Nie, Jingjing; Li, Jie; Sun, Kuixia; Sun, Mishu; Chen, Jie; Ma, Junfeng; Yan, Ling; Zhuang, Hui
Each hepatitis B virus (HBV) genotype and subgenotype is associated with a particular geographic distribution, ethnicity, and anthropological history. The present study investigated the genomic characteristics of HBV from Uyghur patients with chronic HBV infection in Xinjiang, China. Among the 53 Uyghur patients enrolled, HBV/D was found to be the dominant strain, with 64.2 % (34/53), 60.4 % (32/53) with HBV/D1 and 3.8 % (2/53) with HBV/D3. In addition to these findings, 3.8 % HBV/B (2/53), 5.7 % HBV/C (3/53), 11.3 % C+D (6/53), 7.5 % B+D (4/53), 3.8 % B+C (2/53) and 3.8 % B+C+D (2/53) were also detected. The full-length genome of seven HBV/D1 isolates and 144 reference sequences retrieved from GenBank were compared and analyzed by biological information methods. These results demonstrate that the D1 isolates from Xinjiang and Central Asia show a close genetic proximity (0.013±0.0007). Furthermore, four unique amino acid substitutions (sp82(Asn), sp89(His), rt129(Leu), rt151(Leu)) representing background polymorphisms rather than drug resistance mutations or immune escape variants were found in the Uyghur patients of Xinjiang, but these were seldom found in HBV/D1 strains from other regions (0 %-14.3 %). This study indicates that in Xinjiang, unlike HBV-infected Han patients, HBV/D1 is the predominant strain among HBV-infected Uyghur people. Although genetic distance analysis suggests that the HBV/D1 isolates from Xinjiang are closely related to those from Central Asia, unique amino acid substitutions suggest independent evolution of HBV in the Uyghur patients of Xinjiang.
Rodríguez-Íñigo, E.; Bartolomé, J.; Ortiz-Movilla, N.; Platero, C.; López-Alcorocho, J. M.; Pardo, M.; Castillo, I.; Carreño, V.
In this work, we have shown that hepatitis C virus (HCV) and hepatitis B virus (HBV) can coexist in the same hepatocyte using double fluorescent in situ hybridization in liver biopsy samples from patients with chronic HCV infection with occult HBV infection. Digital image analysis of hybridization signals showed that the HBV DNA levels in coinfected hepatocytes were lower than those in cells infected only with HBV. This finding supports the hypothesis of inhibition of HBV replication by HCV. Furthermore, HCV RNA levels were lower in coinfected cells than in cells infected only with HCV, suggesting that HBV may also inhibit HCV replication. PMID:16306629
Rodríguez-Iñigo, E; Bartolomé, J; Ortiz-Movilla, N; Platero, C; López-Alcorocho, J M; Pardo, M; Castillo, I; Carreño, V
In this work, we have shown that hepatitis C virus (HCV) and hepatitis B virus (HBV) can coexist in the same hepatocyte using double fluorescent in situ hybridization in liver biopsy samples from patients with chronic HCV infection with occult HBV infection. Digital image analysis of hybridization signals showed that the HBV DNA levels in coinfected hepatocytes were lower than those in cells infected only with HBV. This finding supports the hypothesis of inhibition of HBV replication by HCV. Furthermore, HCV RNA levels were lower in coinfected cells than in cells infected only with HCV, suggesting that HBV may also inhibit HCV replication.
Mason, William S; Gill, Upkar S; Litwin, Samuel; Zhou, Yan; Peri, Suraj; Pop, Oltin; Hong, Michelle L W; Naik, Sandhia; Quaglia, Alberto; Bertoletti, Antonio; Kennedy, Patrick T F
Chronic infection with hepatitis B virus (HBV) progresses through different phases. The first, called the immune-tolerant phase, has been associated with a lack of disease activity. We examined HBV-DNA integration, clonal hepatocyte expansion, HBV antigen expression, and HBV-specific immune responses in patients in the immune-tolerant phase to assess whether this designation is appropriate or if there is evidence of disease activity. We studied HBV-DNA integration, clonal hepatocyte expansion, and expression of hepatitis B surface antigen and core antigen in liver tissues from 26 patients with chronic HBV infection (ages, 14-39 y); 9 patients were positive for hepatitis B e antigen (HBeAg) in the immune-tolerant phase and were matched for age with 10 HBeAg-positive patients with active disease and 7 HBeAg-negative patients with active disease. Peripheral blood samples were collected and HBV-specific T cells were quantified for each group. Detection of HBV antigens differed among groups. However, unexpectedly high numbers of HBV-DNA integrations, randomly distributed among chromosomes, were detected in all groups. Clonal hepatocyte expansion in patients considered immune tolerant also was greater than expected, potentially in response to hepatocyte turnover mediated by HBV-specific T cells, which were detected in peripheral blood cells from patients in all phases of infection. We measured HBV-specific T cells, HBV-DNA integration, and clonal hepatocyte expansion in different disease phases of young patients with chronic hepatitis B, with emphasis on the so-called immune-tolerant phase. A high level of HBV-DNA integration and clonal hepatocyte expansion in patients considered immune tolerant indicated that hepatocarcinogenesis could be underway-even in patients with early stage chronic HBV infection. Our findings do not support the concepts that this phase is devoid of markers of disease progression or that an immune response has not been initiated. We propose that
Parikh, Pathik; Ryan, John D.
Chronic hepatitis B virus (HBV) infection is a major cause of liver morbidity and mortality worldwide. While a proportion of the 250 million individuals chronically infected with HBV will not come to significant harm or require therapy, many others risk developing complications of the end-stage liver disease such as decompensated cirrhosis and hepatocellular carcinoma (HCC), without intervention. Due to the complex natural history of HBV infection, patients require an expert assessment to interpret biochemistry, viral serology and appropriately stage the disease, and to initiate monitoring and/or therapy where indicated. The detection and quantification of liver fibrosis is a key factor for disease management and prognostication for an individual with HBV. The reliance on invasive liver biopsy to stage disease is diminishing with the advent of robust non-invasive blood- and imaging-based algorithms which can reliably stage disease in many cases. These tests are now incorporated into International guidelines for HBV management and relied upon daily to inform clinical judgement. Both blood- and imaging-based approaches have advantages over liver biopsy, including minimal risks, lower cost, better patient acceptance and speed of results, while disadvantages include lower diagnostic accuracy in intermediate disease stages and variability with co-existing hepatic inflammation or steatosis. This review outlines the methods of fibrosis assessment in chronic HBV infection and focuses on the most commonly used blood- and imaging-based non-invasive tests, reviewing their diagnostic performance and applicability to patient care. PMID:28251119
Manamperi, A; Gunawardene, N S; Wellawatta, C; Abeyewickreme, W; de Silva, H J
Hepatitis B infection causes a wide spectrum of liver diseases. Previous analyses of hepatitis B virus (HBV) genome have revealed eight HBV genotypes (A-H), with distinct geographical distribution worldwide. The epidemiology of HBV genotypes and their implications for natural history of disease progression and response to anti viral therapy have been increasingly recognized. This study was undertaken to determine the HBV genotypes in a group of Sri Lankan patients with chronic infection who presented for investigation prior to treatment. Genotypes were determined (2007-2009) in 25 patients with evidence of chronic HBV infection. A genotyping system based on multiplex-nested PCR using type-specific primers was employed in assigning genotypes A through F. Genotypes G and H were not determined. Among the 25 patients tested, genotypes B [9 (36%)], C [4 (16%)], D [3 (12%)], A [2 (8%)] and E [1 (4%)] were detected. There was a relatively high prevalence of mixed infections with genotypes B+C (3), A+D (1), and B+D (2), which overall constituted 24% of patients. Although this is a non-representative sample, HBV infections among this group of Sri Lankan patients were predominantly genotypes B, C and D.
Goral, Vedat; Ozkul, Hamza; Tekes, Selahattin; Sit, Dede; Kadiroglu, Ali Kemal
AIM: To study the prevalence and clinical effects of occult HBV infection in haemodialysis patients with chronic HCV. METHODS: Fifty chronic hemodialysis patients with negative HbsAg, and positive anti-HCV were included in the study. These patients were divided into two groups: HCV-RNA positive and HCV-RNA negative, based on the results of HCV-RNA PCR. HBV-DNA was studied using the PCR method in both groups. RESULTS: None of the 22 HCV-RNA positive patients and 28 HCV-RNA negative patients revealed HBV-DNA in serum by PCR method. The average age was 47.2 ± 17.0 in the HCV-RNA positive group and 39.6 ± 15.6 in the HCV-RNA negative group. CONCLUSION: The prevalence of occult HBV infection is not high in haemodialysis patients with chronic HCV in our region. This result of our study has to be evaluated in consideration of the interaction between HBsAg positivity (8%-10%) and frequency of HBV mutants in our region. PMID:16733862
Mirandola, S; Campagnolo, D; Bortoletto, G; Franceschini, L; Marcolongo, M; Alberti, A
Drug resistance is a major limitation for the long-term efficacy of antiviral therapy with nucleos(t)ide analogues (NAs) in chronic hepatitis B (CHB). Antiviral resistance mutations may pre-exist in the overall viral population of untreated patients. We aimed to assess the prevalence of such hepatitis B virus (HBV) variants in a large cohort of NAs-naïve patients with CHB and to explore possible association with viral and host variables. Serum samples from 286 NAs-naïve consecutive patients with CHB were tested for serum HBV-DNA, and 255 of them having HBV-DNA > 1000 IU/mL were further analysed for drug resistance mutations by INNO-LiPA HBV DRv2/v3. NAs-naïve patients analysed were mainly men (73%), Caucasians (85%), hepatitis B e Antigen (HBeAg) negative (79%) and genotype D (69%), with a mean age of 43.2 ± 13.4 years. HBV mutations associated with antiviral drug resistance were detected in 13 (5%) patients: three patients infected with HBV genotype C had the rtM204V + rtL180M mutations associated with lamivudine (LMV) resistance. Four patients had the rtI233V mutation that may reduce sensitivity to adefovir, and three patients had the rtM250L/V mutation typical of entecavir resistance. LMV compensatory mutations rtL80V and rtV173L were seen in two and one patients, respectively. No relationship was seen between presence of resistant or compensatory mutations and HBV-DNA levels, HBeAg/anti-HBe status or previous IFN therapy. These results confirm that HBV mutations, which confer resistance against currently available anti-HBV NAs, may already exist in patients who have never received the drug. © 2011 Blackwell Publishing Ltd.
Gunardi, Hartono; Iskandar, Melanie Y; Turyadi; Ie, Susan I; Dwipoerwantoro, Pramita G; Gani, Rino A; Muljono, David H
HBV-infected patients are potential sources of intra-familial transmission. We studied HBV transmission and molecular characteristics within families of HBV-related chronic liver disease (CLD) patients. Family members [index cases (ICs), spouses, and 1-18-year-old children] of HBV-related CLD patients were tested for HBsAg, anti-HBc, and anti-HBs. HBsAg-positive subjects were tested for HBeAg/anti-HBe. Anti-HBc-positive children together with their family members were further investigated for HBV DNA. Sequences of positive isolates were analyzed over surface, precore (PC) and basal core promoter (BCP) regions. Among 94 children of 46 ICs, the prevalence of HBsAg, anti-HBc, and anti-HBs was 10 (10.6 %), 19 (20.2 %), and 46 (48.9 %), respectively. Thirty-eight (40.4 %) children were seronegative, indicating susceptibility to HBV infection. HBV DNA was identified in all ICs, 4 spouses, and 16 children. Having both parents with HBsAg positive and at least two HBV carriers in the households were significant risk factors of intra-familial transmission. HBV genotype/subtype distributions were comparable between children and ICs/spouses, with predominance of genotype B. The majority of HBV DNA sequences found in children were identical to their corresponding ICs-particularly mothers-including mutation patterns in the surface, PC, and BCP regions. Recognized mutations associated with HBsAg detection and/or vaccination failure, T140I, T143S/M, G145R, and Y161F, were identified in 20 subjects; while mutations linked to HBeAg-defective variants, PC G1896A and BCP A1762T/G1764A, were found in 7 and 11 subjects, respectively. Children of HBV-related CLD patients were at increased risk of HBV infection through multi-modal transmission routes despite negative parental HBsAg and HBeAg status.
Lu, Hai-Ying; Zhuang, Li-Wei; Yu, Yan-Yan; Ivan, Hadad; Si, Chong-Wen; Zeng, Zheng; Li, Jun; Hou, Dong-Ming; Chen, Xin-Yue; Han, Zhong-Hou; Chen, Yong
AIM: To evaluate the effect of antiviral agents on intrahepatic HBV DNA in HBeAg-positive chronic hepatitis B patients. METHODS: Seventy-one patients received treatment with lamivudine, interferon alpha (IFN-α2b) or sequential therapy with lamivudine-IFN-α2b for 48 wk. All subjects were followed up for 24 wk. Serum and intrahepatic HBV DNA were measured quantitatively by PCR. HBV genotypes were analyzed by PCR-RFLP. RESULTS: At the end of treatment, the intrahepatic HBV DNA level in 71 patients decreased from a mean of (6.1 ± 1.0) log10 to (4.9 ± 1.4) log10. Further, a larger decrease was seen in the intrahepatic HBV DNA level in patients with HBeAg seroconversion. Intrahepatic HBV DNA level (before and after treatment) was not significantly affected by the patients’ HBV genotype, or by the probability of virological flare after treatment. CONCLUSION: Intrahepatic HBV DNA can be effectively lowered by antiviral agents and is a significant marker for monitoring antivirus treatment. Low intrahepatic HBV DNA level may achieve better efficacy of antivirus treatment. PMID:17569128
Background Little is known about HBV-specific T-cell responses in chronic Hepatitis B patients (HBV) that are co-infected with Human immunodeficiency virus type 1 (HIV-1), especially those with normal alanine aminotransferase (ALT) levels. Methods Twenty-five patients with chronic HBV (11 hepatitis B e antigen [HBeAg]-positive, 14 HBeAg-negative) were enrolled in a cross-sectional study. A longitudinal study as also conducted in which follow-up was done at 3, 12, and 24 months, after acute HIV-1 infection, in 11 individuals who also had chronic HBV. Peripheral blood mononuclear cells were stimulated with recombinant HBV surface protein (S protein), core protein (C protein) or gag peptide. IFN-γ-secreting T cells were identified by ELISPOT assay. Results In the cross-sectional study, co-infected chronic HBV patients had lower C protein-specific T-cell responses compared with mono-infected individuals, though the difference was not significant. In co-infected, chronic HBV patients, the magnitude of C protein-specific T-cell responses was significantly greater in HBeAg-positive subjects compared to HBeAg-negative subjects (p = 0.011). C protein-specific T-cell responses were positively correlated with HBV viral load (rs = 0.40, p = 0.046). However, gag-specific T-cell responses were negatively correlated with HIV viral load (rs = −0.44, p = 0.026) and positively correlated with CD4+ count (rs = 0.46, p = 0.021). The results were different in mono-infected individuals. PBMCs from co-infected HBeAg-positive patients secreted more specific-IFN-γ in cultured supernatants compared with PBMCs from co-infected HBeAg-negative patients (p = 0.019). In the longitudinal study, S protein- and C protein-specific T-cell responses were decreased as the length of follow-up increased (p = 0.034, for S protein; p = 0.105, for C protein). Additionally, the S protein- and C protein-specific T-cell responses were significantly higher in HBe
Li, Man; Sun, Xuehua; Zhou, Zhenhua; Zhang, Xin; Jin, Shugen; Gao, Yating; Gao, Yueqiu
To investigate the regulatory roles of cytokines expressed on peripheral blood T cells in chronic hepatitis B virus (HBV) infection. Sixty patients with chronic HBV infection were categorized into immune tolerance phase (IT), immune clearance phase (IC), and inactive carrier phase (IA) groups. Twenty healthy individuals were enrolled as healthy controls. Another 21 HBeAg-positive chronic hepatitis (CHB) patients were administrated with entecavir (0.5 mg/d) for 6 months. Serum alanine transaminase (ALT) levels were tested by automatic biochemistry analyzer, and HBV DNA loads were tested by PCR, and cytokines expressed on T cells were examined by flow cytometry. There were negative correlations between IFN-γ levels expressed by peripheral blood CD4(+)T cells and CD8(+)T cells and serum HBV DNA loads in patients with chronic HBV infection, and there were negative correlations between the ratio of IFN-γ/IL-4 in peripheral blood CD4(+)T cells and CD8(+)T cells and serum HBV DNA loads. In addition, the expression levels of IFN-γ were gradually elevated and the expression levels of IL-4 were gradually lowered from IT to IA. In IT, the level of IFN-γ expressed by T cells in patients was lower than that in healthy controls and the level of IL-4 was higher than that in healthy controls. In IA, the levels of IFN-γ and IL-4 were recovered to the normal. Anti-virus therapy reduced serum HBV DNA load and ALT levels in patients, which was accompanied with the increase of IFN-γ level and IFN-γ/IL-4 ratio in CD8(+)T cells. During chronic HBV infection, IFN-γ and IL-4 expressed by peripheral blood T cells play dual immunoregulatory roles, which are correlated with the efficacy of entecavir.
Ke, Chang-Zheng; Chen, Yue; Gong, Zuo-Jiong; Meng, Zhong-Ji; Liu, Li; Ren, Ze-Jiu; Zhou, Zuo-Hua
AIM: To study the dynamic changes of hepatits B virus (HBV) DNA in serum and peripheral blood mononuclear cells (PBMCs) of patients after lamivudine therapy. METHODS: A total of 72 patients with chronic HBV infection were included in this study. All patients were confirmed to have the following conditions: above 16 years of age, elevated serum alanine amonotransferase (ALT), positive hepatitis B e antigen (HBeAg), positive HBV DNA in serum and PBMCs, negative antibodies against HAV, HCV, HDV, HEV. Other possible causes of chronic liver damages, such as drugs, alcohol and autoimmune diseases were excluded. Seventy-two cases were randomly divided into lamivudine treatment group (n = 42) and control group (n = 30). HBV DNA was detected both in serum and in PBMCs by fluorescence quantitative polymerase chain reaction (PCR), during and after lamivudine treatment. RESULTS: In the treatment group, HBV DNA became negative both in serum and in PBMC, of 38 and 25 out of 42 cases respectively during the 48 wk of lamivudine treatment, the negative rate was 90.5% and 59.5% respectively. In the control group, the negative rate was 23.3% and 16.7% respectively. It was statistically significant at 12, 24 and 48 wk as compared with the control group (P < 0.005). The average conversion period of HBV DNA was 6 wk (2-8 wk) in serum and 16 wk (8-24 wk) in PBMC. CONCLUSION: Lamivudine has remarkable inhibitory effects on HBV replication both in serum and in PBMCs. The inhibitory effect on HBV DNA in PBMCs is weaker than that in serum. PMID:16810760
Tahaei, Seyed Mohammad Ebrahim; Mohebbi, Seyed Reza; Azimzadeh, Pedram; Vahedi, Mohsen; Almasi, Shohreh; Romani, Sara; Sharifian, Afsaneh; Derakhshan, Faramarz; Zali, Mohammad Reza
Co-infection with hepatitis C virus (HCV) and/or human immunodeficiency virus (HIV) in patients with chronic hepatitis B virus (HBV) infection can alter the course of the disease. In this study, we investigated the frequency of HIV and/or HCV co-infection in chronic HBV patients and related risk factors in acquiring the HCV and or HIV co-infectionit. We studied 264 chronic HBV patients who visited the Gastrointestinal and Liver Ward of the Taleghani Hospital, Tehran, Iran between 2006 and 2010. Demographic information and records of possible risky behavior were obtained. Antibodies against HBV, HCV, and HIV, levels of alanine transaminase (ALT) and aspartate transaminase (AST), and conversion from hepatitis B e antigen (HBeAg) to hepatitis B e antibody (HBeAb) were evaluated. Of 264 patients with chronic HBV in this study, 184 patients (70%) were men and 78 patients (30%) were women. Only 1 patient (0.37%) was positive for anti-HIV antibody, whereas 12 patients (4.54%) were positive for anti-HCV antibody. None of the patients had co-infection with all 3 viruses (HBV, HIV, and HCV). This study demonstrated that the prevalence of HCV is higher than that of HIV in chronic HBV patients. Since HCV or HIV co-infection affects the therapeutic outcome in chronic HBV patients, testing for HIV and HCV is recommended, especially for patients with a history of risky behavior.
Sayan, Murat; Buğdacı, Mehmet Sait
The hepatitis B virus (HBV) polymerase (pol) gene completely overlaps with the envelope (S) gene. Nucleos(t)ide analogue (NA) resistance mutations in the pol gene of HBV, either from selection of primary or secondary resistance mutations, typically result in changes in the overlapping hepatitis B surface antigen (HBsAg). Recent studies have conferred a new acronym to these HBV pol/S gene overlap mutants; ADAPVEMs, for antiviral drug-associated potential vaccine-escape mutants. The present report aimed to assess the determined multiple HBV vaccine-escape mutants in a Turkish patient with chronic hepatitis B (CHB), undergoing NAs treatment. The liver biopsy of HBsAg positive, HBeAg negative 53-year old female patient with CHB, revealed a score as histological activity index; 9 and fibrosis; 2 according to Ishak classification. NA treatment backgrounds consisted of 24 months lamivudine, followed by 18 months entacavir and lastly 3 months tenofovir monotherapies. Since HBV DNA load was determined as 7.030.000 IU/ml at the 4th month of tenofovir therapy, entecavir was added as current treatment regimen, and tenofovir + entecavir therapy decreased the HBV DNA load (400 IU/ml). Sequence analysis was performed for HBV pol/S gene and overlapping pol/S gene amino acid substitutions, primary/compensatory NA resistance mutations and antiviral drug-associated potential vaccine-escape mutations (ADAPVEM) were analysed. The patient isolate was identified as genotype D/subgenotype D1 of HBV. Primary drug resistance mutations (rtV173L + rtL180M + rtM204V) to lamivudine and telbivudine and a compensatory mutation (rtQ215H) to lamivudine and adefovir were described in the HBV pol gene sequence. However, multiple HBV vaccine-escape mutations (sS143T + sD144E + sG145R + sE164D + sI195M) have been determined on the HBV overlapping pol/S gene region. Lamivudine and telbivudine which are the frequently preferred drugs for the treatment of CHB in Turkey, have the potential to lead to
To investigate the effect of Entecavir treatment on HBV-specific immunity in patient with chronic hepatitis B and its relationship to HBeAg sero-conversion. Serum aminotransferase (ALT), HBV DNA and HBeAg were monitored before the after entecavir treatment. At the same time point, HBV-specific T cell proliferation was determined by [3H] T-dR incorporation assay, while HBV-specific IFN-alpha secretion was measured by ELISA. The level of HBV DNA and ALT was significantly decreased after entecavir treatment. Same is the titer of HBeAg. In addition, HBeAg sero-conversion was observed in some of them, in whom the HBV-specific T cell proliferation and IFN-alpha production were significantly increased. Entecavir treatment resulted in increased HBV-specific immunity along with the inhibition of HBV replication.
Miyauchi, Tomoo; Kanda, Tatsuo; Shinozaki, Masami; Kamezaki, Hidehiro; Wu, Shuang; Nakamoto, Shingo; Kato, Kazuki; Arai, Makoto; Mikami, Shigeru; Sugiura, Nobuyuki; Kimura, Michio; Goto, Nobuaki; Imazeki, Fumio; Yokosuka, Osamu
Nucleos(t)ide analogues (NAs) lead to viral suppression and undetectable hepatitis B virus (HBV) DNA in some individuals infected with HBV, but the rate of virological rebound has been unknown in such patients. We examined the prevalence of virological rebound of HBV DNA among NA-treated patients with undetectable HBV DNA. We retrospectively analyzed 303 consecutive patients [158 entecavir (ETV)- and 145 lamivudine (LAM)-treated] who achieved HBV DNA negativity, defined as HBV DNA < 3.7 log IU/mL for at least 3 months. They were followed up and their features, including their rates of viral breakthrough, were determined. Viral rebound after HBV DNA negativity was not observed in the ETV-group. Viral rebound after HBV DNA negativity occurred in 38.7% of 62 HBe antigen-positive patients in the LAM-group. On multivariate analysis, age was an independent factor for viral breakthrough among these patients (P = 0.035). Viral rebound after HBV DNA negativity occurred in 29.1% of 79 HBe antigen-negative patients in the LAM-group. Differently from LAM, ETV could inhibit HBV replication once HBV DNA negativity was achieved. In contrast, LAM could not inhibit HBV replication even if HBV negativity was achieved in the early phase. Attention should be paid to these features in clinical practice.
Meng, Zhongji; Zhang, Yonghong; Wei, Zhiqiang; Liu, Ping; Kang, Jian; Zhang, Yinhua; Ma, Deqiang; Ke, Changzheng; Chen, Yue; Luo, Jie; Gong, Zuojiong
Studies have revealed that resistin plays a role as an intrahepatic cytokine with proinflammatory activities. This study investigated the association between serum resistin and fibrosis severity and the possible marker role of resistin in the inflammatory process of chronic hepatitis B. In this study, 234 subjects with HBV infection were retrospectively selected, including 85 patients with chronic hepatitis B (CHB), 70 patients with HBV-related liver cirrhosis (LC-B), and 79 patients with HBV-related liver failure (LF-B). Serum levels of resistin, IL-1, IL-6, IL-17, IL-23, TNF-α, and TGF-β1 were assayed by ELISA. Demographic and clinical characteristics of patients were extracted from clinical databases of Taihe Hospital, Hubei University of Medicine, including serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), and liver stiffness (LS). All the selected patients with HBV infection showed significantly increased levels of serum resistin, which was rarely detectable in the healthy controls. Serum resistin levels in patients with CHB, LC-B, and LF-B were 4.119 ± 5.848 ng/mL, 6.370 ± 6.834 ng/mL, and 6.512 ± 6.076 ng/mL, respectively. Compared with the CHB group, patients with LC-B or LF-B presented with significantly higher serum levels of resistin (p < 0.01). On the other hand, all of the enrolled patients had high serum levels of IL-1, IL-6, IL-17, TNF-α, and TGF-β1, but not IL-23. Interestingly, serum levels of resistin was significantly positively correlated with serum levels of TGF-β1 in LC-B patients (R = 0.3090, p = 0.0290), with IL-17 in LC-B (R = 0.4022, p = 0.0038) and LF-B patients (R = 0.5466, p < 0.0001), and with AST (R = 0.4501, p = 0.0036) and LS (R = 0.3415, p = 0.0310) in CHB patients. High serum resistin associates with intrahepatic inflammation and necrosis and may be used as an index of disease severity for patients with
Tajiri, Hitoshi; Takano, Tomoko; Tanaka, Hideo; Ushijima, Kosuke; Inui, Ayano; Miyoshi, Yoko; Ozono, Keiichi; Abukawa, Daiki; Endo, Takeshi; Brooks, Stephen; Tanaka, Yasuhito
The aims of the study were to elucidate the clinical characteristics of patients who developed hepatocellular carcinoma (HCC) related to persistent HBV infection since childhood and to investigate usefulness of assessing alpha-fetoprotein (AFP) in this population. A nationwide multicenter survey of children with chronic HBV infection was performed. Among 548 patients, 15 patients developed HCC at the median age of 15 years (range 9-36), including 13 males and 2 females. A case-control comparison showed that HBeAg seroconversion and liver cirrhosis were associated with the occurrence of HCC. Of the 15 HCC patients, 5 were treated with interferon and none of them responded to interferon therapy as compared with 12 of the 17 responders in the control group. Of the 15 patients, 10 died and 9 of the 10 who died never visited any medical facilities until diagnosis of HCC, while the remaining 5 surviving patients never stopped their clinic visits. The usefulness of AFP assessment was shown by the findings that AFP levels were elevated in all HCC cases, that elevations in AFP levels were detected prior to the diagnosis in the surviving patients, and that sensitivity of AFP as a diagnostic test for HCC was very high among 40 patients including our 14 and an additional 26 collected from the literature. HBeAg seroconversion and liver cirrhosis are associated with the occurrence of HCC. Regular measurement of AFP might be helpful to watch for the occurrence of HCC when following children and young patients with chronic HBV infection since childhood.
Hoff, J; Bani-Sadr, F; Gassin, M; Raffi, F
The effect of lamivudine on chronic coinfection with hepatitis B virus (HBV) in human immunodeficiency virus (HIV)--infected patients was studied prospectively. Nineteen patients with HIV infection, who were receiving an anti-HIV regimen containing lamivudine (150 mg twice daily), and who had replicative chronic HBV infection, were followed for a median of 14 months. Twelve patients' regimens contained protease inhibitors. Serum HBV DNA became undetectable, by means of molecular hybridization, in 14. Seroconversion of hepatitis B e antigen to antibody occurred in 6 of 17 patients, and seroconversion of hepatitis B surface antigen to antibody occurred in 1 of 19. The median serum alanine aminotransferase concentration had decreased by the time of the final evaluation. The median CD4 cell count increased and plasma HIV RNA was undetectable in 10 of 19 patients. Five patients had recurrence of detectable serum HBV DNA despite good compliance with treatment, and 2 mutations related to the resistance of HBV were detected. These patients had a significantly longer duration of treatment (21 versus 13 months; P<.05). In conclusion, resistant strains of HBV emerge at high detectable levels while patients receive anti-HIV regimens containing lamivudine.
Milosevic, Ivana; Delic, Dragan; Lazarevic, Ivana; Pavlovic, Ivana Pesic; Korac, Milos; Bojovic, Ksenija; Jevtovic, Djordje
Hepatitis B virus (HBV) genotypes influence disease progression and treatment outcome. To determine natural history and treatment outcome in patient chronically infected with HBV. A cohort study included 162 treatment naive patients with chronic HBV infection in order to analyze factors influencing natural history of infection and survival. Genotype A was far less prevalent, detected in 14.2%. The prevalence of HbeAg+ serology of 60.8% among patients infected with genotype A was significantly higher then 30.9% recorded among those with genotype D (P=0.02). Even though patients from two genotypes subgroups had significantly different prevalence of HBeAg serology, their viral loads were similar at the time of diagnosis (2.90 log10 and 3.31 log10 HBV DNK IU/μl plasma, for genotypes A and D, respectively). The analyses of viral loads across three serologic patterns of chronic HBV infection were: for HBeAg+/HBeAb-, HbeAg-/HBAb+, and both "e" antigen and antibodies negative: 4.24, 2.67 and 2.69 log10 IU/ml of HBV DNA IU/μl, respectively (P=0.01). Mean time to liver cirrhosis was 23.2±3.4 years and 15.1±8.4 years, for genotypes A and D, respectively (P=0.02). The overall estimated mean survival of patients with chronic HBV infection was 28.4 years, and was influenced by the stage of liver disease, but not by gender, age above 40, viral genotype and lamivudine therapy. Patients infected with genotype D had more rapid progression to ESLD regardless of levels of viral replication. All clinical and laboratory differences between genotypes did not affect survival of patients with chronic hepatitis B, regardless of lamivudine therapy. Copyright © 2013 Elsevier B.V. All rights reserved.
Pereira, J S F; Gonçales, N S L; Silva, C; Lazarini, M S K; Pavan, M H P; Fais, V C; Gonçales Júnior, F L
Anti-HBc positivity is a frequent cause of donation rejection at blood banks. Hepatitis B virus (HBV) infection may also occur in HBsAg-negative patients, a situation denoted occult infection. Similarly, very low levels of HBV-DNA have also been found in the sera of patients with chronic hepatitis C virus (HCV) infection, even in the absence of serum HBsAg. Initially we searched for HBV-DNA in serum of 100 blood donors and 50 HCV-infected patients who were HBsAg negative/anti-HBc positive by nested-PCR and by an HBV monitor commercial test for HBV-DNA. Anti-HBs seroconversion rates were measured in 100 blood donors and in 22 patients with chronic HCV infection after HBV vaccination to determine if the HBV vaccination could eliminate an occult HBV infection in these individuals. Occult HBV infection was detected in proportionally fewer blood donors (6/100 = 6%) than chronic hepatitis C patients (12/50 = 24%) (P < 0.05). We noted seroconversion in 6/6 (100%) HBV-DNA(+) and in 84/94 (89.4%) HBV-DNA(-) blood donors (P > 0.05). All subjects who were HBV-DNA(+) before the first dose of HBV vaccine (D1), became HBV-DNA(-) after D1, D2, and D3. Among 22 HCV-positive patients, 10 HBV-DNA(+) and 12 HBV-DNA(-), seroconversion was observed in 9/10 (90%) HBV-DNA(+) and in 9/12 (75%) HBV-DNA(-) subjects (P > 0.05). The disappearance of HBV-DNA in the majority of vaccinated patients suggests that residual HBV can be eliminated in patients with occult infection.
Zhao, Jianqiang; Liu, Jiafa
In order to investigate the mutation of HBV polymerase gene reverse transcription conserved region (P region) in chronic hepatitis B (CHB) patients, 212 CHB patients who took antiretroviral treatment with nucleotide analogues were chosen. The drug resistance mutations of HBV P region and HBV genotype were detected by Pyrosequencing. Sequence analysis showed that the drug resistance sites of HBV P region located at sites 173; 180; 181; 184; 204; 236 and 250. The main site of HBV P region drug resistance was 204 and 180, accounting for 35.8% and 23.5%, respectively. There were significant differences in the mutation rate of site 180 among different age groups. There were also significant differences in the mutation rate of site 204 among younger than 30 age group, 41 to 50 age group and 51 to 60 age group. (P < 0.05, P < 0.01). The mutation rate of site 180 combined with site 204 was 66.6%. The mutation rate of site 181 combined with site 236 was 23.3%. The age of C genotype infected patients was significantly older than B genotype infected patients (P < 0.01). M204V/I mutation mostly existed in the form of joint L180M mutation, the mutation rate was age-related. The detection of HBV genotypes and drug resistance sites of HBV P region have important clinical implications for the treatment and prognosis of patients with CHB.
Praneenararat, Surat; Chamroonkul, Naichaya; Sripongpun, Pimsiri; Kanngurn, Samornmas; Jarumanokul, Roongrueng; Piratvisuth, Teerha
Non-invasive models and methods to substitute liver biopsy in chronic hepatitis B (CHB) patients were investigated but their roles as predictors of significant liver histology for diagnosis of HBeAg-negative CHB patients who had indication for liver biopsy according to The American Association for the Study of Liver Diseases (AASLD) and The Asian Pacific Association for the Study of the Liver (APASL) guidelines are still unknown. This study was designed to identify predictors of significant liver necroinflammation as defined by a Histology Activity Index of necroinflammatory score ≥ 4 or Metavir necroinflammatory activity score ≥ 2 and significant liver fibrosis as defined by a Metavir fibrosis score ≥ 2 in HBeAg-negative CHB patients that had a hepatitis B virus (HBV) DNA level ≥ 2,000 IU/ml and age ≥ 40 years or elevated alanine aminotransferase level between 1-2 times the upper limit of normal. Twenty-two patients were prospectively included and performed liver biopsies. Clinical and laboratory parameters including age, gender, underlying disease, family history of cirrhosis or hepatocellular carcinoma, body mass index (BMI), HBV DNA level, HBsAg level, liver function test, complete blood count, aspartate aminotransferase-to-platelet ratio index and transient elastography were collected and analyzed with liver histology profiles. Five patients (23%) had significant liver inflammation and 7 patients (32%) had significant liver fibrosis. Factors associated with significant liver inflammation were a lower BMI and higher alkaline phosphatase level while a factor associated with significant liver fibrosis was lower age. On multivariate analysis, only HBV DNA level > 5.5 log IU/ml could predict significant liver fibrosis (odds ratio 28.012, 95% CI, 1.631-481.240, p = 0.022) and its sensitivity, specificity, positive predictive value and negative predictive value were 71.4%, 93.3%, 83.3% and 87.5% respectively. An HBV DNA level
Li, Zhu; Li, Na; Zhu, Qianqian; Zhang, Guoyu; Han, Qunying; Zhang, Pingping; Xun, Meng; Wang, Yawen; Zeng, Xiaoyan; Yang, Cuiling; Liu, Zhengwen
Cooperation or interaction of programmed cell death-1 (PD-1) and T cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3) molecules is more relevant than either molecule alone to immune dysfunction in chronic viral infection and cancers. This study simultaneously investigated polymorphisms at PD1 +8669 and TIM3 -1516 loci in 845 hepatitis B virus (HBV) chronically infected patients [151 asymptomatic carriers, 202 chronic hepatitis, 221 cirrhosis and 271 hepatocellular carcinoma (HCC)], 141 HBV infection resolvers and 318 healthy controls. Multivariate analysis showed that, in addition to gender, age, ALT, albumin and HBV DNA, PD1 +8669 genotype AA was associated with cirrhosis compared with patients without cirrhosis (OR, 2.410; P=0.001). TIM3 -1516 genotypes GT+TT, together with gender, age, ALT, AST, direct bilirubin, albumin and HBeAg status, were associated with HCC compared with cirrhosis patients without HCC (OR, 2.142; P=0.011). The combined carriage of PD1 +8669 AA/TIM3 -1516 GT or TT was higher in cirrhosis and HCC pooled patients than in patients without cirrhosis (OR, 2.326; P=0.020) and in HCC patients than in cirrhosis patients (OR, 2.232; P=0.013). These data suggest that PD1 and TIM3 polymorphisms may differentially and interactively predispose cirrhosis and HCC in chronic HBV infection.
Martinot-Peignoux, Michelle; Lapalus, Martine; Laouénan, Cédric; Lada, Olivier; Netto-Cardoso, Ana Carolina Ferreira; Boyer, Nathalie; Ripault, Marie Pierre; Carvalho-Filho, Roberto; Asselah, Tarik; Marcellin, Patrick
Differentiating 'inactive carriers' (ICs) of hepatitis B virus (HBV) from hepatitis B e antigen-negative (HBeAg[-]) patients in remission is challenging. We investigated whether serum-based monitoring of hepatitis B surface antigen (HBsAg) and HBV-DNA in asymptomatic HBeAg(-) patients could distinguish these groups. 129 HBeAg(-) chronic hepatitis B (CHB) patients (HBV genotypes A-E) with normal alanine aminotransferase (ALT) levels at baseline were classified after 1 year of follow-up as either IC (HBV-DNA ≤2000 IU/mL) or 'active carrier' (AC, HBV-DNA >2000 IU/mL) if they exhibited normal ALT throughout, or classified as 'reactivation patient' (RP) if they exhibited marked, transient increases in ALT and HBV-DNA. There were 64%, 18%, and 19% patients in the IC, AC, and RP groups, respectively. Combined HBsAg and HBV-DNA cutoffs (>1000 IU/mL and >200 IU/mL, respectively) differentiated RPs with 92% sensitivity and negative predictive value (NPV) of 96%. HBsAg sero-clearance was associated with baseline HBsAg <1000 IU/mL, annual decrease of ≥0.3 log IU/mL (NPV 95%: PPV 89%) and IFNL3 genotype CC. Applying combined HBsAg and HBV-DNA cutoffs to baseline measurements accurately differentiated RPs. These results suggest that HBsAg should be included in the monitoring of asymptomatic HBeAg(-) CHB patients. Copyright © 2013 Elsevier B.V. All rights reserved.
