of whom about 68% (22.5 million) live in sub-Saharan Africa (http://www.avert.org/worldstats.htm). A number of antiretroviral (ARV) drugs have been approved for treatment of HIV/AIDS. Inhibitors of HIV reverse transcriptase (RTIs) include the nucleoside/nucleotide drugs zidovudine, lamivudine, abacavir, didanosine, stavudine, emtricitabine and tenofovir disoproxil fumarate. Non-nucleoside RTIs include nevirapine, efavirenz and etravirine. Inhibitors of HIV protease (PIs) include saquinavir, ritonavir, lopinavir, nelfinavir, indinavir, fosamprenavir and atazanavir. Enfuvirtide inhibits the HIV fusion protein. The CCR5 chemokine antagonist maraviroc and the integrase inhibitor raltegravir were very recently approved by the US FDA. Fixed-dose combinations (FDCs) have been formulated to increase tolerability, convenience and compliance. First-line drug combinations are offered to treatment-naive patients, while second-line drugs are reserved for those who no longer respond adequately to first-line therapy. In developing countries a modest but increasing fraction of those infected have access to ARVs. The Clinton HIV/AIDS Initiative estimates that 2.4 million of the nearly 8 million individuals needing treatment in developing nations have access to some drugs. First-line FDCs used in resource-poor settings are largely combinations of two nucleoside RTIs and a non-nucleoside RTI or PI. The effectiveness of these combinations decreases over time, requiring a switch to combinations that retain potency in the presence of viral resistance. Increasing access to second-line FDCs and new developments in first-line ARV therapy are cost challenges. In high-income countries the cost of ARV therapy is largely

Gateways to clinical trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2005-06-01

, vildagliptin, vincristine sulfate, voriconazole, VRX-496, VX-385; Warfarin sodium; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan; Zanolimumab, zidovudine. Copyright (c) 2005 Prous Science. All rights reserved.

Pregnancy and infant outcomes among HIV-infected women taking long-term ART with and without tenofovir in the DART trial.

PubMed

Gibb, Diana M; Kizito, Hilda; Russell, Elizabeth C; Chidziva, Ennie; Zalwango, Eva; Nalumenya, Ruth; Spyer, Moira; Tumukunde, Dinah; Nathoo, Kusum; Munderi, Paula; Kyomugisha, Hope; Hakim, James; Grosskurth, Heiner; Gilks, Charles F; Walker, A Sarah; Musoke, Phillipa

2012-01-01

Few data have described long-term outcomes for infants born to HIV-infected African women taking antiretroviral therapy (ART) in pregnancy. This is particularly true for World Health Organization (WHO)-recommended tenofovir-containing first-line regimens, which are increasingly used and known to cause renal and bone toxicities; concerns have been raised about potential toxicity in babies due to in utero tenofovir exposure. Pregnancy outcome and maternal/infant ART were collected in Ugandan/Zimbabwean HIV-infected women initiating ART during The Development of AntiRetroviral Therapy in Africa (DART) trial, which compared routine laboratory monitoring (CD4; toxicity) versus clinically driven monitoring. Women were followed 15 January 2003 to 28 September 2009. Infant feeding, clinical status, and biochemistry/haematology results were collected in a separate infant study. Effect of in utero ART exposure on infant growth was analysed using random effects models. 382 pregnancies occurred in 302/1,867 (16%) women (4.4/100 woman-years [95% CI 4.0-4.9]). 226/390 (58%) outcomes were live-births, 27 (7%) stillbirths (≥22 wk), and 137 (35%) terminations/miscarriages (<22 wk). Of 226 live-births, seven (3%) infants died <2 wk from perinatal causes and there were seven (3%) congenital abnormalities, with no effect of in utero tenofovir exposure (p>0.4). Of 219 surviving infants, 182 (83%) enrolled in the follow-up study; median (interquartile range [IQR]) age at last visit was 25 (12-38) months. From mothers' ART, 62/9/111 infants had no/20%-89%/≥90% in utero tenofovir exposure; most were also zidovudine/lamivudine exposed. All 172 infants tested were HIV-negative (ten untested). Only 73/182(40%) infants were breast-fed for median 94 (IQR 75-212) days. Overall, 14 infants died at median (IQR) age 9 (3-23) months, giving 5% 12-month mortality; six of 14 were HIV-uninfected; eight untested infants died of respiratory infection (three), sepsis (two), burns (one), measles (one

Total lymphocyte count as a predictor of absolute CD4+ count and CD4+ percentage in HIV-infected persons.