Lutgehetmann, M; Meyer, F; Volz, T; Lohse, A W; Fischer, C; Dandri, M; Petersen, Jörg
The incidence of chronic hepatitis B in Germany is approximately 0.5 %. Data regarding knowledge about HBV, prevention behaviour and treatment adherence in patients with chronic HBV are scarce. In this prospective study 201 consecutive patients with CHB infection were studied from a large urban academic outpatient clinic at the University Medical Centre in Hamburg. Patients were interviewed with a questionnaire that contained 47 questions covering social demographic dates, knowledge about HBV, treatment adherence and prevention. The success rate of interviews was 100 % with free translation service offered. 20.4 % of the CHB patients were born in Germany, but the majority of the patients were immigrants (80.6 %). 51 % of the patients had a good, 34 % a moderate and 15 % a poor knowledge about HBV. 89 % of the patients knew that HBV can be transmitted through blood contacts, but 34 % believed that inadequate hygienic conditions and 24 % that food products may transmit the virus. 96 % of the patients had knowledge about the existence of an HBV vaccine. Furthermore, 82 % considered a vaccination of all persons in the household important. Despite the knowledge of the existence and importance of a vaccine, only 61,7 % of the 300 affected children/siblings of HBV-positive family members were vaccinated. However, the child vaccination rate was significantly higher among patients with knowledge about the protective effect of the vaccine (p < 0.001), the free of charge vaccination program for children up to 18 years (p < 0.001) and higher school education (p < 0.001). Migrants with poor German language skills had lower knowledge scores (p < 0.001) and showed lower vaccination rates (p = 0.016) compared to immigrants with good German language skills. 43 % of all patients were treated with nucleot(s)ide analogues with a median treatment duration of 2 - 5 years. 65 % of these patients declared to never have missed a dose and 27 % missed less than one dose per month. 90 % of
Zhang, Geng-lin; Zhang, Ting; Ye, Yi-nong; Liu, Jing; Zhang, Xiao-hong; Xie, Chan; Peng, Liang; Gao, Zhi-liang
The complement is thought to be involved in the pathogenesis of multiple liver disorders. However, its role in patients with HBV related acute-on-chronic liver failure (HBV-ACLF) remains unclear. Serum levels of the third and fourth complement components (C3, C4) and complement function (CH50) were examined in this prospective, observational study. Associations between their expression and disease activity were analyzed. Survival was analyzed by Kaplan-Meier curves. Predictors of clinical outcome were determined by Cox regression analysis. C3, C4, and CH50 levels were significantly lower in HBV-ACLF patients compared to controls. C3, C4, and CH50 levels were negatively correlated with Tbil levels but positively associated with PTA levels. C3 levels were negatively associated with MELD-Na. C3 levels were significantly lower in HBV-ACLF patients who died compared to patients who survived. In a median hospital stay of 39 days, mortality occurred in 41 patients with a progressive increase based on C3 grade (P = 0.008). The actuarial probability of developing mortality was significantly higher in patients with low C3 grade compared to those with high C3 grade (P < 0.001). Multivariate Cox regression analysis showed that C3 levels were an independent predictor of mortality. Complement played a pathogenic role in HBV-ACLF patients and C3 was an independent predictor of mortality. PMID:27144164
Li, Hai; Xia, Qiang; Zeng, Bo; Li, Shu-Ting; Liu, Heng; Li, Qi; Li, Jun; Yang, Shu-Yin; Dong, Xiao-Jun; Gao, Ting; Munker, Stefan; Liu, Yan; Liebe, Roman; Xue, Feng; Li, Qi-Gen; Chen, Xiao-Song; Liu, Qiang; Zeng, Hui; Wang, Ji-Yao; Xie, Qing; Meng, Qin-Hua; Wang, Jie-Fei; Mertens, Peter R; Lammert, Frank; Singer, Manfred V; Dooley, Steven; Ebert, Matthias P A; Qiu, De-Kai; Wang, Tai-Ling; Weng, Hong-Lei
Distinguishing between acute on chronic liver failure (ACLF) and decompensated liver cirrhosis is difficult due to a lack of pathological evidence. A prospective single-center study investigated 174 patients undergoing liver transplantation due to acute decompensation of hepatitis B virus (HBV)-associated liver cirrhosis. Two groups were distinguished by the presence or absence of submassive hepatic necrosis (SMHN, defined as necrosis of 15-90% of the entire liver on explant). Core clinical features of ACLF were compared between these groups. Disease severity scoring systems were applied to describe liver function and organ failure. Serum cytokine profile assays, gene expression microarrays and immunohistochemical analyzes were used to study systemic and local inflammatory responses. SMHN was identified in 69 of 174 patients proven to have cirrhosis by histological means. Characteristic features of SMHN were extensive necrosis along terminal hepatic veins and spanning multiple adjacent cirrhotic nodules accompanied by various degrees of liver progenitor cell-derived regeneration, cholestasis, and ductular bilirubinostasis. Patients with SMHN presented with more severely impaired hepatic function, a higher prevalence of multiple organ failure (as indicated by higher CLIF-SOFA and SOFA scores) and a shorter interval between acute decompensation and liver transplantation than those without SMHN (p<0.01 for all parameters). Further analyzes based on serum cytokine profile assays, gene expression microarrays and immunohistochemical analyzes revealed higher levels of anti-inflammatory cytokines in patients with SMHN. SMHN is a critical histological feature of HBV-associated ACLF. Identification of a characteristic pathological feature strongly supports that ACLF is a separate entity in end-stage liver disease. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Calvaruso, V; Ferraro, D; Licata, A; Bavetta, M G; Petta, S; Bronte, F; Colomba, G; Craxì, A; Di Marco, V
Anecdotal reports suggest that patients with chronic hepatitis C virus (HCV) hepatitis and overt or occult hepatitis B virus (HBV) coinfection may reactivate HBV when HCV is suppressed or cleared by direct-acting antivirals (DAAs). We assessed the prevalence of overt or previous HBV coinfection and the risk of HBV reactivation in patients with HCV cirrhosis treated with DAAs. This was a retrospective cohort of 104 consecutive patients with HCV cirrhosis treated with DAAs. Serum HCV-RNA and HBV-DNA were tested at weeks 4, 8 and 12 of DAAs therapy and at week 12 of follow-up. At the start of DAAs, eight patients (7.7%) were HBsAg positive/HBeAg negative with undetectable HBV-DNA and low levels of quantitative HBsAg (four on nucleos(t)ide analogues [NUCs] and four inactive carriers), 37 patients (35.6%) had markers of previous HBV infection (25 anti-HBc positive, 12 anti-HBc/anti-HBs positive) and 59 (56.7%) had no evidence of HBV infection. Sixty-seven patients (64.4%) were HCV-RNA negative at week 4 and 98 (94.2%) achieved sustained virological response. All four HBsAg-positive patients treated with NUCs remained HBV-DNA negative, but three of four untreated patients showed an increase in HBV-DNA of 2-3 log without a biochemical flare and achieved HBV-DNA suppression when given NUCs. During or after DAAs, by conventional assay, HBV-DNA remained not detectable in all 37 anti-HBc-positive patients but in three of them (8.1%) HBV-DNA became detectable with a highly sensitive PCR. HBV reactivation is likely to occur in untreated HBV/HCV-coinfected cirrhotic patients when they undergo HCV treatment with DAAs. Pre-emptive therapy with NUCs should be considered in this setting. Anti-HBc-positive patients rarely reactivate HBV without clinical or virological outcomes. © 2017 John Wiley & Sons Ltd.
Ormeci, Aslı; Aydın, Yucel; Sumnu, Abdullah; Baran, Bulent; Soyer, Ozlem Mutluay; Pınarbasi, Binnur; Gokturk, Suut; Gulluoglu, Mine; Onel, Derya; Badur, Selim; Akyuz, Filiz; Karaca, Cetin; Demir, Kadir; Besisik, Fatih; Kaymakoglu, Sabahattin
Serum alanine aminotransferase (ALT) is a controversial marker for disease monitoring in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients. The aim of this study was to determine the fibrosis stage and histological activity index (HAI) in HBeAg-negative CHB patients with persistently normal ALT (PNALT) and high serum HBV DNA (≥2000 IU/ml) and to investigate clinical risk factors for the requirement of treatment through the examination of liver biopsy specimens. HBeAg-negative CHB patients with PNALT (≤40 IU/l) and high serum HBV DNA (≥2000 IU/ml) were included. HBV fibrosis stage and HAI were scored according to the Ishak system. Multivariate logistic regression analysis was used to estimate the independent risk factors for fibrosis stage ≥2 and/or HAI ≥6. Receiver operating characteristic curve analysis was used to determine an optimal age cut-off for liver biopsy. A total 120 patients were enrolled. These patients had a mean HBV DNA level of 123680±494500 IU/ml; the HBV DNA load was 2000-20000 IU/ml in 68 patients (56.6%) and ≥20000 IU/ml in 52 (43.4%). Eighteen patients (15%) had moderate-to-severe histological activity (HAI ≥6). Forty-three patients (35.9%) had a fibrosis stage ≥2. Forty-eight patients (40%) had a fibrosis stage ≥2 and/or HAI ≥6. On multivariate logistic regression analysis, independent variables associated with fibrosis stage ≥2 and/or HAI ≥6 included age and HBV DNA viral load. Patients with HBV DNA 2000-20000 IU/ml were more likely to require treatment compared to those with a viral load ≥20000 IU/ml. The optimal age cut-off to predict fibrosis stage ≥2 and/or HAI ≥6 was 46 years. Significant liver damage was detected in 40% of CHB patients with PNALT and high HBV DNA upon biopsy. Age and HBV DNA viral load were independent predictors of significant liver damage. A biopsy to determine the degree of liver damage is advisable for CHB patients older than 46 years. Copyright © 2016 The
Chen, Yuan-sheng; Liang, Xiao-feng; Hu, Jun-feng
The serum markers of hepatitis B virus (HBV) infection are complex, mainly including HBV surface antigen (HBsAg) and antibody to HBsAg, HBV e antigen (HBeAg) and antibody to HBeAg, antibody to HBV core antigen. The natural history of chronic HBV infection is complex and variable and greatly influenced by the age of infection, the level of HBV replication, HBV genotype and mutations, presence of HBeAg, ALT level, coinfection with HCV and/or HDV, host immune status. Four stages of chronic HBV infection are the immune tolerant phase, the immune clearance phase, the low or non-replicative phase, and the reactivation phase. Some patients with HBeAg positive, high level of ALT and HBV DNA>105 copies/mL would develop liver-related complications, such as cirrhosis, hepatocellular carcinoma and liver failure. Available evidences indicate that control of HBV replication with antiviral drugs can decrease the incidence of these complications and mortality.
da Silva, Edvaldo F; Mazo, Daniel F; Oliveira, Claudia P; Medeiros, Roseane P; Carrilho, Flair J; Pessôa, Mário G
Background. Patients with chronic HCV infection and superinfection by hepatitis A virus (HAV) or hepatitis B virus (HBV) have higher morbidity and mortality when compared with those without HCV infection. Therefore, HAV and HBV active immunization has become mandatory in this population and hence their serological markers must be determined. The aim of this study was to evaluate the prevalence of serological markers of HAV and HBV infection in patients with chronic HCV. One thousand chronic HCV patients at the University of São Paulo School of Medicine were evaluated for the prevalence of serological markers of HAV and HBV infection. Anti-HAV IgG was positive in 92.3% of patients. When stratified by age, anti-HAV IgG was found in 61% of patients between 20-29 years, 70% on patients between 30-39 years, 85% on patients between 40-49 years, 94% on patients between 50-59 years, and in 99% on patients over 60 years of age. Anti-HBc IgG was positive in 244 patients (24%). Stratified by age, in 4.3% of patients between 20-29 years, 17% 30-39 years, 21% 40-49 years, 24% 50-59 years, and in 28% of patients over 60 years. Of the 244 anti-HBc IgG positive patients, 0.8% were HBsAg positive, 8.5% were anti-HBc IgG isolated and 16% were also anti-HBs positive. In conclusion, the prevalence of anti-HAV IgG was similar to the general Brazilian population. However, anti-HBc IgG was higher in our patients, when compared to general population of Western countries, emphasizing the importance of immunization programs for this population.
Ogawa, Eiichi; Furusyo, Norihiro; Murata, Masayuki; Toyoda, Kazuhiro; Hayashi, Takeo; Ura, Kazuya
Despite a known risk of hepatitis B virus (HBV) reactivation during direct-acting antiviral (DAA) treatment for patients with hepatitis C virus (HCV)-HBV coinfection, it remains unclear whether patients with past HBV infection are at risk for reactivation. This study evaluated the risk of HBV reactivation during treatment with sofosbuvir (SOF)-based regimens, focusing on patients with resolved HBV infection. This study analyzes the data of 183 consecutive patients treated with SOF-based regimens. From these patients, 63 with resolved HBV infection (negative for hepatitis B surface antigen [HBsAg] and undetectable HBV DNA but positive for hepatitis B core antibody) were eligible for this study. HBV reactivation was defined as a quantifiable HBV DNA level >20 IU/mL. Among the patients antibody to HBsAg (anti-HBs) positive (10-500 mIU/mL) (n = 30), the titre of anti-HBs was significantly decreased with time, as shown by the results of repeated-measures analysis of variance (P = .0029). Overall, four patients (6.3%) with resolved HBV infection came to have detectable HBV DNA during treatment, including one who had HBV reactivation at week 4 (HBV DNA 80 IU/mL). However, none developed hepatic failure. Among four patients who had detectable HBV DNA during treatment, all were negative or had very low-titre (<20 mIU/mL) anti-HBs at baseline. The titre of anti-HBs was significantly decreased from the early stage of DAA treatment. Chronic hepatitis C patients with resolved HBV infection and negative or very low-titre anti-HBs at baseline are at risk for having detectable HBV DNA transiently during treatment. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Banerjee, Priyanka; Chakraborty, Abhijit; Mondal, Rajiv Kumar; Khatun, Mousumi; Datta, Somenath; Das, Kausik; Pandit, Pratap; Mukherjee, Souvik; Banerjee, Soma; Ghosh, Saurabh; Chakrabarti, Saikat; Chowdhury, Abhijit; Datta, Simanti
The present study sought to evaluate the structure of HBV quasispecies in Lamivudine (LMV)-failed chronic hepatitis B (CHB) patients and its impact in defining the subsequent virological responses to Tenofovir (TDF)-based rescue-therapy. By analyzing HBV clones encompassing reverse transcriptase (RT) and surface (S) region from LMV-failed and treatment-naïve CHB patients, we identified 5 classical and 12 novel substitutions in HBV/RT and 9 substitutions in immune-epitopes of HBV/S that were significantly associated with LMV failure. In silico analysis showed spatial proximity of some of the newly-identified, mutated RT residues to the RT catalytic centre while most S-substitutions caused alteration in epitope hydrophobicity. TDF administration resulted in virological response in 60% of LMV-failed patients at 24-week but non-response in 40% of patients even after 48-weeks. Significantly high frequencies of 6 S-substitutions and one novel RT-substitution, rtH124N with 6.5-fold-reduced susceptibility to TDF in vitro, were noted at baseline in TDF non-responders than responders. Follow-up studies depicted greater evolutionary drift of HBV quasispecies and significant decline in frequencies of 3 RT and 6 S-substitutions in responder-subgroup after 24-week TDF-therapy while most variants persisted in non-responders. Thus, we identified the HBV-RT/S variants that could potentially predict unfavorable response to LMV/TDF-therapy and impede immune-mediated viral clearance. PMID:28303969
Banerjee, Priyanka; Chakraborty, Abhijit; Mondal, Rajiv Kumar; Khatun, Mousumi; Datta, Somenath; Das, Kausik; Pandit, Pratap; Mukherjee, Souvik; Banerjee, Soma; Ghosh, Saurabh; Chakrabarti, Saikat; Chowdhury, Abhijit; Datta, Simanti
The present study sought to evaluate the structure of HBV quasispecies in Lamivudine (LMV)-failed chronic hepatitis B (CHB) patients and its impact in defining the subsequent virological responses to Tenofovir (TDF)-based rescue-therapy. By analyzing HBV clones encompassing reverse transcriptase (RT) and surface (S) region from LMV-failed and treatment-naïve CHB patients, we identified 5 classical and 12 novel substitutions in HBV/RT and 9 substitutions in immune-epitopes of HBV/S that were significantly associated with LMV failure. In silico analysis showed spatial proximity of some of the newly-identified, mutated RT residues to the RT catalytic centre while most S-substitutions caused alteration in epitope hydrophobicity. TDF administration resulted in virological response in 60% of LMV-failed patients at 24-week but non-response in 40% of patients even after 48-weeks. Significantly high frequencies of 6 S-substitutions and one novel RT-substitution, rtH124N with 6.5-fold-reduced susceptibility to TDF in vitro, were noted at baseline in TDF non-responders than responders. Follow-up studies depicted greater evolutionary drift of HBV quasispecies and significant decline in frequencies of 3 RT and 6 S-substitutions in responder-subgroup after 24-week TDF-therapy while most variants persisted in non-responders. Thus, we identified the HBV-RT/S variants that could potentially predict unfavorable response to LMV/TDF-therapy and impede immune-mediated viral clearance.
Lu, Hai-Ying; Zhuang, Li-Wei; Yu, Yan-Yan; Si, Chong-Wen; Li, Jun; Zhang, Jian-Jun; Zeng, Zheng; Chen, Xin-Yue; Han, Zhong-Hou; Chen, Yong
AIM: To evaluate the effects of antiviral agents and HBV genotypes on intrahepatic covalently closed circular DNA (ccc DNA) in HBeAg-positive chronic hepatitis B patients. METHODS: Seventy-one patients received lamivudine (n = 35), or sequential therapy with lamivudine- interferon alpha 2b (IFN-α 2b, n = 24) for 48 wk, or IFN-α 2b (n = 12) for 24 wk. All subjects were followed up for 24 wk. Intrahepatic ccc DNA was measured quantitatively by PCR. HBV genotypes were analyzed by PCR-RFLP. RESULTS: Sequential lamivudine- INF-α therapy, lamivudine and INF-α monotherapy reduced ccc DNA of 1.7 log, 1.4 log and 0.8 log, respectively (P < 0.05). Seventeen out of the 71 patients developed HBeAg seroconversion, the reduction of ccc DNA in the HBeAg seroconversion patients was more significant than that in the HBeAg positive patients (3.0 log vs 1.6 log, P = 0.0407). Twenty-four weeks after antiviral therapy withdrawal, 16 patients had a sustained virological response, the baseline intrahepatic ccc DNA in the patients with a sustained virological response was significantly lower than that in the patients with virological rebound (4.6 log vs 5.4 log, P = 0.0472). HBV genotype C accounted for 85.9% (n = 61), and genotype B for 14.1% (n = 10), respectively, in the 71 patients. There was no significant difference in the change of ccc DNA level between HBV genotypes C and B (2.1 log vs 1.9 log). CONCLUSION: Forty-eight week sequential lamivudine-INF-α therapy and lamivudine monotherapy reduce ccc DNA more significantly than 24-wk INF-α monotherapy. Low baseline intrahepatic ccc DNA level may predict the long-term efficacy of antiviral treatment. HBV genotypes C and B have no obvious influence on ccc DNA load. PMID:18300356
Ye, F; Jin, Y; Kong, Y; Shi, J Z; Qiu, H T; Zhang, X; Zhang, S L; Lin, S M
This study aimed to confirm that vertical transmission of hepatitis B virus (HBV) can occur via the infected ovum. Specimens studied were obtained from discarded test-tube embryos from mothers with chronic HBV infection who had received in vitro fertilization treatment. Single-cell reverse transcriptase-polymerase chain reaction was used to detect HBV mRNA in the embryos. HBV mRNA was detected in the cleavage embryos of patients with chronic HBV infection, with a detection rate of 13.2% (5/38). The level of serum HBV DNA was not related to the HBV mRNA positivity rates in embryos. In this study, HBV mRNA was detected in test-tube embryos from HBV-infected mothers who had received in vitro fertilization treatment. This confirms the theory of vertical transmission of HBV via the ovum, thereby providing an important theoretical basis for further study on the mechanism of HBV vertical transmission, influencing factors and blocking measures.
Zhang, Ka; Xu, Qi-Huan; Chen, Lu-Biao; Shu, Xin; Chen, Ni; Li, Gang
To investigate the level of the serum chemokine RANTES and its correlation with serum biochemical indices of liver function test, HBeAg and HBV DNA load in patients with chronic hepatitis B. 144 patients with chronic hepatitis B (observed group) and 18 normal cases (control group) were enrolled in this study. The serum level of chemokine RANTES was detected with an ABC-ELISA assay. Statistical analysis was performed on the software of SPSS13.0. The serum chemokine RANTES level in the observed group (3930.12 ng/ml 2856.96) ng/ml was significantly higher than that in the control group (329.46 ng/ml +/- 152.23) ng/ml. The results from the observed group indicated the positive correlation of serum RANTES level with indices of liver function test, including ALT (r = 0.197, P = 0.018), AST(r = 0.239, P = 0.004) and TBil (r = 0.316, P = 0.001), but did not with PTA (r = - 0.078, P = 0.357). Neither difference of serum chemokine RANTES level between HBeAg-positive group and HBeAg-negative group nor that between high HBV DNA load group (> or = 10(5) copies/ml) and low HBV DNA load group (< 10(5) copies/ml) were statistically significant (P = 0.407 and 0.185, respectively). Serum chemokine RANTES level in patients with chronic hepatitis B elevates significantly and is not affected by HBeAg or HBV DNA load. Its positive correlation with indices of liver function test indicates that RANTES might play an important role in the pathogenesis of chronic hepatitis B.
Ghosh, S; Banerjee, P; Deny, P; Mondal, R K; Nandi, M; Roychoudhury, A; Das, K; Banerjee, S; Santra, A; Zoulim, F; Chowdhury, A; Datta, S
Genome diversity is a hallmark of hepatitis B virus (HBV), which allowed its classification into 10 genotypes (A-J) and numerous subgenotypes. Among them, Genotype D is currently segregated into eight subgenotypes (D1-D8). Here, we report the identification and characterization of a novel subgenotype within genotype D of HBV from chronic hepatitis B e antigen (HBeAg)-negative patients of Eastern India. Phylogenetic tree analysis based on complete genome sequences revealed that six of 39 HBV/D isolates formed a distinct cluster supported by high bootstrap value and had nucleotide divergence >4% relative to the known D subgenotypes (D1-D8), justifying their assignment into a new subgenotype (D9). By comparing the amino acid sequences of the four ORFs of HBV/D9 with D1-D8, 36 specific residues, including a unique one (E(112) in the core region), were identified that could be considered as a signature of D9. Further analysis by Simplot, BootScan and jpHMM demonstrated that D9 resulted from a discrete recombination with genotype C over the precore-core region. This type of recombination has not been described previously as all C/D recombinants reported so far possessed genotype C backbones with mosaic fragments derived from HBV/D. Interestingly, compared to other subgenotypes of HBV/D, D9 isolates had a higher frequency of mutations (A1762T and G1764A) in the basal core promoter region that had been implicated in the development of hepatocellular carcinoma. Further investigations are needed to determine the overall prevalence and clinical significance of these newly characterized D9 strains and to assess the impact of inter-genotypic recombination on viral properties.
Boni, Carolina; Amadei, Barbara; Urbani, Simona; Fisicaro, Paola; Zerbini, Alessandro; Mori, Cristina; Missale, Gabriele; Bertoni, Roberto; Azzurri, Annalisa; Del Prete, Gianfranco; Ferrari, Carlo
Hepatitis B virus (HBV) superinfection in chronic hepatitis C represents a natural model to investigate whether or not hepatitis C virus (HCV) can influence priming and maturation of antiviral T cells; whether or not HBV superinfection, which is known to determine control of HCV replication, can restore HCV-specific T cell responsiveness; and whether or not cytokines stimulated by HBV infection can contribute to HCV control. To address these issues, the function of CD8 cells specific for HBV and HCV was studied longitudinally in two chronic HCV patients superinfected with HBV. Patients with acute hepatitis B were also examined. Frequency and function of HBV tetramer+ CD8 cells were comparable in patients acutely infected with HBV with or without chronic HCV infection. HBV-specific CD8 cell function was efficiently expressed irrespective of serum HCV-RNA levels. Moreover, fluctuations of HCV viremia at the time of HBV superinfection were not associated with evident changes of CD8 responsiveness to HCV. Finally, no correlation was found between serum levels of interferon alpha, interleukin (IL)-12, IL-10, or IL-18 and control of HCV replication. In conclusion, HCV did not affect the induction of primary and memory HBV-specific CD8 responses. HCV-specific CD8 responses were undetectable when HCV-RNA was negative, showing that inhibition of HCV replication in the setting of a HBV superinfection was not sufficient to induce a restoration of CD8 reactivity against HCV.
Lin, Chih-Lin; Kao, Jia-Horng
Molecular epidemiologic studies reveal remarkable differences in the geographical distribution of hepatitis B virus (HBV) genotypes. The frequency of mutants among HBV genotypes also varies. The role of HBV genotypes/mutants in the pathogenesis of HBV infection and natural history of HBV infection has been extensively investigated. The distribution of HBV genotypes in acute hepatitis B patients reflects the predominant genotypes in a given geographic area. In chronic hepatitis B patients, genotype C and D have a higher frequency of basal core promoter A1762T/G1764A mutations than genotype A and B. HBV genotypes C, D and F carry a higher lifetime risk of cirrhosis and HCC development than genotype A and B. HBV pre-S/S gene mutations were associated with immune escape of hepatitis B immunoglobulin or vaccine-induced immunity. Mutations in the pre-S, core promoter and X regions correlate with an increased risk of cirrhosis and HCC. In summary, HBV genotypes and mutants are associated with the disease progression and long-term outcome of HBV infection. They may serve as viral genetic markers for risk stratification of chronic hepatitis B patients in clinical practice. Copyright © 2017 Elsevier Ltd. All rights reserved.
Virine, Boris; Osiowy, Carla; Gao, Shan; Wang, Tong; Castillo, Eliana; Martin, Steven R.; Lee, Samuel S.; Simmonds, Kimberley; van Marle, Guido; Coffin, Carla S.
Background Chronic hepatitis B (CHB) is a dynamic disease that may be affected by immune changes in pregnancy. Guidelines suggest consideration of nucleos/tide analogs (NA), i.e., tenofovir, (TDF) in highly viremic mothers to reduce vertical transmission risk. HBV variability affects CHB outcome, but little is known about HBV genetic changes in pregnancy due to immune or NA selection. Objectives To evaluate HBV diversity in NA treated or untreated pregnant vs. post-partum CHB carriers. Study Design In plasma collected from 21 mothers (7 matching pre/post-partum), HBV serological tests, genotype and viral load were assayed. The HBV pre-surface (S) /S overlapping polymerase (P) (N = 20), pre-core (C) /C (N = 11) and/or full genome PCR amplicons (N = 3) underwent clonal sequence analysis. Results The median age was 31 y, 71% Asian, 68% genotype B or C, 33% HBV eAg+, 5 received TDF (median HBV DNA 8.5 log IU/ml). In untreated mothers, median antepartum vs. post-partum ALT was 21 vs. 24 U/L and HBV DNA was 2.7 vs. 2.4 log(10) IU/ml. ALT and/or HBV DNA flares occurred during pregnant and/or post-partum period in 47% (10/21). Clonal sequencing antepartum showed the presence of minor “a determinant” and/or vaccine escape mutants (VEM) but drug resistant variants were infrequent. Analysis of pregnant vs. post-partum samples showed different HBV variants and viral diversity. Conclusions Differences in immune and/or by NA selective pressures during pregnancy may affect HBV evolution during pregnancy. The presence of minor VEM warrant infant follow-up. PMID:26474400
Zheng, Qing-Fen; Zhang, Jing-Yun; Wu, Ju-Shan; Zhang, Ying; Liu, Mei; Bai, Li; Zhang, Jin-Yan; Zhao, Jing; Chen, Yu; Duan, Zhong-Ping; Zheng, Su-Jun
Prompt and accurate prediction of the outcome is the key to make correct medical decision and to reduce the mortality in patients with HBV-related acute-on-chronic liver failure (ACLF). Increasing evidence have certified that small, noncoding microRNAs (miRNAs) play critically regulatory roles in the pathogenesis of liver diseases. However, it remains unclear whether and how miRNAs involve in the prognosis of ACLF.Microarray analysis was performed to characterize the miRNA expression profiles in liver tissues from 1 HBV-related ACLF patient and 1 matched healthy control. Nine miRNAs with at least 5 folds difference between these 2 persons were picked out. The present prospective study involving 39 HBV-related ACLF patients including 20 recovered and 19 nonrecovered patients, which include death (n = 9) and liver transplantation (n = 10). The serum expression of these miRNAs detected by quantitative real-time Polymerase Chain Reaction (qRT-RCR) was then compared between the 2 groups. Moreover, the correlation between the serum miRNAs and the prognostic indexes for ACLF was analyzed.The result of microarray analysis showed 9 miRNAs had different expression in liver tissues of ACLF patient compared with healthy control (upregulated: miRNA-130a, -21, -143, and -200a; downregulated: miRNA-486-5p, -192, -148a, -122, and -194). Unlike the expression profiles in liver tissue, 8 serum miRNAs except miRNA-194 were markedly upregulated in ACLF patients (P < 0.05). Remarkably, the serum expression of miRNA-130a and miRNA-486-5p was higher in recovered than nonrecovered ACLF patients (P < 0.05). Especially, the serum miRNA-130a was negatively correlated with international normalized ratio, prothrombin time, Model for End-Stage Liver Disease score, and positively correlated with prothrombin time activity. The AUC for recovered versus nonrecovered patients of miRNA-130a was 0.741 (P = 0.02).miRNA-130a might be a useful prognosis biomarker in patients with HBV
Cuomo, Gianluca; Borghi, Vanni; Andreone, Pietro; Massari, Marco; Villa, Erica; Pietrangelo, Antonello; Verucchi, Gabriella; Ferrari, Carlo
Very little is known about the access to treatment for Chronic Hepatitis B in the real clinical practice and the characteristics of the patients who do not receive antiviral therapy. HBV-RER is an observational multicenter network that collected data of patients with HBV infection during a 3 years observational period (2009-2012). Among 2527 HBsAg positive patients, 1099 were never treated (NT); only 280 were included in the analysis due to different exclusion causes A minority was HBeAg-positive. The median age was 42. At liver biopsy most patients had Metavir score of F0-F1. Univariate analysis between 280 NT patients and the 290 naïve to treatment showed that NT patients were mostly female (P=0.002), not Italian (P=0.044), younger (P<0.001). Metavir score was lower in NT (P0.002), such as the Fib4 score (P<0.001). HBV DNA level was significantly higher in NT. At multivariate analysis, independent variables associated with no-treatment were younger age, female gender, Metavir score F0-F1, Fib4 lower than 1.6 and lower blood level of HBV-DNA. There is a large number of patients eligible to treatment who do not receive it. A younger age and a less severe disease seem to be associated to deferral of treatment. Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
Background Although hepatectomy is often performed with the Pringle maneuver, the problem of hepatic ischemia-reperfusion injury (HIRI) can also be serious. Thus, the present study was designed to investigate the protective effect of S-adenosylmethionine (SAMe) on HIRI, especially for patients with hepatocellular carcinoma (HCC) associated with chronic hepatitis B virus (HBV) infection and cirrhosis. Methods Eighty-one HCC patients with chronic HBV infection, undergoing partial hepatectomy with inflow occlusion, were divided into three groups. In the pretreatment group (PR group, n = 26), patients were given SAMe two hours before surgery. In the post-treatment group (PO group, n = 25), patients were given SAMe six hours after surgery. And in the control group (control group, n = 30), patients received partial hepatectomy without any SAMe. All pre-, intra- and postoperative blood samples were collected to measure the plasma levels of transaminases, bilirubin and cytokines. The results were compared among the three groups. Results There were no statistically significant intergroup differences observed in age, gender, hepatic inflow occlusion time and the results of liver function tests. Preoperative administration of SAMe (PR group) significantly reduced the plasma levels of alanine transaminase (ALT), aspartate transferase (AST), total bilirubin (TBIL) and direct bilirubin (DBIL) as compared to the other two groups. In the PO group, TBIL and DBIL were significantly lower than in the control group. Significant differences were also seen in IL-6 and TNF-α between the PR group and the other groups. In all groups, postoperative liver reserve function in the PR group as revealed by ICGR15 (Post ICGR15) was at its best before abdominal closure. Compared to the control group, the risk of complications and the hospital stay after surgery were significantly meliorated in the PR group. Additionally, patients with cirrhosis had a more acute rate of change in ALT
Bruder Costa, Juliana; Dufeu-Duchesne, Tania; Leroy, Vincent; Bertucci, Inga; Bouvier-Alias, Magali; Pouget, Noelle; Brevot-Lutton, Ophelie; Bourliere, Marc; Zoulim, Fabien; Plumas, Joel; Aspord, Caroline
Pegylated interferon α-2a (Peg-IFN-α) represents a therapeutic alternative to the prolonged use of nucleos(t)ide analog (NA) in chronic hepatitis B (CHB) infection. The mechanisms leading to a positive clinical outcome remain unclear. As immune responses are critical for virus control, we investigated the effects of Peg-IFN-α on both innate and adaptive immunity, and related it to the clinical evolution. The phenotypic and functional features of the dendritic cells (DCs), natural killer (NK) cells and HBV-specific CD4/CD8 T cells were analyzed in HBeAg-negative CHB patients treated for 48-weeks with NA alone or together with Peg-IFN-α, before, during and up to 2-years after therapy. Peg-IFN-α induced an early activation of DCs, a potent expansion of the CD56bright NK subset, and enhanced the activation and functionality of the CD56dim NK subset. Peg-IFN-α triggered an increase in the frequencies of Th1- and Th17-oriented HBV-specific CD4/CD8 T cells. Peg-IFN-α reversed the unresponsiveness of patients to a specific stimulation. Most of the parameters returned to baseline after the stop of Peg-IFN-α therapy. Peg-IFN-α impacts both innate and adaptive immunity, overcoming dysfunctional immune responses in CHB patients. These modulations were not associated with seroconversion, which questioned the benefit of the add-on Peg-IFN-α treatment.
Bruder Costa, Juliana; Dufeu-Duchesne, Tania; Leroy, Vincent; Bertucci, Inga; Bouvier-Alias, Magali; Pouget, Noelle; Brevot-Lutton, Ophelie; Bourliere, Marc; Zoulim, Fabien
Pegylated interferon α-2a (Peg-IFN-α) represents a therapeutic alternative to the prolonged use of nucleos(t)ide analog (NA) in chronic hepatitis B (CHB) infection. The mechanisms leading to a positive clinical outcome remain unclear. As immune responses are critical for virus control, we investigated the effects of Peg-IFN-α on both innate and adaptive immunity, and related it to the clinical evolution. The phenotypic and functional features of the dendritic cells (DCs), natural killer (NK) cells and HBV-specific CD4/CD8 T cells were analyzed in HBeAg-negative CHB patients treated for 48-weeks with NA alone or together with Peg-IFN-α, before, during and up to 2-years after therapy. Peg-IFN-α induced an early activation of DCs, a potent expansion of the CD56bright NK subset, and enhanced the activation and functionality of the CD56dim NK subset. Peg-IFN-α triggered an increase in the frequencies of Th1- and Th17-oriented HBV-specific CD4/CD8 T cells. Peg-IFN-α reversed the unresponsiveness of patients to a specific stimulation. Most of the parameters returned to baseline after the stop of Peg-IFN-α therapy. Peg-IFN-α impacts both innate and adaptive immunity, overcoming dysfunctional immune responses in CHB patients. These modulations were not associated with seroconversion, which questioned the benefit of the add-on Peg-IFN-α treatment. PMID:27348813
Desmond, Christopher P; Gaudieri, Silvana; James, Ian R; Pfafferott, Katja; Chopra, Abha; Lau, George K; Audsley, Jennifer; Day, Caroline; Chivers, Sarah; Gordon, Adam; Revill, Peter A; Bowden, Scott; Ayres, Anna; Desmond, Paul V; Thompson, Alexander J; Roberts, Stuart K; Locarnini, Stephen A; Mallal, Simon A; Lewin, Sharon R
Hepatitis B virus (HBV)-specific T-cell responses are important in the natural history of HBV infection. The number of known HBV-specific T-cell epitopes is limited, and it is not clear whether viral evolution occurs in chronic HBV infection. We aimed to identify novel HBV T-cell epitopes by examining the relationship between HBV sequence variation and the human leukocyte antigen (HLA) type in a large prospective clinic-based cohort of Asian patients with chronic HBV infection recruited in Australia and China (n = 119). High-resolution 4-digit HLA class I and II typing and full-length HBV sequencing were undertaken for treatment-naïve individuals (52% with genotype B, 48% with genotype C, 63% HBV e antigen [HBeAg] positive). Statistically significant associations between HLA types and HBV sequence variation were identified (n = 49) at 41 sites in the HBV genome. Using prediction programs, we determined scores for binding between peptides containing these polymorphisms and associated HLA types. Among the regions that could be tested, HLA binding was predicted for 14/18 (78%). We identified several HLA-associated polymorphisms involving likely known anchor residues that resulted in altered predicted binding scores. Some HLA-associated polymorphisms fell within known T-cell epitopes with matching HLA restriction. Enhanced viral adaptation (defined as the presence of the relevant HLA and the escaped amino acid) was independently associated with HBeAg-negative disease (P = 0.003). Thus, HBV appears to be under immune pressure in chronic HBV infection, particularly in HBeAg-negative disease.
Desmond, Christopher P.; Gaudieri, Silvana; James, Ian R.; Pfafferott, Katja; Chopra, Abha; Lau, George K.; Audsley, Jennifer; Day, Caroline; Chivers, Sarah; Gordon, Adam; Revill, Peter A.; Bowden, Scott; Ayres, Anna; Desmond, Paul V.; Thompson, Alexander J.; Roberts, Stuart K.; Locarnini, Stephen A.; Mallal, Simon A.
Hepatitis B virus (HBV)-specific T-cell responses are important in the natural history of HBV infection. The number of known HBV-specific T-cell epitopes is limited, and it is not clear whether viral evolution occurs in chronic HBV infection. We aimed to identify novel HBV T-cell epitopes by examining the relationship between HBV sequence variation and the human leukocyte antigen (HLA) type in a large prospective clinic-based cohort of Asian patients with chronic HBV infection recruited in Australia and China (n = 119). High-resolution 4-digit HLA class I and II typing and full-length HBV sequencing were undertaken for treatment-naïve individuals (52% with genotype B, 48% with genotype C, 63% HBV e antigen [HBeAg] positive). Statistically significant associations between HLA types and HBV sequence variation were identified (n = 49) at 41 sites in the HBV genome. Using prediction programs, we determined scores for binding between peptides containing these polymorphisms and associated HLA types. Among the regions that could be tested, HLA binding was predicted for 14/18 (78%). We identified several HLA-associated polymorphisms involving likely known anchor residues that resulted in altered predicted binding scores. Some HLA-associated polymorphisms fell within known T-cell epitopes with matching HLA restriction. Enhanced viral adaptation (defined as the presence of the relevant HLA and the escaped amino acid) was independently associated with HBeAg-negative disease (P = 0.003). Thus, HBV appears to be under immune pressure in chronic HBV infection, particularly in HBeAg-negative disease. PMID:22072755
Laaribi, A B; Zidi, I; Hannachi, N; Ben Yahia, H; Chaouch, H; Bortolotti, D; Zidi, N; Letaief, A; Yacoub, S; Boudabous, A; Rizzo, R; Boukadida, J
Identification of an HLA-G 14-bp Insertion/Deletion (Ins/Del) polymorphism at the 3' untranslated region of HLA-G revealed its importance in HLA-G mRNA stability and HLA-G protein level variation. We evaluated the association between the HLA-G 14-bp Ins/Del polymorphism in patients with chronic Hepatitis B virus (HBV) infection in a case-control study. Genomic DNA was extracted from 263 patients with chronic HBV hepatitis and 246 control subjects and was examined for the HLA-G 14-bp Ins/Del polymorphism by PCR. The polymorphic variants were genotyped in chronic HBV seropositive cases stratified according to HBV DNA levels, fibrosis stages and in a control population. There was no statistical significant association between the 14-bp Ins/Del polymorphism and increased susceptibility to HBV infection neither for alleles (P = 0.09) nor for genotypes (P = 0.18). The stratification of HBV patients based on HBV DNA levels revealed an association between the 14-bp Ins/Del polymorphism and an enhanced HBV activity with high HBV DNA levels. In particular, the Ins allele was significantly associated with high HBV DNA levels (P = 0.0024, OR = 1.71, 95% CI 1.2-2.4). The genotype Ins/Ins was associated with a 2.5-fold (95% CI, 1.29-4.88) increased risk of susceptibility to high HBV replication compared with the Del/Del and Ins/Del genotypes. This susceptibility is linked to the presence of two Ins alleles. No association was observed between the 14-bp Ins/Del polymorphism and fibrosis stage of HBV infection. We observed an association between the 14-bp Ins/Del polymorphism and high HBV replication characterized by high HBV DNA levels in chronic HBV patients. These results suggest a potential prognostic value for disease outcome evaluation.
Palumbo, Emilio; Scotto, Gaetano; Faleo, Giuseppina; Cibelli, Donatella Concetta; Angarano, Gioacchino
This study evaluated the prevalence of HBV infection in a population of South American immigrants in Italy and to determine in patients with detectable serum HBV-DNA the HBV genotypes. Between April 2005 and April 2006 a total of 130 South American immigrants were tested for HBsAg. In HBsAg positive patients the biochemical and virological activity of infection and the possible presence of co-infections (HCV, HDV, HIV) were evaluated. In patients with detectable serum HBV DNA, the HBV genotype was determined by INNOLiPA. Among the 130 subjects tested, 14 (10.7%) resulted HBsAg positive. All were men, with a mean age of 22 years (range 19-37) and 12 (85.7 %) came from Brazil, while 2 (14.3%) came from Ecuador. All patients infected by HBV had elevated alanine-aminotransferase serum levels (mean level was 127 IU/L, range 74-312) and serum HBV DNA detectable by PCR-Real Time (mean level 1,037,652 copies/mL, range 19,876-1,377,648). Genotype distribution was as follow: genotype D, 9 (64.2%), genotype A, 5 (35.8%). All patients infected by genotype D came from Brazil, while among the patients infected by genotype A, three came from Brazil and two from Ecuador. Our study evidences a moderate prevalence of HBV-infection in South American immigrants with the identification of two genotypes, D and A. These genotypes are not the most prevalent in the South America and this is probably the expression of a possible geographical redistribution of HBV genotypes.
Tavakoli, S; Mederacke, I; Herzog-Hauff, S; Glebe, D; Grün, S; Strand, D; Urban, S; Gehring, A; Galle, P R; Böcher, W O
Persistence of hepatitis B virus (HBV) infection is associated with reduced anti-viral T cell responses. Impaired dendritic cell (DC) function was suggested as the cause of reduced T cell stimulation in chronic HBV carriers. Thus, we compared myeloid (mDC) and plasmacytoid DC (pDC) from chronic HBV carriers and controls. Frequency and phenotype of isolated DC were analysed by fluorescence activated cell sorter staining, DC function by mixed lymphocyte reaction, cytokine bead array, intracellular cytokine staining, enzyme-linked immunosorbent assay and enzyme-linked immunospot. Expression of HBV DNA and mRNA was studied by polymerase chain reaction (PCR). Circulating total DC, mDC or pDC were not reduced in chronic HBV carriers. Isolated mDC and pDC from chronic HBV carriers exhibited similar expression of co-stimulatory molecules and alloreactive T helper cell stimulation as control DC, whether tested directly ex vivo or after in vitro maturation. Secretion of pro- and anti-inflammatory cytokines by CD40 or Toll-like receptor ligand-stimulated patient DC was intact, as was human leucocyte antigen A2-restricted HBV-specific cytotoxic lymphocyte stimulation. Although both DC populations contained viral DNA, viral mRNA was undetectable by reverse transcription–PCR, arguing against viral replication in DC. We found no quantitative, phenotypic or functional impairment of mDC or pDC in chronic hepatitis B, whether studied ex vivo or after in vitro maturation. PMID:18031557
Fabris, Paolo; Biasin, Maria R; Giordani, Maria T; Berardo, Laura; Menini, Vania; Carlotto, Antonio; Miotti, Maria G; Manfrin, Vinicio; Baldo, Vincenzo; Nebbia, Gaia; Infantolino, Domenico
Prevalence and impact of occult HBV infection in HIV positive patients is controversial. The aims of this study were to determine the prevalence of occult HBV infection and its impact on histological and virological parameters. 52 HIV/HCV (but HBsAg-negative) co-infected patients, 29 HBsAg and anti-HCV negative chronic hepatitis, and 20 HBsAg positive chronic hepatitis controls were studied. DNA was extracted from frozen biopsies and amplified with primers for S, C and X regions, and for (ccc) HBV-DNA. Sera were tested for HBV-DNA with two quantitative assays (Cobas Amplicor HBV Monitor, and the real-time COBAS (r) Taqman HBV Test, Roche Diagnostics, UK). Occult HBV infection was detected in 7 (13.4%) liver biopsies of the study group, and in none case of the non viral chronic hepatitis group (p=0.04). All serum samples were HBV-DNA negative with Cobas Amplicor HBV monitor assay, while 3 cases were found positive with real time PCR. Statistical analysis didn't show any impact of occult HBV infection on liver histology, CD4+ cells count, HIV and HCV load, and ALT levels. Occult B infection is relatively frequent in HIV/HCV co-infected patients, and is underestimated by common HBV-DNA serological assays. However, it doesn't seem to exert a relevant impact.
Zampino, Rosa; Pisaturo, Maria A; Cirillo, Grazia; Marrone, Aldo; Macera, Margherita; Rinaldi, Luca; Stanzione, Maria; Durante-Mangoni, Emanuele; Gentile, Ivan; Sagnelli, Evangelista; Signoriello, Giuseppe; Miraglia Del Giudice, Emanuele; Adinolfi, Luigi E; Coppola, Nicola
Hepatocellular carcinoma (HCC) is a development of severe liver disease frequently due to HBV and/or HCV infection. The aim of this retrospective study was to evaluate the development of HCC in patients with HBV-HCV chronic infection compared with patients with single HBV or HCV infection and the viral and host factors correlated to HCC in co-infected patients. We studied 268 patients with histology proven chronic hepatitis: 56 had HBV-HCV co-infection (HBV-HCV group), 46 had HBV infection (HBV group) and 166 had HCV infection (HCV group). Patients were followed up for at least 3 years. Viral and host factors were studied. HCC was more frequent in HBV-HCV group (14%) compared with HBV (2%, p = 0.006) and HCV monoinfected (4%, p = 0.006). The Mantel-Haenszel test used to investigate the relationship between HBV-HCV co-infection and development of HCC indicated an association between development of HCC and HBV-HCV co-infection (p < 0.001). In the HBV-HCV group, patients with HCC were significantly older (p = 0.000), had longer disease duration (p = 0.001), higher blood glucose levels (p = 0.001), lower levels of steatosis (p = 0.02), higher levels of fibrosis (p = 0.000), higher HCV RNA (p = 0.01) than those without HCC. ALT, lipid profile, PNPLA3 variant distribution and HBV viral load did not differ among co-infected patients with or without HCC. In conclusion HCC was more frequent in our patients with HBV-HCV co-infection, than in those with HBV or HCV mono-infection; possible associated risk factors for HCC development seem a long duration of disease, high levels of fibrosis and carbohydrate intolerance.
Dong, Xueyan; He, Hui; Zhang, Weiying; Yu, Daojun; Wang, Xianjun; Chen, Yueming
Hypermethylation of the promoter region of the RAS association domain family 1A gene (RASSF1A) occurs widely in hepatocellular carcinoma (HCC) tissues. While the diagnostic performance of the use of RASSF1A methylation as a serum or plasma marker in patients with HCC has varied largely in the literature,we confirmed the clinical application value of serum RASSF1A methylation for HBV related HCC in this study. A total of 584 participants were recruited into this study, including 190 patients with HCC, 114 patients with liver cirrhosis (LC), 120 patients with chronic hepatitis B (CHB) and 160 healthy individuals. Serum RASSF1A methylation was determined by the MethyLight method. In addition, we followed up 43 HCC patients who were unable to undergo surgery for 24 months. Serum RASSF1A methylation occurred significantly more frequently in patients with HCC (122/190, 64.2%) than in patients with LC (20/114, 17.5%), patients with CHB (6/120, 5.0%) and in healthy individuals (0/160, 0) (P < 0.001); moreover, it allowed for the discrimination of patients with HCC from those with CHB with an areas under the ROC curves (AUC) of 0.796 (64.2% sensitivity and 89.8% specificity). Furthermore, the AUC for the combination of serum RASSF1A methylation and AFP level (≥20 ng/L) was 0.876 (80.9% sensitivity and 93.4% specificity). Serum RASSF1A methylation positive in patients with HCC was associated with more malignant clinical characteristics and a worse overall survival (OS) (P < 0.05). Serum RASSF1A methylation demonstrated a satisfactory value for in the diagnosis of HBV related HCC, and could predict clinical progression and prognosis. In addition, our findings suggested that the combination of serum RASSF1A methylation and AFP level may be a promising non-invasive biomarker for the discrimination of patients with HCC from those with CHB. The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_DPAT-D-15-00090.1.
Khorramdelazad, Hossein; Hakimizadeh, Elham; Hassanshahi, Gholamhossein; Rezayati, Mohammadtaghi; Sendi, Hossein; Arababadi, Mohammad Kazemi
CCR5 is an important chemokine receptor involved in the recruitment of specific anti-viral immune cells (e.g., NK cells and T cytotoxic cells) to the liver. Previous studies indicated that the Δ 32 mutation in CCR5 gene led to inactivation of CCR5. Several conflicting studies have suggested that this mutation may be associated with either recovery or persistence of HBV infection. The main purpose of this study was to compare the frequency of the Δ 32 mutation within the CCR5 gene in a group of patients infected chronically with HBV with healthy individuals from South-East of Iran. Sixty patients with chronic HBV infection as well as 300 age-, and sex-match healthy individuals were enrolled in this study. Gap-PCR was applied to determine the frequency of CCR5 Δ 32 mutation in both groups. The results demonstrated that none of the patients infected with HBV carried the CCR5 Δ 32 mutation while, 3 (1%) of the healthy individuals were found to be heterozygotic for this mutation. The CCR5 Δ 32 mutation is not a prevalent mutation in either the patients infected chronically with HBV or their health counterparts in the South-East region of Iran. This may be attributed to either different genetic settings of the investigated population or lack of any significant correlation between this mutation and HBV pathogenicity.
Rajbhandari, R; Jun, T; Khalili, H; Chung, R T; Ananthakrishnan, A N
We examined the impact of HBV/HIV coinfection on outcomes in hospitalized patients compared to those with HBV or HIV monoinfection. Using the 2011 US Nationwide Inpatient Sample, we identified patients who had been hospitalized with HBV or HIV monoinfection or HBV/HIV coinfection using ICD-9-CM codes. We compared liver-related admissions between the three groups. Multivariable logistic regression was performed to identify independent predictors of in-hospital mortality, length of stay and total charges. A total of 72 584 discharges with HBV monoinfection, 133 880 discharges with HIV monoinfection and 8156 discharges with HBV/HIV coinfection were included. HBV/HIV coinfection was associated with higher mortality compared to HBV monoinfection (OR 1.67, 95% CI 1.30-2.15) but not when compared to HIV monoinfection (OR 1.22, 95% CI 0.96-1.54). However, the presence of HBV along with cirrhosis or complications of portal hypertension was associated with three times greater in-hospital mortality in patients with HIV compared to those without these complications (OR 3.00, 95% CI 1.80-5.02). Length of stay and total hospitalization charges were greater in the HBV-/HIV-coinfected group compared to the HBV monoinfection group (+1.53 days, P < 0.001; $17595, P < 0.001) and the HIV monoinfection group (+0.62 days, P = 0.034; $8840, P = 0.005). In conclusion, HBV/HIV coinfection is a risk factor for in-hospital mortality, particularly in liver-related admissions, compared to HBV monoinfection. Overall healthcare utilization from HBV/HIV coinfection is also higher than for either infection alone and higher than the national average for all hospitalizations, thus emphasizing the healthcare burden from these illnesses. © 2016 John Wiley & Sons Ltd.
Komatsu, Haruki; Inui, Ayano; Sogo, Tsuyoshi; Tateno, Akihiko; Shimokawa, Reiko; Fujisawa, Tomoo
Body fluids such as saliva, urine, sweat, and tears from hepatitis B virus (HBV) carriers are potential sources of HBV transmission. Thirty-nine children and 8 adults who were chronically infected with HBV were enrolled. Real-time polymerase chain reaction was used for the quantification of HBV DNA. HBV DNA was detected in 73.7% of urine samples (14 of 19), 86.8% of saliva samples (33 of 38), 100% of tear samples (11 of 11), and 100% of sweat samples (9 of 9). Mean HBV DNA levels (±SD) in urine, saliva, tears, and sweat were 4.3 ± 1.1 log copies/mL, 5.9 ± 1.2 log copies/mL, 6.2 ± 0.7 log copies/mL, and 5.2 ± 0.6 log copies/mL, respectively. A statistically significant correlation was observed between the HBV DNA level in serum specimens and HBV DNA levels in saliva and tear specimens (r = 0.88; P < .001). Tear specimens from a child were injected intravenously into 2 human hepatocyte-transplanted chimeric mice. One week after inoculation, both chimeric mice had serum positive for HBV DNA. The levels of HBV DNA in tear specimens from young children were high. Tears were confirmed to be infectious, using chimeric mice. Strict precautions should be taken against direct contact with body fluids from HBV carriers with high-level viremia.
Elefsiniotis, Ioannis S; Hero, Brokalaki; Mariolis, Anargiros; Pantazis, Konstantinos D; Fotos, Nikolaos V; Ketikoglou, Ioannis; Saroglou, George
The aim of this study was to evaluate the serological status of HBV infection and liver histology in chronic HCV-infected injecting drug users (IDUs) and to correlate them with the possible time of infection and the principal HCV genotype. Some 130 prior IDUs with chronic HCV infection were consecutively evaluated for the serological status of HBV infection. Fifty-eight (44.62%) reported intravenous drug use beginning before 1992 (group A) and 72 (55.38%) after 1992 (group B). HCV genotyping was available in 86 patients (PCR). Liver biopsy was performed in 48 patients (Ishak scoring system). There was no available data about alcohol consumption in the study population. Statistical analysis was based on the t-test and the chi(2) test (p<0.05). Some 82.8% of group A patients had previous HBV infection, whereas only 22.2% of group B patients did (p<0.001). Among group A patients, 10.3% were HBV-seronegative whereas 61.1% of group B patients were (p<0.001). Only 3.4% of group A patients were HBV-vaccinated compared to 16.7% in group B (p=0.016). HCV genotype was not associated with HBV serological status. No significant differences were detected in age, sex, possible time of infection, HBV serological status, or HCV genotype among those with higher vs. lower total grading scores. Seventy-five percent of patients had mild or no detectable fibrosis unrelated to the possible period of infection, the HBV serological status, and the HCV genotype. The serological profile of HBV infection is changing among Greek chronic HCV-infected IDUs, while the percentages of successfully HBV-vaccinated IDUs are relatively low. Severe liver disease is an uncommon finding in these patients, irrespective of the possible time of infection, the HBV serological status, and the HCV genotype.
Anastasiou, Olympia E; Widera, Marek; Verheyen, Jens; Korth, Johannes; Gerken, Guido; Helfritz, Fabian A; Canbay, Ali; Wedemeyer, Heiner; Ciesek, Sandra
The presence of anti-HBc antibodies indicates direct encounter of the immune system with hepatitis B virus (HBV). Aim of our study was to seek for anti-HBc negative but HBV replicating patients and analyze their clinical course and preconditions. From 1568 HBV-DNA positive patients, 29 patients (1.85%) tested negative for anti-HBc. The absence of anti-HBc could be confirmed in 19 patients using an alternative assay. In 16 of 19 cases, a partial or full HBV genome analysis was performed with NGS sequencing to evaluate if specific mutations were associated with anti-HBc absence. As a control group samples from 32 matched HBV infected patients with detectable anti-HBc were sequenced. Patients with detectable HBV-DNA and sequenced HBV core region in the confirmed absence of anti-HBc were diagnosed with acute HBV infection (n=3), HBV reactivation (n=9) and chronic hepatitis B (n=4). Most patients (12/16) were immunosuppressed: 3/16 patients had an HIV coinfection, 7/16 patients suffered from a malignant disease and 4/16 patients underwent solid organ transplantation (from which 2/4 had a malignant disease). Compared to the control cohort, HBV variants from anti-HBc negative patients showed less variability in the core region. In the absence of anti-HBc, HBV-DNA was most often found in immunocompromised hosts. Distinct mutations or deletions in the core region did not explain anti-HBc negativity. It would be advisable not to rely only on a single result of anti-HBc negativity to exclude HBV infection in immunocompromised hosts, but to measure anti-HBc repeatedly or with different methods. Copyright © 2017 Elsevier B.V. All rights reserved.
Xie, Yun; Yao, Qinwei; Butt, Azeem Mehmood; Guo, Jia; Tian, Zhou; Bao, Xuli; Li, Hongxia; Meng, Qinghua; Lu, Jun
MicroRNAs (miRNAs) represent a class of evolutionarily conserved, non-coding small RNAs (18–25 nt) that have emerged as master regulators of several biological processes. Recently, circulating miRNAs have also been reported to be promising biomarkers for various pathological conditions. In the present study, we report the comparative expression profiling of microRNA-101 (miR-101) in serum and tissue samples from chronic hepatitis B (CHB), HBV-associated liver cirrhosis (HBV-LC), and HBV-associated hepatocellular carcinoma (HBV-HCC) patients and healthy controls. The serum miR-101 levels were found to be significantly downregulated in the HBV-HCC patients compared with the HBV-LC patients (P < 0.001), CHB patients (P < 0.001) and healthy controls but were upregulated in the HBV-LC patients compared with the CHB patients (P < 0.001) and healthy controls (P < 0.001). Consistent with the serum data, the expression of miR-101 was also upregulated and downregulated in the HBV-LC and HBV-HCC tissue samples, respectively. A receiver operating characteristic (ROC) analysis of serum miR-101 yielded an area under the ROC curve (AUC) of 0.976 with 95.5% sensitivity and 90.2% specificity when differentiating between HBV-HCC and HBV-LC. Our results suggest that the serum miR-101 level can serve as a potential non-invasive biomarker to differentiate HBV-HCC from HBV-LC. PMID:24971953
Background It has been proved that hepatitis B virus (HBV) infection alters the metastatic pattern and affects survival in colorectal cancer (CRC) and hepatocellular carcinoma (HCC), while the influence of HBV infection on metastatic pattern and survival in patients with pancreatic cancer (PC) has not been investigated yet. Methods We conducted an investigation to evaluate the impact of HBV infection on metastatic pattern and overall survival in PC. We collected the data of 460 PC patients treated in our hospital from 1999 to 2010. Serum HBV markers were tested with enzyme-linked immunosorbent assay. The impact of HBV infection on metastatic pattern and overall survival was analyzed. Results We found that the incidence of synchronous liver metastasis was significantly higher in patients with HBsAg positive than those with HBsAg negative (46.0% vs 32.0%, P < 0.05), and higher in chronic HBV infection (CHB) group than both non HBV infection and resolved HBV infection group (61.1% vs 33.9%, P < 0.05, and 61.1% vs 28.7%, P < 0.05, respectively). What’s more, Kaplan-Meier analysis showed that CHB, resolved HBV infection and non HBV infection group had significant longer overall survival (OS) compared with inactive HBsAg carriers (IC) group (P=0.037, P=0.009, and P=0.019 respectively). But, in the multivariate analysis, only the CHB and non HBV infection group had significant better overall survival compared with IC group (P=0.010 and P=0.018 respectively). Conclusions Our study found that HBV infection increased synchronous liver metastasis rate, and HBV infection status was an independent prognostic factor in PC patients. PMID:24099678
Zhao, Zhidan; Liu, Jianhua; Wang, Jiaxin; Xie, Tinyan; Zhang, Qiuhuan; Feng, Sisi; Deng, Hui; Zhong, Baiyun
This retrospective study aimed to investigate the associations between the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) and disease severity in patients with chronic HBV infection-related liver disease (CHB). Patients with CHB were retrospectively identified. Clinical data for 172 HBV-infected patients and 40 healthy controls were collected from the electronic patient medical record system database of our hospital. HBV-related-compensated-cirrhosis patients (HBV-CC patients) had a significantly lower mean PLR than did other patients (P<0.001). HBV-related-decompensated-cirrhosis patients (HBV-DC patients) had a significantly higher mean NLR than did any other patients (P<0.001). In the entire cohort of CHB patients, significant correlations were observed between the PLR and both serum HBV DNA (r=0.264, P<0.001) and serum HBeAg (r=0.240, P=0.002). The PLR was significantly correlated with serum HBV DNA in both HBV-CC patients (r=-0.116, P=0.044) and HBV-DC patients (r=0.456, P=0.008). In HBV-Active-Carriers patients (HBV-AC patients), the PLR was positively correlated with serum HBeAg level (r=0.321, P=0.023). In HBV-DC patients, the NLR was positively correlated with serum HBeAg level (r=0.372, P=0.033). In the logistic regression prediction model, a predictive probability cutoff of 0.392 had the highest sensitivity and specificity (sensitivity, 91.2%; specificity, 84.0%) in distinguishing between HBV-CC and HBV-AC patients. A NLR cutoff value of 2.94 had the highest sensitivity and specificity (sensitivity, 81.8%; specificity, 88.2%) in distinguishing between HBV-DC and HBV-CC patients. The PLR and NLR partially reflect the amounts of serum HBV DNA and serum HBeAg levels circulating in CHB patients. The logistic regression model including the PLR and age most accurately distinguished between HBV-CC and HBV-AC patients. The NLR may be useful for follow-up in HBV-CC patients to predict disease progression. In summary, the PLR and NLR
Esmaeelzadeh, Abbas; Saadatnia, Hassan; Memar, Bahram; Mokhtari Amirmajdi, Elham; Ganji, Azita; Goshayeshi, Ladan; Meshkat, Zahra; Pasdar, Alireza; Vosoughinia, Hassan; Farzanehfar, Mohammadreza; Tehranian, Shahrzad; Ghaffarzadehgan, Kamran; Rajabzadeh, Farnood; Ahadi, Mitra
Aim: To evaluate the association between biochemical, virologic and histologic features in patients with HBeAg-negative chronic hepatitis B (CHB). Background: Hepatitis-B e-antigen (HBeAg)-negative is common in Iran, is progressive with poor prognosis. Therefore, it seems necessary to perform a comprehensive evaluation of different spectrum of laboratory measurements accompanying histological findings. Methods: HBeAg- negative CHB patients referring to two university hospitals during two years were enrolled. Alcohol consumption, liver mass, fatty liver and positive results of Anti HDV, Anti HCV or Anti HIV were excluded. The relationship between viral loads, liver enzymes (old and new cutoffs) and histopathological features was analyzed using descriptive and analytic statistical methods. Results: A total of 150 HBeAg-negative CHB (males=110, mean age=38.44±11.34 years) were assessed. ALT had a significant relation with the logarithm of serum HBV-DNA (P<0.0001), grade and stage on liver biopsy (P<0.001, P=0.034, respectively). Serum viral load, AST and ALT were independent predictors of histological grade, age was the only independent predictor of the stage of liver fibrosis. There was a significant relationship between serum ALT and stage of liver fibrosis (P<0.0001) when new cutoff values for ALT were considered. We found that age had a significant relation with histological grade but it showed a reverse relation with ALT levels (P=0.009). Conclusion: In HBeAg-negative CHB, AST had a better prediction for liver necrosis and inflammation. Age could be an independent predictor for liver fibrosis. New cutoff values for ALT had superiority over conventional values to identify higher risk of liver fibrosis. PMID:28331563
Sulka, Agnieszka; Simon, Krzysztof; Piszko, Paweł; Kalecińska, Ewa; Dominiak, Marzena
The aim of the study was to evaluate the character of lesions within oral mucosa in patients suffering from chronic hepatitis and cirrhosis of the liver due to either HBV or HCV infection. A total of 74 patients treated at the Clinic of Infectious Diseases in Wrocław for chronic hepatitis B (20 patients, group I) and for chronic hepatitis C (23 patients group III) and cirrhosis of the liver due to HBV (15 patients , group II) and HCV (16 patients, group IV) infection. The control group comprised 29 healthy subjects. Lesions within the oral mucosa found on clinical examinations were confirmed with a histopathological evaluation. Patients suffering from chronic hepatitis B revealed leukoplakia (1/20), melanoplakia (1/20), petechiae (1/20), 17 patients from this group did not show any changes. Patients suffering from chronic hepatitis C revealed leukoplakia (6/23), Delbanco's disease (2/23), melanoplakia (1/23), lichen planus (1/23), petechiae (1/23), 12 patients from this group did not show any changes. Patients suffering from cirrhosis of the liver due of HBV infection revealed leukoplakia (3/15) petechiae (2/15), Delbanco's disease (1/15), angular cheilitis (1/15), aphthae (1/15), 7 patients from this group did not reveal any changes. Patients suffering from cirrhosis of the liver due of HCV infection revealed petechiae (2/16), melanoplakia (1/16), candidosis (1/16), labial herpes (1/16), 11 patients from this group did not reveal any changes. In control group we observed leukoplakia (3/29), Delbanco's disease (1/29), labial herpes (1/29), petechiae (1/29), and 23 subjects did not present pathological lesions within the oral mucosa. Results indicate the lack of connection between chronic HBV and HCV infection as well as the stage of the disease with the incidence and character of oral lesions in oral mucosa.
Background Lamivudine (3TC) is a potent inhibitor of both Hepatitis B virus (HBV) and Human Immunodeficiency Virus (HIV) replication and is part of first-line highly active antiretroviral therapy (HAART) in the Gambia. Unfortunately, the effectiveness of 3TC against HBV is limited by the emergence of resistant strains. Aim The aim of this retrospective study was to characterise 3TC-resistant mutations in HBV from co-infected patients receiving HAART, by generating HBV polymerase sequence data and viral loads from HBV genotype E infected patients, both at initiation and during a course of 3TC therapy. Method Samples from 21 HBV chronic carriers co-infected with HIV-1 (n = 18), HIV-2 (n = 2) and HIV-dual (n = 1) receiving HAART for a period of 6-52 months were analysed for the emergence of 3TC-resistance mutations. Findings Sixteen out of 21 HBV/HIV co-infected patients responded well to HAART treatment maintaining suppression of HBV viraemia to low (≤ 104 copies/mL) (n = 5) or undetectable levels (< 260 copies/ml) (n = 11). Out of the 5 non-responders, 3 had developed 3TC-resistant HBV strains showing mutations in the YMDD motif at position 204 of the RT domain of the HBV polymerase. One patient showed the M204V+ L180M+ V173L+ triple mutation associated with a vaccine escape phenotype, which could be of public health concern in a country with a national HBV vaccination programme. All except one patient was infected with HBV genotype E. Conclusions Our findings confirm the risk of 3TC mutations in HAART patients following monotherapy. This is a novel study on 3TC resistance in HBV genotype E patients and encourage the use of tenofovir (in association with 3TC), which has not shown unequivocally documented HBV resistance to date, as part of first-line therapy in HIV/HBV co-infected patients in West Africa. HBV- hepatitis B infection; HIV- human immunodeficiency virus; HAART- antiretroviral therapy. PMID:22195774
Meier, M-A; Suslov, A; Ketterer, S; Heim, M H; Wieland, S F
Current treatment options for patients with chronic hepatitis B virus (HBV) infection are not curative as they are not effective in eliminating covalently closed circular DNA (cccDNA). cccDNA is a stable template for HBV transcription in the nucleus of hepatocytes and is thought to be one of the main factors responsible for HBV persistence. Recently, activation of the lymphotoxin beta receptor (LTβR) has been shown to trigger degradation of cccDNA through induction of cytidine deaminases of the APOBEC3 family in HBV cell culture model systems. To assess the presence and relevance of such mechanisms in the liver of chronically HBV-infected patients, we compared intrahepatic cccDNA levels with the expression levels of lymphotoxins and some of their target genes (eg APOBEC deaminases) in liver biopsy tissue. Our results confirm elevated gene expression levels of components of the lymphotoxin pathway including lymphotoxin alpha (LTα), lymphotoxin beta (LTβ), APOBEC3B (A3B) and APOBEC3G (A3G) in the chronically HBV-infected liver compared to uninfected liver. Furthermore, expression levels of the genes of the APOBEC deaminase family were correlated with those of LTα and LTβ gene expression, consistent with lymphotoxin-mediated upregulation of APOBEC gene expression. However, intrahepatic cccDNA and HBV replication levels were not correlated with LTα, LTβ and APOBEC gene expression. In conclusion, these results suggest that although the lymphotoxin pathway is activated in the chronically HBV-infected liver, it has no major impact on HBV cccDNA metabolism in chronic HBV infection. © 2017 John Wiley & Sons Ltd.
Mo, Ruidong; Wang, Peng; Lai, Rongtao; Li, Fanlu; Liu, Yuhan; Jiang, Shaowen; Zhao, Gangde; Guo, Simin; Zhou, Huijuan; Lin, Lanyi; Lu, Jie; Cai, Wei; Wang, Hui; Yu, Hong; Bao, Shisan; Xiang, Xiaogang; Xie, Qing
Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is an acute deterioration of liver function on chronic liver disease with immune disorder. Th22 cells and IL-22 were correlated with inflammatory and autoimmune diseases. However, Th22 cells and IL-22 in the pathogenesis of HBV-ACLF remains to be elucidated. It was investigated the correlation between Th22 and prognosis in HBV-ACLF. Seventy-one HBV-ACLF and 65 chronic hepatitis B patients were recruited. The peripheral frequencies of Th22, Th17 and Th1, or IL-22 and IL-17 were determined, using flow cytometry or ELISA, respectively. It was further analyzed the correlation between Th22 mediated circulating IL-22 and survival rate of HBV-ACLF patients. It was upregulated that the peripheral frequencies of Th22/Th17 cells as well as plasma IL-22 and IL-17 in HBV-ACLF patients, but the frequency of Th1 cells was decreased, compared with health controls. Elevated Th22 cells and IL-22 were correlated with HBV-ACLF disease severity. Elevated plasma IL-22 level (>29.5 pg/ml) was correlated with poor survival rate of HBV-ACLF patients at baseline, using Kaplan-Meier analysis. Persistently elevated circulating Th22 reversely correlates with prognosis in HBV-ACLF. Th22 cells/IL-22 might be served as biomarkers for evaluating the prognosis of HBV-ACLF. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.
Lu, F M; Wang, J; Chen, X M; Jiang, J N; Zhang, W H; Zhao, J M; Ren, H; Hou, J L; Xia, N S
Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in infected hepatocytes is the main cause of off-therapy viral rebound. The half-life of cccDNA is only 33-50 days, so the conversion of newly synthesized rcDNA to cccDNA in the nucleus is essential for the maintenance of cccDNA pool in infected hepatocytes. Though not directly targeting the existing cccDNA, current nucleos(t)ide analogues (NAs) may exhaust the cccDNA reservoir by blocking the rcDNA formation. Indeed, a prolonged consolidation therapy post loss of serum HBV DNA can achieve sustained remission and thus safe drug discontinuation in a small proportion of chronic hepatitis B (CHB) patients. In recent studies, we and others have demonstrated that it is the serum HBV RNA that reflects the cccDNA activity in infected hepatocytes, particularly among the patients on NAs. Here we suggest that instead of measuring serum HBV DNA only, simultaneous measurement of both viral DNA and RNA would improve the accuracy to reflect the cccDNA activity; therefore, the virological response should be redefined as consistent loss (less than the lower limit of detection) of both serum HBV DNA and RNA, which indicates the safety of drug discontinuation. Accumulating evidence has suggested that for the CHB patients with lower serum HBsAg, switch-to or add-on pegylated interferon (Peg-IFN) treatment would result in loss of serum HBsAg in a relatively large proportion of CHB patients. Since serum HBV RNA is an ideal biomarker to reflect the intrahepatic cccDNA activity, for the patients with a serum HBsAg level lower than 1 500 IU/ml after long-term NAs treatment, the serum HBV RNA should be measured. If serum HBV RNA is detected, peg-IFN should be added on; if serum HBV RNA is not detected, NAs treatment should be switched to peg-IFN treatment. We believe the therapy based on serum HBV RNA would make the functional cure of CHB (serum HBsAg loss or even conversion to anti-HBs) more efficient.
Xu, Zhengju; Liu, Liguan; Pan, Xingnan; Wei, Kaipeng; Wei, Meijuan; Liu, Lifei; Yang, Huanwen; Liu, Qian
Abstract Alanine aminotransferase (ALT) is the most commonly used marker of liver injury, but normal ALT levels are seen in a proportion of chronic hepatitis B virus (HBV)-infected patients with severe liver injury. Golgi protein 73 (GP73) is a promising alternative marker of liver injury. This study assessed the relation between GP73 levels and liver disease severity, monitored the kinetic changes in GP73 levels in chronic HBV patients receiving entecavir (ETV) therapy, and investigated the potential diagnostic and prognostic values of serum GP73 as a new liver injury biomarker in chronic HBV infections. This study enrolled 1150 patients with chronic HBV infections, 200 of whom were retrospectively enrolled in this study after receiving 1 year of ETV treatment. GP73 expression in liver tissue was detected by immunohistochemistry. GP73 levels in single or serial serum samples were measured by enzyme-linked immunosorbent assay. Immunohistochemical analysis indicated that GP73 protein expression in the liver increased progressively with pathologic progression from nonexistent or mild hepatitis to severe hepatitis and cirrhosis during chronic HBV infection. Serum GP73 levels were positively correlated with the disease severity of chronic HBV infections (r = 0.58, P < 0.001). In patients with normal ALT levels, serum GP73 concentrations were significantly higher in patients with prominent hepatic inflammatory injury and fibrosis than in patients without hepatic inflammatory injury or fibrosis. Serum GP73 concentrations and GP73 protein expression were decreased in the liver tissues of patients whose ALT levels normalized after 1 year of ETV antiviral therapy. Changes in serum GP73 levels were closely associated with changes in liver injury severity, and, therefore, GP73 may be an effective new liver inflammatory injury biomarker, and could be useful for monitoring the prognosis of chronic HBV infectious patients with normal ALT levels. PMID:25816035
Salpini, Romina; Piermatteo, Lorenzo; Gill, Upkar; Battisti, Arianna; Stazi, Francesca; Guenci, Tania; Giannella, Sara; Serafini, Valentina; Kennedy, Patrick T F; Perno, Carlo Federico; Svicher, Valentina; Ciotti, Marco
Intrahepatic total HBV DNA (it-HBV DNA) level might reflect the size of virus reservoir and correlate with the histological status of the liver. To quantitate it-HBV DNA in a series of 70 liver biopsies obtained from hepatitis B chronic patients, a modified version of the COBAS(®)Ampliprep/COBAS(®)TaqMan HBV test v2.0 was used for this purpose. The linearity and reproducibility of the modified protocol was tested by quantifying serial dilutions of a full-length HBV containing plasmid and it-HBV DNA from a reference patient. A good linear trend between the expected values and those generated by the assay was observed at different concentrations of both plasmid and reference patient (R (2) = 0.994 and 0.962, respectively). Differences between the values obtained in two independent runs were ≤0.3 log IU for the plasmid and ≤0.6 log IU/mg for the reference patient, showing a high inter-run reproducibility. In the 70 liver biopsies, it-HBV DNA level ranged from 1.4 to 5.4 log IU/mg, with a good linearity and reproducibility between the values obtained in two runs [R (2) = 0.981; median (IQR) difference of it-HBV DNA 0.05 (0.02-0.09) IU/mg]. The modified COBAS(®)Ampliprep/COBAS(®)TaqMan HBV test v2.0 allows an accurate quantitation of it-HBV DNA. Its determination may have prognostic value and may be a useful tool for the new therapeutic strategies aimed at eradicating the HBV infection.
Bivigou-Mboumba, Berthold; François-Souquière, Sandrine; Deleplancque, Luc; Sica, Jeanne; Mouinga-Ondémé, Augustin; Amougou-Atsama, Marie; Chaix, Marie-Laure; Njouom, Richard; Rouet, François
Integrated data on hepatitis B virus (HBV) patterns, HBV genotypes and mutations are lacking in human immunodeficiency virus type 1 (HIV-1) co-infected patients from Africa. This survey was conducted in 2010-2013 among 762 HIV-1-positive adults from Gabon who were predominantly treated with 3TC-based antiretroviral treatment. HBV patterns were identified using immunoassays detecting total antibody to hepatitis B core antigen (HBcAb), hepatitis B surface antigen (HBsAg), IgM HBcAb, hepatitis B e antigen (HBeAg), antibody to HBsAg (HBsAb) and an in-house real-time PCR test for HBV DNA quantification. Occult hepatitis B (OBI) was defined by the presence of isolated anti-HBc with detectable serum HBV DNA. HBV genotypes and HBV mutations were analyzed by PCR-direct sequencing method. Seventy-one (9.3%) patients tested positive for HBsAg, including one with acute hepatitis B (0.1%; 95% CI, 0.0%-0.2%), nine with HBeAg-positive chronic hepatitis B (CHB) (1.2%; 95% CI, 0.6%-2.2%), 16 with HBeAg-negative CHB (2.1%; 95% CI, 1.2%-3.3%) and 45 inactive HBV carriers (5.9%; 95% CI, 4.4%-7.8%). Sixty-one (8.0%; 95% CI, 6.2%-10.1%) patients showed OBI. Treated patients showed similar HBV DNA levels to those obtained in untreated patients, regardless of HBV patterns. Around 15.0% of OBI patients showed high (>1,000 UI/mL) viremia. The mutation M204V/I conferring resistance to 3TC was more common in HBV/A (47.4%) than in HBV/E isolates (0%) (P = .04). Our findings encouraged clinicians to promote HBV vaccination in patients with no exposure to HBV and to switch 3TC to universal TDF in those with CHB.
Bivigou-Mboumba, Berthold; François-Souquière, Sandrine; Deleplancque, Luc; Sica, Jeanne; Mouinga-Ondémé, Augustin; Amougou-Atsama, Marie; Chaix, Marie-Laure; Njouom, Richard; Rouet, François
Integrated data on hepatitis B virus (HBV) patterns, HBV genotypes and mutations are lacking in human immunodeficiency virus type 1 (HIV-1) co-infected patients from Africa. This survey was conducted in 2010–2013 among 762 HIV-1-positive adults from Gabon who were predominantly treated with 3TC-based antiretroviral treatment. HBV patterns were identified using immunoassays detecting total antibody to hepatitis B core antigen (HBcAb), hepatitis B surface antigen (HBsAg), IgM HBcAb, hepatitis B e antigen (HBeAg), antibody to HBsAg (HBsAb) and an in-house real-time PCR test for HBV DNA quantification. Occult hepatitis B (OBI) was defined by the presence of isolated anti-HBc with detectable serum HBV DNA. HBV genotypes and HBV mutations were analyzed by PCR-direct sequencing method. Seventy-one (9.3%) patients tested positive for HBsAg, including one with acute hepatitis B (0.1%; 95% CI, 0.0%-0.2%), nine with HBeAg-positive chronic hepatitis B (CHB) (1.2%; 95% CI, 0.6%–2.2%), 16 with HBeAg-negative CHB (2.1%; 95% CI, 1.2%–3.3%) and 45 inactive HBV carriers (5.9%; 95% CI, 4.4%–7.8%). Sixty-one (8.0%; 95% CI, 6.2%–10.1%) patients showed OBI. Treated patients showed similar HBV DNA levels to those obtained in untreated patients, regardless of HBV patterns. Around 15.0% of OBI patients showed high (>1,000 UI/mL) viremia. The mutation M204V/I conferring resistance to 3TC was more common in HBV/A (47.4%) than in HBV/E isolates (0%) (P = .04). Our findings encouraged clinicians to promote HBV vaccination in patients with no exposure to HBV and to switch 3TC to universal TDF in those with CHB. PMID:26764909
Urabe, Ayako; Imamura, Michio; Tsuge, Masataka; Kan, Hiromi; Fujino, Hatsue; Fukuhara, Takayuki; Masaki, Keiichi; Kobayashi, Tomoki; Ono, Atsushi; Nakahara, Takashi; Kawaoka, Tomokazu; Hiramatsu, Akira; Kawakami, Yoshiiku; Aikata, Hiroshi; Hayes, Clair Nelson; Maki, Noboru; Ohdan, Hideaki; Chayama, Kazuaki
Post-transplant hepatitis B virus (HBV) reinfection is one of the major problems facing patients who undergo HBV-related liver transplantation (LT). We analyzed the clinical impact of serum hepatitis B core-related antigen (HBcrAg) on HBV reinfection in post-LT patients with HBV-related liver diseases. Serum hepatitis B surface antigen (HBsAg), HBV DNA, and HBcrAg were measured over time in 32 post-LT patients. Twenty-one out of 32 patients had HCC at LT. The effects of HBcrAg, hepatocellular carcinoma (HCC) recurrence, and HBs gene mutation on HBV reinfection and withdrawal from hepatitis B immune globulin (HBIG) were analyzed. Sixteen out of 32 patients (50 %) were positive for HBcrAg even though only six patients were thought to have experienced HBV reinfection based on reappearance of either HBV DNA or HBsAg during a median follow-up time of 75 months. Three of these six patients who became re-infected with HBV experienced HCC recurrence after LT. The HBV DNA reappearance rate was significantly higher in patients with HCC recurrence after LT (p < 0.001). Two HBV re-infected patients without HCC recurrence had HBs gene mutations G145R and G145A, respectively. Anti-HBs antibody development rate by HB vaccination was similar between HBcrAg-positive and negative patients (p = 0.325). HBV reinfection is more common than is usually considered based on conventional measurement of HBsAg and HBV DNA. HCC recurrence and mutations in the HBV S gene were associated with HBV reinfection after LT.
Yeh, Ming-Lun; Huang, Chung-Feng; Huang, Ching-I; Liu, Shu-Fen; Yang, Hua-Ling; Hsieh, Ming-Yen; Huang, Jee-Fu; Dai, Chia-Yen; Chuang, Wan-Long; Yu, Ming-Lung
Selection of drug-resistant strains may lead to failure of HBV antiviral therapy. There is little information whether there is detection difference in drug resistant mutations between different viral load assays of HBV. This study is aimed to investigate whether there is drug-resistant strains related detection difference between Abbott RealTime HBV (RealTime) and CobasAmpliPrep/CobasTaqMan HBV assays 2.0 (TaqMan). One hundred and thirty-four CHB patients who received HBV anti-viral therapy were enrolled. HBV virological markers were tested 3 months apart regularly. Serum HBV DNA levels were determined using the TaqMan and RealTime. YMDD (rt180M and rt204V) mutation was checked in patients who experienced virologic breakthrough (VBT). The correlation of HBV DNA observed between the RealTime and TaqMan was good for all 571 samples (R2 = 0.797; P<0.001). However, the correlation in the 434 samples with HBV DNA level <3 log10 IU/ml was not as good as in all samples (R2 = 0.457). Overall, 21.5% of samples had a detection difference of ≥ 1 log10 IU/ml with 91.9% of these having HBV DNA level <3 log10 IU/ml. Twenty-four patients experienced VBT. Three of these patients had acquired the YMDD mutation and exhibited discordant viral load results between the two methods tested. In each case, persistent HBV DNA was detected by RealTime and undetectable with TaqMan. Of the patients who experienced a VBT and had acquired YMDD mutation, 4.7% had undetectable HBV DNA by TaqMan while all were detectable with RealTime. RealTime assay is more sensitive and is little impacted by the development of drug resistant mutation.
Maylin, Sarah; Sire, Jean-Marie; Mbaye, Papa Saliou; Simon, François; Sarr, Anna; Evra, Marie-Louise; Fall, Fatou; Daveiga, Jean; Diallo, Aboubakry; Debonne, Jean-Marc; Chartier, Loic; Vray, Muriel
We evaluated the short-term spontaneous fluctuations of HBV DNA and HBsAg levels in Senegalese patients with chronic infection with hepatitis B virus and normal ALT and determined factors related to these fluctuations. A total of 87 patients with persistent normal ALT values were enrolled in the study. Serum samples were obtained at three different visits, with an interval of 2 months (M0, M2, and M4), and without initiating anti HBV treatment. Levels of HBV DNA, quantitative HBsAg, ALT and AST, genotyping and viral DNA mutations were analyzed. Among the 87 patients, genotype E was predominant (75%). The median HBV DNA level was 2.9 log10 IU/mL [2.2-3.4], 2.7 log10 IU/mL [2.1-3.6] and 2.7 log10 IU/mL [2.1-3.4] at M0, M2 and M4, respectively. The values ranged from <1.1 to 7 log10 IU/mL and 55 (63%) had HBV DNA fluctuations≥0.5 log10 IU/mL between two visits. Patients in whom HBV DNA fluctuated ≥0.5 log10 IU/mL between M0 and M2 also had significant fluctuations between M2 and M4, while patients with stable HBV DNA between M0 and M2 showed a stable viral load between M2 and M4. The only factor found to be associated with HBV DNA fluctuations≥0.5 log10 IU/mL was a low BMI (<21 kg/ m2). HBsAg levels were not correlated with HBV DNA levels. Sixty-three percent of the enrolled Senegalese population showed a large, short-term fluctuation of HBV DNA levels. Such fluctuations may have an impact on therapeutic management, requiring closer monitoring.