PubMed

Blatt, S P; Lucey, C R; Butzin, C A; Hendrix, C W; Lucey, D R

1993-02-03

To determine whether the total lymphocyte count (TLC) accurately predicts a low absolute CD4+ T-cell count and CD4+ percentage in persons infected with human immunodeficiency virus (HIV). Retrospective analysis of data collected in the US Air Force HIV Natural History Study. Military medical center that performs annual medical evaluation of all HIV-infected US Air Force personnel. A total of 828 consecutive patients with no prior history of zidovudine use, evaluated from January 1985 through July 1991. For patients with multiple observations over time, a single data point within each 6-month interval was included in the analysis (N = 2866). The sensitivity, specificity, and likelihood ratio (LR) of the TLC, in the range of 1.00 x 10(9)/L to 2.00 x 10(9)/L, in predicting an absolute CD4+ T-cell count less than 0.20 x 10(9)/L or a CD4+ percentage less than 20% were calculated. In addition, the LR and pretest probability of significant immunosuppression were used to calculate posttest probabilities of a low CD4+ count for a given TLC value. The LR of the TLC in predicting an absolute CD4+ count < 0.20 x 10(9)/L increased from 2.4 (95% confidence interval, 2.2 to 2.5) for all TLCs less than 2.00 x 10(9)/L, to 33.2 (95% confidence interval, 24.1 to 45.7) for all TLCs less than 1.00 x 10(9)/L. The specificity for this prediction increased from 57% to 97% over this range. The LR also increased from 1.4 (95% confidence interval, 1.3 to 1.6) for all TLCs less than 2.00 x 10(9)/L to 9.7 (95% confidence interval, 7.1 to 13.1) for all TLCs less than 1.00 x 10(9)/L in predicting a CD4+ percentage less than 20%. The TLC, between 1.00 x 10(9)/L and 2.00 x 10(9)/L, appears to be a useful predictor of significant immunosuppression as measured by a CD4+ T-cell count less than 0.20 x 10(9)/L in HIV-infected persons. The LR for a given TLC value and the pretest probability of immunosuppression can be used to determine the posttest probability of significant immunosuppression in

Prevention of mother-to-child transmission of HIV-1 through breastfeeding by treating mothers with triple antiretroviral therapy in Dar es Salaam, Tanzania: the Mitra Plus study.

PubMed

Kilewo, Charles; Karlsson, Katarina; Ngarina, Matilda; Massawe, Augustine; Lyamuya, Eligius; Swai, Andrew; Lipyoga, Rosina; Mhalu, Fred; Biberfeld, Gunnel

2009-11-01

The main aim of this study was to reduce breast-milk transmission of HIV-1 by treating HIV-1-infected women with highly active antiretroviral therapy (HAART) during breastfeeding. Mitra Plus was an open-label, nonrandomized, prospective cohort study. HIV-1-infected pregnant women in Dar es Salaam were treated with zidovudine (ZDV) + lamivudine (3TC) + nevirapine (NVP). NVP was later replaced by nelfinavir for mothers with CD4 cell counts >200 cells per microliter or with adverse reaction to NVP. HAART was initiated at 34 weeks of gestation. For women with symptomatic HIV infection or CD4 cell counts below 200 cells per microliter, HAART was started earlier if possible. Treatment of the mothers was stopped at 6 months except for those mothers who needed HAART for their own health. The infants received ZDV + 3TC for 1 week after birth. Mothers were advised to exclusively breastfeed and to wean abruptly between 5 and 6 months. Transmission of HIV-1 was analyzed using the Kaplan-Meier survival technique. Cox regression was used for comparison with the breastfeeding population of the Petra trial arm A. There were 441 infants included in the analysis of HIV-1 transmission. The cumulative transmission of HIV-1 was 4.1 % [95% confidence interval (CI): 2.2 to 6.0] at 6 weeks, 5.0% (95% CI: 2.9 to 7.1) at 6 months, and 6.0% (95% CI: 3.7 to 8.3) at 18 months after delivery. The cumulative risk of HIV transmission between 6 weeks and 6 months was 1.0% and between 6 months and 18 months 1.1%. The cumulative HIV infection or death rate was 8.6% (95% CI: 6.0 to 11.2) at 6 months and 13.6% (95% CI: 10.3 to 16.9) at 18 months after delivery. Viral load at enrollment and duration of HAART before delivery were significantly associated with transmission but CD4 cell count at enrollment was not. The median time of breastfeeding was 24 weeks. The transmission in the Mitra Plus study was about half of the transmission in the breastfeeding population in the Petra trial arm A at 6 months

[Effect of highly active anti-retroviral therapy on prevention of mother to child transmission of HIV and on infant growth and development].

PubMed

He, Yan; Luo, Yan; Ding, Yi-ling; Zheng, Yu-huang; Li, Jing; Huang, Jian; Li, Jie-min

2011-10-01

To identify the effect of highly active anti-retroviral therapy (HAART) on prevention of mother to child transmission (PMTCT) of HIV and on infant growth and development. A total of 16 HIV-infected women or pregnant women selected in this study received HAART before or 18 - 24 weeks after pregnancy. The treatment included taking Zidovudine (AZT) 0.3 g each time, twice a day, Lamivudine (3TC) 0.3 g each time, once a day and Nevirapine (NVP) 0.2 g each time, twice a day or Efavirenz (EFV) 0.6 g each time, once a day, as well as labor intervention and artificial feeding. The growth index for 17 infants from HIV-infected mothers (experimental group) and 16 normal infants (control group) were observed for 18 months. Neonatal hemoglobin (Hb), liver and kidney function, serum iron and calcium were detected at neonatal period and at 12(th) month, respectively. All the pregnant women were in good conditions and had tolerance with HAART. The birth weight, length and Apgar score of the newborns in the experimental group were (3.5 ± 0.9) kg, (54.2 ± 3.8) cm and 7 - 10 scores respectively, however those in the control group were (3.6 ± 0.8) kg, (55.6 ± 3.6) cm and 8 - 10 scores (t(weight) = 1.01, t(length) = 6.98, P > 0.05). Weight and length of infants in experimental group were (9.36 ± 1.8) kg and (76.3 ± 2.7) cm at 12(th) month, while those in control group were (9.86 ± 2.5) kg and (76.8 ± 2.9) cm (t(weight) = 0.83, t(length) = 1.00, P > 0.05). The level of Hb in experimental group was (126.2 ± 16.7) g/L, and was (148.6 ± 20.5) g/L in control group (t = -5.89, P = 0.11). At 12(th) month, the levels of Hb and the total bilirubin (TB) were (125.9 ± 19.8) g/L and (11.7 ± 3.5) µmol/L in experimental group; and those in the control group were (130.1 ± 18.7) g/L and (13.2 ± 3.7) µmol/L (t(Hb) = -3.82, t(TB) = -2.14, P > 0.05). Serum iron and calcium were (25.4 ± 5.7) µmol/L and (26.4 ± 7.2) µmol/L at neonatal period and were (2.3 ± 0.6) mol/L and (2.8 ± 0

Geographic and Temporal Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted HIV-1 Drug Resistance: An Individual-Patient- and Sequence-Level Meta-Analysis

PubMed Central

Rhee, Soo-Yon; Blanco, Jose Luis; Jordan, Michael R.; Taylor, Jonathan; Lemey, Philippe; Varghese, Vici; Hamers, Raph L.; Bertagnolio, Silvia; de Wit, Tobias F. Rinke; Aghokeng, Avelin F.; Albert, Jan; Avi, Radko; Avila-Rios, Santiago; Bessong, Pascal O.; Brooks, James I.; Boucher, Charles A. B.; Brumme, Zabrina L.; Busch, Michael P.; Bussmann, Hermann; Chaix, Marie-Laure; Chin, Bum Sik; D’Aquin, Toni T.; De Gascun, Cillian F.; Derache, Anne; Descamps, Diane; Deshpande, Alaka K.; Djoko, Cyrille F.; Eshleman, Susan H.; Fleury, Herve; Frange, Pierre; Fujisaki, Seiichiro; Harrigan, P. Richard; Hattori, Junko; Holguin, Africa; Hunt, Gillian M.; Ichimura, Hiroshi; Kaleebu, Pontiano; Katzenstein, David; Kiertiburanakul, Sasisopin; Kim, Jerome H.; Kim, Sung Soon; Li, Yanpeng; Lutsar, Irja; Morris, Lynn; Ndembi, Nicaise; NG, Kee Peng; Paranjape, Ramesh S.; Peeters, Martine; Poljak, Mario; Price, Matt A.; Ragonnet-Cronin, Manon L.; Reyes-Terán, Gustavo; Rolland, Morgane; Sirivichayakul, Sunee; Smith, Davey M.; Soares, Marcelo A.; Soriano, Vincent V.; Ssemwanga, Deogratius; Stanojevic, Maja; Stefani, Mariane A.; Sugiura, Wataru; Sungkanuparph, Somnuek; Tanuri, Amilcar; Tee, Kok Keng; Truong, Hong-Ha M.; van de Vijver, David A. M. C.; Vidal, Nicole; Yang, Chunfu; Yang, Rongge; Yebra, Gonzalo; Ioannidis, John P. A.; Vandamme, Anne-Mieke; Shafer, Robert W.