Ouzan, Denis; Pénaranda, Guillaume; Joly, Hélène; Khiri, Hacène; Pironti, Antonnella; Halfon, Philippe
The aim of this study was to prospectively evaluate whether the addition of peg-IFN to a stable NA regimen leads to loss of HBsAg in HBeAg-negative patients with chronic hepatitis and HBV DNA fully suppressed by long-term NA treatment. We analyzed HBsAg levels in 10 HBsAg-positive, HBeAg-negative patients who received peg-IFN alpha-2a in addition to a NA regimen. Treatment lasted a maximum of 96 weeks, according to changes in the HBsAg titer. Before peg-IFN therapy, HBV DNA levels had been below the limit of detection for at least three years. HBsAg levels declined in nine patients. Among these nine, four became HBsAg-negative after 48 weeks of peg-IFN treatment; these patients received peg-IFN for only 48 weeks. NAs were stopped in these four patients, and these levels remained stable for at least 18 months (loss of HBsAg; HBV-DNA negative). HBs seroconversion was observed in two patients. The remaining five patients received 96 weeks of peg-IFN therapy. One patient became HBsAg-negative at the end of peg-IFN therapy; another became HBsAg-negative six months later. Three patients did not become HBsAg-negative. NAs were stopped in the two patients who became HBsAg-negative with no relapse during 12 months of follow up. In HBsAg-positive, HBeAg-negative patients with HBV DNA were fully suppressed by long-term NA treatment, the addition of peg-INF for a maximum of 96 weeks based on HBsAg-titer monitoring led to a loss of HBsAg and cessation of NA therapy in six out of ten patients, with no relapse for 12-18 months of follow up. HBs seroconversion was observed in two patients. Copyright © 2013 Elsevier B.V. All rights reserved.
Han, Li-Hui; Sun, Wen-Sheng; Ma, Chun-Hong; Zhang, Li-Ning; Liu, Su-Xia; Zhang, Qiu; Gao, Li-Fen; Chen, You-Hai
AIM: To detect the expression of soluble TRAIL (TNF-related apoptosis inducing ligand, TRAIL) in the peripheral blood of HBV infected patients and try to elucidate whether the expression level of sTRAIL have any correlativity with the clinical staging, the expression level of HBV markers and the degree of liver damage. METHODS: 52 cases of HBV infected patients were investigated, including 8 HBV carriers, 30 chronic hepatitis B, 11 cirrhotics and 3 HBV infection related hepatocellular carcinoma. Expression of soluble TRAIL and markers of the hepatitis B were mearsured by enzyme-linked immunosorbent assay. RESULTS: The expression level of sTRAIL in the peripheral blood of the HBV infected patients was significantly higher than that of healthy controls (1378.35 ± 540.23 pg/mL vs 613.75 ± 175.80 pg/mL, P < 0.001). In the group of chronic hepatitis, the expression level of sTRAIL was coincident with the status of the disease and was significantly correlated with the level of ALT. In the group of cirrhosis and liver cancer, its expression level was significantly higher than that of the healthy persons and HBV carriers, but lower than that of the hepatitis B patients; meanwhile, the expression of sTRAIL did not have any correlativity with the functional indexes of the liver. CONCLUSION: The soluble TRAIL in the HBV infected people may participate in the liver damage. Our results indicated that the expression level of soluble TRAIL may reflect the ravage of liver caused by host immune reaction to a certain degree. PMID:12439929
Dissection of a circulating and intrahepatic CD4(+)Foxp3(+) T-cell subpopulation in chronic hepatitis B virus (HBV) infection: a highly informative strategy for distinguishing chronic HBV infection states.
Zhang, Mengjun; Zhou, Jijun; Zhao, Tingting; Huang, Guangyu; Tan, Yulong; Tan, Shun; Fu, Xiaolan; Niu, Wei; Meng, Gang; Chen, Xiaoling; Shang, Xiaoyun; Liu, Dong; Ni, Bing; Wang, Li; Wu, Yuzhang
The definition of CD4(+)Foxp3(+) regulatory T cells (Tregs) is challenging as it relates to chronic hepatitis B virus (HBV) infection. Recently, the heterogeneity of human CD4(+)Foxp3(+) T cells has been confirmed. Three circulating CD4(+)Foxp3(+) T-cell subpopulations in chronic HBV patients were identified, and their frequencies associated with clinical parameters were analyzed. Antigen specificity of Tregs was further studied. We found that circulating and intrahepatic CD4(+)CD45RA(-)Foxp3(hi)-activated Tregs (aTregs) were selectively increased in patients with chronic active hepatitis B and acute-on-chronic liver failure (ACLF) but not in asymptomatic carriers. The aTreg frequency was strongly correlated with HBV DNA load but not liver damage. In both peripheral blood mononuclear cells and livers, ACLF patients showed a dramatically elevated frequency of interleukin 17A-secreting CD45RA(-)Foxp3(lo) nonsuppressive T cells (non-Tregs), which were shown to be associated with severe liver damage. Interestingly, an HBV core antigen (HBcAg)-derived peptide could preferentially expand CD4(+)CD25(+)Foxp3(+) T cells and aTregs in HLA-DR9(+) chronic active hepatitis B patients, and these Tregs required ligand-specific reactivation for suppressor function. The delineation of a CD4(+)Foxp3(+) T-cell subpopulation is a highly informative strategy for distinguishing different chronic HBV infection states. HBcAg-derived peptides may be responsible for activation of Tregs that, in turn, specifically inhibit anti-HBV immune response but not liver inflammation.
Li, Yijia; Zhu, Ting; Song, Xiaojing; Huang, Ying; Yang, Feifei; Guan, Shuo; Xie, Jing; Gohda, Jin; Hosoya, Noriaki; Kawana-Tachikawa, Ai; Liu, Wenjun; Gao, George Fu; Iwamoto, Aikichi; Li, Taisheng; Ishida, Takaomi
In China, HIV-1-infected patients typically receive antiretroviral therapy (ART) that includes lamivudine (3TC) as a reverse-transcriptase inhibitor (RTI) (ART-3TC). Previous studies from certain developed countries have shown that, in ART-3TC, 3TC-resistant HBV progressively emerges at an annual rate of 15–20% in patients coinfected with HIV-1 and HBV. This scenario in China warrants investigation because >10% of all HIV-infected patients in China are HBV carriers. We measured the occurrence of 3TC-resistant HBV during ART-3TC for HIV-HBV coinfection and also tested the effect of tenofovir disoproxil fumarate (TDF) used as an additional RTI (ART-3TC/TDF) in a cohort study in China. We obtained 200 plasma samples collected from 50 Chinese patients coinfected with HIV-1 and HBV (positive for hepatitis B surface antigen) and examined them for the prevalence of 3TC-resistant HBV by directly sequencing PCR products that covered the HBV reverse-transcriptase gene. We divided the patients into ART-3TC and ART-3TC/TDF groups and compared the efficacy of treatment and incidence of drug-resistance mutation between the groups. HIV RNA and HBV DNA loads drastically decreased in both ART-3TC and ART-3TC/TDF groups. In the ART-3TC group, HBV breakthrough or insufficient suppression of HBV DNA loads was observed in 20% (10/50) of the patients after 96-week treatment, and 8 of these patients harbored 3TC-resistant mutants. By contrast, neither HBV breakthrough nor treatment failure was recorded in the ART-3TC/TDF group. All of the 3TC-resistant HBV mutants emerged from the cases in which HBV DNA loads were high at baseline. Our results clearly demonstrated that ART-3TC is associated with the emergence of 3TC-resistant HBV in patients coinfected with HIV-1 and HBV and that ART-3TC/TDF reduces HBV DNA loads to an undetectable level. These findings support the use of TDF-based treatment regimens for patients coinfected with HIV-1 and HBV. PMID:26288093
van Dommelen, Laura; Verbon, Annelies; van Doorn, H Rogier; Goossens, Valère J
We present a case of a clinical manifest hepatitis B virus infection and a potentially misleading HBV serological profile in an HIV-1 positive patient despite previous HBV vaccination. The patient presented with an acute hepatitis B and there was no indication of chronic HBV infection or the presence of a mutation in the 'a' determinant. Remarkably, simultaneously with high HBV surface antigen and HBV viral load, high anti-HBs antibodies were present. If, due to previous HBV vaccination only anti-HBs was tested in this patient, the result of the high anti-HBs antibodies could be very misleading and offering a false sense of security. Our findings contribute to the ongoing discussion on how to assess HBV specific immunological memory and determining the role of HBV booster vaccinations in immunocompromised individuals.
Rapicetta, M.; di Nardo, V.; Rozera, C.; Marinucci, G.; Francisci, D.; Sarrecchia, B.; Ricci, C.; Albertoni, F.
A population of 488 HBsAg carrier individuals, from central Italy, classified on the basis of biochemical, clinical and histological parameters, was analysed for the presence of HBV-DNA in serum and its relationship with HBeAg/anti-HBe markers. The prevalence of HBV-DNA was 32.8% in chronic patients with biopsy-proven liver disease, and 20 and 4.3% respectively in asymptomatic carriers with and without altered ALT levels. The values in chronic patients were correlated with the histological activity. Concordance of HBV-DNA presence and HBeAg positivity was observed in only 61.4% of cases. However HBV-DNA prevalence in sera of anti-HBe positive individuals was very low in asymptomatic carriers with normal ALT levels (2.5%). Higher values were observed in anti-HBe positive chronic patients (15.8%) and in carriers occasionally found with changes in ALT without any other clinical sign of illness (16.7%). These data would indicate that HBV-DNA is the serological marker which is most closely related to liver disease. PMID:2347388
Sarvari, Jamal; Mojtahedi, Zahra; Kuramitsu, Yasuhiro; Malek‑Hosseini, Seyed-Ali; Shamsi Shahrabadi, Mahmoud; Ghaderi, Abbas; Nakamura, Kazuyuki
The three main complications of hepatitis B virus (HBV) infection are chronic active hepatitis (CAH), liver cirrhosis, and hepatocellular carcinoma (HCC). The aim of this study was to identify differentially expressed serum proteins among the three liver complications in patients with HBV infection. Differentially expressed proteins have been shown to be potential biomarkers for disease diagnosis, prognosis and therapy guidance. Two-dimensional polyacrylamid gel electrophoresis (2DE) combined with liquid chromatography tandem mass spectrometry (LC-MS/MS) was performed on sera from CAH, cirrhosis and HCC patients with HBV infection, as well as those obtained from healthy individuals. Of 54 differentially expressed (≥1.5-fold and p<0.05) protein spots, 35 spots were identified by LC-MS/MS. The identified spots correlated to 13 proteins. The proteins included haptoglobolin α-2 and β isoforms, haptoglobin cleaved β isoforms, retinol-binding protein, transthyretin, ficolin, leucine-rich-α-2-glycoprotein, α-1-antitrypsin and clusterin. Of particular interest is the significant increase of haptoglobin α-2 isoforms in HCC patients compared to cirrhosis ones. In contrast, a significant decrease of the isoforms was noted among cirrhosis patients. PMID:22866143
McMahon, Brian J; Bulkow, Lisa; Simons, Brenna; Zhang, Yuhong; Negus, Susan; Homan, Chriss; Spradling, Philip; Teshale, Eyasu; Lau, Daryl; Snowball, Mary; Livingston, Stephen
In a population-based cohort of Alaska Native persons with chronic HBV infection who were HBeAg-negative, we aimed to determine the prevalence of immune active HBV infection over time and to determine the relationship between demographic and viral factors on severity of disease on liver biopsy. We examined 777 patients infected with five HBV genotypes (A2, B6, C2, D2/3, F1). Alanine aminotransferase (ALT) measurements were assessed every 6 months during an 8-year period. HBV DNA levels were performed at baseline in 2001 and whenever ALT levels exceeded the upper limit of normal (ULN). Immune active chronic HBV infection was defined as an ALT >30 U/L men, >20 U/ml women and HBV DNA >2,000 IU/ml during one or more times from 2001 and 2008. Liver biopsies were scored using the modified hepatic activity index score (HAI) of Knodell and the Ishak fibrosis score. A total of 201 (26%) patients met the criteria for immune active HBV. HBV genotype D was less likely to be associated with immune active hepatitis than the other 4 genotypes. Of the 46 patients with liver biopsy results, none of the 15 patients with ALT always below twice the ULN and only 2/19 of those with HBV DNA between 2,000 and 20,000 IU/ml had moderate or severe hepatitis, or moderate or severe fibrosis. In contrast, 18(58%) of 31 with ALT ≥ twice ULN, and 16 (62%) of 26 with one or more HBV DNA levels > 20,000 IU/ml had moderate to severe fibrosis scores (p<0.001). Conclusion Of participants, 26% met criteria for immune active HBV. An HBV DNA level of > 20,000 IU/ml was strongly correlated with persons meeting the current guidelines for antiviral therapy. PMID:24035774
Cañero-Velasco, M C; Mutti, J E; Gonzalez, J E; Alonso, A; Otegui, L; Adragna, M; Antonuccio, M; Laso, M; Montenegro, M; Repetto, L; Brandi, M; Canepa, J; Baimberg, E
Hemodialized pediatric patients are a risk population for the hepatitis B and C virus infection. The aim of this paper was to study the serum prevalence of HBV and HCV infection in hemodialized children. We study 61 pediatric patients at hemodialisis, 12 on renal transplant, range between 2 and 20 years old (mean: 12.9 years), 23 male and 38 female. The specific anti-HCV IgC were measured by enzyme immunoassay (ELISA Abbott) and confirmed by LIA-TEK (Organon). The anti-HBV were measured by ELISA Abbott and transaminases by cinetic method (ASAT: 29 UI/L and ALT: 33 UI/L). The 19.7% of studied children were HCV (+) and 29.5% were HBV (+), 38.9% of them were HbsAg (+) and 50% anti-HBs (+). The HCV and HBV infection was more elevated in relation to the transfusion number and the hemodilisis time. The elevation of ALT/ASAT activity isn't a right infection index for HCV and HBV in this children.
Fu, Sha; Li, Ning; Zhou, Peng-Cheng; Huang, Yan; Zhou, Rong-Rong; Fan, Xue-Gong
Hepatitis B virus (HBV) markers include HBV deoxyribonucleic acid (DNA) and HBV antigens. The former involves HBV covalently closed circular DNA (cccDNA) as well as total HBV DNA, whereas the latter involves HBsAg, HBcAg, and HBx. Samples of tumor and adjacent non-tumor liver tissue were collected from 28 HBV-associated HCC patients. Intrahepatic total HBV DNA and cccDNA were measured using the real-time PCR Taqman assay. HBV antigens in hepatocytes were detected using immunohistochemical staining. Intrahepatic levels of total HBV DNA or cccDNA in HCC patients with different intrahepatic HBV antigen expression patterns were compared, and the correlation between serum HBV DNA and intrahepatic HBV DNA was analyzed. No significant differences in intrahepatic cccDNA levels were observed between tumor and non-tumor liver tissue (median -3.00 vs. -2.30 log copies/cell, P=0.298). However, the tumor tissue had significantly higher levels of total HBV DNA (median -0.60 vs. -1.24 log copies/cell, P=0.045) but significantly lower proportion of intrahepatic HBV DNA in the form of cccDNA (median 0.25% vs. 4%, P=0.023) than the corresponding values in the non-tumor tissue. Also, HBV antigen levels were lower in the tumor tissue than in the non-tumor tissue. Analysis of the correlation between serum HBV DNA and intrahepatic HBV DNA indicated that the viral status in the tumor tissue was more complicated in HBV-HCC patients-the detected serum HBV DNA failed to accurately reflect intrahepatic viral load. HBV DNA may play an important role in hepatocarcinogenesis, and cccDNA was not the predominant form of HBV DNA in the tumor tissue. Copyright © 2017 Elsevier Masson SAS. All rights reserved.
Park, Jang-June; Wong, David K.; Wahed, Abdus S.; Lee, William M.; Feld, Jordan J.; Terrault, Norah; Khalili, Mandana; Sterling, Richard K.; Kowdley, Kris V.; Bzowej, Natalie; Lau, Daryl T.; Kim, W. Ray; Smith, Coleman; Carithers, Robert L.; Torrey, Keith W.; Keith, James W.; Levine, Danielle L.; Traum, Daniel; Ho, Suzanne; Valiga, Mary E.; Johnson, Geoffrey S.; Doo, Edward; Lok, Anna S. F.; Chang, Kyong-Mi
Background & Aims T cells play a critical role in in viral infection. We examined whether T-cell effector and regulatory responses can define clinical stages of chronic hepatitis B (CHB). Methods We enrolled 200 adults with CHB who participated in the NIH-supported Hepatitis B Research Network from 2011 through 2013 and 20 uninfected individuals (controls). Peripheral blood lymphocytes from these subjects were analyzed for T-cell responses (proliferation and production of interferon-γ and interleukin-10) to overlapping hepatitis B virus (HBV) peptides (preS, S, preC, core, and reverse transcriptase), influenza matrix peptides, and lipopolysaccharide. T-cell expression of regulatory markers FOXP3, programmed death-1 (PD1), and cytotoxic T lymphocyte-associated antigen-4 (CTLA4) was examined by flow cytometry. Immune measures were compared with clinical parameters, including physician-defined immune-active, immune-tolerant, or inactive CHB phenotypes, in a blinded fashion. Results Compared to controls, patients with CHB had weak T-cell proliferative, interferon-γ, and interleukin-10 responses to HBV, with increased frequency of circulating FOXP3+CD127− regulatory T cells and CD4+ T-cell expression of PD1 and CTLA4. T-cell measures did not clearly distinguish between clinical CHB phenotypes, although the HBV core-specific T-cell response was weaker in HBeAg+ than HBeAg− patients (% responders: 3% vs 23%, P=.00008). Although in vitro blockade of PD1 or CTLA4 increased T-cell responses to HBV, the effect was weaker in HBeAg+ than HBeAg− patients. Furthermore, T-cell responses to influenza and lipopolysaccharide were weaker in CHB patients than controls. Conclusion HBV persists with virus-specific and global T-cell dysfunction mediated by multiple regulatory mechanisms including circulating HBeAg, but without distinct T-cell–based immune signatures for clinical phenotypes. These findings suggest additional T-cell independent or regulatory mechanisms of CHB
Sarkar, Jayeeta; Saha, Debraj; Bandyopadhyay, Bhaswati; Saha, Bibhuti; Kedia, Deepika; Guha Mazumder, D.N.; Chakravarty, Runu; Guha, Subhasish Kamal
Background & objectives: Hepatitis B virus (HBV) and HIV co-infection has variable prevalence worldwide. In comparison to HBV mono-infection, the course of chronic HBV infection is accelerated in HIV/HBV co-infected patients. The present study was carried out to analyse the baseline characteristics (clinical, biochemical, serological and virological) of treatment naïve HIV/HBV co-infected and HIV mono-infected patients. Methods: Between July 2011 and January 2013, a total number of 1331 HIV-seropositive treatment naïve individuals, enrolled in the ART Centre of Calcutta School of Tropical Medicine, Kolkata, India, were screened for hepatitis B surface antigen (HBsAg). A total of 1253 HIV mono-infected and 78 HIV/HBV co-infected patients were characterized. The co-infected patients were evaluated for HBeAg and anti-HBe antibody by ELISA. HIV RNA was quantified for all co-infected patients. HBV DNA was detected and quantified by real time-PCR amplification followed by HBV genotype determination. Results: HIV/HBV co-infected patients had proportionately more advanced HIV disease (WHO clinical stage 3 and 4) than HIV mono-infected individuals (37.1 vs. 19.9%). The co-infected patients had significantly higher serum bilirubin, alanine aminotransferase (ALT), alkaline phosphatase and ALT/platelet ratio index (APRI). CD4 count was non-significantly lower in co-infected patients. Majority (61.5%) were HBeAg positive with higher HIV RNA (P<0.05), HBV DNA (P<0.001) and APRI (P<0.05) compared to those who were HBeAg negative. HBV/D was the predominant genotype (73.2%) and D2 (43.7%) was the commonest subgenotype. Interpretation & conclusions: HIV/HBV co-infected patients had significantly higher serum bilirubin, ALT, alkaline phosphatase and lower platelet count. HBeAg positive co-infected patients had higher HIV RNA and HBV DNA compared to HBeAg negative co-infected patients. Prior to initiation of antiretroviral treatment (ART) all patients should be screened for HBsAg to
Huang, Yi-Jie; Chang, Chi-Sen; Yeh, Hong-Zen; Yang, Sheng-Shun
Background & aims Virological breakthrough (VBT) could be a manifestation of chronic hepatitis B (CHB) in patients treated with long-term nucleot(s)ide analogues. We aimed to determine the association of on-treatment serum hepatitis B virus (HBV) DNA with VBT in HBeAg-positive CHB patients receiving entecavir (ETV) treatment. Methods A retrospective cohort study, including 162 consecutive patients (95 men and 67 women; mean age, 43.1±13.4 years) with HBeAg-positive CHB treated with ETV for at least 48 weeks between August 2008 and May 2015, was conducted. Univariate and multivariate cox regression analysis were used to identify associations with VBT and clinical factors, including HBV DNA and HBeAg serum status. Results Among the 162 ETV-treated HBeAg-positive CHB patients, eighteen patients (11.1%) experienced VBT (VBT group), whereas the other 144 patients were without VBT (non-VBT group). The cumulative rate of HBV DNA < 100 IU/mL in the VBT group and the non-VBT group at week 48 were 44.44% and 70.14%, and at week 96 were 58.33% and 92.56%, respectively (p = 0.015). The cumulative rate of HBeAg seroclearance in the VBT group and non-VBT group at week 48 and week 96 were statistically significant (p = 0.014). Multivariate analysis disclosed that failure to achieve HBeAg seroclearance were the factors significantly associated with VBT. Conclusions Our results demonstrated that on-treatment HBV DNA could probably predict VBT in ETV-treated HBeAg-positive chronic hepatitis B patients. Failure to achieve HBeAg seroclearance was associated with VBT in ETV-treated HBeAg-positive CHB patients. HBV DNA >100IU/mL at 48 weeks is potentially a predictor for VBT. PMID:28350873
Tang, Shengli; Liu, Zhisu; Zhang, Yongxi; He, Yueming; Pan, Dingyu; Liu, Yuanyuan; Liu, Quanyan; Zhang, Zhonglin; Yuan, Yufeng
Interleukin-6 plays an important role in chronic inflammation as well as tumor growth and progression. Here, a case-control study was undertaken to investigate the association of rs1800796 polymorphism of IL-6 gene and serum levels with disease progression of chronic HBV infection. Rs1800796 polymorphism was genotyped in 641 Chinese Han patients with chronic HBV infection, including 23 IT, 25 IC, 292 CHB, 153 LC, and 148 HCC patients and 265 healthy controls. Serum IL-6 levels were measured in 23 IT, 25 IC, 47 CHB, 41 LC, and 49 HCC patients and 45 healthy controls, and the classifications of HCC were accorded to BCLC staging system. We found no significant association between rs1800796 polymorphism and disease progression of chronic HBV infection; however, serum IL-6 levels showed significant statistical differences between patients with CHB, LC, and HCC. Moreover, statistical differences can be observed in patients with terminal stage HCC compared with those of early to intermediate or advanced stage HCC. Our findings suggest that rs1800796 polymorphism unlikely contribute significantly to affect the progression of chronic HBV infection, and serum IL-6 levels can act as a useful indicator for disease progression and severity of chronic HBV infection. PMID:24371367
Qiu, Hai-Bo; Zhang, Li-Yi; Zeng, Zhao-Lei; Wang, Zhi-Qiang; Luo, Hui-Yan; Keshari, Rajiv Prasad; Zhou, Zhi-Wei; Xu, Rui-Hua
AIM: To evaluate the effect of hepatitis B virus (HBV) infection on liver metastasis of colorectal cancer. METHODS: A total of 1298 colorectal cancer patients were recruited from January 2001 to March 2005 in this study. Enzyme-linked immunosorbent assay was used to test serum HBV markers for colorectal cancer. Patients were divided into study (infection) group and control (non-infection) group. Clinical features of patients in two groups were compared. RESULTS: Liver metastasis was found in 319 out of the 1298 colorectal cancer patients. The incidence of liver metastasis was significantly lower in study group than in control group (14.2% vs 28.2%, P < 0.01). HBV infection significantly decreased the risk of liver metastasis [hazard ratio (HR): 0.50, 95% confidence interval (95% CI): 0.38-0.66], but the incidence of extrahepatic metastasis was significantly higher in study group than in control group (31.9% vs 17.0%, P < 0.01). The HR was the lowest in chronic hepatitis B group (HR: 0.29, 95% CI: 0.12-0.72). The number of liver metastatic lesions was significantly less in study group than in control group with a higher surgical resection rate. However, no significant difference was found in survival rate between the two groups (P = 0.95). CONCLUSION: HBV infection decreases the risk of liver metastasis in patients with colorectal cancer and elevates the surgical resection rate of liver metastatic lesions. PMID:21390153
Wang, Jing; Yu, Yiqi; Li, Guojun; Shen, Chuan; Meng, Zhefeng; Zheng, Jianming; Jia, Yanhong; Chen, Shaolong; Zhang, Xiao; Zhu, Mengqi; Zheng, Jiangjiang; Song, Zhangzhang; Wu, Jing; Shao, Lingyun; Qian, Peiyu; Mao, Xiaona; Wang, Xuanyi; Huang, Yuxian; Zhao, Caiyan; Zhang, Jiming; Qiu, Chao; Zhang, Wenhong
In diagnostics, serum hepatitis B virus (HBV)-RNA levels are valuable when the HBV-DNA load in circulation is effectively suppressed by nucleos(t)ide analogue (NUC) therapy. This study aimed to determine the intrahepatic viral replication activity reflected in serum HBV-RNA and whether HBV-RNA contributes to liver histological changes in patients treated with NUC. A cross-sectional set of serum and liver biopsy samples was obtained from patients treated with entecavir, who had undetectable levels of serum HBV-DNA. The correlations between serum HBV-RNA concentration and levels of peripheral and intrahepatic viral replicative forms, as well as histological scores, were analyzed. Quasispecies of serum HBV-RNA and intrahepatic viral replicative forms were examined by deep sequencing. HBV-RNA-positive hepatocytes were visualized by in situ hybridization. Serum HBV-RNA was detected in 35 of 47 patients (74.47%, 2.33-4.80log10copies/ml). These levels correlated not only with the intrahepatic HBV-RNA level and the ratio of intrahepatic HBV-RNA to covalently closed circular DNA (cccDNA), but also with the histological scores for grading and staging. Regarding quasispecies, serum HBV-RNA was dynamic and more genetically homogenous to simultaneously sampled intrahepatic HBV-RNA than to the cccDNA pool. In situ histology revealed that HBV-RNA-positive hepatocytes were clustered in foci, sporadically distributed across the lobules, and co-localized with hepatitis B surface antigen. Serum HBV-RNA levels reflect intrahepatic viral transcriptional activity and are associated with liver histopathology in patients receiving NUC therapy. Our study sheds light on the nature of HBV-RNA in the pathogenesis of chronic HBV infection and has implications for the management of chronic hepatitis B during NUC therapy. Serum HBV-RNA levels are indicative of the intrahepatic transcriptional activity of covalently closed circular DNA and are associated with liver histological changes in
Kim, Beom Kyung; Revill, Peter A; Ahn, Sang Hoon
Although chronic HBV infection is the leading cause of chronic liver disease and death worldwide, there are substantial differences in its clinical courses regarding prevalence, mode of transmission, characteristics of each phase, responses to antiviral therapy, and development of cirrhosis and hepatocellular carcinoma, according to geographical areas (Asia versus Western Europe and North America versus Africa). Furthermore, the clinical course in infected individuals depends on a complex interplay among various factors including viral, host, environmental and other factors. Recently, understanding of molecular characteristics of the prevailing HBV genotypes, frequently accompanied mutations and their clinical implications might explain these geographical differences more pertinently. Hence, in this article, we review the global epidemiology and the natural history of HBV infection, with emphasis on summarizing the different HBV genotypes according to regions.
Song, Guangjun; Yang, Ruifeng; Rao, Huiying; Feng, Bo; Ma, Hui; Jin, Qian; Wei, Lai
Early prediction of spontaneous hepatitis B virus e antigen (HBeAg) seroconversion is pivotal in the prevention of unnecessary drug prescription, corresponding financial burden, and adverse reactions. One hundred and thirteen chronic hepatitis B patients with HBeAg-positive in the immune active phase were followed up for about 1.5 years. Patients were classified into two groups: spontaneous HBeAg seroconversion group (group A, n = 18) and non-spontaneous HBeAg seroconversion group. Among the non-spontaneous HBeAg seroconversion group, 35 patients were selected as controls (group B, n = 35). At week 12, there was a significant difference in hepatitis B core-related antigen (HBcrAg) levels between the two groups (group A 4.32 ± 1.05 log10 kU/ml, and group B 5.16 ± 0.53 log10 kU/ml, P = 0.004), and this significance magnified at week 28. Only two variables, HBcrAg level and the reduction in the HBcrAg levels (ΔHBcrAg) at week 28 were enrolled, with the odds ratio of 4.19 and 0.21, respectively. The optimal cutoffs of HBcrAg levels and the ΔHBcrAg at week 28 were 4.90 and 2.00 log10 kU/ml, respectively. The positive predictive value and negative predictive value of HBcrAg levels at week 28 were 73.9% and 96.7%, respectively. The positive predictive value and negative predictive value of the ΔHBcrAg at week 28 were 76.2% and 93.8%, respectively. The measurement of HBcrAg is useful for monitoring the natural course of chronic hepatitis B virus infection. The dynamics of HBcrAg levels could accurately predict the spontaneous HBeAg seroconversion. J. Med. Virol. 89:463-468, 2017. © 2016 Wiley Periodicals, Inc.
Many HBsAg-positive/HBeAg-negative patients show normal alanine aminotransferase levels. However, in this group of patients two different virological and clinical subsets do exist: inactive HBV carriers and patients with chronic hepatitis B with transient virological and biochemical remission. Natural history and outcome, severity of liver damage and need for liver biopsy and antiviral treatment differ significantly between these groups of patients. It is not always easy to distinguish between inactive HBV carriers and patients suffering from HBeAg-negative chronic hepatitis with transient disease remission, as they share similar biochemical (normal serum ALT values) and virological (HBeAg negativity and low HBV DNA levels) features. In clinical practice, it is very important to differentiate inactive carriers from patients with chronic hepatitis B with spontaneous transient remission, as the former have a good prognosis with a very low risk of complications, while the latter have active liver disease with a high risk of progression to advanced hepatic fibrosis, cirrhosis and hepatocellular carcinoma. Thus, a careful assessment and adequate follow-up periods are needed. The aim of this review, written in the form of a dialog between a hepatologist and a newly diagnosed patient with HBV infection and normal alanine aminotransferase levels, is to give evidence-based suggestions for the management in clinical practice of HBsAg patients, on the basis of more recent international guidelines, covering many aspects of the condition, including advice on lifestyle and vaccination, indications for liver biopsy and treatment, the types and side effects of treatment and treatment endpoints. Copyright © 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Shi, M; Qian, S; Chen, W-W; Zhang, H; Zhang, B; Tang, Z-R; Zhang, Z; Wang, F-S
To investigate whether hepatitis B virus (HBV) antigen-pulsed monocyte-derived dendritic cells (MoDC) could mount a T cell response in hepatocellular carcinoma (HCC) patients associated with chronic HBV infection, peripheral blood mononuclear cells (PBMCs) from 36 HBV-associated HCC patients were induced into MoDC and pulsed with hepatitis B core antigen (HBcAg) and hepatitis B surface antigen (HBsAg), alone and in combination. Co-stimulatory molecules CD80, CD86 and CD40, as well as human leucocyte antigens D-related (HLA-DR) were found to express at the highest level on MoDC pulsed with HBcAg or HBsAg + HBcAg, at a median level on MoDC pulsed with HBcAg or HBsAg alone, and at the lowest level on non-antigen-pulsed MoDC. Interleukin (IL)-10 and IL-12 cytokines were released by antigen-pulsed MoDC at increased levels in the order: no-antigen < HBsAg < HBcAg < HBcAg + HBsAg. MoDC pulsed with HBcAg or HBsAg + HBcAg also had the strongest ability to stimulate autologous T cell proliferation and intracellular interferon (IFN)-gamma production. HBcAg- or HBsAg + HBcAg-pulsed MoDC could also induce HBV core peptide-specific CD8(+) T cell proliferation determined by tetramer staining. In addition, the antigen-pulsed MoDC were found to have a stronger capacity to produce IL-12 and induce T cell response in vitro for patients with higher alanine transaminase (ALT) levels than those with lower ALT levels, indicating that antigen pulse could substantially reverse the impaired function of MoDC in primary HCC patients with active chronic hepatitis B. In conclusion, HBV antigen-pulsed MoDC from HCC patients with chronic hepatitis B could induce HBV-specific T cell response in vitro.
Manna, Kalyan; Chakrabarty, Siddhartha P.
We analyze the dynamics of chronic HBV infection taking into account both uninfected and infected hepatocytes along with the intracellular HBV DNA-containing capsids and the virions. While previous HBV models have included either the uninfected hepatocytes or the intracellular HBV DNA-containing capsids, our model accounts for both these two populations. We prove the conditions for local and global stability of both the uninfected and infected steady states in terms of the basic reproduction number. Further, we incorporate a time lag in the model to encompass the intracellular delay in the production of the infected hepatocytes and find that this delay does not affect the overall dynamics of the system. The results for the model and the delay model are finally numerically illustrated.
Ren, Shan; Yu, Haibin; Zhang, Hongwei; Liu, Ying; Huang, Yanxiang; Ma, Lina; Wei, Lai; Wu, Hao; Chen, Xinyue
To evaluate the role of host single nucleotide polymorphisms (SNPs) of 2',5'-oligoadenylate synthetase (OAS) in predicting IFN response in patients with HBV infection, OAS gene and four SNPs were examined in 363 patients with chronic HBV infection (including 41 patients with HBsAg seroconversion) and 57 healthy controls. One SNP and three haplotypes were identified after adjustment for age, sex, HBV DNA. The frequency of OAS3T/C heterozygotes is 52.2% in responders (R) and 38.2% in non-responders (NR), with an odds ratio (OR) of 1.511 (P = 0.018). For complete responders (CR) and NR, the OR reached 2.323(P = 0.023). Haplotype analyses revealed significant association between three OAS haplotypes and response to IFN-α treatment. Genotype combination and interaction between gene-gene analyses disclosed that there was a positive interaction between OAS2/OAS3 and OAS3/OASL, and the rate of OR was 2.46 (likelihood test, P = 0.004) and 4.46 (likelihood test, P = 0.004), respectively. Our results suggest that OAS gene variations may play an important role in response to IFN-α and provide a novel strategy for the resolution of HBV infection.
Villa, Erica; Fattovich, Giovanna; Mauro, Antonella; Pasino, Michela
The evaluation of the natural history of chronic hepatitis B virus (HBV) infection requires the precise definition of the various clinical conditions that can be encountered (i.e. inactive carrier state or subject with liver disease activity). This can be achieved by repeat monitoring of ALT, serum HBV-DNA levels (over a period of at least 1 year, according to international guidelines) and/or evaluation of HBsAg titre. Liver biopsy may offer additional information although it is not mandatory. Overall, the natural history of the true inactive carrier is benign: reactivation of hepatitis, especially in Western countries, is rare and is usually due to co-factors (like alcohol or drugs); spontaneous HBsAg loss is frequent (around 1% per year) and HCC development rare. On the other hand, in patients with chronic hepatitis B or cirrhosis, the risk of reactivation, of HCC development and of liver-related mortality is much higher, especially in Eastern countries, and should therefore lead to antiviral therapy. Copyright Â© 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd.. All rights reserved.
Kowazaki, Yuka; Osawa, Yosuke; Imamura, Jun; Ohashi, Kazuteru; Sakamaki, Hisashi; Kimura, Kiminori
Patients with resolved hepatitis B virus (HBV) infection undergoing chemo- or immunosuppressive therapy are at potential risk for HBV reactivation. To determine whether the host immune response contributes to liver injury, we performed an immunological analysis of a patient with HBV reactivation. Consistent with the detection of HBV DNA in the sera, the number of polyclonal HBV-specific cytotoxic T lymphocytes (CTLs) gradually increased; however, the number of CD4(+)CD25(+) regulatory T cells (Treg) decreased. The interaction between HBV-specific CTLs and CD4(+)CD25(+) Treg is an important determinant of liver injury during HBV reactivation. Therefore, monitoring the number of these cells might be a useful modality for the diagnosis of acute hepatitis resulting from HBV reactivation.
Eschlimann, Marine; Malvé, Brice; Velay, Aurélie; Fenaux, Honorine; Berger, Sibel; Frippiat, Jean-Pol; Zoulim, Fabien; Bensenane, Mouni; Bronowicki, Jean-Pierre; Goehringer, François; May, Thierry; Jeulin, Hélène; Schvoerer, Evelyne
More than 240 million people are chronically infected by hepatitis B virus (HBV) worldwide. Envelope proteins play a crucial role in viral cellular entry and immune recognition. The loss of HBs antigen (HBsAg) correlated with a good clinical prognosis is rarely achieved with or without treatment (3-16%). HBV envelope variability was investigated according to HBsAg persistence. The cohort consisted of 15 HBV genotype A-infected patients divided into "resolvers", with HBsAg clearance, and "non-resolvers", with HBsAg persistence and in subgroups: acute (n=5, AHBV) or chronic infection (n=4, CHBV) and HBV/HIV coinfection (n=6, CHBV/HIV). HBV S and preS sequences were studied by direct and ultra-deep sequencing. Amino acid sequences were analyzed with bioinformatics for predicted antigenicity. In S gene, the complexity was lower in AHBV than in chronic-infected patients (p=0.046). Major mutations, detected using direct sequencing, were more frequent in AHBV developing chronicity (p=0.01) than in AHBV resolvers. In the Major Hydrophilic Region, more frequent mutations were observed in non-resolvers versus resolvers (p=0.047) and non-resolvers tended to have more haplotypes with a reduced predicted antigenicity (p=0.07). Most of the mutations in preS/S region were found rather in epitopic than in non-epitopic areas (p=0.025). Interestingly, the mutation sY161F found in 3/8 non-resolvers was associated with a decrease in predicted antigenicity (28%; AnTheProt). HBsAg persistence was correlated with mutations and deletions in areas playing a key role in immune recognition. These data suggest that variability in HBV envelope could favor immune escape in various clinical settings of HBV genotype A-infected patients. Copyright © 2017 Elsevier B.V. All rights reserved.
Amponsah-Dacosta, Edina; Rakgole, J Nare; Gededzha, Maemu P; Lukhwareni, Azwidowi; Blackard, Jason T; Selabe, Selokela G; Mphahlele, M Jeffrey
Reports on the concomitant impact of HIV co-infection and long term highly active anti-retroviral therapy (HAART) on the genetic stability and molecular evolution of HBV are limited in sub-Saharan Africa. This retrospective study investigated the molecular evolution of chronic HBV in HIV co-infected patients on lamivudine (3TC)-based HAART over a 5year period. Four HIV co-infected patients, consecutively recruited and followed-up, were screened for hepatitis B serological markers, and their viral loads determined. The HBV genome was amplified from longitudinal samples and characterized by Bayesian inference, mutational analysis, and identification of immune selection pressure. All patients exhibited persistent chronic HBV infection at baseline, as well as over the course of follow-up despite exposure to 3TC-based HAART. The polymerase gene in all isolates was relatively variable prior to HAART initiation at baseline and during the course of follow-up, although primary drug resistance mutations were not detected. All but one patient were infected with HBV subgenotype A1. The divergence rates between baseline and the last follow-up sequences ranged from 0 to 2.0×10(-3) substitutions per site per year (s/s/y). Positive selection pressure was evident within the surface and core genes. Despite persistent HBV infection in the HIV co-infected patients exposed to long term 3TC-based HAART, the molecular evolution of HBV over a 5year period was unremarkable. In addition, HBV exhibited minimal genetic variability overtime. Copyright © 2016 Elsevier B.V. All rights reserved.
León, Bernal; Taylor, Lizeth; Vargas, Minor; Luftig, Ronald B; Albertazzi, Federico; Herrero, Libia; Visona, Kirsten
Background Around 400 million people worldwide are chronically infected with Hepatitis B virus (HBV). An estimated 10% of these chronic patients develop progressive liver damage including cirrhosis and Hepatocellular Carcinoma (HCC). The HBx gene encodes a protein of 154 amino acids which is a transactivator and has been associated with HBV pathogenesis. A change in the amino acid sequences at positions 130 and 131 in the HBV-X protein (M130K and V131I) produced by T-A point mutations at the nucleic acids level has been associated with severe liver damage and HCC in patients from China and Africa. Further, such changes have been proposed as a prognostic marker for progressive liver damage and HCC. The purpose of this study was to determine if T-A mutations are present in HBV chronic carriers with genotype F (the major genotype in Costa Rica) and further, if these mutations are associated with HBV disease progression in Costa Rica HBV patients from 1972 to 1985. Results Serum samples from 50 HBV positive individuals were amplified and directly sequenced, 48 belonged to genotype F, 1 from genotype D and another was classified as D or E. T-;A mutations were absent in 17 acute patients who recovered, but was present in 12 of 29 chronic carrier samples (42.8%), in one sample the T-A mutations were detected as early as 29 days after clinical onset of disease. In 17 carriers with available liver biopsies, T-;A mutations were found in 8 sera of 13 (61.5%) classified as moderate or severe, and none in 4 biopsies with mild liver damage. However, it was not possible to demonstrate a statistical association between the presence of T-A mutations and moderate/severe liver damage, using a Fischer exact test, 1 tail, p = 0.05. In 4 patients HCC was diagnosed, and 2 of them presented the T-A mutations in their sera. Conclusion T-A mutations were found in HBV genotype F in chronic carriers but not in patients who recovered from acute infection. These mutations could be developing
Santos, Eneida A; Sucupira, Michel VF; Arabe, Juçara; Gomes, Selma A
Background Lamivudine inhibits replication of both human immunodeficiency virus (HIV) and hepatitis B virus (HBV) and is commonly used as part of antiretroviral therapy. The main limitation in the use of lamivudine is resistant mutation selection. Most of these mutations affect the YMDD motif of the HBV DNA polymerase. The resistance occurs through M550V or M550I aminoacid replacements. The M550V variation may be accompanied by L526M mutation, notably in HIV-HBV co-infected patients. The aim of this study was to investigate mutations associated with lamivudine resistance in a hemodialysis patient chronically co-infected with HIV-1 and HBV, who was submitted to several antiretroviral treatments. Methods HBV isolates derived from three blood samples collected at different times of antiretroviral therapies with and without lamivudine, were titred and submitted to nucleotide sequencing. Results HBV isolate derived from a sample collected in 1999 during an antiretroviral treatment with lamivudine showed the lamivudine resistant double mutation (L526M, M550V). However, no mutation associated with lamivudine resistance was observed in the HBV genome derived from the sample collected during a period of treatment without lamivudine (2001). After reinstitution of lamivudine (2002), the predominant HBV population exhibited a rare triple mutation (V519L, L526M, M550V), which has previously been associated with an in vitro reduction of virus antigenicity (escape mutant). HBV DNA was detected at high levels (108–109 copies/ml) in the three blood samples. Conclusions Reintroduction of lamivudine as part of antiretroviral treatment in a patient who had developed lamivudine resistant HBV strains favored the predominance of an HBV isolate with reduced antigenicity. The absence of hepatitis acute exacerbation in this patient may be correlated to the absence of significant variations of the viral load, which was independent of the presence of mutations in the HBV DNA polymerase
Li, Zhonghu; Zhao, Xin; Jiang, Peng; Xiao, Senlin; Wu, Guo; Chen, Kai; Zhang, Xi; Liu, Hui; Han, Xiuguo; Wang, Shuguang; Li, Xiaowu
Abstract Controversy exists regarding pathological factors affecting the prognosis of hepatocellular carcinoma (HCC) patients with hepatitis B virus (HBV-HCC). Their postoperative clinical behaviors and the exact HBV Deoxyribonucleic Acid (DNA) thresholds that distinguish good and poor prognoses are unknown. This study aimed to compare clinicopathological, pre- and postoperative clinical factors and overall and recurrence-free survival (RFS) between HBV-HCC patients and nonhepatitis B and nonhepatitis C HCC (NBC-HCC) patients to determine the optimal prognostic HBV DNA threshold. Data from 1440 patients with HBV-HCC and NBC-HCC who underwent curative hepatectomy were retrospectively analyzed. Liver function in the HBV-HCC group was significantly worse than in the NBC-HCC group. Compared with NBC-HCC patients, HBV-HCC patients had significantly more vascular invasion and advanced HCC. The HBV-HCC patients also had significantly worse liver function and more complications. Further survival analysis showed significantly lower overall and RFS rates and a higher early recurrence rate in the HBV-HCC group. Univariate analysis indicated that HBV was a risk factor for overall and RFS. Finally, X-tile analysis revealed that the optimal HBV DNA cutoff points for predicting RFS and overall survival in HCC patients were 10,100 and 12,800 IU/mL, respectively. After hepatectomy for HCC, HBV-HCC patients had more complications and a worse prognosis than NBC-HCC patients. Antiviral therapy should be considered before hepatectomy in patients with high (more than approximately 104 IU/mL) HBV DNA levels. PMID:27495026
Lanini, Simone; Garbuglia, Anna Rosa; Puro, Vincenzo; Solmone, Mariacarmela; Martini, Lorena; Arcese, William; Nanni Costa, Alessandro; Borgia, Piero; Piselli, Pierluca; Capobionchi, Maria Rosaria; Ippolito, Giuseppe
Introduction In western countries the transmission of hepatitis B virus (HBV) transmission through multi-patients lancing devices has been inferred since early ‘90s, however no study has ever provided biological evidence which directly link these device with HBV cross-infection. Here we present results of an outbreak investigation which could associate, by molecular techniques, the use of lancing device on multiple patients with HBV transmission in an Italian oncohematology unit. Methods The outbreak investigation was designed as a retrospective cohort study to identify all potential cases. All cases identified were eventually confirmed through molecular epidemiology techniques. Audit of personnel including extensive review of infection control measures and reviewing personnel's tests for HBV was done identify transmission route. Results Between 4 May 2006 and 21 February 2007, six incident cases of HBV infection were reported among 162 patients admitted in the oncohematology. The subsequent molecular instigation proved that 3 out 6 incident cases and one prevalent cases (already infected with HBV at the admission) represented a monophyletic cluster of infection. The eventual environmental investigation found that an identical HBV viral strain was present on a multi-patients lancing device in use in the unit and the inferential analysis showed a statistically significant association between undergoing lancing procedures and the infection. Discussion This investigation provide molecular evidence to link a HBV infection cluster to multi-patients lancing device and highlights that patients undergoing capillary blood sampling by non-disposable lancing device may face an unacceptable increased risk of HBV infection. Therefore we believe that multi-patients lancing devices should be banned from healthcare settings and replace with disposable safety lancets that permanently retract to prevent the use of the same device on multiple patients. The use of non
Yang, Li; Lu, Mengji
Hepatitis B virus (HBV) infection is still a major health problem worldwide. The current available antiviral drugs for the treatment of chronic HBV infection do not achieve satisfactory results. Thus, it is desirable to develop novel anti-HBV drugs based the recent advances of basic research on molecular biology of HBV. HBV nucleocapsid assembly is now considered as a potential target of anti-HBV therapy. Structural and functional analysis provided essential insight of molecular interaction of the components of HBV nucleocapsid. Prototypes of small molecule modulators of HBV nucleocapsid assembly were developed and partly tested in clinical phase I. In the present review, the recent advances in HBV molecular biology and approach to develop inhibitors for anti-HBV treatment based on the disruption of viral nucleocapsids by either prevention of assembly or induction of misassembly will be summarized. We will discuss the future concepts of anti-HBV treatment based on such new approaches. Copyright© Bentham Science Publishers; For any queries, please email at email@example.com.
Huang, Yan; Chen, Tingjin; Kong, Xiangzhan; Sun, Hengchang; Yu, Xinbing; Xu, Jin
Background Clonorchis sinensis (C. sinensis) is considered to be an important parasitic zoonosis because it infects approximately 35 million people, while approximately 15 million were distributed in China. Hepatitis B virus (HBV) infection is a major public health issue. Two types of pathogens have the potential to cause human liver disease and eventually hepatocellular carcinoma. Concurrent infection with HBV and C. sinensis is often observed in some areas where C. sinensis is endemic. However, whether C. sinensis could impact HBV infection or vice versa remains unknown. Principal Findings Co-infection with C. sinensis and HBV develops predominantly in males. Co-infected C. sinensis and HBV patients presented weaker liver function and higher HBV DNA titers. Combination treatment with antiviral and anti-C. sinensis drugs in co-infected patients could contribute to a reduction in viral load and help with liver function recovery. Excretory-secretory products (ESPs) may, in some ways, increase HBV viral replication in vitro. A mixture of ESP and HBV positive sera could induce peripheral blood mononuclear cells (PBMCs) to produce higher level of Th2 cytokines including IL-4, IL-6 and IL-10 compared to HBV alone, it seems that due to presence of ESP, the cytokine production shift towards Th2. C. sinensis/HBV co-infected patients showed higher serum IL-6 and IL-10 levels and lower serum IFN-γ levels. Conclusions/Significance Patients with concomitant C. sinensis and HBV infection presented weaker liver function and higher HBV DNA copies. In co-infected patients, the efficacy of anti-viral treatment was better in patients who were prescribed with entecavir and praziquantel than entecavir alone. One possible reason for the weaker response to antiviral therapies in co-infected patients was the shift in cytokine production from Th1 to Th2 that may inhibit viral clearance. C. sinensis/HBV co-infection could exacerbate the imbalance of Th1/Th2 cytokine. PMID:27348302
Fourati, Slim; Challine, Dominique; Poveda, Jean-Dominique; Laperche, Syria; Rallier, Sandrine; Pawlotsky, Jean-Michel; Chevaliez, Stéphane
Detection and quantification of HBV DNA are essential to diagnose chronic HBV infection, monitor the virological response to treatment and the possible selection of resistant viruses in order to tailor therapy. The VERIS/MDx System HBV Assay is a random-access system that quantifies HBV DNA in clinical samples using unique single sample and reagent access during the workflow process without the need to reload other tests and delivers results within 1.2h following sampling. The goal of this study was to evaluate the analytical performance of the VERIS HBV assay for HBV DNA detection and quantification in clinical samples from a series of patients chronically infected with different HBV genotypes. The specificity of the VERIS HBV assay was estimated to be over 99.5%. The limit of detection (LOD) was estimated to be 4.1IU/mL (95%CI: 3.20-5.90IU/mL). Using an HBV linearity panel and controls (Seracare LifeScience), intra-assay and inter-assay coefficients of variation ranged from 0.12% to 3.64% and from 1.05% to 7.35%, respectively. The influence of the HBV genotype was evaluated from 120 clinical specimens containing HBV genotypes A to G tested in parallel with the VERIS HBV assay and the COBAS AmpliPrep/COBAS TaqMan HBV v2.0 assay. A linear relationship between the HBV DNA levels measured with both assays was found. A modest bias of HBV DNA levels was observed in the VERIS assay as compared to CAP/CTM HBV v2.0 in most of the samples tested (mean VERIS minus CAP/CTM difference: -0.395 log IU/mL). Overall, the VERIS HBV assay is well suited to monitoring clinical HBV DNA levels in infected patients according to current clinical practice guidelines. Copyright © 2017 Elsevier B.V. All rights reserved.
Detection of rtN236T and rtA181V/T mutations associated with resistance to adefovir dipivoxil in samples from patients with chronic hepatitis B virus infection by the INNO-LiPA HBV DR line probe assay (version 2).
Osiowy, Carla; Villeneuve, Jean-Pierre; Heathcote, E Jenny; Giles, Elizabeth; Borlang, Jamie
The nucleotide analog adefovir dipivoxil (ADV) is an effective antiviral treatment for chronic hepatitis B virus (HBV) infection, with resistance to ADV estimated to occur less frequently than resistance to lamivudine treatment. The detection of ADV resistance mutations is necessary during therapy to monitor and anticipate possible treatment failure. The INNO-LiPA HBV DR v2 (LiPA; Innogenetics, Ghent, Belgium) is a DNA hybridization line probe assay for the detection of HBV polymerase mutations associated with resistance to lamivudine and ADV. Evaluation of this assay to detect ADV resistance mutations was performed by analyzing 38 patients treated with ADV. Serial samples taken at 6-month intervals during treatment were available for most patients. A total of 124 samples were analyzed by both LiPA and sequencing. By LiPA analysis, 12 patients (31.5%) were found to have mutations associated with resistance to ADV (rtA181V/T and/or rtN236T). This contrasted with sequence analysis, which found nine patients (24%) with either or both mutations. Twice as many samples were rtN236T positive by LiPA (18 of 124) compared to sequence analysis (9 of 124). LiPA detected the rtN236T mutation at least 6 months earlier than its detection by sequencing in patients for whom consecutive serum samples were available. Although less sensitive, sequencing has the advantage of providing information on other polymerase mutations not represented on LiPA strips. The INNO-LiPA HBV DR v2 assay is a very sensitive and specific assay for the detection of the rtN236T mutation associated with resistance to ADV.
Truong, Bui Xuan; Yano, Yoshihiko; Seo, Yasushi; Phuong, Tran Minh; Tanaka, Yasuhito; Kato, Hirotaka; Miki, Akira; Utsumi, Takako; Azuma, Takeshi; Trach, Nguyen Khanh; Mizokami, Masashi; Hayashi, Yoshitake; Kasuga, Masato
Hepatitis B virus (HBV) subgenotypes Cs (C1) and Ce (C2) are common in East Asia. To investigate the genomic difference of HBV genotype C between two separated regions, 50 subgenotype Cs-infected Vietnamese and 70 subgenotype Ce-infected Japanese patients were enrolled for analysis. The patients were categorized to either a hepatocellular carcinoma group (HCC) or a non-HCC group including liver cirrhosis, chronic hepatitis, and asymptomatic carriers. HBV serology, HBV-DNA level, and variations in core promoter/pre-core region were examined. Phylogenetic analysis based on the full genome sequences and nucleotide sequences partly in the S gene and in the P gene revealed that all Japanese strains (70/70) were subgenotype Ce, and nearly all of the Vietnamese strains (50/51) were subgenotype Cs, excluding one subgenotype C5. C1858 and G1775 were common in the Vietnamese (64% and 40%) but not in the Japanese (0%). The prevalence of C/A1753 in Vietnamese was higher than that in the Japanese (32% vs. 17.1%), however the frequency of A1896 in the Japanese was significantly higher (32.9% vs. 12%, P < 0.05). Most of the Vietnamese patients with HCC had a high level of HBV-DNA, the Japanese HCC had a relatively low level. In the Vietnamese, C/A1753 and C1858 were associated closely with T1762A1764, higher HBV-DNA levels and higher HCC incidence. The multivariate analysis revealed that male, T1653 and C/A1753 were independent risk factors for HCC. The subgenotypes and unique mutations of HBV genotype C in the Vietnamese and Japanese differed, and C/A1753 and C1858 variants might play a role in the pathogenesis of liver disease in Vietnamese patients.
Roche, Bruno; Samuel, Didier
Antiviral therapy using newer nucleos(t)ide analogs with lower resistance rates could suppress hepatitis B virus (HBV) replication, improve liver function in patients with compensated or decompensated cirrhosis, delay or obviate liver transplantation in some patients, and reduce the risk of HBV recurrence. Some form of HBV prophylaxis needs to be continued indefinitely posttransplant. However, in patients with a low-risk of HBV recurrence it is possible to discontinue hepatitis B immunoglobulins and maintain long-term nucleos(t)ide analog therapy. Currently, treatment of posttransplantation hepatitis B is a less important clinical problem than it was historically because effective antiviral therapies exist to rescue patients who failed initial prophylaxis.
Fabbri, Gabriele; Mastrorosa, Ilaria; Vergori, Alessandra; Mazzotta, Valentina; Pinnetti, Carmela; Grisetti, Susanna; Zaccarelli, Mauro; Ammassari, Adriana; Antinori, Andrea
Reactivation of occult or inactive Hepatitis B virus (HBV) infection during immunosuppressant treatments is well known and widely described in literature. The same observation has been made in Hepatitis C (HCV)-infected patients previously exposed to HBV and treated with interferon-free DAA treatments. Because of common transmission routes, persons may have been exposed to HCV, HBV and HIV, but few cases have been reported in this scenario to date. Frequency of HBV reactivation in HIV/HCV co-infected patients previously exposed to HBV and treated with DAA remains unclear. Herein, we report an episode of HBV reactivation in an HIV/HCV co-infected patient prescribed with sofosbuvir/ledipasvir for HCV. The patient is a Caucasian 54-years old female, with HIV/HCV co-infection (genotype 4), and a previous exposure to HBV, documented by negativity of HBsAg and positivity of HBsAb and HBcAb. Her medical history included: myocardial infarct, chronic kidney disease stage 3, chronic obstructive pulmonary disease, and mild pulmonary hypertension. HCV had not been treated with interferon (IFN)-based regimens and liver stiffness was 10.5 KPa (Metavir stage F3) at hepatic elastography. Because of CKD, she was prescribed with a nucleoside reverse transcriptase (NRTI)-sparing regimen including darunavir/ritonavir plus etravirine, and thereafter with sofosbuvir/ledipasvir for 12 weeks. Four weeks after DAA termination, the patient was hospitalized with symptoms of acute hepatitis. Blood tests showed HCV RNA <12 IU/ml, but positivity of HBAg, HBeAg, and of anti-core antibodies (IgM and IgG), while anti-HBs and anti-HBe antibodies were negative. HBV DNA was 6.06 Log10 IU/ml. Entecavir was started obtaining resolution of symptoms, normalization of liver enzymes, as well as reduction of HBV DNA and of quantitative HBV surface antigen. This case-report highlights the risk of HBV reactivation with interferon-free DAA treatment in HIV/HCV co-infected patients previously exposed to HBV
Roll, M; Norder, H; Magnius, L O; Grillner, L; Lindgren, V
An outbreak of hepatitis B virus (HBV) infection in a haemodialysis unit is described. Four patients in the unit contracted subclinical HBV infection within three months. DNA sequence analysis of the S gene of HBV isolates from chronic carriers and newly infected patients in the unit aided in tracing possible transmission pathways. Three newly infected patients had received partial or complete HBV vaccination previously. HBV was rapidly cleared from all three although the anti-HBs titre had not reached 10 IU L-1 in any of them at the time of infection.
Sun, H Q; Zhang, J Y; Zhang, H; Zou, Z S; Wang, F S; Jia, J H
T helper (Th) 17 cells have been demonstrated to participate in the pathogenesis of HBV-associated liver damage. However, little is known regarding the immunopathogenic role of liver fibrosis in patients with HBV-associated liver cirrhosis. The aims of this study were to evaluate whether Th17 cells are related to disease progression in patients and to explore the possible mechanisms. The frequencies of circulating Th17 cells were analysed in 78 patients with hepatitis B and cirrhosis (Child A: 34; Child B: 22; Child C 22) and matched controls. Liver samples were collected from 13 patients with HBV-associated cirrhosis, 23 patients with chronic hepatitis B and 12 healthy controls for immunohistochemical analysis. IL-17 receptor expression was studied on liver biopsies and in human hepatic stellate cells as well as their response to recombinant IL-17 by flow cytometry. Patients with hepatitis B-associated cirrhosis with more severe disease displayed significant increases in peripheral numbers of Th17 cells as well as in IL-17 plasma levels. The increased intrahepatic IL-17(+) cells correlated positively with fibrotic staging scores and clinical progression from CHB to cirrhosis. Moreover, many IL-17(+) cells were located in fibrotic areas in the liver of patients with cirrhosis. In vitro, IL-17 together with IL-17-activated monocytes, could promote the activation of stellate cells, which, in turn, aggravated liver fibrosis and the inflammatory response. In summary, increased peripheral and intrahepatic Th17 cells are enriched in patients with hepatitis B and cirrhosis and contribute further to the severity of disease progression through induction of stellate cell activation.
Sun, Tao; Liu, Li; Wu, Ao; Zhang, Yujiao; Jia, Xiaofang; Yin, Lin; Lu, Hongzhou; Zhang, Lijun
Human immunodeficiency virus (HIV) and hepatitis B virus (HBV) share similar routes of transmission, and rapid progression of hepatic and immunodeficiency diseases has been observed in coinfected individuals. Our main objective was to investigate the molecular mechanism of HIV/HBV coinfections. We selected HIV infected and HIV/HBV coinfected patients with and without Highly Active Antiretroviral Therapy (HAART). Low abundance proteins enriched using a multiple affinity removal system (MARS) were labeled with isobaric tags for relative and absolute quantitation (iTRAQ) kits and analyzed using liquid chromatography-mass spectrometry (LC-MS). The differential proteins were analyzed by Gene Ontology (GO) database. A total of 41 differential proteins were found in HIV/HBV coinfected patients as compared to HIV mono-infected patients with or without HAART treatment, including 7 common HBV-regulated proteins. The proteins involved in complement and coagulation pathways were significantly enriched, including plasma kallikrein (KLK) and complement component C9 (C9). C9 and KLK were verified to be down-regulated in HIV/HBV coinfected patients through ELISA analysis. The present iTRAQ based proteomic analyses identified 7 proteins that are related to HIV/HBV coinfection. HBV might influence hepatic and immune functions by deregulating complement and coagulation pathways. C9 and KLK could potentially be used as targets for the treatment of HIV/HBV coinfections. Copyright © 2017. Published by Elsevier Ltd.
Plaza, Zulema; Aguilera, Antonio; Mena, Alvaro; Vispo, Eugenia; Sierra-Enguita, Rocío; Tomé, Santiago; Pedreira, José; Rodriguez, Carmen; Barreiro, Pablo; del Romero, Jorge; Soriano, Vicente; Poveda, Eva
HIV worsens the natural history of chronic hepatitis B virus (HBV) infection. Suppression of HBV replication slows progression of liver damage. Information about the influence of HIV on response to tenofovir in HIV/HBV-coinfected patients is scarce. All individuals with persistent HBsAg+ at four clinics in Spain were identified. Information from the subset that initiated tenofovir therapy was examined. A total of 176 patients with chronic hepatitis B were evaluated, of whom 138 (78.4%) were coinfected with HIV. Prior lamivudine exposure was extensive in both groups, and nearly half of HBV viremic patients harboured drug resistance mutations. Most patients took tenofovir coformulated along with emtricitabine (Truvada). Of 101 HBV viremic patients at the time of beginning tenofovir (78 with HIV coinfection and 33 with HBV alone), a similar proportion achieved undetectable HBV-DNA at weeks 24, 48 and 96 of tenofovir therapy. Interestingly, HIV/HBV-coinfected patients with positive HBeAg showed a lower response than HBeAg-negatives. In multivariate analysis, however, baseline serum HBV-DNA was the only predictor of virological response to tenofovir. The antiviral efficacy of tenofovir is similar in HIV/HBV-coinfected and HBV-monoinfected patients, achieving undetectable HBV-DNA nearly 90% of patients at week 96 of therapy. Baseline serum HBV-DNA is the major determinant of time-trends in virological response, with no significant influence of HBeAg, drug resistance mutations nor coinfection with hepatitis C or delta viruses.
Guarino, Maria; Picardi, Marco; Vitello, Anna; Pugliese, Novella; Rea, Matilde; Cossiga, Valentina; Pane, Fabrizio; Caporaso, Nicola; Morisco, Filomena
HBV and HCV reactivation has been widely reported in patients undergoing immunosuppressive therapy for oncohaematological diseases. We aimed to evaluate the HBV and HCV reactivation events in patients with non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL) underwent cytotoxic chemotherapy containing or not rituximab. This is a retrospective observational study, including all patients with NHL and HL attending an Italian tertiary referral hospital, the University of Naples "Federico II". A total of 322 patients were enrolled. We evaluated serum HBV and HCV markers. A total of 47 (38%) patients with occult HBV infection were enrolled. Seven/47 were treated with therapeutic cytotoxic schedule containing rituximab. Of them, 6/7 received prophylaxis with lamivudine. HBV reactivation was observed in two patients treated with rituximab. A reactivation was observed in the only patient (HBcAb+/HBsAb+) not receiving lamivudine prophylaxis, and the other one was observed in 1 patient with isolated HBcAb positivity during lamivudine prophylaxis. Moreover, 8 patients with HCV-Ab positivity were enrolled. No viral reactivation was observed in these patients. In conclusion, patients with occult HBV infection receiving chemotherapy containing rituximab for lymphoma without antiviral prophylaxis are at risk of viral reactivation. On the contrary, there is no risk of reactivation in patients undergoing rituximab-free schedule. Our findings suggest that there is also very low risk of HCV reactivation. This preliminary report underlines the concept that HBV reactivationis strongly related to the type of immunosuppressive therapy administered and that antiviral prophylaxis needs to be tailored.
Wahle, Raul Carlos; Perez, Renata Mello; Pereira, Patrícia Fucuta; Oliveira, Elze Maria Gomes; Emori, Christini Takemi; Uehara, Silvia Naomi de Oliveira; Silva, Ivonete Sandra de Souza; Silva, Antônio Eduardo Benedito; Ferraz, Maria Lucia Gomes
In coinfected HBV/HCV patients, HBV replication is usually suppressed by HCV over the time. No study to date has evaluated the HBV viremia in long-term follow-up after HCV treatment in hemodialysis patients with HBV/HCV coinfection. This study aimed to assess the evolution of HBV viremia after HCV treatment in this special population. Ten hemodialysis patients with HBV/HCV coinfection with dominant HCV infection (HBV lower than 2000 IU/mL) and significant fibrosis were treated with interferon-alpha 3 MU 3×/week for 12 months and could be followed for at least 36 months after HCV treatment. Six cases of HBV reactivation (60%) during follow-up were observed and 5/6 had been successfully treated for HCV. Patients with HBV reactivation received anti-HBV therapy. Our preliminary findings indicate that treatment of hepatitis C in HBV/HCV coinfected hemodialysis patients may favor HBV reactivation. Thus, continued monitoring of HBV viremia must be recommended and prompt anti-HBV therapy should be implemented.
Background Occult hepatitis B virus (HBV) infection (OBI) is characterized by HBV DNA persistence even though the pattern of serological markers indicates an otherwise resolved HBV infection. Although OBI is usually clinically silent, immunocompromised patients may experience reactivation of the liver disease. Case presentation We report the case of an individual with human immunodeficiency virus (HIV) infection and anti-HBV core antibody positivity, who experienced severe HBV reactivation after discontinuation of lamivudine-including antiretroviral therapy (ART). HBV sequencing analysis showed a hepatitis B surface antigen escape mutant whose presence in an earlier sample excluded reinfection. Molecular sequencing showed some differences between two isolates collected at a 9-year interval, indicating HBV evolution. Resumption of ART containing an emtricitabine/tenofovir combination allowed control of plasma HBV DNA, which fell to undetectable levels. Conclusion This case stresses the ability of HBV to evolve continuously, even during occult infection, and the effectiveness of ART in controlling OBI reactivation in HIV-infected individuals. PMID:22054111
Wang, Mingjie; Gong, Qiming; Zhang, Jiming; Chen, Liang; Zhang, Zhanqing; Lu, Lungen; Yu, Demin; Han, Yue; Zhang, Donghua; Chen, Peizhan; Zhang, Xiaonan; Yuan, Zhenghong; Huang, Jinyan; Zhang, Xinxin
Although hepatitis B virus (HBV) infection is the leading cause of liver fibrosis (LF), the mechanisms underlying liver fibrotic progression remain unclear. Here, we investigated the gene expression profiles of HBV-related LF patients. Whole genome expression arrays were used to detect gene expression in liver biopsy samples from chronically HBV infected patients. Through integrative data analysis, we identified several pathways and key genes involved in the initiation and exacerbation of liver fibrosis. Weight gene co-expression analysis revealed that integrin subunit β-like 1 (ITGBL1) was a key regulator of fibrogenesis. Functional experiments demonstrated that ITGBL1 was an upstream regulator of LF via interactions with transforming growth factor β1. In summary, we investigated the gene expression profiles of HBV-related LF patients and identified a key regulator ITGBL1. Our findings provide a foundation for future studies of gene functions and promote the development of novel antifibrotic therapies. PMID:28262670
Sakamoto, Tomoyuki; Tanaka, Yasuhito; Orito, Etsuro; Co, Jonard; Clavio, Joseph; Sugauchi, Fuminaka; Ito, Kiyoaki; Ozasa, Atsushi; Quino, Alvin; Ueda, Ryuzo; Sollano, Jose; Mizokami, Masashi
Several hepatitis B virus (HBV) subtypes (subgenotypes), HBV/Aa (A1 : Asia/Africa), Ae (A2 : Europe), Bj (B1 : Japan) and Ba (B2 : Asia), have been reported with respect to clinical differences between patients infected with these subtypes (subgenotypes). HBV genotype distribution among patients with chronic liver diseases was investigated in the Philippines, where such studies have not been carried out previously. One hundred sera were obtained from such patients, consisting of 32 chronic hepatitis (CH), 37 cirrhosis and 31 hepatocellular carcinoma (HCC) patients. Nine complete genomes and 100 core promoter/precore genes of HBV were sequenced directly. Phylogenetic analyses revealed 51 HBV/A (Aa/A1), 22 HBV/B and 27 HBV/C strains. Interestingly, most HBV/C strains in the Philippines formed a specific cluster distinct from previous HBV/C strains (C1-4), indicating a novel subtype (subgenotype), HBV/C5. Moreover, most HBV/B strains fell within the specific cluster of the HBV/B subtype (subgenotype) B5, with viral characteristics of HBV/Ba (B2) carrying a recombination with HBV/C over the precore and core genes. Of the three genotypes, HBV/B and HBV/C were significantly more prevalent than HBV/A in cirrhosis and HCC patients (P<0.02). The prevalence of the core promoter mutations T1762/A1764 was higher in HCC patients with HBV/B and HBV/C. Multivariate analysis indicated that age [odds ratio (OR) 3.43; 95 % confidence interval (CI) 1.04-11.36; P=0.044] and the core promoter mutation (OR 14.08; 95% CI 3.62-4.74; P<0.001) were significant factors for HCC development. In conclusion, novel HBV subtypes (subgenotypes) C5 and B5 are prevalent in the Philippines, as well as HBV/Aa (A1).
Yan, Ying; Mai, Li; Zheng, Yu-Bao; Zhang, Shao-Quan; Xu, Wen-Xiong; Gao, Zhi-Liang; Ke, Wei-Min
AIM: To investigate optimal timing for therapeutic efficacy of entecavir for acute-on-chronic hepatitis B liver failure (ACLF-HBV) in hepatitis B e antigen (HBeAg)-negative patients. METHODS: A total of 109 inpatients with ACLF-HBV were recruited from the Department of Infectious Diseases of the Third Affiliated Hospital, Sun Yat-sen University from October 2007 to October 2010. Entecavir 0.5 mg/d was added to each patient’s comprehensive therapeutic regimen. Patients were divided into three groups according to model for end-stage liver disease (MELD) score: high (≥ 30, 20 males and 4 females, mean age 47.8 ± 13.5 years); intermediate (22-30, 49 males and 5 females, 45.9 ± 12.4 years); and low (≤ 22, 28 males and 3 females, 43.4 ± 9.4 years). Statistical analysis were performed using SPSS 11.0 software. Data with normal distribution were expressed as mean ± SD and comparisons were made with Student’s t tests. A value of P < 0.05 was considered statistically significant. Viral loads were related exponentially and logarithmic data were used for analysis. RESULTS: For 24 patients with MELD score ≥ 30, treatment lasted 17.2 ± 16.5 d. Scores before and after treatment were significantly different (35.97 ± 4.87 and 40.48 ± 8.17, respectively, t = -2.762, P = 0.011); HBV DNA load was reduced (4.882 ± 1.847 copies log10/mL to 3.685 ± 1.436 copies log10/mL); and mortality rate was 95.83% (23/24). Of 54 patients with scores of 22-30, treatment lasted for 54.0 ± 43.2 d; scores before and after treatment were 25.87 ± 2.33 and 25.82 ± 13.92, respectively (t = -0.030, P = 0.976); HBV DNA load decreased from 6.308 ± 1.607 to 3.473 ± 2.097 copies log10/mL; and mortality was 51.85% (28/54). Of 31 patients with scores ≤ 22, treatment lasted for 66.1 ± 41.9 d; scores before and after treatment were 18.88 ± 2.44 and 12.39 ± 7.80, respectively, (t = 4.860, P = 0.000); HBV DNA load decreased from 5.841 ± 1.734 to 2.657 ± 1.154 copies log10/mL; and
Kishk, R; Atta, H Aboul; Ragheb, M; Kamel, M; Metwally, L; Nemr, N
Chronic hepatitis C virus (HCV) infection combined with occult hepatitis B virus (HBV) infection has been associated with increased risk of hepatitis, cirrhosis and hepatocellular carcinoma. This study aimed to determine the prevalence of occult HBV infection among Egyptian chronic HCV patients, the genotype and occurrence of surface gene mutations of HBV and the impact of co-infection on early response to treatment. The study enrolled 162 chronic HCV patients from Ismailia Fever Hospital, Egypt, who were HBV surface antigen-negative. All patients were given clinical assessment and biochemical, histological and virological examinations. HBV-DNA was detectable in sera from 3 patients out of the 40 patients who were positive for hepatitis B core antibody. These 3 patients were responsive to combination therapy at treatment week 12; only 1 of them had discontinued therapy by week 24. HBV genotype D was the only detectable genotype in those patients, with absence of "a" determinant mutations among those isolates.
Penna, Amalia; Laccabue, Diletta; Libri, Irene; Giuberti, Tiziana; Schivazappa, Simona; Alfieri, Arianna; Mori, Cristina; Canetti, Diana; Lampertico, Pietro; Viganò, Mauro; Colombo, Massimo; Loggi, Elisabetta; Missale, Gabriele; Ferrari, Carlo
The effect of IFN-α therapy on HBV-specific T-cell responses in HBeAg-negative, genotype D, chronic hepatitis B is largely undefined. Understanding to what extent IFN-α can modulate HBV-specific T-cells is important to define strategies to optimize IFN efficacy and to identify immunological parameters to predict response to therapy. HBV-specific T-cell responses were analyzed longitudinally ex vivo and after expansion in vitro in 15 patients with genotype D, HBeAg-negative chronic hepatitis B treated with peginterferon-α-2a. HBV proteins and synthetic peptides were used to stimulate T-cell responses. Analysis of the CD4 and CD8 T-cell functions was performed by ELISPOT, intracellular cytokine and tetramer staining. The effect of anti-PD-L1 on T-cell functions was also analyzed. Ex vivo IFN-γ production by total HBV-specific T-cells was significantly greater before therapy in patients who showed HBV DNA <50 IU/ml at weeks 24 and/or 48 of therapy. No significant improvement of T-cell proliferation, Th1 cytokine production and cytotoxicity was observed during IFN therapy by both ex vivo and in vitro analysis. PD-1/PD-L1 blockade showed a modest improvement of cytokine production in a total of 15% of T-cell lines. IFN-α did not improve peripheral blood HBV-specific T-cell responses in the first 24 weeks of treatment, consistent either with a predominant antiviral/antiproliferative effect or with an immunomodulatory activity on other arms of the immune system which were not analyzed in our study. A better pre-treatment ex vivo IFN-γ production was associated with better chances to control HBV replication during therapy and represents a promising predictor of IFN efficacy. Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Sagnelli, Caterina; Ciccozzi, Massimo; Coppola, Nicola; Minichini, Carmine; Lo Presti, Alessandra; Starace, Mario; Alessio, Loredana; Macera, Margherita; Cella, Eleonora; Gualdieri, Luciano; Caprio, Nunzio; Pasquale, Giuseppe; Sagnelli, Evangelista
In a recent testing in the metropolitan area of Naples, Italy, on 945 irregular immigrants or refugees, 87 HBsAg chronic carriers were identified, 53 of whom were infected by HBV-genotype E. The aim of the present study was to identify the genetic diversity of HBV-genotype E in these 53 immigrants. The 53 immigrant patients with HBV-genotype-E infection were born in Africa, central or eastern Asia, eastern Europe or Latin America. These patients had been seen for a clinical consultation at one of the four first-level units from January 2012 to 2013. The first dataset contained 53 HBV-S gene isolates plus 128 genotype/subgenotype specific reference sequences downloaded from the National Center for Biotechnology Information. The second dataset, comprising the 53 HBV-S gene isolates, previously classified as HBV-genotype E, was used to perform the time-scaled phylogeny reconstruction using a Bayesian approach. Phylogenetic analysis showed that all 53 HBV-S isolates belonged to HBV-genotype E. Bayes factor analysis showed that the relaxed clock exponential growth model fitted the data significantly better than the other models. The time-scaled Bayesian phylogenetic tree of the second dataset showed that the root of the tree dated back to the year 1990 (95% HPD:1984-2000). Four statistically supported clusters were identified. Cluster A dated back to 2012 (95% HPD:1997-2012); cluster B dated back to 2008 (95% HPD:2001-2015); cluster C to 2006 (95% HPD:1999-2013); cluster D to 2004 (95% HPD:1998-2011). This study disclosed the genetic evolution and phylogenesis in a group of HBV-genotype-E-infected immigrants. J. Med. Virol. © 2016 Wiley Periodicals, Inc.
Qin, Yannan; Zhong, Yaogang; Ma, Tianran; Zhang, Jiaxu; Yang, Ganglong; Guan, Feng; Li, Zheng; Li, Baozhen
Hepatitis B is a potentially life-threatening liver infection caused by the hepatitis B virus (HBV), which can lead to chronic liver disease and put people at high risk of death from cirrhosis of the liver and liver cancer. However, little is known about the correlation of salivary N-linked glycans related to HBV-infected liver diseases. Here we investigated N-linked glycome in saliva from 200 subjects (50 healthy volunteers (HV), 40 HBV-infected patients (HB), 50 cirrhosis patients (HC), and 60 hepatocellular carcinoma patients (HCC) using MALDI-TOF/TOF-MS. Representative MS spectra of N-glycans with signal-to-noise ratios >6 were annotated using the GlycoWorkbench program. A total of 40, 47, 29, and 33 N-glycan peaks were identified and annotated from HV, HB, HC, and HCC groups, respectively. There were 15 N-glycan peaks (e.g., m/z 1647.587, 1688.613 and 2101.755) were present in all groups. Three N-glycan peaks (m/z 2596.925, 2756.962, and 2921.031) were unique in HV group, 2 N-glycan peaks (m/z 1898.676 and 1971.692) were unique in HB group, 5 N-glycan peaks (m/z 1954.677, 2507.914, 2580.930, 2637.952, and 3092.120) were unique in HC group, and 3 N-glycan peaks (m/z 2240.830, 2507.914, and 3931.338) were unique in HCC group. The proportion of fucosylated N-glycans was apparently increased in the HCC group (84.8%) than in any other group (73.1% ± 0.01), however, the proportion of sialylated N-glycans was decreased in HCC group (12.1%) than in any other group (17.23% ± 0.003). Our data provide pivotal information to distinguish between HBV-associated hepatitis, cirrhosis and HCC, and facilitate the discovery of biomarkers for HCC during its early stages based on precise alterations of N-linked glycans in saliva.
Noterdaeme, Timothée; Longrée, Luc; Bataille, Christian; Deroover, Arnaud; Lamproye, Anne; Delwaide, Jean; Beguin, Yves; Honoré, Pierre; Detry, Olivier
Hepatitis B (HBV) reactivation induced by chemotherapy is problem encountered recently in the management of malignant diseases. Chemotherapy-induced HBV reactivation may ultimately lead to terminal acute liver failure. Liver transplantation (LT) currently remains the only definitive treatment option for such cases, but is generally denied to patients suffering from malignancy. Here, the authors describe 2 cases of cancer-free and HBV graft re-infection-free survival after LT performed for terminal liver failure arising from HBV reactivation induced by chemotherapy for advanced stage lymphoma. These 2 cases, and some other reports in the literature, may suggest that patients suffering from hematologic malignancies and terminal liver disease can be considered for LT if the prognosis of their hematologic malignancy is good. PMID:21799656
Starkey, Jason L; Chiari, Estelle F; Isom, Harriet C
Hepatitis B virus (HBV) covalently closed circular (CCC) DNA is the source of HBV transcripts and persistence in chronically infected patients. The novel aspect of this study was to determine the effect of RNA interference (RNAi) on HBV CCC DNA when administered prior to establishment of HBV replication or during chronic HBV infection. HBV replication was initiated in HepG2 cells by transduction with HBV baculovirus. Subculture of HBV-expressing HepG2 cells at 10 days post-transduction generates a system in which HBV replication is ongoing and HBV is expressed largely from CCC DNA, thus simulating chronic HBV infection. HepG2 cells were transduced with short hairpin RNA (shRNA)-expressing baculovirus prior to initiation of HBV replication or during chronic HBV replication, and the levels of HBV RNA, HBV surface antigens (HBsAg) and replicative intermediates (RI), extracellular (EC) and CCC DNA species were measured. HBsAg, HBV RNA and DNA levels were markedly reduced until day 8 whether cells were transduced with shRNA prior to or during a chronic infection; however, the CCC DNA species were only affected when shRNA was administered prior to initiation of infection. We conclude that RNAi may have a therapeutic value for controlling HBV replication at the level of RI and EC DNA and for reducing establishment of CCC DNA during HBV infection. Our data support previous findings demonstrating the stability of HBV CCC DNA following antiviral therapy. This study also reports the development of a novel HBV baculovirus subculture system that can be used to evaluate antiviral effects on chronic HBV replication.
Lee, Jong Ho; Hong, Sun Pyo; Jang, Eun Sun; Park, Sang Jong; Hwang, Seong Gyu; Kang, Sook-Kyoung; Jeong, Sook-Hyang
Acute hepatitis B, caused by hepatitis B virus (HBV) strains with drug resistant mutations or pre-core/basal core promoter (PC/BCP) mutations, is a public health concern, because this infection is often associated with poor disease outcome or difficulty in therapeutic choice. The HBV genotype, the prevalence of drug resistant mutations, and PC/BCP mutations in Korean patients with acute hepatitis B were studied. From 2006 to 2008, 36 patients with acute hepatitis B were enrolled prospectively in four general hospitals. Among them, 20 showed detectable HBV DNA (median value was 4.8 log copies/mL). HBV genotyping and analysis of HBV mutations that conferred resistance against lamivudine, adefovir, or entecavir and of PC/BCP mutations were performed using highly sensitive restriction fragment mass polymorphism (RFMP) analysis. All 20 patients were infected with HBV genotype C, which causes almost all cases of chronic hepatitis B in Korea. No patient showed mutations that conferred resistance against lamivudine (L180M, M204V/I), adefovir (A181T, N236S), or entecavir (I169M, A184T/V, S202I/G, M250V/I/L). However, four patients had BCP mutations, and two had PC mutations. Platelet counts were significantly lower in the four patients with PC/BCP mutations compared to those with wild type. In this study, all acute hepatitis B patients had genotype C HBV strains with no drug resistant mutations. However, 20% showed PC/BCP mutations. This highlights the need for further study on the significance of PC/BCP mutations.