2015-01-01

NNRTI SDRMs—K101E, K103N, Y181C, and G190A—accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling. Conclusions Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen. PMID:25849352

Geographic and temporal trends in the molecular epidemiology and genetic mechanisms of transmitted HIV-1 drug resistance: an individual-patient- and sequence-level meta-analysis.

PubMed

Rhee, Soo-Yon; Blanco, Jose Luis; Jordan, Michael R; Taylor, Jonathan; Lemey, Philippe; Varghese, Vici; Hamers, Raph L; Bertagnolio, Silvia; Rinke de Wit, Tobias F; Aghokeng, Avelin F; Albert, Jan; Avi, Radko; Avila-Rios, Santiago; Bessong, Pascal O; Brooks, James I; Boucher, Charles A B; Brumme, Zabrina L; Busch, Michael P; Bussmann, Hermann; Chaix, Marie-Laure; Chin, Bum Sik; D'Aquin, Toni T; De Gascun, Cillian F; Derache, Anne; Descamps, Diane; Deshpande, Alaka K; Djoko, Cyrille F; Eshleman, Susan H; Fleury, Herve; Frange, Pierre; Fujisaki, Seiichiro; Harrigan, P Richard; Hattori, Junko; Holguin, Africa; Hunt, Gillian M; Ichimura, Hiroshi; Kaleebu, Pontiano; Katzenstein, David; Kiertiburanakul, Sasisopin; Kim, Jerome H; Kim, Sung Soon; Li, Yanpeng; Lutsar, Irja; Morris, Lynn; Ndembi, Nicaise; Ng, Kee Peng; Paranjape, Ramesh S; Peeters, Martine; Poljak, Mario; Price, Matt A; Ragonnet-Cronin, Manon L; Reyes-Terán, Gustavo; Rolland, Morgane; Sirivichayakul, Sunee; Smith, Davey M; Soares, Marcelo A; Soriano, Vincent V; Ssemwanga, Deogratius; Stanojevic, Maja; Stefani, Mariane A; Sugiura, Wataru; Sungkanuparph, Somnuek; Tanuri, Amilcar; Tee, Kok Keng; Truong, Hong-Ha M; van de Vijver, David A M C; Vidal, Nicole; Yang, Chunfu; Yang, Rongge; Yebra, Gonzalo; Ioannidis, John P A; Vandamme, Anne-Mieke; Shafer, Robert W

2015-04-01

��accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling. Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen.

Evolution of antiretroviral drug costs in Brazil in the context of free and universal access to AIDS treatment.

PubMed

Nunn, Amy S; Fonseca, Elize M; Bastos, Francisco I; Gruskin, Sofia; Salomon, Joshua A

2007-11-13

/r, efavirenz, tenofovir, atazanavir, enfuvirtide, and a locally produced generic, fixed-dose combination of zidovudine and lamivudine (AZT/3TC). Because prices declined for many of the patented drugs that constitute the largest share of drug costs, nearly the entire increase in overall drug expenditures between 2001 and 2005 is attributable to increases in drug quantities. Had all drug quantities been held constant from 2001 until 2005 (or for those drugs entering treatment guidelines after 2001, held constant between the year of introduction and 2005), total costs would have increased by only an estimated US$7 million. We estimate that in the absence of price declines for patented drugs, Brazil would have spent a cumulative total of US$2 billion on drugs for HAART between 2001 and 2005, implying a savings of US$1.2 billion from price declines. Finally, in comparing Brazilian prices for locally produced generic ARVs to the lowest international prices meeting global pharmaceutical quality standards, we find that current prices for Brazil's locally produced generics are generally much higher than corresponding global prices, and note that these prices have risen in Brazil while declining globally. We estimate the excess costs of Brazil's locally produced generics totaled US$110 million from 2001 to 2005. Despite Brazil's more costly generic ARVs, the net result of ARV price changes has been a cost savings of approximately US$1 billion since 2001. HAART costs have nevertheless risen steeply as Brazil has scaled up treatment. These trends may foreshadow future AIDS treatment cost trends in other developing countries as more people start treatment, AIDS patients live longer and move from first-line to second and third-line treatment, AIDS treatment becomes more complex, generic competition emerges, and newer patented drugs become available. The specific application of the Brazilian model to other countries will depend, however, on the strength of their health systems, intellectual

Recombinant Granulocyte-Macrophage Colony-Stimulating Factor (rGM-CSF) : A Review of its Pharmacological Properties and Prospective Role in the Management of Myelosuppression.