Gan, Q R; Jiang, X Y; Zhang, X; Chen, M S; Pan, C
Objective: To investigate the association between serum keratin 18 (K18) level and prognosis in patients with HBV-related acute-on-chronic liver failure (ACLF). Methods: A total of 120 patients who visited Department of Hepatology in Fuzhou Infectious Disease Hospital and were diagnosed with HBV-related ACLF from December 2012 to March 2014 were enrolled and followed up for 3 months. The patients were divided into death group and survival group. The serum levels of K18 fragments (M30 and M65) were measured and related laboratory data were collected to analyze the differences in M30, M65, M30/M65, and other laboratory markers. Binary logistic regression analysis was performed to screen out independent risk factors for death in patients with HBV-related ACLF, and the corresponding logistic regression model (LRM) was established. Another 51 patients with HBV-related ACLF from April to October, 2014 were enrolled; M30 and M65 were measured and related clinical data were collected to calculate LRM value and validate the diagnostic value of LRM. Results: The 120 patients with HBV-related ACLF were followed up for 3 months, and 40 of them died, resulting in a mortality rate of 33.3%. Compared with the survival group, the death group had significantly higher age, percentage of neutrophils, blood ammonia, international normalized ratio, Model for End-Stage Liver Disease (MELD) score, and M65, as well as significantly lower prothrombin time activity and alpha-fetoprotein level. The death group also had significantly higher incidence rates of underlying diseases and complications such as diabetes, liver cirrhosis, hepatic encephalopathy (HE), pulmonary infection, upper gastrointestinal bleeding, and hepatorenal syndrome than the survival group. Age, HE, upper gastrointestinal bleeding, direct bilirubin (DBil), and M30/M65 were independent risk factors for the prognosis of patients with HBV-related ACLF. The model established was LRM = 0.061 × age + 0.69 × HE + 4.11 × upper
Background Epidemiological studies have clearly validated the association between hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). Patients with chronic HBV infection are at increased risk of HCC, in particular those with active liver disease and cirrhosis. Methods We catalogued all published interactions between HBV and human proteins, identifying 250 descriptions of HBV and human protein interactions and 146 unique human proteins that interact with HBV proteins by text mining. Results Integration of this data set into a reconstructed human interactome showed that cellular proteins interacting with HBV are made up of core proteins that are interconnected with many pathways. A global analysis based on functional annotation highlighted the enrichment of cellular pathways targeted by HBV. Conclusions By connecting the cellular proteins targeted by HBV, we have constructed a central network of proteins associated with hepatocellular carcinoma, which might be to regard as the basis of a detailed map for tracking new cellular interactions, and guiding future investigations. PMID:21078198
Background Chronic hepatitis B (CHB) is a clinical concern in human immunodeficiency virus (HIV)-infected individuals due to substantial prevalence, difficulties to treat, and severe liver disease outcome. A large nationwide cross-sectional multicentre analysis of HIV-HBV co-infected patients was designed to describe and identify parameters associated with virological and clinical outcome of CHB in HIV-infected individuals with detectable HBV viremia. Methods A multicenter collaborative cross-sectional study was launched in 19 French University hospitals distributed through the country. From January to December 2007, HBV load, genotype, clinical and epidemiological characteristics of 223 HBV-HIV co-infected patients with an HBV replication over 1000 IU/mL were investigated. Results Patients were mostly male (82%, mean age 42 years). Genotype distribution (A 52%; E 23.3%; D 16.1%) was linked to risk factors, geographic origin, and co-infection with other hepatitis viruses. This genotypic pattern highlights divergent contamination event timelines by HIV and HBV viruses. Most patients (74.7%) under antiretroviral treatment were receiving a drug with anti-HBV activity, including 47% receiving TDF. Genotypic lamivudine-resistance detected in 26% of the patients was linked to duration of lamivudine exposure, age, CD4 count and HIV load. Resistance to adefovir (rtA181T/V) was detected in 2.7% of patients. Advanced liver lesions were observed in 54% of cases and were associated with an older age and lower CD4 counts but not with viral load or genotype. Immune escape HBsAg variants were seldom detected. Conclusions Despite the detection of advanced liver lesions in most patients, few were not receiving anti-HBV drugs and for those treated with the most potent anti-HBV drugs, persistent replication suggested non-optimal adherence. Heterogeneity in HBV strains reflects epidemiological differences that may impact liver disease progression. These findings are strong arguments
Liu, Xiao-Fang; Zhang, Tong; Tang, Kun; Sui, Lu-Lu; Xu, Gang; Liu, Qiang
To study preoperative HBV-DNA negative HBV-related hepatocellular carcinoma (HCC) which was reactivated after surgery and could influence liver function and HCC recurrence. Patients were divided into two groups according to preoperative antiviral therapy status. The control group comprised of 102 preoperative HBV-DNA-negative patients who had not undergone antiviral therapy before surgery. In the treatment group, all HBV-DNA-negative patients (n=63) received entecavir 3-5 days before surgery and for 12 months after surgery. Patients were followed-up regularly, during the preoperative period, and at 1, 3, 6, 12, 18, 24, 30 and 36 months postoperatively. The data for the two groups were analyzed including the level of HBV-DNA and HBV-DNA activation; liver function; 1-, 2- and 3-year survival rate; cumulative survival time; and tumor recurrence. Liver function in the treatment group was better than that of the control group12 months after surgery. Compared to the control group, total bilirubin in the treatment group was significantly better at 6 and 12 months after surgery (p<0.05 and p<0.001, respectively). Serum albumin, alanine aminotransferase and prothrombin time in the treatment group was significantly better than that of controls 12 months after surgery (p<0.001). In the treatment group, two cases (3.17%) had HBV-DNA activation while there were 13 cases (12.75%) with HBV-DNA activation in the control group (p<0.05). There were 51 cases with tumor recurrence in the control group, that was statistically significantly higher than recurrent cases in the treatment group (p<0.05). Postoperative 1-, 2- and 3-year cumulative overall survival rates were 94.12%, 81.37% and 52.94%, respectively, for the control group and 93.65%, 77.78% and 71.43%, respectively, for the treatment group (p=0.006). There was no statistically significant difference in disease-free survival between the two groups (p=0.231). Antiviral treatment of HBV-related HCC with negative HBV-DNA is
Zhang, Yong; Li, Junxia; Peng, Weihua; Yu, Guoqing; Wang, Liping; Chen, Jian; Zheng, Feng
Postinfectious acute glomerulonephritis (PIGN) may occur after various bacterial and viral infections. Hepatitis B virus (HBV) infection is a cause of chronic glomerulonephritis. We report here 10 cases (ages 7–20 years-old) of chronic HBV carriers with acute glomerulonephritis, with positive glomerular staining of hepatitis B surface antigen, and detectable presence of HBV DNA in the glomeruli. This form of PIGN, HBV-PIGN, has not been previously identified. To further characterize clinical and pathological features of HBV- PIGN, we selected 10 cases of age-matched non-HBV PIGN for comparison. While both HBV associated PIGN and non-HBV PIGN similarly presented as proteinuria, hematuria, and hypertension, there was a trend of higher acute kidney injury and worsened prognosis in HBV-PIGN. 6 months after the onset, 4 patients with HBV associated PIGN did not show improvement from the disease, whereas all patients with non-HBV PIGN had complete or partial recovery. Pathologically, both HBV associated PIGN and non-HBV PIGN showed typical diffuse glomerular endocapillary proliferation, but HBV associated PIGN differed from classical PIGN with much fewer sub-epithelial glomerular “hump-shape” immune complex depositions. In conclusion, we have identified a novel association of HBV infection with acute glomerulonephritis. PMID:27512989
Ganczak, Maria; Dmytrzyk-Daniłów, Gabriela; Korzeń, Marcin; Drozd-Dąbrowska, Marzena; Szych, Zbigniew
It is well known that community awareness of hepatitis B (HB) can lead to vaccination and testing. The study objectives were to assess the prevalence of HBV infection and knowledge of HB among adult patients attending randomly selected primary care clinics. A cross-sectional sero-survey was conducted in March 2013 in the Zgorzelec region, Poland, with the use of an investigator-developed questionnaire containing 22 questions regarding HB knowledge. Serum samples were assayed for anti-HBc total and anti-HBs with enzyme immunoassay. The prevalence of anti-HBc total among 410 participants (median age 56 years) was 10.3 % (95 % CI 7.6-13.8 %), nobody was aware of an infection. The main sources of HB knowledge were the media and medical staff. The mean knowledge score was 14.8 ± 4.9; 76.7 % of the respondents had scores >50 %. Particular gaps were detected relating to knowledge of unprotected sexual intercourse and MTCT; 45.6 % patients were not aware of the potential asymptomatic course of HBV infection, 41.2 % about chronic HB treatment. A patient's low educational level was negatively associated with a high knowledge level; the willingness for further education on HB and HBV vaccination in the past were independently associated with good knowledge. In conclusion, the HBV infection remains a public health threat in Poland, since the prevalence of infection markers in asymptomatic adult patients was high. Knowledge gaps call for awareness campaigns which may increase testing and diagnosis, audiences representing lower education level should be targeted first. Knowledge on HB might serve as an effective tool in decision making regarding vaccination.
Pawlowska, Malgorzata; Pniewska, Anna; Pilarczyk, Malgorzata; Kozielewicz, Dorota; Domagalski, Krzysztof
An appropriate management of HBV infection is the best strategy to finally reduce the total burden of HBV infection. Mother-to-child transmission (MTCT) is responsible for more than one third of chronic HBV infections worldwide. Because HBV infection in infancy or early childhood often leads to chronic infection, appropriate prophylaxis and management of HBV in pregnancy is crucial to prevent MTCT. The prevention of HBV vertical transmission is a complex task and includes: universal HBV screening of pregnant women, administration of antivirals in the third trimester of pregnancy in women with high viral load and passive-active HBV immunoprophylaxis with hepatitis B vaccine and hepatitis B immune globulin in newborns of all HBV infected women. Universal screening of pregnant women for HBV infection, early identification of HBV DNA level in HBV-infected mothers, maternal treatment with class B according to FDA antivirals and passive/active anti-HBV immunoprophylaxis to newborns of HBV-positive mothers are crucial strategies for reducing vertical HBV transmission rates. Consideration of caesarean section in order to reduce the risk of vertical HBV transmission should be recommend in HBV infected pregnant women with high viral load despite antiviral therapy or when the therapy in the third trimester of pregnancy is not available.
Bengsch, Bertram; Martin, Bianca; Thimme, Robert
The upregulation of several inhibitory signalling pathways by exhausted HBV-specific CD8+ T cells in chronic infection is thought to contribute to viral persistence. Blockade of inhibitory receptors to reinvigorate exhausted T cell function is a promising novel therapeutic approach. However, little information is available regarding the relative contribution of individual inhibitory pathways to HBV-specific CD8+ T cell failure and the impact of inhibitory receptor blockade on restoration of T cell function in chronic HBV. 98 HLA-A2+ chronically infected patients were analysed ex vivo for HBV-specific CD8+ T cell responses, the expression of multiple inhibitory receptors and T cell differentiation markers. The effects of inhibitory receptor blockade targeting PD-1, 2B4, Tim-3, CTLA-4, and BTLA were assessed in vitro. In our cohort, ex vivo HBV-specific CD8+ T cell responses were identified preferentially in HBeAg patients with low ALT and low viral load (inactive carriers). We observed a clear hierarchy of inhibitory receptor expression dominated by PD-1. The response to inhibitory receptor blockade was heterogeneous. Compared to the blockade of other inhibitory receptors, blockade of the PD-1 pathway resulted in the strongest increase in function. Of note, a positive effect of PD-1 blockade was linked to intermediate T cell differentiation. Despite the expression of multiple inhibitory receptors by HBV-specific CD8+ T cells, expression and response to blockade was dominated by PD-1. However, PD-1 expression did not predict response to blockade. Rather, response to blockade was associated with intermediate T cell differentiation. These findings have important implications for our understanding of inhibitory receptor blockade as a novel therapeutic strategy. Copyright © 2014. Published by Elsevier B.V.
Zhang, Ka; Pan, Xingfei; Shu, Xin; Cao, Hong; Chen, Lubiao; Zou, Yong; Deng, Hong; Li, Gang; Xu, Qihuan
Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, played an important role in immune-mediated diseases. The promoter region of MIF, which had functional polymorphisms, controlled MIF expression. MIF polymorphism was associated with many inflammatory diseases. But the association of MIF polymorphism with chronic hepatitis B (CHB) or HBV-induced liver cirrhosis (HC) had not yet been reported. In present study, polymorphism of MIF-173 was genotyped in 95 CHB patients, 73 HC patients and 90 healthy controls in southern China. The frequency of MIF-173 C/C genotype in patients with CHB or HC was statistically significantly higher than that in healthy controls, respectively. Moreover, difference in the distribution of MIF-173 C allele between CHB patients and healthy controls was statistically significant. However, there was no statistical relationship between MIF-173 genotype and clinical features in patients with CHB or HC. Our results suggest that MIF-173 C/C polymorphism might be associated with increased risk of CHB or HC in Chinese southern population.
Zhang, Xia; Lv, Lizhi; Ouyang, Xuenong; Zhang, Shi'an; Fang, Jian; Cai, Lirong; Li, Dongliang
Altered expression of TIP30, a tumor suppressor, has been observed in many cancers. In this study, we have evaluated the expression of TIP30 in the tissues of 209 hepatocellular carcinomas (HCC) and their adjacent tissues by using a high-density tissue microarray, and analyzed its correlation with the clinical pathological parameters of the patients. The results revealed negative or weak expression of TIP30 in 43.5% (91/209) of the HCC tissues, and in only 27% (56/209) of the adjacent tissues. The expression level of TIP30 in HCC was inversely correlated with serum alpha-fetoprotein (AFP) levels, HBV infection, and tumor differentiation. Multivariate analysis for survival indicated that serum HBV infection was the most significant predictor of poor prognosis in HCC (P = 0.0023), and TIP30 expression and tumor differentiation were also independent indicators in this respect (P = 0.0364 and P = 0.0397, respectively). Patients with medium or high expression levels of TIP30 (TIP30(++/+++) ) had a better 5-year overall survival rate than those with low/negative (TIP30(+/-) ) expression (P < 0.001). TIP30(+/-/) HBV(+) patients had the worst 5-year overall survival rate, whereas TIP30(++/+++) /HBV(-) patients had the best. To further explore the correlation between TIP30 and HBV infection in HCC, HBV(+) hepatoblastoma cell-line HepG2 2.2.15 and HCC cell-line Hep3B were used. Upon silencing of HBV, we observed an upregulation of TIP30 and decreased cell proliferation. In the in vivo studies, we found that the mice inoculated with HepG2 2.2.15 cells with HBV silencing had a prolonged tumor latency and a longer life span, as compared to the control mice inoculated with untreated control cells. In conclusion, the results suggest that downregulation of TIP30 may result from HBV infection, and subsequently promotes the progression of HCC. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
Zampino, Rosa; Marrone, Aldo; Ragone, Enrico; Costagliola, Loredana; Cirillo, Grazia; Karayiannis, Peter; Ruggiero, Giuseppe; Utili, Riccardo
We evaluated clinical evolution and hepatitis B virus (HBV) molecular changes in heart recipients with chronic HBV infection before transplantation, and studied the effects of lamivudine treatment in patients who experienced HBV reactivation. Nine patients with chronic HBV infection who underwent heart transplantation were investigated. HBV surface/core-promoter/precore/core regions were sequenced. Prior to transplantation, all nine patients had consistently normal ALT and low HBV-DNA levels. Seven experienced HBV reactivation after transplantation (ALT elevated, HBV-DNA>200.000 cps/ml). Lamivudine treatment was initially effective in all patients; three patients during the second year of treatment developed lamivudine resistance-associated mutations (rt-L180M, rt-M204V) with severe disease reactivation, remitted after switch to adefovir treatment. No other significant HBV mutations were identified in the genomic regions studied. Immune suppression is crucial in the reactivation of previous inactive HBV infection and in the liver disease progression in heart recipients. Preemptive lamivudine treatment could be useful in the early management of these patients.
Mendes-Correa, Maria Cássia; Gomes-Gouvêa, Michele S; Alvarado-Mora, Mónica V; Da Silva, Mariliza H; Lázari, Carolina; Cavalcanti, Norma C S; Alonso, Flaviane K; Carpinelli, Cátia C; Uip, David E; Pinho, João R R
This study was carried out to evaluate the prevalence of hepatitis delta virus (HDV) among human immunodeficiency virus (HIV)/hepatitis B virus (HBV) co-infected patients from São Paulo, in the Southeast Region of Brazil. A total of 3259 HIV patients with serological markers for HBV were initially enrolled in the study. Among these patients, 154 (4.7%) were hepatitis B surface antigen (HBsAg)-reactive. Serum samples were obtained from 86 HBsAg-positive patients and were submitted to anti-HDV serological assay. One (1.2%) HIV/HBV patient was found to be anti-HDV-positive, and the HDV infection was confirmed by PCR. Phylogenetic analysis showed that this HDV sequence grouped with other HDV genotype 1 sequences from Mediterranean European countries, suggesting that this virus has a common ancestor with HDV from that region. This patient was probably infected by sexual transmission, as he reported unprotected sexual intercourse with multiple partners over the course of many years but denied intravenous drug use or any travel to the Brazilian Amazon, an area known to have a high HDV prevalence. HDV infection is infrequent in the Southeast Region of Brazil, however there have been a few cases in this region. HIV/HBV patients are at potential risk for HDV infection, therefore investigations for the presence of HDV infection must be carried out in these patients. Copyright © 2011 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
At least 250 million people worldwide are chronically infected with HBV, a small hepatotropic DNA virus that replicates through reverse transcription. Chronic infection greatly increases the risk for terminal liver disease. Current therapies rarely achieve a cure due to the refractory nature of an intracellular viral replication intermediate termed covalently closed circular (ccc) DNA. Upon infection, cccDNA is generated as a plasmid-like episome in the host cell nucleus from the protein-linked relaxed circular (RC) DNA genome in incoming virions. Its fundamental role is that as template for all viral RNAs, and in consequence new virions. Biosynthesis of RC-DNA by reverse transcription of the viral pregenomic RNA is now understood in considerable detail, yet conversion of RC-DNA to cccDNA is still obscure, foremostly due to the lack of feasible, cccDNA-dependent assay systems. Conceptual and recent experimental data link cccDNA formation to cellular DNA repair, which is increasingly appreciated as a critical interface between cells and viruses. Together with new in vitro HBV infection systems, based on the identification of the bile acid transporter sodium taurocholate cotransporting polypeptide as an HBV entry receptor, this offers novel opportunities to decipher, and eventually interfere with, formation of the HBV persistence reservoir. After a brief overview of the role of cccDNA in the HBV infectious cycle, this review aims to summarise current knowledge on cccDNA molecular biology, to highlight the experimental restrictions that have hitherto hampered faster progress and to discuss cccDNA as target for new, potentially curative therapies of chronic hepatitis B. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Laaribi, A B; Bortolotti, D; Hannachi, N; Mehri, A; Hazgui, O; Ben Yahia, H; Babay, W; Belhadj, M; Chaouech, H; Yacoub, S; Letaief, A; Ouzari, H I; Boudabous, A; Di Luca, D; Boukadida, J; Rizzo, R; Zidi, I
Hepatitis B virus (HBV) infection is a global health problem. The mechanisms of immune tolerance in HBV infection are still unclear. The host immune response plays a critical role in determining the outcome of HBV infection. Human leucocyte antigen-G (HLA-G) is involved in immunotolerogenic process and infectious diseases. This study aimed to explore the implication of soluble HLA-G (sHLA-G) and its isoforms in HBV infection. Total sHLA-G (including shedding HLA-G1 and HLA-G5) was analysed by ELISA in 95 chronic HBV patients, 83 spontaneously resolvers and 100 healthy controls (HC). To explore the presence of sHLA-G dimers, we performed an immunoprecipitation and a Western blot analysis on positive samples for sHLA-G in ELISA. The serum levels of sHLA-G were significantly increased in patients with chronic HBV patients compared to spontaneously resolvers and HC (P<.0001). Interestingly, we found an increased level of sHLA-G1 in chronic HBV patients than in spontaneously resolvers and HC (P<.001). In addition, the expression of HLA-G5 seems to be higher in the sera of chronic HBV patients than spontaneously resolvers (P=.026). The analysis of HLA-G dimers showed the presence of homodimers in 93% of chronic HBV patients, 67% in spontaneously resolvers and 60% in HC. These results provide evidence that sHLA-G may have a crucial role in the outcome of HBV infection and could be proposed as a biomarker for infection outcome. Based on its tolerogenic function, HLA-G might be considered as a new promising immunotherapeutic approach to treat the chronic infection with HBV. © 2017 John Wiley & Sons Ltd.
Zarski, J-P; Leroy, V
The treatment of chronic hepatitis B is now based on the using of pegylated interferon or nucleoside or nucleotide analogs. In the majority of cases, these drugs can control viral replication with an hepatitis B virus (HBV) DNA negativation after approximately 6 months of therapy. In case of primary non response, it is necessary to modify antiviral therapy and if resistance appears to combine a nucleoside and a nucleotide analog. In patients treated by nucleoside analog, if HBV DNA is not negative or do not dramatically decreases at the week 24, it is also necessary to add a nucleotide analog. However, for adefovir therapy, it is usually preferable to wait at week 48. In summary, a regular following every 3 months of HBV DNA detection by a sensitive method (Real Time PCR) allows to evaluate the therapeutic efficacy and to prevent the risk of biochemical and clinical rebound due to appearance of resistance mutations.
Lin, Yu-Long; Hou, Jin-Lin; Wang, Zhan-Hui; Sun, Jian; Yan, Li; Luo, Kang-Xian
OBJECTIVE: To investigate the association of hot-spot mutations in hepatitis B virus (HBV) pre-C region with the occurrence and outcome of severe hepatitis B. METHODS: A total of 68 patients with severe hepatitis B negative for hepatits B e antigen (HBeAg) were enrolled in this study, including 6 cases of acute, 38 cases of subacute and 24 chronic severe hepatitis B, with another 44 HBeAg-positive patients with chronic hepatitis B serving as control. Mismatch PCR and restriction fragment length polymorphism analysis were employed to examine the mutations of T1862 and A1896 in this 2 groups of patients. RESULTS: The mutation rates at A1896 and T1862 were 66.7% (4/6) and 0 (0/6) respectively in acute severe hepatitis B cases, 42.1% (16/38) and 15.8% (6/38) in subacute severe hepatitis, 25.0% (6/24) and 16.7% (4/24) in chronic severe hepatitis, and 45.5% (20/24) and 2.3% (1/44) in chronic hepatitis cases. There were significant differences in terms of T1862 mutation between patients with severe hepatitis and chronic hepatitis (P<0.01). CONCLUSION: T1862 mutation is closely related to the exacerbation of chronic hepatitis, while the role of A1896 mutation in this process requires further investigation.
Musyoki, Andrew M; Msibi, Thembeni L; Motswaledi, Mojakgomo H; Selabe, Selokela G; Monokoane, Tshweu S; Mphahlele, M Jeffrey
Human immunodeficiency virus (HIV), Hepatitis B virus (HBV) and Hepatitis C virus (HCV) share routes of transmission. There is limited data on the incidence of active co-infection with HBV and/or HCV in cancer patients infected with HIV in Africa. This was a prospective study based on 34 patients with varied cancer diagnosis, infected with HIV and awaiting cancer therapy in South Africa. HIV viral load, CD4+ cell counts, Alanine-aminotransferase and aspartate aminotransferase levels were tested. Exposure to HBV and HCV was assessed serologically using commercial kits. Active HBV and/or HCV co-infection was detected using viral specific nested PCR assays. HCV 5'-UTR PCR products were sequenced to confirm active HCV infection. Active viral infection was detected in 64.7% of patients for HBV, 38.2% for HCV, and 29.4% for both HBV and HCV. Occult HBV infection was observed in 63.6% of the patients, while seronegative HCV infection was found in 30.8% of patients. In addition, CD4+ cell count < 350 cells/µl was not a risk factor for increased active HBV, HCV or both HBV and HCV co-infections. A total of 72.7%, 18.2% and 9.1% of the HCV sequences were assigned genotype 5, 1 and 4 respectively.The study revealed for the first time a high active HBV and/or HCV co-infection rate in cancer patients infected with HIV. The findings call for HBV and HCV testing in such patients, and where feasible, appropriate antiviral treatment be indicated, as chemotherapy or radiotherapy has been associated with reactivation of viral hepatitis and termination of cancer therapy.
Wang, Li; Zou, Zhi-Qiang; Wang, Kai
Host gene variants may influence the natural history of hepatitis B virus (HBV) infection. The human leukocyte antigen (HLA) system, the major histocompatibility complex (MHC) in humans, is one of the most important host factors that are correlated with the clinical course of HBV infection. Genome-wide association studies (GWASs) have shown that single nucleotide polymorphisms (SNPs) near certain HLA gene loci are strongly associated with not only persistent HBV infection but also spontaneous HBV clearance and seroconversion, disease progression, and the development of liver cirrhosis and HBV-related hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB). These variations also influence the efficacy of interferon (IFN) and nucleot(s)ide analogue (NA) treatment and response to HBV vaccines. Meanwhile, discrepant conclusions were reached with different patient cohorts. It is therefore essential to identify the associations of specific HLA allele variants with disease progression and viral clearance in chronic HBV infection among different ethnic populations. A better understanding of HLA polymorphism relevance in HBV infection outcome would enable us to elucidate the roles of HLA SNPs in the pathogenesis and clearance of HBV in different areas and ethnic groups, to improve strategies for the prevention and treatment of chronic HBV infection. PMID:27243039
Puro, V; Scognamiglio, Paola; Ippolito, G
The report of transmission of viruses, such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), from health care workers (HCWs) to patient has alarmed public opinion with potential repercussions on health organisation. To review available information on cases of transmission of HIV, HBV and HCV from HCW to patient reported worldwide. A literature review was conducted with a Medline search of English language full papers, using the following key terms: HIV, HBV, HCV; healthcare workers, occupational and hospital transmission, outbreak, look back investigation. The Medline search was supplemented by a manual search using reference lists of published studies and proceedings of meetings, including some personal communications already reported in a previous review. Since 1972, 50 outbreaks have been reported in which 48 HBV infected HCWs (39 surgeons) transmitted the infection to approximately 500 persons. To date, 3 cases of transmission of HIV and 8 confirmed cases of transmission of HCV (to a total of 18 patients) from infected healthcare workers to patients have been reported. The factors influencing the transmissibility of infection include: type of procedures performed, surgical techniques used, compliance with infection control precautions, the clinical status and viral burden of the infected HCW and susceptibility of the patient to infection. The risk of transmission of HIV, HBV and HCV from HCWs to patients is associated primarily with certain types of surgical specialties (obstetrics and gynaecology, orthopaedics, cardiothoracic surgery) and surgical procedures that can expose the patient to the blood of the HCW: exposure-prone procedures. Since the early 90's industrialized countries have issued recommendations for preventing transmission of blood-borne pathogens to patients during "exposure prone" invasive procedures. With regard to HBV there is common consent to restricting or excluding HCWs tested HbeAg positive or
Cantini, Fabrizio; Boccia, Stefania; Iannone, Florenzo; Leoncini, Emanuele; Prignano, Francesca; Gaeta, Giovanni Battista
Introduction. Antitumor necrosis factor-alpha (TNF-α) agents are widely used for treatment of rheumatic and dermatological diseases. We conducted the systematic review and meta-analysis to assess the prevalence of HBV reactivation among patients treated with anti-TNF-α. Methods and Findings. A comprehensive literature search of MEDLINE, Scopus, and ISI Web of Knowledge databases was conducted. From 21 studies included in the systematic review, 9 included patients with occult chronic HBV infection and 6 included patients with overt infection while 6 addressed both groups. Based on 10 studies eligible for meta-analysis we report pooled estimate of HBV reactivation of 4.2% (95% CI: 1.4–8.2%, I 2: 74.7%). The pooled prevalence of reactivation was 3.0% (95% CI: 0.6–7.2, I 2: 77.1%) for patients with occult infection, and 15.4% (95% CI: 1.2–41.2%, I 2: 79.9%) for overt infection. The prevalence of reactivation was 3.9% (95% CI: 1.1–8.4%, I 2: 51.1%) for treatment with etanercept and 4.6% (95% CI: 0.5–12.5%, I 2: 28.7%) for adalimumab. For subgroup of patients without any antiviral prophylaxis the pooled reactivation was 4.0% (95% CI: 1.2–8.3%, I 2: 75.6%). Conclusion. Although HBV reactivation rate is relatively low in patients treated with anti-TNF-α for rheumatic and dermatological conditions, the antiviral prophylaxis would be recommended in patients with overt chronic HBV infection. PMID:25114684
Nikolopoulos, Georgios K; Paraskevis, Dimitrios; Psichogiou, Mina; Hatzakis, Angelos
The coinfection of Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) has been associated with increased death rates. However, the relevant research has mostly relied on serologic HBV testing [HBV surface antigen (HBsAg)]. The aim of this work was to explore the relationship of HBV viraemia with overall mortality among HIV/HBV coinfected individuals. The analysis included 1,609 HIV seropositives of a previously described cohort (1984-2003) with limited exposure to tenofovir (12%) and a median follow-up of approximately 5 years. Those with persistent expression of HBsAg were further tested for HBV-DNA. The data were analyzed using Poisson regression models. Totally, 101 participants were chronic carriers of HBsAg (6.28%). Of these, 81 were tested for HBV-DNA. The median HBV-DNA levels were 3.81 log (base-10) International Units (IU)/ml. A third (31%) of those tested for HBV-DNA had received tenofovir. Before developing acquired immune deficiency syndrome (AIDS), the adjusted incidence rate ratio (IRR) for all-cause mortality of coinfected patients with HBV viraemia above the median value versus the HIV monoinfected group was 3.44 [95% confidence interval (CI): 1.05-11.27]. Multivariable regressions in the coinfected group only (n = 81) showed that one log-10 increase in HBV-DNA levels was associated with an elevated risk for death (IRR: 1.24, 95%CI: 1.03-1.49). HBV-DNA levels predict overall mortality in the setting of HIV/HBV coinfection, especially during the period before developing AIDS, and could thus help prioritize needs and determine the frequency of medical monitoring.
Comparative study on the clinical and virological characteristics among patients with single occult hepatitis B virus (HBV), single occult hepatitis C virus (HCV) and occult HBV and HCV dual infection.
Castillo, Inmaculada; Rodríguez-Iñigo, Elena; López-Alcorocho, Juan Manuel; Bartolomé, Javier; Pardo, Margarita; Carreño, Vicente
Occult hepatitis B virus (HBV) and occult hepatitis C virus (HCV) infection are two recently described different forms of HBV and HCV infections. This work compares the clinical, virologic, and histologic characteristics of patients with occult dual infection to those of patients with single occult HBV or HCV infection. Seventy-six patients with abnormal liver function tests of unknown etiology (serum HBsAg, anti-HCV, HBV-DNA, and HCV-RNA negative) were included in the study. Viral genomes were tested in liver by real-time PCR and confirmed by in situ hybridization. Of the 76 patients, 17 had occult HBV infection (intrahepatic HBV-DNA positive, HCV-RNA negative), 35 had occult HCV infection (intrahepatic HCV-RNA positive, HBV-DNA negative) and 24 occult dual infection (intrahepatic HCV-RNA and HBV-DNA). No differences among the three groups were found regarding clinical and epidemiologic data. The median load of intrahepatic genomic and antigenomic HCV-RNA strands was similar between single occult HCV infection and occult HBV and HCV dual infection. The percentage of HCV-infected hepatocytes did not differ between these groups. In occult single HBV infection, intrahepatic levels of HBV-DNA and percentage of HBV-infected hepatocytes were similar to the group of patients with occult dual infection. Finally, no differences were found in histological liver damage among the three groups. In conclusion, liver disease in patients with occult dual infection was not more severe than in patients with single occult HBV or occult HCV infection. Moreover, in occult dual infection there is no a reciprocal inhibition of the viral genomes.
Chang, J Judy; Sirivichayakul, Sunee; Avihingsanon, Anchalee; Thompson, Alex J V; Revill, Peter; Iser, David; Slavin, John; Buranapraditkun, Supranee; Marks, Pip; Matthews, Gail; Cooper, David A; Kent, Stephen J; Cameron, Paul U; Sasadeusz, Joe; Desmond, Paul; Locarnini, Stephen; Dore, Gregory J; Ruxrungtham, Kiat; Lewin, Sharon R
Hepatitis B virus (HBV)-specific T cells play a key role both in the control of HBV replication and in the pathogenesis of liver disease. Human immunodeficiency virus type 1 (HIV-1) coinfection and the presence or absence of HBV e (precore) antigen (HBeAg) significantly alter the natural history of chronic HBV infection. We examined the HBV-specific T-cell responses in treatment-naïve HBeAg-positive and HBeAg-negative HIV-1-HBV-coinfected (n = 24) and HBV-monoinfected (n = 39) Asian patients. Peripheral blood was stimulated with an overlapping peptide library for the whole HBV genome, and tumor necrosis factor alpha and gamma interferon cytokine expression in CD8+ T cells was measured by intracellular cytokine staining and flow cytometry. There was no difference in the overall magnitude of the HBV-specific T-cell responses, but the quality of the response was significantly impaired in HIV-1-HBV-coinfected patients compared with monoinfected patients. In coinfected patients, HBV-specific T cells rarely produced more than one cytokine and responded to fewer HBV proteins than in monoinfected patients. Overall, the frequency and quality of the HBV-specific T-cell responses increased with a higher CD4+ T-cell count (P = 0.018 and 0.032, respectively). There was no relationship between circulating HBV-specific T cells and liver damage as measured by activity and fibrosis scores, and the HBV-specific T-cell responses were not significantly different in patients with either HBeAg-positive or HBeAg-negative disease. The quality of the HBV-specific T-cell response is impaired in the setting of HIV-1-HBV coinfection and is related to the CD4+ T-cell count.
Haché, Chantal; Villeneuve, Jean-Pierre
Chronic hepatitis B is a common disease and approximately 20% of infected patients with compensated cirrhosis will decompensate over 5 years. If untreated, the survival of decompensated cirrhosis is poor (15% at 5 years). The extent of hepatitis B virus (HBV) replication, as assessed by serum HBV-DNA level, is a strong predictor of the risk of disease progression and hepatocellular carcinoma. This provides a rationale for antiviral therapy to arrest progression of liver disease. Lamivudine is a pyrimidine analogue that inhibits HBV-DNA reverse transcriptase. It decreases HBV replication, normalises alanine aminotransferase levels and reduces hepatic inflammation and fibrosis in patients with chronic hepatitis B. This article will focus on the use of lamivudine in patients with HBV-cirrhosis. In patients with compensated HBV-cirrhosis, a randomised, placebo-controlled trial has shown that lamivudine significantly reduced the rate of disease progression and hepatocellular carcinoma development over a 3-year period. In patients with decompensated cirrhosis, treatment with lamivudine can produce spectacular improvements of liver function, but the improvement is slow and a clinical benefit is usually not observed until after at least 3-6 months of treatment. A major drawback of lamivudine treatment is the development of resistance, observed in 15-20% of patients after 1 year and up to 70% after 5 years of continued treatment. Thus, patients with HBV-cirrhosis treated with lamivudine should have regular monitoring of serum HBV-DNA levels and prompt institution of additional antiviral therapy if viral breakthrough is observed. Adefovir, tenofovir and entecavir have demonstrated efficacy in patients with lamivudine resistance. In patients with decompensated cirrhosis, in whom the development of resistance can be fatal, combination therapy (such as lamivudine plus adefovir) may prove more effective than monotherapy and this issue needs further study.
Matsuura, Kentaro; Tanaka, Yasuhito; Hige, Shuhei; Yamada, Gotaro; Murawaki, Yoshikazu; Komatsu, Masafumi; Kuramitsu, Tomoyuki; Kawata, Sumio; Tanaka, Eiji; Izumi, Namiki; Okuse, Chiaki; Kakumu, Shinichi; Okanoue, Takeshi; Hino, Keisuke; Hiasa, Yoichi; Sata, Michio; Maeshiro, Tatsuji; Sugauchi, Fuminaka; Nojiri, Shunsuke; Joh, Takashi; Miyakawa, Yuzo; Mizokami, Masashi
Acute hepatitis B virus (HBV) infection has been increasing through promiscuous sexual contacts, and HBV genotype A (HBV/A) is frequent in patients with acute hepatitis B (AHB) in Japan. To compare the geographic distribution of HBV genotypes in patients with chronic hepatitis B (CHB) in Japan between 2005 and 2006 and between 2000 and 2001, with special attention to changes in the proportion of HBV/A, a cohort study was performed to survey changes in genotypes of CHB patients at 16 hospitals throughout Japan. Furthermore, we investigated the clinical characteristics of each genotype and examined the genomic characteristics of HBV/A isolates by molecular evolutionary analyses. Of the 1,271 patients, 3.5%, 14.1%, and 82.3% were infected with HBV/A, -B, and -C, respectively. In comparison with our previous survey during 2000 and 2001, HBV/A was twice as frequent (3.5% versus 1.7%; P = 0.02). The mean age was lower in the patients with HBV/A than in those with HBV/B or -C. Based on phylogenetic analyses of 11 full-length genomes and 29 pre-S2/S region sequences from patients, HBV/A isolates were imported from Europe and the United States, as well as the Philippines and India. They clustered with HBV/A from AHB patients and have spread throughout Japan. HBV/A has been increasing in CHB patients in Japan as a consequence of AHB spreading in the younger generation through promiscuous sexual contacts, aided by a tendency of HBV/A to induce chronic hepatitis. The spread of HBV/A infection in Japan should be prevented by universal vaccination programs. PMID:19297602
Kaleli, Ilknur; Demir, Melek; Cevahir, Nural; Yılmaz, Mustafa; Demir, Suleyman
Background Infection by hepatitis B virus (HBV) causes complicated biochemical, immunological and histological changes in host immune response against the virus which can be specific or non-specific. Recent attention has focused on neopterin as a marker for the activation of cell mediated immunity. The aim of this study was to define the pattern of neopterin levels in replicative and nonreplicative HBV carriers. Methods Thirty HBV replicative carriers and 25 nonreplicative HBV carriers and 30 healthy adult patients were included this study. Hepatitis markers were determined by commercial kit based on chemilumminesans assay. HBV DNA was quantified by hybrid capture system. Serum neopterin levels were measured by the method of competitive enzyme-linked immunosorbent assay. Results were expressed as mean ± SD and ranges. Results In the nonreplicative group, except for one patient, all the patients' HBeAg were negative and anti-HBe were positive. That particular patient was HBeAg positive and anti-HBe negative. In the replicative group, 23 out of 30 patients have positive HBeAg and negative anti-HBe; 7 out of 30 patients have negative HBeAg and positive anti-HBe. Serum neopterin concentrations were 14.5 ± 10.0 (4.2–41) nmol/L in replicative HBV carriers, 8.9 ± 4.3 (2.1–22) nmol/L in nonreplicative HBV carriers and 7.1 ± 2.2 (4.0–12) nmol/L in the control group. Serum neopterin levels and the rates of abnormal serum neopterin levels in the replicative group were higher than the control group (P < 0.01 and P < 0.05). In the nonreplicative group, serum neopterin levels were not different from those of the control. There was a difference between replicative and nonreplicative groups in the respect of neopterin levels. Conclusion In the hepatitis B infected carriers, elevated neopterin levels may be an indicator of the presence of replication. PMID:17076882
Piroth, Lionel; Launay, Odile; Michel, Marie-Louise; Bourredjem, Abderrahmane; Miailhes, Patrick; Ajana, Faiza; Chirouze, Catherine; Zucman, David; Wendling, Marie-Josee; Nazzal, Dani; Carrat, Fabrice; Rey, David; Binquet, Christine
Although an isolated anti-hepatitis B virus (HBV) core antibody (anti-HBc) serological profile is frequent in human immunodeficiency virus (HIV)-infected patients, data on HBV vaccination in these patients are scarce. A prospective multicenter study was conducted to assess the immunogenicity of HBV vaccination in 54 patients with an isolated anti-HBc profile and undetectable HIV load. They were vaccinated with 1 dose (20 µg) of recombinant HBV vaccine. Those with an anti-HBV surface antibody (anti-HBs) level of <10 mIU/mL 4 weeks after vaccination received 3 additional double doses (40 µg) at weeks 5, 9, and 24. At week 4, 25 patients (46%) were responders. Only the ratio of CD4(+) T cells to CD8(+) T cells was associated with this response in multivariate analysis (odds ratio for +0.1, 1.32; 95% confidence interval, 1.07-1.63; P = .008). At week 28 and month 18, 58% of these patients (14 of 24) and 50% (10 of 20), respectively, maintained anti-HBs level of ≥10 mIU/mL.Among nonresponding patients at week 4, who received further vaccinations, 89% (24 of 27) and 81% (21 of 26) had an anti-HBs level of ≥10 mIU/mL at week 28 and month 18, respectively. The preS2-specific interferon γ T-cell response increased between week 0 and week 28 in patients who finally responded to reinforced vaccination (P = .03). All of the patients with an isolated anti-HBc profile who did not have an anti-HBs titer of >100 mIU/mL 4 weeks after a single recall dose of HBV vaccine should be further vaccinated with a reinforced triple double-dose scheme. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail firstname.lastname@example.org.
Cai, Gang; Nie, Xiaomeng; Li, Lei; Hu, Liang; Wu, Beiying; Lin, Jiafei; Jiang, Cen; Wang, Huaizhou; Wang, Xuefeng; Shen, Qian
T cell antiviral function is impaired during chronic hepatitis B (CHB). Programmed death-1 (PD-1) impairs antiviral T cell responses, but dysfunction is not always reversed by blockade of PD-1 pathway. Whether distinct T cell populations expressing different sets of inhibitory molecules exist has not been determined. We studied the expression of the B and T lymphocyte attenuator (BTLA) on both peripheral blood mononuclear cells (PBMC) and intrahepatic lymphocytes, and the effects of blocking BTLA on circulating and intrahepatic T cells in CHB patients. Sixty-three CHB patients who underwent liver biopsy were enrolled. The expression of BTLA and PD-1 on PBMC and intrahepatic T cells was assessed by flow cytometry with antibodies to T cell differentiation molecules. Functional recovery was evaluated by analyzing production of interferon (IFN)-γ and interleukin (IL)-2 after incubation of T cells with anti-CD3 and irradiated mature dendritic cells in the presence of anti-BTLA, anti-PD-1, or both. Intrahepatic T cells expressed higher levels of BTLA than their peripheral counterparts. A significant fraction of intrahepatic T cells coexpressed BTLA and PD-1 and showed deep exhaustion of T cell responses. Blockade of the BTLA pathway enhanced both intrahepatic and PBMC T cell proliferation and cytokine secretion, and exhibited an additive effect upon blockage of PD-1. Upregulation of inhibitory receptor BTLA restricts T cell responses in CHB. T cell exhaustion by high antigen concentrations exacerbates dysfunction of peripheral and intrahepatic T cells. Blockage of BTLA is a potential therapeutic approach for chronic HBV infection that may act by restoring antiviral T cell responses.
Li, Feng; Cheng, Liang; Murphy, Christopher M.; Reszka-Blanco, Natalia J.; Wu, Yaxu; Chi, Liqun; Hu, Jianming; Su, Lishan
Chronic Hepatitis B Virus (HBV) infection is generally not curable with current anti-viral drugs. Virus rebounds after stopping treatment from the stable HBV covalently-closed-circular DNA (cccDNA). The development of drugs that directly target cccDNA is hampered by the lack of robust HBV cccDNA models. We report here a novel HBV cccDNA technology that will meet the need. We engineered a minicircle HBV cccDNA with a Gaussia Luciferase reporter (mcHBV-GLuc cccDNA), which serves as a surrogate to measure cccDNA activity. The mcHBV-GLuc cccDNA was easily produced in bacteria, and it formed minichromosomes as HBV cccDNA episome DNA does when it was transfected into human hepatocytes. Compared to non-HBV minicircle plasmids, mcHBV-GLuc cccDNA showed persistent HBV-GLuc activity and HBx-dependent gene expression. Importantly, the mcHBV-GLuc cccDNA showed resistance to interferons (IFN) treatment, indicating its unique similarity to HBV cccDNA that is usually resistant to long-term IFN treatment in chronic HBV patients. Most importantly, GLuc illuminates cccDNA as a surrogate of cccDNA activity, providing a very sensitive and quick method to detect trace amount of cccDNA. The mcHBV-GLuc cccDNA model is independent of HBV infection, and will be valuable for investigating HBV cccDNA biology and for developing cccDNA-targeting drugs. PMID:27819342
Liu, Jian-Ying; He, Yi-Feng; Dai, Zhi; Chen, Cai-Zhong; Cheng, Wei-Zhong; Zhou, Jian; Wang, Xin
Purpose Excessive brain iron accumulation contributes to cognitive impairments in hepatitis B virus (HBV)-related cirrhotic patients. The underlying mechanism remains unclear. Hepcidin, a liver-produced, 25-aminoacid peptide, is the major regulator of systemic iron metabolism. Abnormal hepcidin level is a key factor in some body iron accumulation or deficiency disorders, especially in those associated with liver diseases. Our study was aimed to explore the relationship between brain iron content in patients with HBV-related cirrhosis and serum hepcidin level. Methods Seventy HBV-related cirrhotic patients and forty age- sex-matched healthy controls were enrolled. Brain iron content was quantified by susceptibility weighted phase imaging technique. Serum hepcidin as well as serum iron, serum transferrin, ferritin, soluble transferrin receptor, total iron binding capacity, and transferrin saturation were tested in thirty cirrhotic patients and nineteen healthy controls. Pearson correlation analysis was performed to investigate correlation between brain iron concentrations and serum hepcidin, or other iron parameters. Results Cirrhotic patients had increased brain iron accumulation compared to controls in the left red nuclear, the bilateral substantia nigra, the bilateral thalamus, the right caudate, and the right putamen. Cirrhotic patients had significantly decreased serum hepcidin concentration, as well as lower serum transferring level, lower total iron binding capacity and higher transferrin saturation, compared to controls. Serum hepcidin level negatively correlated with the iron content in the right caudate, while serum ferritin level positively correlated with the iron content in the bilateral putamen in cirrhotic patients. Conclusions Decreased serum hepcidin level correlated with excessive iron accumulation in the basal ganglia in HBV-related cirrhotic patients. Our results indicated that systemic iron overload underlined regional brain iron repletion. Serum
Lin, Dong; Ding, Jing; Liu, Jian-Ying; He, Yi-Feng; Dai, Zhi; Chen, Cai-Zhong; Cheng, Wei-Zhong; Zhou, Jian; Wang, Xin
Excessive brain iron accumulation contributes to cognitive impairments in hepatitis B virus (HBV)-related cirrhotic patients. The underlying mechanism remains unclear. Hepcidin, a liver-produced, 25-aminoacid peptide, is the major regulator of systemic iron metabolism. Abnormal hepcidin level is a key factor in some body iron accumulation or deficiency disorders, especially in those associated with liver diseases. Our study was aimed to explore the relationship between brain iron content in patients with HBV-related cirrhosis and serum hepcidin level. Seventy HBV-related cirrhotic patients and forty age- sex-matched healthy controls were enrolled. Brain iron content was quantified by susceptibility weighted phase imaging technique. Serum hepcidin as well as serum iron, serum transferrin, ferritin, soluble transferrin receptor, total iron binding capacity, and transferrin saturation were tested in thirty cirrhotic patients and nineteen healthy controls. Pearson correlation analysis was performed to investigate correlation between brain iron concentrations and serum hepcidin, or other iron parameters. Cirrhotic patients had increased brain iron accumulation compared to controls in the left red nuclear, the bilateral substantia nigra, the bilateral thalamus, the right caudate, and the right putamen. Cirrhotic patients had significantly decreased serum hepcidin concentration, as well as lower serum transferring level, lower total iron binding capacity and higher transferrin saturation, compared to controls. Serum hepcidin level negatively correlated with the iron content in the right caudate, while serum ferritin level positively correlated with the iron content in the bilateral putamen in cirrhotic patients. Decreased serum hepcidin level correlated with excessive iron accumulation in the basal ganglia in HBV-related cirrhotic patients. Our results indicated that systemic iron overload underlined regional brain iron repletion. Serum hepcidin may be a clinical
Background Hepatitis B virus (HBV) can be classified into nine genotypes (A-I) defined by sequence divergence of more than 8% based on the complete genome. This study aims to identify the genotypic distribution of HBV in 40 HBsAg-positive patients from Rondônia, Brazil. A fragment of 1306 bp partially comprising surface and polymerase overlapping genes was amplified by PCR. Amplified DNA was purified and sequenced. Amplified DNA was purified and sequenced on an ABI PRISM® 377 Automatic Sequencer (Applied Biosystems, Foster City, CA, USA). The obtained sequences were aligned with reference sequences obtained from the GenBank using Clustal X software and then edited with Se-Al software. Phylogenetic analyses were conducted by the Markov Chain Monte Carlo (MCMC) approach using BEAST v.1.5.3. Results The subgenotypes distribution was A1 (37.1%), D3 (22.8%), F2a (20.0%), D4 (17.1%) and D2 (2.8%). Conclusions These results for the first HBV genotypic characterization in Rondônia state are consistent with other studies in Brazil, showing the presence of several HBV genotypes that reflects the mixed origin of the population, involving descendants from Native Americans, Europeans, and Africans. PMID:21073730
Li, Wei; Jin, Ronghua; Chen, Peng; Zhao, Guoxian; Li, Ning; Wu, Hao
Bacterial infections are common in patients suffering viral hepatitis and critical for prognosis. However, any correlation between HBV and concomitant bacterial infections is not well characterized. A retrospective study was conducted from Jan 2012 to Jan 2014 on 1333 hospitalized patients infected with bacteria. Among them, 491 HBV-infected patients were co-infected with E. coli (268), S. aureus (61), P. aeruginosa (64) or K. pneumoniae (98). A group of 300 complication-free chronically HBV-infected patients were controls. We found that HBV DNA levels were elevated in patients with each of the bacterial infections (all P < 0.05). ALT and HBeAg were strong determinants of high HBV DNA concentration. Patterns of determinants varied in infections by Gram-positive and Gram-negative bacteria. Patients with HBV DNA ≥ 2000 IU/mL had higher rates of all four concomitant bacterial infections (all P < 0.001). All types of strains isolated from HBV-positive patients showed less resistance to tested antimicrobials. The HBV DNA serum concentrations were inversely correlated to the number of ineffective antimicrobials in E. coli, P. aeruginosa and K. pneumoniae infections (P = 0.022, 0.017 and 0.016, respectively), but not S. aureus (P = 0.194). In conclusion, bacterial infections are associated with a high level of HBV replication, which, in turn, has a significant positive impact on bacterial resistance to antimicrobials. These correlations vary between Gram-negative and Gram-positive bacteria.
Niculescu, Irina; Cupşa, A.M.; Stoian, Andreea Cristina; Dumitrescu, FLorentina; Giubelan, L.I.; Alexandru, D.O.
Background: There are few studies on pediatric HIV-HBV coinfection, so evidences about relationships between the two viruses are scarce. Objectives: influence of HBV infection on virological and immunological response to antiretroviral therapy (ART) in antiretroviral-naïve horizontally HIV-HBV coinfected subjects during early childhood. Material and methods: observational study on 826 HIV+ subjects in evidence of Craiova Regional Centre (CRC); we analyzed the immunological and virological response at 6-12 months after starting first antiretroviral regimens compared in 2 groups: horizontally HIV-HBV coinfected subjects during early childhood (CoS) versus horizontally HIV infected subjects during early childhood without HBV infection (non-CoS). Results: Number of subjects: CoS-66 subjects, non-CoS-132 subjects. Demographic data: CoS-gender ratio F:M=0.886, the majority lived in rural area (57.58%), mean age on diagnosis-9.288±4.607 years, non-CoS-gender ratio F:M=0.859, the majority lived in urban area (53.79%), mean age on diagnosis-10.742±5.107 years. At baseline, HIV category was: CoS-A-1.52%, B-80.30%, C-18.18%, non-CoS-A-2.27%, B-70.45%, C-27.27% (p Chi2=0.332), the mean CD4+ cell count was: CoS-148.33±148.10 cells/ml, non-CoS-163.17±155.39 cells/ml (p Student=0.521) and the mean HIV viral load (HIV VL) was: CoS-5.06±0.80 lgcopies/ml (for 29 subjects), non-CoS-5.04±0.84 lgcopies/ml (for 61 subjects) (p Student=0.978). At the end of the studied period, the mean increase in CD4+ cell count was: CoS-177.068±141.676 cells/ml, non-CoS-176.015±191.751 cells/ml (p Student=0.969) and the mean decrease in HIV VL was: CoS-5.04±0.79 lgcopies/ml, non-COS-4.69±2.04 lgcopies/ml (p Student=0.911). Conclusions: The presence of HBV coinfection does not influence immunological or virological response to ART. PMID:24778861
Bowyer, S.M.; Dusheiko, G.M.; Schoub, B.D.; Kew, M.C.
The authors examined the methylation status of CCGG sites in hepatitis B virus (HBV) DNA to determine whether methylation could be responsible for the selective expression of the HBV surface gene in chronic hepatitis B infection and hepatocellular carcinoma. Infected liver tissue from patients with low levels of viral replication was analyzed for HBV DNA copy number per haploid cell genome. Total cellular DNA, with sufficient HBV DNA, was digested with the restriction endonucleases Msp I and Hpa II, to determine whether the HBV DNA was methylated, or HindIII, to determine whether the HBV DNA was integrated or episomal. The cleavage fragments were analyzed by Southern blotting and hybridization to /sup 32/P-labeled HBV DNA. In replicative chronic hepatitis B, hypomethylation of the HBV genome correlated with HBV expression in both virions and infected tissue. In carriers with nonreplicative infection, it was difficult to ascertain the role of methylation as copy number was low. HBV DNA copy number was also low in 17 out of 29 of the rumor tissues tested and as many as 14 out of 16 of the adjacent non-neoplastic tissues tested. Integrated sequences were hypermethylated in the PLC/PRF/5 cell line and in six of the tumor tissues suggesting that methylation plays a role in HBV gene repression. However, since DNA from five other tumors was hypomethylated, the belief that methylation per se is an absolute determinant of HBV core gene repression does not hold for human hepatocellular carcinoma tissue.
Schinazi, Raymond F; Asselah, Tarik
Approximately 170 million people are chronically infected with HCV and 350 million are chronically infected with HBV worldwide. It is estimated that more than one million patients die from complications related to chronic viral hepatitis, mainly HCC which is one of the most frequent cancers in many countries, especially Africa, the Middle East and Asia. HCV drug development has been impressive, and this revolution led to several direct-acting antiviral agents achieving an HCV cure after only 6-12 weeks. This progress could theorically lead to HCV global elimination making HCV and its consequences a rarity. HBV research and development programs can learn from the HCV experience, to achieve an HBV functional or sterilizing cure. This review will summarize key steps which have been realized for an HCV cure, and discuss the next steps to achieve for an HCV elimination. And also, how this HCV revolution has inspired scientists and clinicians to achieve the same for HBV.
Gao, Shan; Duan, Zhong-Ping; Chen, Yu; van der Meer, Frank; Lee, Samuel S; Osiowy, Carla; van Marle, Guido; Coffin, Carla S
Hepatitis B virus (HBV) variants are associated with nucleos/tide analogue (NA) response and liver disease but it is unknown whether NA influences extrahepatic HBV persistence. To investigate HBV replication and genetic evolution in hepatic and extrahepatic sites of chronic hepatitis B (CHB) before and after NA therapy. A total of 13 paired plasma, peripheral blood mononuclear cells (PBMC), were collected from chronic HBV carriers at baseline and after a median 53 weeks NA therapy as well as liver biopsy (N=7 baseline, N=5 follow-up). HBV covalently closed circular DNA (cccDNA) and messenger (m) RNA in liver and PBMC were analyzed. HBV polymerase (P)/surface (S), basal core promoter (BCP)/pre-core (PC)/C gene clonal sequencing was done in plasma, peripheral blood mononuclear cells (PBMC), and liver. Compare to baseline, at ∼53 weeks follow-up, there was no significant change in HBV cccDNA levels in liver (0.2-0.08 copies/hepatocyte, p>0.05) or in PBMC 0.003-0.02 copies/PBMC, p>0.05), and HBV mRNA remained detectable in both sites. At baseline, BCP variants were higher in PBMC vs. liver and plasma. After therapy, drug resistant (DR) and immune escape (IE) variants increased in liver but IE and PC variants were more frequent in PBMC. HBV P/S diversity was significantly higher in PBMC compared to plasma. Continuous HBV replication occurs in liver and PBMC and shows compartmentalized evolution under selective pressure of potent NA therapy. Copyright © 2017 Elsevier B.V. All rights reserved.
Yan, Li; Han, Ying; Wang, Jingbo; Liu, Jingmei; Hong, Liu; Fan, Daiming
Peripheral blood monocytes (PBMCs) have the potential to differentiate into various progenitor cells. Here we have investigated the differentiation potential of PBMCs derived from patients with HBV related decompensated liver cirrhosis into hepatocyte-like cells. In our clinical trial, the PBMCs from 2 patients were mobilized by the recombinant human granulocyte colony stimulating factor, followed by leukapheresis and transplantation of PBMCs. PBMCs, induced by recombinant human hepatocyte growth factors, were identified by the expression of hepatocyte markers and specific biological functions with biochemical assays in vitro. Patients showed a lasting clinical amelioration for more than one year after transplantation, and hepatocyte-like cells were identified by expressing liver specific genes, synthesizing albumin, urea, aspirate transaminase, and glycogen, which were all similar to the human normal hepatic cell line QZG. Our results clearly demonstrated that mobilized PBMCs from patients with HBV related decompensated liver cirrhosis could differentiate into functional hepatocyte-like cells, indicating the possibility of autologous cell transplantation for treating patients with HBV related decompensated liver cirrhosis.
Cao, Wei; Qiu, Zhifeng; Zhu, Ting; Li, Yanling; Han, Yang; Li, Taisheng
Chronic hepatitis B virus (HBV) infection includes a set of heterogeneous clinical patterns, and core-protein-specific T cell response is important for virus control and disease progression, yet is not well elucidated. To analyze the phenotypic and functional profiles of HBV-core-protein-specific CD8+ T cells in different clinical patterns of chronic HBV infection. A total of 46 HBV patients were recruited and classified according to their clinical status. CD8+ T cell responses in different patterns of chronic HBV infections were tested with flow cytometry using overlapping 15-mer peptides covering HBV core protein. Meanwhile, the CCR7/CD27 phenotypes of these CD8+ T cells were also determined. Frequencies of gamma interferon (IFN-γ) positive CD8+ T cells in inactive HBV surface antigen (HBsAg) carriers in response to the core protein peptide pools were generally stronger than those of chronic HBV carriers and resolved individuals, especially with regards to peptide pool C13-C24. Moreover, phenotypic studies further highlighted the group of CD8+ CCR7-CD27+ T memory cells, which showed significantly higher levels of IFN-γ secretion in inactive HBsAg carriers than those in chronic hepatitis B patients, chronic HBV carriers and resolved individuals. Core-protein-specific T cell response plays an important role in chronic HBV infection. Inactive HBsAg carriers showed a much stronger core-protein-specific cytotoxic T cell response than other types of chronically infected patients. CD8+ CCR7-CD27+ T memory lymphocytes may be crucial in the immune pathogenesis of chronic HBV infection. Copyright © 2014. Published by Elsevier B.V.
Hayes, C Nelson; Chayama, Kazuaki
While an effective vaccine against hepatitis B virus (HBV) has long been available, chronic HBV infection remains a severe global public health concern. Current treatment options have limited effectiveness, and long-term therapy is required to suppress HBV replication; however, complete elimination of the virus is rare. The lack of suitable animal models and infection systems has hindered efforts to unravel the HBV life cycle, particularly the early events in HBV entry, which appear to be highly species- and tissue-specific. Human primary hepatocytes remain the gold standard for HBV replication studies but are limited by availability and variability. While the HepaRG cell line is permissive for HBV replication, other hepatoma cell lines such as HepG2 do not support HBV replication. The recent discovery of sodium taurocholate transporting peptide (NTCP) as a primary receptor for HBV binding has led to the development of replication-competent cell lines such as HepG2-NTCP. Human hepatocytes grown in chimeric mice have provided another approach that allows primary human hepatocytes to be used while overcoming many of their limitations. Although the difficulty in developing HBV infection systems has hindered development of effective treatments, the variability and limited replication efficiency among cell lines point to additional liver-specific factors involved in HBV infection. It is hoped that HBV infection studies will lead to novel drug targets and therapeutic options for the treatment of chronic HBV infection.
Fabrizi, F; Martin, P; Lunghi, G; Ponticelli, C
Dialysis patients remain at risk of acquiring hepatitis B virus (HBV) infection. The issue of the natural history of HBV among patients undergoing long-term dialysis remains unclear. Assessing the natural history of hepatitis B in patients on maintenance dialysis is problematic because of the unique characteristics of this population: serum aminotransferase activity is lower in dialysis patients compared with patients without renal disease; also, chronic hepatitis B has an insidious and prolonged natural history, and the competing mortality from complications of end-stage renal disease may obscure the long-term consequences of hepatitis B. HBV-related liver disease frequently runs an asymptomatic course in dialysis patients and the liver-related mortality in this population is very low; thus, the prognosis for chronic HBV infection in dialysis patients has been reported as benign. However, the frequency of liver cancer in dialysis patients appears higher than that observed in the general population, this has been related to a greater exposure to HBV/HCV. Cirrhosis is not a frequent comorbid condition in the dialysis population of industrialised countries, but the death rate for dialysis patients with cirrhosis is 35% higher than for those without it. In addition, it has been observed that liver disease remains a significant cause of mortality among HbsAg-positive carriers on dialysis in developing countries. The low viral load measured in dialysis patients with persistent HBsAg carriage could be accounted for by the relatively benign course of HBV-related liver disease in this population. Prospective clinical trials are under way to better define the virological features of HBV in the dialysis population.
Mata Marín, José Antonio; Arroyo Anduiza, Carla Ileana; Calderón, Gloria María; Cazares Rodríguez, Sergio; Fuentes Allen, José Luis; Arias Flores, Rafael; Gaytán Martínez, Jesús
We estimated the prevalence and identified the resistance pattern of HBV genotypes H and G in HBV monoinfected and HIV co-infected patients. A cross-sectional prevalence and analytic study were performed in chronic hepatitis B patients at the Hospital de Infectología, La Raza National Medical Center in Mexico City. Chronic HBV monoinfected and HIV co-infected patients were included. HBeAg, HBV viral load and genetic analysis of mutations were collected; CD4+ cells count from HIV co-infected patients and HIV RNA were measured. We calculated the prevalence and exact 95% binomial confidence interval and the Odds ratios (OR) with 95% confidence intervals to assess the relationship between the presence of risk factors and HBV genotypes H or G. We enrolled 77 patients, 67 men and 10 women with 37 HIV co-infected patients. The distribution of HBV genotypes was: HBV genotype H 55 (71% [95% CI 60% to 80%]), HBV genotype G 16 (20.7%), HBV genotype F 4 (5.1%) and HBV genotype A 2 (2.6%). The most frequent mutations presented in 8 HIV co-infected patients and one mono-infected patient with antiretroviral therapy (ART) experience were rtM204V and six of them showed genotype G (6/9). Mono-infected HBV patients exposed more probability to HBV genotype H than co-infected HIV patients OR 13.0 (CI 95% 3.40-49.79), p = 0.0001. In contrast co-infected patients presented less possibility to have genotype H, 0.56 (CI 95% 0.42-0.75). This study confirms the high prevalence of HBV genotype H in Mexico; furthermore, our results suggest that HBV genotype G predominates in co-infected patients. As well, rtM204V and rtL180M mutations are common in HBV-HIV co-infected patients with genotype G and ART experience.
Hasan, K N; Rumi, M A K; Hasanat, M A; Azam, M G; Ahmed, S; Salam, M A; Islam, L N; Hassan, M S
Serological markers of hepatitis B virus (HBV), liver function tests and quantitative estimation of HBV-DNA are important in the assessment of the state of infection and prognosis following treatment for hepatitis B. This study aimed to determine whether low-cost assays, eg hepatitis B e antigen (HBeAg) and liver function tests, could be used for the assessment of infectivity as an alternative to HBV-DNA estimation. We tested 125 hepatitis B carriers for HBeAg, antibody to HBeAg (anti-HBe), and serum HBV-DNA; we also carried out a range of standard liver function tests. Seventy-three subjects were positive and 52 were negative for HBeAg. Of the HBeAg positive cases, 3 were also positive for anti-HBe; of the HBeAg negative cases, 5 were also negative for anti-HBe. Of these 8 cases, 7 had no detectable HBV-DNA. Most of the HBeAg positive but anti-HBe negative subjects were positive for HBV-DNA (74.3%; 52/ 70) whereas most of the HBeAg negative and anti-HBe positive subjects (93.6%; 44/47) were also negative for HBV-DNA. Of 56 HBV-DNA positive individuals, alanine transaminase (ALT) was found to be raised in 69.6% (p=0.066) and aspartate transaminase (AST) was raised in 66.1% (p=0.011), while 67.9% had normal alkaline phosphatase (ALP) (p=0.054). HBeAg (p=0.018) and raised ALT (p=0.008) were found to be independent predictors for HBV-DNA positivity among HBV carriers. This study suggests that HBeAg positive and anti-HBe negative hepatitis B carriers with raised ALT and AST are likely to be positive for HBV-DNA; the combination of routine serology and biochemical tests may be considered as an alternative to HBV-DNA in evaluating the state of chronic HBV infection. However, HBV-DNA should be specifically assessed if discordance is observed between seromarkers and transaminases.
Hamamci, Mevlut; Karaahmet, Fatih; Akinci, Hakan; Kilincalp, Serta; Acıkgoz, Ruchan; Coban, Sahin; Yuksel, Ilhami
HCC is the most common type of primary liver tumor. The Practice Guideline, AASLD, for HCC recommended surveillance of HBV carriers at high risk of HCC with US every 6-12 months. Laboratory surveillance option is the measurement of serum α-fetoprotein level which has long been used for the diagnosis of HCC. But, increased serum levels of α-fetoprotein are also seen in acute hepatitis, cirrhosis, and malignancies include yolk sac carcinoma, neuroblastoma, hepatoblastoma, gastric and lung carcinoma. Because of elevation α-fetoprotein in these malignancies, liver mass with an elevated α-fetoprotein does not directly indicate HCC. For these reason, clinicians evaluating patient with liver mass and HBV-related cirrhosis should be vigilant for other case of α-fetoprotein elevation.
Zhou, Fen; Li, Jianju; Lin, Keke; Ji, Ping; Sun, Yumei
To investigate the anxiety and pregnancy-associated stress of pregnant women with chronic hepatitis B virus (HBV) infection in the People's Republic of China and analyze the relationship between anxiety and pregnancy-associated stress in the hope of finding ways to reduce the stress or improve the coping skills for these mothers-to-be during pregnancy. A cross-sectional study was conducted. One hundred and sixty chronic HBV-infected pregnant women (HBV group) and 160 healthy pregnant women (control group) selected from three Peking University-affiliated hospitals participated in the study, and completed the State-Trait Anxiety Inventory (STAI) and Pregnancy Stress Rating Scale (PSRS) survey. The mean scores of STAI and PSRS for the HBV group were higher than for the control group. Factor 2 of PSRS (stress caused by worrying about mother and child's health and safety) was the highest, and was significantly higher in the HBV group than in the control group. Correlation analysis showed STAI scores were significantly correlated with economic status and diagnosis, as well as the total score, factor 1 (stress about identifying with the role of mother), and factor 2 of PSRS, but not significantly correlated with factor 3 of PSRS (stress caused by the changes of body shape and physical activity). Pregnant women with chronic HBV infection experienced higher levels of anxiety and stress than healthy pregnant women. Their major stress came from concerns for the health and safety of the mother and the child.
Vargas, Jose Ignacio; Jensen, Daniela; Sarmiento, Valeska; Peirano, Felipe; Acuña, Pedro; Fuster, Felipe; Soto, Sabrina; Ahumada, Rodrigo; Huilcaman, Marco; Bruna, Mario; Jensen, Werner; Fuster, Francisco
HBV-HIV coinfection is prevalent. Frequently, anti-HBc is the only serological marker of HBV, which can be indicative of HBV resolved infection, when found together with anti-HBs reactivity; or present as "isolated anti-HBc," related to HBV occult infection with presence of detectable DNA HBV, more prevalent in HIV-positive individuals. Regional data about this condition are scarce. Anti-HBc rapid test has been used as screening, but its performance has not been described in HIV-positive patients. The aim of this study was determine prevalence of anti-HBc in HIV-positive patients, serological pattern of HBV resolved infection and isolated anti-HBc, evaluating presence of HBV occult infection. Assess anti-HBc rapid test compared to ECLIA. Methods included measurement of anti-HBc and anti-HBs in HIV-positive patients with negative HBsAg. Serum HBV DNA quantification and HBV booster vaccination to "isolated anti-HBc" individuals. Detection of anti-HBc by rapid test and ECLIA. In 192 patients, prevalence of anti-HBc was 42.7% (82/192); associated to male gender, drug use, men-sex-men, positive-VDRL, and longer time HIV diagnosis. 34.4% (66/192) had presence of anti-HBs, mean titers of 637 ui/ml. Isolated anti-HBc in 8.3% (16/192), associated to detectable HIV viral load and no-use of HAART; in them, HBV DNA was undetectable, and 60% responded to HBV vaccination booster. Anti-HBc rapid test showed low sensibility (32.9%) compared to ECLIA. These results show that prevalence of anti-HBc in HIV-positive individuals is high, in most cases accompanied with anti-HBs as HBV resolved infection. Low prevalence of "isolated anti-HBc," with undetectable HBV DNA, and most had anamnestic response to HBV vaccination; suggest low possibility of occult HBV infection. Anti-HBc rapid test cannot be recommended as screening method for anti-HBc.
Castillo, Inmaculada; Bartolomé, Javier; Quiroga, Juan Antonio; Carreño, Vicente
Hepatitis C virus (HCV) infection in the absence of detectable antibodies against HCV and of viral RNA in serum is called occult HCV infection. Its prevalence and clinical significance in chronic hepatitis B virus (HBV) infection is unknown. HCV RNA was tested for in the liver samples of 52 patients with chronic HBV infection and 21 (40 %) of them were positive for viral RNA (occult HCV infection). Liver fibrosis was found more frequently and the fibrosis score was significantly higher in patients with occult HCV than in negative ones, suggesting that occult HCV infection may have an impact on the clinical course of HBV infection.
Soriano, Vincent; Puoti, Massimo; Peters, Marion; Benhamou, Yves; Sulkowski, Mark; Zoulim, Fabien; Mauss, Stefan; Rockstroh, Juergen
Nearly 10% of the estimated 36 million people having HIV worldwide suffer from chronic hepatitis B virus (HBV) infection. The advent of new antiviral agents against HBV and the recent availability of improved molecular diagnostic tools have revolutioned the management of HIV/HBV coinfected patients. The present study represents an update of the current knowledge about HBV/HIV coinfection and an intent to provide practical advise about how to give the best care to HIV-infected persons with chronic hepatitis B.
Iqbal, Sajid; Masood, Khalid; Jafer, Osman
Two types of antiviral treatments, namely, interferon and nucleoside/nucleotide analogues are available for hepatitis infections. The selection of drug and dose determined using known pharmacokinetics and pharmacodynamics data is important. The lack of sufficient information for pharmacokinetics of a drug may not produce the desired results. Artificial neural network (ANN) provides a novel model-independent approach to pharmacokinetics and pharmacodynamics data. ANN model is created by supervised learning of 90 patients sample to predict the treatment strategy (lamivudine only and Lamivudine + Interferon) on the basis of viral load, liver function test, visit number, treatment duration, ethnic area, sex, and age. The model was trained with 68 (77.3%) samples and tested with 20 (22.7%) samples. The model produced 92% accuracy with 92.8% sensitivity and 83.3% specificity. PMID:21738322
Yu, Su-Lin; Deng, Hong; Li, Xin-Hua; Huang, Ya-Xin; Xie, Dong-Ying; Gao, Zhi-Liang
Background Persistent hepatitis B virus (HBV) infection is sustained by inadequate immune responses, either natural or acquired. Recent studies have suggested that immune responses to viral infection may be affected by microRNA (miR)-155, via its involvement in immune cell differentiation and maturation. However, little is known on the specific interaction between miR-155 and HBV in host antiviral immunity. Objectives This study evaluated the levels of miR-155 in peripheral blood mononuclear cells (PBMCs) of chronic hepatitis B (CHB) patients, relative to that of healthy subjects, and investigated an association between miR-155 levels and HBV DNA or alanine aminotransferase (ALT). Patients and Methods Total RNA was extracted from peripheral venous blood samples of 90 treatment-naive patients with chronic HBV infection and 20 healthy volunteers. The levels of miR-155 in the PBMCs were measured by real-time quantitative polymerase chain reaction. Serum HBV DNA and liver enzymes were estimated using standard clinical laboratory methods. Results In the HBV-infected patients, the miR-155 levels were significantly lower than in the healthy controls (P = 0.001). Chronic HBV-infected patients with elevated ALT had higher levels of miR-155 compared with patients with normal ALT (P = 0.014). No correlations were found between miR-155 and ALT or HBV DNA. Conclusions The miR-155 appeared to be suppressed during HBV infection. The significantly higher miR-155 levels in ALT-elevated patients infected with HBV suggest that miR-155 levels in PBMCs correlate with the immune state of patients with chronic HBV infection. PMID:27110261
Dalkılıç, Ediz; Öksüz, Mustafa Ferhat; Tufan, Ayşe Nur; Özbek, Aysun; Nizamoğlu, Ali; Dolarslan, Mürside Esra; Coşkun, Belkıs Nihan; Pehlivan, Yavuz
Objective Rheumatoid factor (RF) positivity that may occur in a number of patients with hepatitis B (HBV) infection poses challenges in terms of differential diagnosis with rheumatoid arthritis (RA). On the other hand, antibodies to cyclic citrullinated peptide (anti-CCP) may prove to be an important marker for differential diagnosis of the two conditions. This study aimed to assess anti-CCP and RF positivity among patients with hepatitis B and rheumatoid arthritis. Material and Methods Anti-CCP and RF seropositivity was assessed in 61 patients with HBV infection (32 patients with chronic hepatitis, 29 patients with inactive HBV carrier status) and 40 patients with RA as the control group. Results RF positivity was found in 18.7% and 34.4% of the patients with chronic hepatitis B and inactive HBV carrier status, respectively. On the other hand, only one patient with chronic HBV had low positive anti-CCP. RF was positive in 24 (60%) and anti-CCP was positive in 26 (65%) patients among the 40 patients with RA. Conclusion Anti-CCP may be helpful in the differential diagnosis between RA and chronic HBV infection or inactive HBV carrier status. PMID:27708928
Ling, Zongxin; Liu, Xia; Cheng, Yiwen; Jiang, Xiawei; Jiang, Haiyin; Wang, Yuezhu; Li, Lanjuan
Increasing evidence suggests that altered gut microbiota is implicated in the pathogenesis of hepatitis B virus-induced chronic liver disease (HBV-CLD). However, the structure and composition of the oral microbiota of patients with HBV-CLD remains unclear. High-throughput pyrosequencing showed that decreased oral bacterial diversity was found in patients with HBV-CLD. The Firmicutes/Bacteroidetes ratio was increased significantly, which indicated that dysbiosis of the oral microbiota participated in the process of HBV-CLD development. However, the changing patterns of the oral microbiota in patients with HBV-induced liver cirrhosis (LC) were almost similar to patients with chronic hepatitis B (CHB). HBV infection resulted in an increase in potential H2S- and CH3SH-producing phylotypes such as Fusobacterium, Filifactor, Eubacterium, Parvimonas and Treponema, which might contribute to the increased oral malodor. These key oral-derived phylotypes might invade into the gut as opportunistic pathogens and contribute to altering the composition of the gut microbiota. This study provided important clues that dysbiosis of the oral microbiota might be involved in the development of HBV-CLD. Greater understanding of the relationships between the dysbiosis of oral microbiota and the development of HBV-CLD might facilitate the development of non-invasive differential diagnostic procedures and targeted treatments of HBV-CLD patients harbouring specific oral phylotypes. PMID:26606973
Ling, Zongxin; Liu, Xia; Cheng, Yiwen; Jiang, Xiawei; Jiang, Haiyin; Wang, Yuezhu; Li, Lanjuan
Increasing evidence suggests that altered gut microbiota is implicated in the pathogenesis of hepatitis B virus-induced chronic liver disease (HBV-CLD). However, the structure and composition of the oral microbiota of patients with HBV-CLD remains unclear. High-throughput pyrosequencing showed that decreased oral bacterial diversity was found in patients with HBV-CLD. The Firmicutes/Bacteroidetes ratio was increased significantly, which indicated that dysbiosis of the oral microbiota participated in the process of HBV-CLD development. However, the changing patterns of the oral microbiota in patients with HBV-induced liver cirrhosis (LC) were almost similar to patients with chronic hepatitis B (CHB). HBV infection resulted in an increase in potential H2S- and CH3SH-producing phylotypes such as Fusobacterium, Filifactor, Eubacterium, Parvimonas and Treponema, which might contribute to the increased oral malodor. These key oral-derived phylotypes might invade into the gut as opportunistic pathogens and contribute to altering the composition of the gut microbiota. This study provided important clues that dysbiosis of the oral microbiota might be involved in the development of HBV-CLD. Greater understanding of the relationships between the dysbiosis of oral microbiota and the development of HBV-CLD might facilitate the development of non-invasive differential diagnostic procedures and targeted treatments of HBV-CLD patients harbouring specific oral phylotypes.
Chronic evolution after acute hepatitis B virus infection. During a 13 months period 1977-1978 a total of 129 cases of acute viral hepatitis type B occurred among patients who were admitted with hepatitis to Roslagstull, Hospital, Stockholm, Sweden. Less than 1% progressed to chronicity. Prevalence of Delta superinfection was studied among 60 patients with chronic hepatitis B. Nineteen (32%) were anti-delta positive. The majority of the positive patients were either non-European immigrants or addicts, both 9/19 (47%). Infections with the delta agent was found to have occurred in Stockholm already in the early 1970s. Rate of HBeAg clearance during chronic HBV was studied among 36 HBeAg positive patients. Seroconversion to anti-HBe was noted in 17 patients (47%), whereas HBeAg persisted in 19 during a mean follow-up period of 53 months. The spontaneous annual HBeAg seroconversion rate was 11%. HBeAg clearance occurred as frequently among homosexual men as among patients in other categories. However, 12/14 homosexual men were HBeAg positive after 2 years follow-up, compared with 1/13 drug addicts. Thus, homosexual men seemed to require a longer time for HBeAg seroconversion than i.v. drug addicts. HBV-DNA in serum, a strong indicator of viral particles and infectivity was analysed among patients with HBeAg seroconversion, initial HBeAg negativity and/or delta superinfection. HBV-DNA was found in 75-80% of our HBeAg positive patients. A correlation between chronic liver disease and presence of HBV-DNA in serum was also found. Thus, HBV DNA was found in 63% of patients with CAH or CAH/CI as compared with only 39% of patients with CPH. Delta infected patients had HBV-DNA more often than those without hepatitis D infection. Seven delta infected, anti-HBe positive, patients were still HBV-DNA positive five to eight years later. Therefore delta infected anti-HBe positive patients can be infectious for prolonged periods. Histological outcome. 63% (12/19) anti-delta positive
Nagao, Yumiko; Kawahigashi, Yuji; Sata, Michio
Background: Periodontal disease and systemic health are closely associated. However, there is no data supporting the association between periodontal disease and patients with liver diseases associated with hepatitis C virus (HCV) and/or hepatitis B virus (HBV) infection. Objectives: The aim of this study was to evaluate the association between periodontitis and progression of liver diseases in patients with HCV and/or HBV infection. Patients and Methods: In this retrospective study, 351 patients with HCV- and/or HBV-related liver diseases underwent screening for periodontal disease using the Salivaster® salivary occult blood test from February 2010 to June 2014. Furthermore, we examined the prevalence of fimbrillin (fimA) genotype of Porphyromonas gingivalis (P. gingivalis) in 28 HCV-infected patients visited at our hospital between January 2013 and June 2014. P. gingivalis with fimA genotype with types I to V was further detected using a PCR method. Results: Of 351 patients, 76 patients (group 1) had a strong positive result for salivary occult blood test and 275 patients (group 2) had weak positive or negative test results. Significant factors between the groups were obesity, level of AST, ALT, LDH, ALP, Alb, D.Bil, T.cho, AFP, platelets (Plt), IRI, HOMA-IR, current interferon (IFN) treatment and the daily frequency of tooth brushing. Between-groups analysis indicated that total protein (T.pro) level and liver fibrosis were significant factors. According to multivariate analysis, five factors were associated with periodontal disease as Plt count below 80000, brushing teeth only once a day, current IFN treatment, aged 65 years or older and obesity. The adjusted odds ratios for these five factors were 5.80, 3.46, 2.87, 2.50 and 2.33, respectively, and each was statistically significant. Twenty-eight saliva specimens had positive results for P. gingivalis with fimA genotype types I to V. The prevalence of fimA genotype II was higher in 14 patients with liver
Fouad, Rabab; Abdo, Mahmoud; Eldeen, Hadeel Gamal; Sabry, Dina; Atef, Mira; Ahmed, Rasha; Zayed, Naglaa
Hepatitis delta virus (HDV) usually have an unfavorable clinical outcome in chronic hepatitis B virus (HBV) patients. In Egypt, data about epidemiology, the spectrum of disease, and impact of HDV on HBV infection are rare. To assess the prevalence, clinical and virological characteristics of HDV infection among Egyptian patients with chronic HBV. Adult patients with Hepatitis B surface antigen (HBsAg)-positive were evaluated for the presence of HDV using anti HDV-IgG and HDV RNA by RT-PCR. Routine laboratory investigations, genotypes and subtypes for both HBV and HDV, abdominal sonography, and transient elastography (TE) were done. Liver biopsy was performed only in whenever indicated. One hundred and twenty-one treatment-naïve chronic HBV patients were included. Wild HBV genotype-D2 was found in 98.2% and 81.9% were HBeAg negative. Prevalence of HDV was 8.3% by anti-HDV IgG and 9.9% by RT-PCR. Wild HDV genotype-IIb was reported in 83.3%. HDV infection was more common in males, 90.9% of delta patients were HBeAg negative. Compared to the mono-infected HBV, concomitant HBV/HDV infection was not associated with more derangment in ALT nor advanced stage of fibrosis. 66.7% of HDV patients had significantly lower HBV-DNA level compared to the non-delta patients (P < 0.001). HDV is not uncommon in Egypt. HBV genotype-D was associated with HDV genotype-IIb. Delta infection was associated with negative HBeAg status, reduction of HBV replication, but neither influenced the clinical course nor increased significant liver damage risk.