PubMed

Grant, Susan M; Heel, Rennie C

1992-04-01

-only treatment groups suggest that, after > 6 months, the rate of transformation to acute leukaemia is similar in both groups but that rGM-CSF recipients have a sustained increase in neutrophil counts and an associated reduction in infection rate. rGM-CSF 1 to 5 µg/kg/day by subcutaneous injection ameliorates leucopenia associated with HIV infection and corrects zidovudine (azidothymidine)-induced neutropenia without affecting the disease course as determined by p24 antigen levels, CD4: CD8 ratios and recovery of HIV from mononuclear cells. Similar dosages ameliorate myelosuppression induced by ganciclovir in the treatment of AIDS-associated cytomegalovirus retinitis and by the combination of zidovudine and interferon-α in treating Kaposi's sarcoma. A trilineage response to rGM-CSF has been seen occasionally (e.g. some children with aplastic anaemia and some patients with myelodysplasia). Disease-or drug-induced anaemia or thrombocytopenia is generally not improved; however, both significant increases and decreases in platelet count have been reported, and the effect of rGM-CSF on megakaryocytosis and splenic phagocyte function require clarification. The combination of rGM-CSF with other recombinant colony-stimulating factors to expand the lineages stimulated is an exciting future possibility. At clinically useful dosages rGM-CSF is generally well tolerated. Limited comparison with placebo suggests that the type and incidence of adverse reactions reported are generally similar in both groups with the possible exception of slightly higher incidences of diarrhoea, asthenia, rash and malaise. However, reports from noncomparative and open-label trials indicate that mild to moderate flu-like symptoms (myalgias, bone pain, fatigue and headache) are common with rGM-CSF. Management of patients in whom this agent is indicated may be complicated by rGM-CSF-induced fever and, rarely, by a capillary leak syndrome causing fluid retention and potentially peripheral oedema, pericardial or

Toxicology and Carcinogenesis Studies of Mixtures of 3'-Azido-3'-Deoxythymidine (AZT), Lamivudine (3TC), and Nevirapine (NVP) (CAS Nos. 30516-87-1, 134678-17-4, 129618-40-2) in Genetically Modified C3B6.129F1-Trp53(tm1Brd) N12 Haploinsufficient Mice (in utero and postnatal gavage studies).

PubMed

2013-10-01

, both the percentage of micronucleated RETs and the percentage of micronucleated NCEs were significantly increased in the group where 3TC was coadministered with AZT compared to the group administered only AZT. Under the conditions of this gavage study, there was clear evidence of carcinogenic activity of AZT alone in male heterozygous F1 p53+/- mice based on increased incidences of hepatocellular adenoma. There was clear evidence of carcinogenic activity of AZT in combination with 3TC, and AZT in combination with 3TC and NVP in male heterozygous F1 p53+/- mice based on increased incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined). The occurrence of malignant lymphoma may have been related to treatment with AZT alone and with AZT in combination with 3TC. There was no evidence of carcinogenic activity of 3TC alone in male heterozygous F1 p53+/- mice administered 150 mg/kg. There was no evidence of carcinogenic activity of NVP alone in male heterozygous F1 p53+/- mice administered 168 mg/kg. There was equivocal evidence of carcinogenic activity of NVP alone, AZT in combination with 3TC, and AZT in combination with 3TC and NVP in female heterozygous F1 p53+/- mice based on the occurrence of malignant lymphoma. There was equivocal evidence of carcinogenic activity of 3TC alone in female heterozygous F1 p53+/- mice based on the occurrence of mammary gland adenoacanthoma or adenocarcinoma (combined). There was no evidence of carcinogenic activity of AZT alone in female heterozygous F1 p53+/- mice administered 240 mg/kg. Synonyms: (3'-AZIDO-3'-DEOXYTHYMIDINE) 3'-azido-2',3'-dideoxythymidine; azidodeoxythymidine; azidothymidine; 3'-azidothymidine; AZT; BW A509U; Compound S; 3'-deoxy-3'-azidothymidine; 3'-deoxy-(8CI) (9CI); ZDV; zidovudine. Trade name: Retrovir® [Combivir® with 3TC] Synonyms: (2',3'-DIDEOXY-3'-THIACYTIDINE) 3TC; 4-amino-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2-dihydropyrimidin-2-one; L-2',3'-dideoxy-3