Lok, Anna S.; Everhart, James E.; Di Bisceglie, Adrian M.; Kim, Hae-Young; Hussain, Munira; Morgan, Timothy R.
Background & Aim Previous studies have suggested that prior exposure to hepatitis B virus (HBV) infection may increase the risk of development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. The aim of this study was to compare the prevalence of previous or occult HBV infection in a cohort of HBsAg-negative patients with histologically advanced chronic hepatitis C in the United States who did or did not develop HCC. Methods Stored sera from 91 patients with HCC and 182 matched controls who participated in the HALT-C Trial were tested for anti-HBc, anti-HBs and HBV DNA. Frozen liver samples from 28 HCC cases and 55 controls were tested for HBV DNA by real-time PCR. Results Anti-HBc (as a marker of previous HBV infection) was present in the serum of 41.8% HCC cases and 45.6% controls (P=0.54); anti-HBc alone was present in 16.5% of HCC cases and 24.7% of controls. HBV DNA was detected in the serum of only one control subject and no patient with HCC. HBV DNA (as a marker of occult HBV infection) was detected in the liver of 10.7% HCC cases and 23.6% controls (P=0.18). Conclusion Although almost half the patients in the HALT-C Trial had serological evidence of previous HBV infection there was no difference in prevalence of anti-HBc in serum or HBV DNA in liver between patients who did or did not develop HCC. In the United States, neither previous nor occult HBV infection is an important factor in HCC development among patients with advanced chronic hepatitis C. PMID:21374690
Kim, Hong; Kim, Bum-Joon
Occult hepatitis B virus infection (HBV) is characterized by HBV DNA positivity but HBV surface antigen (HBsAg) negativity. Occult HBV infection is associated with a risk of HBV transmission through blood transfusion, hemodialysis, and liver transplantation. Furthermore, occult HBV infection contributes to the development of cirrhosis and hepatocellular carcinoma. We recently reported the characteristic molecular features of mutations in the preS/S regions among Korean individuals with occult infections caused by HBV genotype C2; the variants of preS and S related to severe liver diseases among chronically infected patients were also responsible for the majority of HBV occult infections. We also reported that HBsAg variants from occult-infected Korean individuals exhibit lower HBsAg secretion capacity but not reduced HBV DNA levels. In addition, these variants exhibit increased ROS-inducing capacity compared with the wild-type strain, linking HBV occult infections to liver cell damage. Taken together, our previous reports suggest the transmission potential of distinct HBV occult infection-related variants in South Korea. PMID:26084041
Sundquist, Kristina; Sundquist, Jan; Ji, Jianguang
Hepatitis B virus (HBV) infection is one of most common viral infections worldwide. While chronic HBV infection has been shown consistently to be associated with hepatocellular carcinoma, data on associations with cancers at other sites are limited. In this study a total of 10,197 patients were diagnosed with chronic HBV infection in Sweden, and they were retrieved from the nationwide Swedish Hospital Discharge Register and Outpatient Register and linked to Cancer Registry data. Standardized incidence ratios (SIRs) for cancers were calculated for these patients in comparison with the population without HBV infection. Five hundred sixty-seven of whom developed cancer (SIR 1.82 (95% confidence interval (CI) 1.67-1.97)) during the study period. The SIR for hepatocellular carcinoma in patients with HBV infection was 40.58 (95% CI 30.50-50.07). In addition, a total of seven other cancer sites/types showed increased SIRs: cancers of the upper aerodigestive tract, lung, kidney, skin (squamous cell carcinoma), and thyroid gland, and lymphoma and leukemia. The risks of non-Hodgkin lymphoma and acute myeloid leukemia were increased in both Swedish- and foreign-born patients with HBV infection. In summary, chronic HBV infection is a strong risk factor for hepatocellular carcinoma and also increases the risk of seven other cancers. These findings illustrate the need for surveillance for cancers other than hepatocellular carcinoma in patients with HBV infection.
Lin, Guigao; Zhang, Kuo; Li, Jinming
More than 240 million people around the world are chronically infected with hepatitis B virus (HBV). Nucleos(t)ide analogs and interferon are the only two families of drugs to treat HBV currently. However, none of these anti-virals directly target the stable nuclear covalently closed circular DNA (cccDNA), which acts as a transcription template for viral mRNA and pre-genomic RNA synthesis and secures virus persistence. Thus, the fact that only a small number of patients treated achieve sustained viral response (SVR) or cure, highlights the need for new therapies against HBV. The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing system can specifically target the conserved regions of the HBV genome. This results in robust viral suppression and provides a promising tool for eradicating the virus. In this review, we discuss the function and application of the CRISPR/Cas9 system as a novel therapy for HBV. PMID:26540039
Al Kadi, Mohamad; Monem, Fawza
Aim: This study aimed to investigate the association of IFN- γ +874 (T/A) polymorphism with susceptibility to chronic HBV infection in the Syrian population. Background: Accumulating evidence indicate that the inadequate immune responses are responsible for HBV persistency. Therefore, polymorphisms in genes encoding the cytokines, which are responsible for regulation of the immune response, can affect the course and outcome of the infection. The IFN-γ +874 T/A polymorphism affects the expression of IFN-γ, which has been shown to be crucial to HBV clearance. Methods: In this case-control study, 140 samples were collected (70 healthy individuals, 70 chronic HBV patients), and genomic DNA was isolated. Sequencing and ARMS-PCR were performed to genotype the IFN-γ +874 T/A polymorphism. Results: Results of this study showed an association between IFN- γ +874 T/A polymorphism and the susceptibility to chronic HBV infection (P < 0.05). In addition, results showed that the AA genotype increased the risk of chronicity (OR = 3.05, 95% CI = 1.35 – 6.89), whereas the AT and TT genotypes reduced the risk of chronicity (OR = 0.33, 95% CI = 0.150 – 0.753). Conclusion: Results of this study conclude that the IFN- γ +874 T/A polymorphism may be associated with the chronic HBV infection, according to the genetic model AA vs. AT&TT. PMID:28331562
Zhou, Fen; Li, Jianju; Lin, Keke; Ji, Ping; Sun, Yumei
Purpose To investigate the anxiety and pregnancy-associated stress of pregnant women with chronic hepatitis B virus (HBV) infection in the People’s Republic of China and analyze the relationship between anxiety and pregnancy-associated stress in the hope of finding ways to reduce the stress or improve the coping skills for these mothers-to-be during pregnancy. Methods A cross-sectional study was conducted. One hundred and sixty chronic HBV-infected pregnant women (HBV group) and 160 healthy pregnant women (control group) selected from three Peking University-affiliated hospitals participated in the study, and completed the State-Trait Anxiety Inventory (STAI) and Pregnancy Stress Rating Scale (PSRS) survey. Results The mean scores of STAI and PSRS for the HBV group were higher than for the control group. Factor 2 of PSRS (stress caused by worrying about mother and child’s health and safety) was the highest, and was significantly higher in the HBV group than in the control group. Correlation analysis showed STAI scores were significantly correlated with economic status and diagnosis, as well as the total score, factor 1 (stress about identifying with the role of mother), and factor 2 of PSRS, but not significantly correlated with factor 3 of PSRS (stress caused by the changes of body shape and physical activity). Conclusion Pregnant women with chronic HBV infection experienced higher levels of anxiety and stress than healthy pregnant women. Their major stress came from concerns for the health and safety of the mother and the child. PMID:26346004
Kramer, Jennifer R; Hachem, Christine Y; Kanwal, Fasiha; Mei, Minghua; El-Serag, Hashem B
Coinfection with hepatitis A virus (HAV) or hepatitis B virus (HBV) in patients with chronic hepatitis C virus (HCV) is associated with increased morbidity and mortality. The Center for Medicare and Medicaid Services has identified HAV and HBV vaccination as a priority area for quality measurement in HCV. It is unclear to what extent patients with HCV meet these recommendations. We used national data from the Department of Veterans Affairs HCV Clinical Case Registry to evaluate the prevalence and predictors of meeting the quality measure (QM) of receiving vaccination or documented immunity to HAV and HBV in patients with chronic HCV. We identified 88,456 patients who had overall vaccination rates of 21.9% and 20.7% for HBV and HAV, respectively. The QM rates were 57.0% and 45.5% for HBV and HAV, respectively. Patients who were nonwhite or who had elevated alanine aminotransferase levels, cirrhosis, or human immunodeficiency virus were more likely to meet the HBV QM. Factors related to HCV care were also determinants of meeting the HBV QM. These factors included receiving a specialist consult, genotype testing, or HCV treatment. Patients who were older, had psychosis, and had a higher comorbidity score were less likely to meet the HBV QM. With a few exceptions, similar variables were related to meeting the HAV QM. The incidence of superinfection with acute HBV and HAV was low, but it was significantly lower in patients who received vaccination than in those who did not. Quality measure rates for HAV and HBV are suboptimal for patients with chronic HCV. In addition, several patient-related factors and receiving HCV-related care are associated with a higher likelihood of meeting QMs. Copyright © 2010 American Association for the Study of Liver Diseases.
Chronic infection by the hepatitis B virus (HBV) is a dynamic process that results from the interaction between HBV replication and the host's immune response. In accordance with the consensus document of the European Association for the Study of the Liver, treatment is not indicated for the immune tolerant and inactive carrier phases. However, there are situations in the 2 phases (which we could call gray areas of chronic HBV infection) in which the correct categorization of patients is not easy and in which the start of treatment can be proposed. In the immune tolerant phase, treatment could be indicated for health professionals whose responsibilities require their participation in invasive procedures. Treatment could also be indicated for pregnant women who are HBeAg-positive, ALT normal and have high HBV DNA values and for whom oral antiviral treatment is indicated during the last trimester of pregnancy to reduce the risk of vertical HBV transmission from mother to child. For patients in the inactive carrier phase who are HBeAg-negative with persistent normal ALT levels and HBV DNA ≥ 2000 IU/mL, the intensity of the hepatic lesion will determine the indication for treatment. If these patients already have established cirrhosis then treatment is indicated if the HBV DNA is detectable, regardless of the ALT level. Copyright © 2014 Elsevier España, S.L. All rights reserved.
Boyd, Anders; Lacombe, Karine; Lavocat, Fabien; Maylin, Sarah; Miailhes, Patrick; Lascoux-Combe, Caroline; Delaugerre, Constance; Girard, Pierre-Marie; Zoulim, Fabien
In the presence of highly-potent antivirals, persistence of hepatitis B virus (HBV) is most well-characterized by covalently-closed circular DNA (cccDNA) and total intrahepatic DNA (IH-DNA). We sought to determine how antiviral therapy could affect their levels during human immunodeficiency virus (HIV)-HBV co-infection. Sixty co-infected patients from a well-defined cohort with ⩾1 liver biopsy were studied. HBV cccDNA and total IH-DNA were extracted from biopsies and quantified by real-time PCR. Factors associated with intrahepatic viral load were determined using mixed-effect linear regression and half-life viral kinetics during reconstructed follow-up using non-linear exponential decay models. At biopsy, 35 (58.3%) patients were hepatitis B "e" antigen (HBeAg)-positive and 33 (55.0%) had detectable plasma HBV-DNA (median=4.58log10IU/ml, IQR=2.95-7.43). Overall, median cccDNA was -0.95log10copies/cell (IQR=-1.70, -0.17) and total IH-DNA was 0.27log10copies/cell (IQR=-0.39, 2.00). In multivariable analysis, significantly lower levels of cccDNA and total IH-DNA were observed in patients with HBeAg-negative serology, nadir CD4(+) cell counts >250/mm(3), and longer cumulative TDF-duration, but not lamivudine- or adefovir-duration. In post-hoc analysis using reconstructed TDF-duration (median 29.6months, IQR=15.0-36.1, n=31), average half-life of cccDNA was estimated at 9.2months (HBeAg-positive=8.6, HBeAg-negative=26.2) and total IH DNA at 5.8months (HBeAg-positive=1.3, HBeAg-negative=13.6). Intrahepatic viral loads remained detectable for all patients, even with prolonged TDF-exposure. In co-infection, TDF-use is associated with lower levels of HBV replication intermediates and cccDNA. Slow decay of intrahepatic viral loads underscores that TDF is unable to completely block intracellular viral DNA synthesis, which possibly accounts for continuous replenishment of the cccDNA pool. Chronic hepatitis B virus (HBV) is a persistent infection, while the only real way of
Sagnelli, Evangelista; Imparato, Michele; Coppola, Nicola; Pisapia, Raffaella; Sagnelli, Caterina; Messina, Vincenzo; Piai, Guido; Stanzione, Maria; Bruno, Marika; Moggio, Giovanni; Caprio, Nunzio; Pasquale, Giuseppe; Del Vecchio Blanco, Camillo
Occult hepatitis B virus (HBV) infection in patients with chronic hepatitis C has been found associated with severe liver damage, low response to interferon treatment and increased risk of developing HCC. However, doubts remain on its clinical impact and the sensitivity and specificity of its detection. HBV-DNA was sought by PCR in plasma, peripheral blood mononuclear cells (PBMCs) and liver compartments of 89 patients with biopsy proven chronic hepatitis C, using sets of primers for core ("c"), surface ("s"), and x ("x") regions of HBV genome. Occult HBV infection was defined by the presence of HBV-DNA in at least two different PCRs in at least one compartment. Occult HBV infection was detected in 37 (41.6%) of the 89 patients investigated. It was more frequent (80.8%) in 26 anti- HBs negative/anti-HBc positive patients than in 18 anti-HBs/anti-HBc positive (61.1%, P < 0.01) and 45 anti-HBs/anti-HBc negative (11.1%, P < 0.0001), and more frequently in liver (91.9%) than in PBMCs (62.2%) and plasma (32.4%). No association was found between occult HBV infection and the degree of liver necroinflammation and fibrosis. However, considering the 52 patients without occult HBV infection, 51.4% of 35 patients with genotype 1 and 5.9% of 17 with genotype non-1 showed severe fibrosis (P = 0.003); patients with occult HBV infection did not show such difference. Instead of seeking occult HBV infection in patients with chronic hepatitis C, both anti-HBs negative/anti-HBc positive and anti-HBs positive/anti-HBc positive, in plasma alone, more reliable information can also be obtained from the liver tissue and PBMCs.
Zhu, ShaoMing; Waili, Yulituzi; Qi, XiaoTing; Chen, YueMei; Lou, YuFeng; Chen, Bo
The serum C-reactive protein (CRP) is an inflammatory marker. The aim of the present study was to elucidate whether CRP could serve as a potential surrogate marker for 30-day mortality in hospitalized patients with HBV-related decompensated cirrhosis (HBV-DeCi).This was a retrospective cohort study that included 140 patients with HBV-DeCi. All patients were followed up for 1-month. A panel of clinical and biochemical variables were analyzed for potential associations with outcomes using multiple regression models.The serum CRP was significantly higher in nonsurviving patients than in surviving patients. Multivariate analysis demonstrated that CRP levels (odds ratio: 1.047, P = 0.002) and the model for end-stage liver disease score (odds ratio: 1.370, P = 0.001) were independent predictors for mortality.Serum CRP is a simple marker that may serve as an additional predictor of 1-month mortality in hospitalized patients with HBV-DeCi.
Zhu, ShaoMing; Waili, Yulituzi; Qi, XiaoTing; Chen, YueMei; Lou, YuFeng; Chen, Bo
Abstract The serum C-reactive protein (CRP) is an inflammatory marker. The aim of the present study was to elucidate whether CRP could serve as a potential surrogate marker for 30-day mortality in hospitalized patients with HBV-related decompensated cirrhosis (HBV-DeCi). This was a retrospective cohort study that included 140 patients with HBV-DeCi. All patients were followed up for 1-month. A panel of clinical and biochemical variables were analyzed for potential associations with outcomes using multiple regression models. The serum CRP was significantly higher in nonsurviving patients than in surviving patients. Multivariate analysis demonstrated that CRP levels (odds ratio: 1.047, P = 0.002) and the model for end-stage liver disease score (odds ratio: 1.370, P = 0.001) were independent predictors for mortality. Serum CRP is a simple marker that may serve as an additional predictor of 1-month mortality in hospitalized patients with HBV-DeCi. PMID:28121954
Kalyoncu, Umut; Emmungil, Hakan; Onat, Ahmet Mesut; Yılmaz, Sedat; Kaşifoglu, Timuçin; Akar, Servet; İnanç, Nevsun; Yıldız, Fatih; Küçükşahin, Orhan; Karadağ, Ömer; Mercan, Rıdvan; Bes, Cemal; Yazısız, Veli; Yılmazer, Barış; Özmen, Mustafa; Erten, Şükran; Şenel, Soner; Yazıcı, Ayten; Taşçılar, Koray; Kalfa, Melike; Kiraz, Sedat; Kısacık, Bünyamin; Pehlivan, Yavuz; Kılıç, Levent; Şimşek, İsmail; Çefle, Ayşe; Akkoç, Nurullah; Direskeneli, Haner; Erken, Eren; Turgay, Murat; Öztürk, Mehmet Akif; Soy, Mehmet; Aksu, Kenan; Dinç, Ayhan; Ertenli, İhsan
Objective The reactivation of hepatitis B virus (HBV) infection is a well-known event in hepatitis B surface antigen (HbsAg)-positive patients receiving immunosuppressive therapy. The objective of this study was to assess the antiviral practice and course of HBV infection in inflammatory arthritis. Material and Methods Nineteen rheumatology centers participated in this retrospective study. HbsAg-positive patients who were taking disease-modifying antirheumatic drugs and who were being tested for HBV viral load at a minimum of two different time points were included. The case report form (CRF) consisted of demographic data, rheumatic diseases, treatment profiles, transaminase levels, viral hepatitis serological markers, and HBV viral load. The reactivation of HBV was defined as the abrupt rise in HBV replication by an increase in serum HBV DNA levels in a patient with a previously inactive HBV infection. Results In total, the data of 101 (female 50.5%) patients were included (76 patients with inactive HBV carriers and 25 patients with chronic HBV infection). The mean age of patients was 44±12 years, and the mean follow-up duration was 31±22 months. Of the 101 patients, 70 (69.3%) received antiviral treatment. HBV reactivation was detected in 13 of 76 (17.1%) patients with inactive HBV carriers. HBV reactivation was observed less frequently, not although significantly, in those patients receiving antiviral prophylaxis compared with those not receiving prophylaxis [5/41 (12.2%) vs. 8/33 (24.2%), p=0.17]. Forty-two patients (31 patients had inactive HBV carriers) were using anti-tumor necrosis factor agents. HBV reactivation was detected in 6 of the 31 (19.3%) patients. Twenty-five patients had chronic hepatitis, and five (20%) of them had not received antiviral prophylaxis. HBV viral loads were persistently elevated in 7 (28%) of 25 patients (three patients under and four patients not under antiviral treatment). Conclusion HBV reactivation was observed in
Saha, Debraj; Pal, Ananya; Biswas, Avik; Panigrahi, Rajesh; Sarkar, Neelakshi; Das, Dipanwita; Sarkar, Jayeeta; Guha, Subhasish Kamal; Saha, Bibhuti; Chakrabarti, Sekhar; Chakravarty, Runu
Previously we reported that the exposure to hepatitis B virus (HBV) infection serves as a major threat among the treatment naive HIV infected population of eastern India. Hence, molecular characterization of these strains is of utmost importance in order to identify clinically significant HBV mutations. A total of 85 treatment naive HIV/HBV co-infected participants were included of whom the complete basal core promoter/precore region, the core and the whole envelope gene could be successfully sequenced for 59, 57 and 39 isolates respectively. Following phylogenetic analysis, it was found that HBV/D was the predominant genotype with HBV/D2 (38.5%) being the most prevalent subgenotype followed by HBV/A1. The major mutations affecting HBeAg expression includes the A1762T/G1764A (13.6%), G1896A (22%) and G1862T mutation (33.9%) which was predominantly associated with HBV/A1. Moreover, the prevalence of G1896A was considerably high among the HBeAg negative HIV/HBV co-infected subjects compared to HBV mono-infection. The main amino acid substitutions within the MHC class II restricted T-cell epitope of HBcAg includes the T12S (15.8%) and T67N (12.3%) mutation and the V27I (10.5%) mutation in the MHC class I restricted T-cell epitope. PreS1/S2 deletion was detected in 3 isolates with all harboring the BCP double mutation. Furthermore, the frequently occurring mutations in the major hydrophilic loop of the S gene include the T125M, A128V and M133I/L. Therefore, this study is the first from India to report useful information on the molecular heterogeneity of the HBV strains circulating among the treatment naive HIV/HBV co-infected population and is thus clinically relevant.
Saha, Debraj; Pal, Ananya; Biswas, Avik; Panigrahi, Rajesh; Sarkar, Neelakshi; Das, Dipanwita; Sarkar, Jayeeta; Guha, Subhasish Kamal; Saha, Bibhuti; Chakrabarti, Sekhar; Chakravarty, Runu
Previously we reported that the exposure to hepatitis B virus (HBV) infection serves as a major threat among the treatment naive HIV infected population of eastern India. Hence, molecular characterization of these strains is of utmost importance in order to identify clinically significant HBV mutations. A total of 85 treatment naive HIV/HBV co-infected participants were included of whom the complete basal core promoter/precore region, the core and the whole envelope gene could be successfully sequenced for 59, 57 and 39 isolates respectively. Following phylogenetic analysis, it was found that HBV/D was the predominant genotype with HBV/D2 (38.5%) being the most prevalent subgenotype followed by HBV/A1. The major mutations affecting HBeAg expression includes the A1762T/G1764A (13.6%), G1896A (22%) and G1862T mutation (33.9%) which was predominantly associated with HBV/A1. Moreover, the prevalence of G1896A was considerably high among the HBeAg negative HIV/HBV co-infected subjects compared to HBV mono-infection. The main amino acid substitutions within the MHC class II restricted T-cell epitope of HBcAg includes the T12S (15.8%) and T67N (12.3%) mutation and the V27I (10.5%) mutation in the MHC class I restricted T-cell epitope. PreS1/S2 deletion was detected in 3 isolates with all harboring the BCP double mutation. Furthermore, the frequently occurring mutations in the major hydrophilic loop of the S gene include the T125M, A128V and M133I/L. Therefore, this study is the first from India to report useful information on the molecular heterogeneity of the HBV strains circulating among the treatment naive HIV/HBV co-infected population and is thus clinically relevant. PMID:24587360
Salama-Hanna, Joseph; Chen, Grace
Preoperative evaluation of patients with chronic pain is important because it may lead to multidisciplinary preoperative treatment of patients' pain and a multimodal analgesia plan for effective pain control. Preoperative multidisciplinary management of chronic pain and comorbid conditions, such as depression, anxiety, deconditioning, and opioid tolerance, can improve patient satisfaction and surgical recovery. Multimodal analgesia using pharmacologic and nonpharmacologic strategies shifts the burden of analgesia away from simply increasing opioid dosing. In more complicated chronic pain patients, multidisciplinary treatment, including pain psychology, physical therapy, judicious medication management, and minimally invasive interventions by pain specialists, can improve patients' satisfaction and surgical outcome. Copyright © 2013 Elsevier Inc. All rights reserved.
Shi, Jijing; Zhao, Juanjuan; Zhang, Xin; Cheng, Yongqian; Hu, Jinhua; Li, Yuanyuan; Zhao, Xin; Shang, Qinghua; Sun, Yanling; Tu, Bo; Shi, Lei; Gao, Bin; Wang, Fu-Sheng; Zhang, Zheng
Natural killer (NK) cells can induce liver fibrosis remission by killing hepatic stellate cells (HSCs) and producing interferon (IFN)-γ in a mouse model; however, their anti-fibrotic immune-characteristics and regulatory mechanisms by HSCs remain to be determined, especially in livers from HBV-infected liver cirrhosis (LC) patients. We analyzed frequency, phenotype and anti-fibrotic function of hepatic and peripheral NK subsets in 43 HBV-LC patients. We found that hepatic NK subsets from LC patients displayed a decreased frequency, activation status and anti-fibrotic activity compared with those from chronic hepatitis B patients, which were mainly mediated by increased intrahepatic tumour-growth factor (TGF)-β because blockade of TGF-β significantly reversed NK anti-fibrotic function in vitro. In vivo, hepatic NK cells were enriched in proximity to the α-smooth muscle actin (α-SMA+) area within mild fibrosis regions; while in severe fibrotic areas, they were either directly attached to or separated from the α-SMA+ region. NK cells from LC patients could enter HSCs to form emperipolesis (a cell-in-cell structure) and become apoptotic; anti-TGF-β treatment ameliorated this emperipolesis. This finding suggested a novel mechanism by which activated HSCs impair NK cells’ anti-fibrosis capacity through a TGF-β-dependent emperipolesis in LC patients, providing an anti-fibrotic rational by enhancing NK cell activity. PMID:28291251
Shi, Jijing; Zhao, Juanjuan; Zhang, Xin; Cheng, Yongqian; Hu, Jinhua; Li, Yuanyuan; Zhao, Xin; Shang, Qinghua; Sun, Yanling; Tu, Bo; Shi, Lei; Gao, Bin; Wang, Fu-Sheng; Zhang, Zheng
Natural killer (NK) cells can induce liver fibrosis remission by killing hepatic stellate cells (HSCs) and producing interferon (IFN)-γ in a mouse model; however, their anti-fibrotic immune-characteristics and regulatory mechanisms by HSCs remain to be determined, especially in livers from HBV-infected liver cirrhosis (LC) patients. We analyzed frequency, phenotype and anti-fibrotic function of hepatic and peripheral NK subsets in 43 HBV-LC patients. We found that hepatic NK subsets from LC patients displayed a decreased frequency, activation status and anti-fibrotic activity compared with those from chronic hepatitis B patients, which were mainly mediated by increased intrahepatic tumour-growth factor (TGF)-β because blockade of TGF-β significantly reversed NK anti-fibrotic function in vitro. In vivo, hepatic NK cells were enriched in proximity to the α-smooth muscle actin (α-SMA+) area within mild fibrosis regions; while in severe fibrotic areas, they were either directly attached to or separated from the α-SMA+ region. NK cells from LC patients could enter HSCs to form emperipolesis (a cell-in-cell structure) and become apoptotic; anti-TGF-β treatment ameliorated this emperipolesis. This finding suggested a novel mechanism by which activated HSCs impair NK cells' anti-fibrosis capacity through a TGF-β-dependent emperipolesis in LC patients, providing an anti-fibrotic rational by enhancing NK cell activity.
Chevaliez, Stéphane; Dauvillier, Claude; Dubernet, Fabienne; Poveda, Jean-Dominique; Laperche, Syria; Hézode, Christophe; Pawlotsky, Jean-Michel
Sensitive and accurate hepatitis B virus (HBV) DNA detection and quantification are essential to diagnose HBV infection, establish the prognosis of HBV-related liver disease, and guide the decision to treat and monitor the virological response to antiviral treatment and the emergence of resistance. Currently available HBV DNA platforms and assays are generally designed for batching multiple specimens within an individual run and require at least one full day of work to complete the analyses. The aim of this study was to evaluate the ability of the newly developed, fully automated, one-step Aptima HBV Quant assay to accurately detect and quantify HBV DNA in a large series of patients infected with different HBV genotypes. The limit of detection of the assay was estimated to be 4.5 IU/ml. The specificity of the assay was 100%. Intra-assay and interassay coefficients of variation ranged from 0.29% to 5.07% and 4.90% to 6.85%, respectively. HBV DNA levels from patients infected with HBV genotypes A to F measured with the Aptima HBV Quant assay strongly correlated with those measured by two commercial real-time PCR comparators (Cobas AmpliPrep/Cobas TaqMan HBV test, version 2.0, and Abbott RealTime HBV test). In conclusion, the Aptima HBV Quant assay is sensitive, specific, and reproducible and accurately quantifies HBV DNA in plasma samples from patients with chronic HBV infections of all genotypes, including patients on antiviral treatment with nucleoside or nucleotide analogues. The Aptima HBV Quant assay can thus confidently be used to detect and quantify HBV DNA in both clinical trials with new anti-HBV drugs and clinical practice. Copyright © 2017 American Society for Microbiology.
Helaly, Ghada F; El Ghazzawi, Ebtisam F; Shawky, Sherine M; Farag, Farag M
The prevalence of end-stage renal disease has increased dramatically in developing countries. Hepatitis B virus (HBV) infection is a global health problem that represents a significant co-morbidity event that has led to outbreaks of hepatitis B. There are inadequate data concerning occult HBV infection among Egyptian chronic hemodialysis patients. This study aimed to detect occult HBV infection among chronic hemodialysis patients in Alexandria, Egypt. A cross-sectional study was performed on 100 patients with end-stage renal disease that received maintenance hemodialysis and had tested negative for HBV surface antigen. Blood samples were collected before the initiation of hemodialysis. Sera were tested for hepatitis C virus (HCV) and hepatitis B core (HBc) antibodies using ELISA, and HBV DNA was detected by SYBR Green real-time PCR using specific primers for the s and c genes and by nested PCR using pol gene-specific primers. The serum activity of alanine and aspartate aminotransferase (ALT and AST) were also measured. Anti-HCV and anti-HBc antibodies were detected in 34% and 48% of patients, respectively, and 70.6% of anti-HCV positive patients were also positive for anti-HBc antibodies. This association was statistically significant (p=0.001). HBV DNA was detected in 32% of the hemodialysis patients. A significant association was determined between the presence of HBV DNA and anti-HCV positivity (p=0.021). Aminotransferases were elevated in 21% of the studied patients, more often in patients with positive anti-HCV profiles than in patients negative for anti-HCV (p<0.05). In conclusion, the serological markers of HBV infection should be verified with molecular tests to investigate possible occult infections, especially among anti-HBc-positive hemodialysis patients, to improve our understanding of their clinical, laboratory, and epidemiological characteristics.
Enomoto, Hirayuki; Aizawa, Nobuhiro; Nishikawa, Hiroki; Ikeda, Naoto; Sakai, Yoshiyuki; Takata, Ryo; Hasegawa, Kunihiro; Nakano, Chikage; Nishimura, Takashi; Yoh, Kazunori; Ishii, Akio; Takashima, Tomoyuki; Iwata, Yoshinori; Iijima, Hiroko; Nishiguchi, Shuhei
Abstract Nonalcoholic fatty liver disease has been suggested to be associated with alanine aminotransferase (ALT) elevation in hepatitis B virus (HBV)-infected patients with HBe antigen (HBeAg)-negativity and a low HBV-DNA level. However, few studies have evaluated the association according to histological findings of the liver. Among a total of 198 HBV-infected patients who received a percutaneous liver biopsy, we studied the histological and laboratory findings of HBeAg-negative patients without receiving nucleoside/nucleotide analogues treatment (N = 70) in order to evaluate whether hepatic steatosis and its related metabolic disorders were associated with an elevation in ALT levels in HBeAg-negative patients. In HBeAg-negative patients with a high serum HBV-DNA level (≥2000 IU/mL), the level of HBV-DNA was the only significant factor related to ALT elevation. However, in HBeAg-negative patients with a low HBV-DNA level, the serum ferritin level, and histologically observed hepatic steatosis were significantly associated factors with ALT elevation. When we evaluated 2 metabolic variables (serum ferritin and fasting insulin) that are suggested to be relevant to the presence of progressive disease in Japanese patients, we found that the rate of metabolic disorders was significantly higher among patients with a high ALT level and a low HBV-DNA level than it was among those with other conditions. The triglyceride level and the frequency of moderate or severe hepatic steatosis were significantly higher in patients with a low HBV-DNA level than in those with a high HBV-DNA level. Histologically proven hepatic steatosis and its related metabolic disorders are suggested to be involved in the elevation of aminotransferases of HBeAg-negative patients, particularly those with low HBV-DNA levels. PMID:27124068
Omar, Hanan H; Taha, Samaa A; Hassan, Wafaa H; Omar, Hamdy H
Co-infection of schistosomiasis, HBV and HCV is common in countries where schistosomiasis is endemic. Occult hepatitis B occurs in patients at high risk for HBV infection (e.g., patients on hemodialysis, patients receiving blood transfusions). Schistosomal infection is a risk factor of HBV infection that can increase the incidence of occult hepatitis B. We aimed to determine the prevalence of occult hepatitis B in chronic hepatitis C patients with and without schistosomiasis and to assess the effect of schistosomal infection on the increased risk of exposure to HBV infection and to occult hepatitis B. Two hundred chronic hepatitis C patients who were negative for HBsAg participated. All patients were tested for the following: Anti-schistosome antibodies, Anti-HBc, serum HBV DNA, CBC and liver function. The prevalence of occult hepatitis B in CHC patients with/without schistosomiasis were 12.8% and 8.5% (P=0.042), respectively. Next, 63.8% of CHC patients with schistosomiasis were exposed to HBV infection (Anti-HBc +ve) during their lifetime. In conclusion, the prevalence of occult hepatitis B is higher in CHC patients with schistosomiasis compared to those without schistosomiasis. Periodic laboratory investigations of Schistosoma mansoni, HBV and HCV are recommended for the early detection of the infection and, especially in endemic areas, to avoid infection complications.
Yang, Tingting; Chen, Qixia; Li, Dongdong; Wang, Tingting; Gou, Yu; Wei, Bin; Tao, Chuanmin
Background and Aims To investigate the epidemiological features and risk factors of HBV, HCV and syphilis infection among HIV-infected patients in West China Hospital. Methods A retrospective study was conducted with HIV-infected patients from 2014 to 2016 in West China hospital, SCU. Serum makers for HBV, HCV and syphilis were detected. Results Among 894 HIV-infected patients, the prevalence of HIV/HBV, HIV/HCV, HIV/syphilis co-infections was 14.4%, 5.7%, and 18.9% respectively. HIV/HBV/HCV, HIV/HCV/syphilis and HIV/HBV/syphilis triple co-infection was 7 (0.7%), 12(1.3%), 29(3.2%) respectively. The rate of effective vaccination against HBV was only 7.7% in HIV-infected patients. Age (OR = 0.243 95% CI: 0.114 -0.518), ethnicity (OR = 3.654 95% CI: 1.849-7.218) and education level (OR = 0.140 95% CI: 0.033-0.606) are risk factors affecting HIV/HCV co-infection. Conclusions A high prevalence of HIV/syphilis, HIV/HBV and HIV/ HCV co-infection can be observed in west China. The rate for HIV-infected patients who were effectively vaccinated against HBV was fewer than 10%. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Vilajeliu, Alba; Sequera, Víctor-Guillermo; García-Basteiro, Alberto L; Sicuri, Elisa; Aldea, Marta; Velasco, César; Bayas, José M
Hepatitis B virus (HBV) vaccination is recommended for all susceptible chronic pre-hemodialysis and hemodialysis patients. This study assessed the immunogenicity of HBV vaccines (adjuvanted and non-adjuvanted) in chronic kidney disease patients vaccinated at the Hospital Clinic of Barcelona (Spain) between January 2007 and July 2012. In addition, the costs for the health system were evaluated accor-ding to the proportion of vaccine responders after receiving either vaccine. Patients receiving 3 doses of hepatitis B adjuvanted vaccine were 3 times more likely to seroconvert than patients immunized with non-adjuvanted vaccines, OR 3.56 (95% CI 1.84-6.85). This resulted in fewer patients requiring a second course of HBV vaccination and fewer outpatient visits, saving more than €9,500 per 100 patients. The higher immunogenicity of the adjuvanted HBV vaccine would counterbalance the lower costs associated with the non-adjuvanted vaccine.
de Artaza Varasa, Tomás; Sánchez Ruano, Juan José; García Vela, Almudena; Gómez Rodríguez, Rafael; Romero Gutiérrez, Marta; de la Cruz Pérez, Gema; Gómez Moreno, Ana Zaida; Carrobles Jiménez, José María
Vaccination to protect against hepatitis A and B should be part of the routine management of patients with chronic liver disease (CLD). To evaluate the efficacy and safety of hepatitis A virus (HAV) and hepatitis B virus (HBV) vaccination in a group of patients with CLD and to assess the presence of factors predictive of response. We performed a prospective, single-center study in 194 patients (123 men, 71 women; mean age, 48.9+/-10.7 years) with CLD: 107 with chronic hepatitis (CH) and 87 with hepatic cirrhosis (HC), all Child-Pugh class A. The most frequent causes of CLD were HCV infection and alcohol. Patients negative for anti-HAV IgG received the HAV vaccination (1440 ELISA units in two doses) and those with negative HBV serology received the HBV vaccination ( three 20 microg doses). Patients with inadequate response to the latter vaccine received an additional double dose. Thirty patients received a combination vaccine (three doses). Sixty patients (31%) received the HAV vaccine and 150 (77%) patients received the HBV vaccine. Seroconversion was achieved by 91.6% of patients for HAV and by 57% of the patients for HBV. After the additional dose, the response increased to 74%. Efficacy was similar between CH and HC. HBV vaccination was less effective in HC than in CH and the seroconversion rate was significantly lower in patients with HC and previous decompensation. The combination vaccine (30 patients) was highly immunogenic. No adverse effects were registered. HAV vaccination has high efficacy in patients with CLD. Patients with HC respond weakly to HBV vaccination compared with those with CH and especially if there is prior decompensation. The combination vaccine seems particularly effective in patients with CLD. The three vaccines are safe.
Huang, Xin; Tan, Hongzhuan; Li, Xun; Zhou, Shujin; Wen, Shi Wu; Luo, Meiling
The relationship between maternal HBV (hepatitis B virus) infection and pregnancy-induced hypertension (PIH) is inconclusive. Few studies have been conducted in rural areas of China. In order to examine the association between maternal chronic HBV infection and risk of PIH in Liuyang rural area China, we enrolled 6,195 eligible pregnant women in 2010-2011 in selected 14 towns of Liuyang on their first prenatal visit to local maternity care unit. A total of 461 subjects (7.44% (95%CI: 6.79%, 8.10%)) were identified with positive HBsAg status (exposed group) and 5734 were non-HBV carriers (unexposed group). Multivariate log-binomial regression models were used to estimate the risk of PIH, gestational hypertension (GH), and preeclampsia (PE) in relation to maternal chronic HBV infection. There are total of 455 subjects diagnosed with PIH (7.34% (95%CI: 6.70%, 7.99%)), including 371 GH (5.99% (95%CI: 5.40%, 6.58%)) and 81 PE (1.31% (95%CI: 1.07%, 1.64%)). The crude risk ratio between PIH, GH, PE and maternal HBV infection were 1.20 (95%CI: 0.88, 1.64), 1.30(95%CI: 0.93, 1.81) and 0.79 (95%CI: 0.32, 1.93), respectively. After adjustment for gravidity history, abortion history, family history of Diabetes Mellitus (DM) and family history of hypertension, positive HBsAg status was still not significantly associated with PIH (RR = 1.18, 95%CI: 0.87, 1.62), GH (RR = 1.27, 95%CI: 0.91, 1.78) or PE (RR = 0.79, 95%CI: 0.32, 1.95). Additional adjustment for maternal age, marital status, parity history, family history of DM, Body Mass Index at first antenatal visit, folic acid supplementation, smoking status during pregnancy and economic status of living area, multivariate analysis provided similar results. In conclusion, our study found that maternal chronic HBV infection prevalence rate is 7.4% among Liuyang rural area and there is no significant association between maternal HBV infection and the risk of PIH, GH or PE.
Tang, Zong-Sheng; Hao, You-Hua; Zhang, E-Juan; Xu, Chun-Li; Zhou, Yun; Zheng, Xin; Yang, Dong-Liang
The aim of the present study was to investigate the overall clinical expression characteristics of the cluster of differentiation (CD)28 family receptors [CD28, inducible T-cell co-stimulator, programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 and B- and T-lymphocyte attenuator] on T cells in patients with chronic hepatitis B (CHB), analyze the correlations among these receptors and the clinical parameters, and to investigate the effects of PD-1 blockade on the receptor expression profiles, T-cell function and other biological effects. The expression characteristics of the CD28 family of receptors, the effects of PD-1 blockade on the receptor expression profiles and the levels of interferon (IFN)-γ were investigated in the T cells of patients with CHB. In addition, the transcription factor, T-box 21 (T-bet) and GATA binding protein 3 (GATA-3) mRNA expression levels were investigated in the peripheral blood mononuclear cells (PBMCs) of patients with CHB. The expression levels of the CD28 family receptors in the T cells of patients with CHB demonstrated distinct characteristics, for example levels of PD-1 and CTLA-4 on CD4 T cells and ICOS, PD-1, and BTLA on CD8 T cells were increased in cells from patients with CHB compared with those from the healthy individuals. A significant positive correlation was demonstrated among the serum HBV DNA titers and the levels of PD-1 on CD8+ T cells with the highest expression of PD-1 corresponding to viral levels >106 IU/ml. A significant positive correlation was observed between the serum HBV DNA titers and the expression levels of BTLA on CD8+ T cells with the highest expression of BTLA corresponding to viral levels >106 IU/ml. PD-1 blockade altered the expression profiles of CD28 family receptors in the T cells of patients with CHB, partly enhanced T cell function and increased the ratio of T-bet/GATA-3 mRNA in PBMCs. Thus, CD28 family receptors are potential clinical indicators for the rapid
Kramer, Erik Seth; Hofmann, Charlotte; Smith, Paula G; Shiffman, Mitchell L; Sterling, Richard K
Patients with advanced fibrosis are at increased risk of severe outcomes if they develop acute infection with hepatitis A (HAV) or hepatitis B (HBV) viruses. There are no data on the efficacy of combined HAV/HBV vaccination in patients with advanced fibrosis. Our aim was to evaluate the response to the HAV and HBV vaccine alone or in combination for patients with chronic hepatitis C (HCV) and advanced fibrosis and to evaluate the impact of administering the vaccine while patients were receiving peginterferon for treatment of chronic HCV. In this prospective study of patients with advanced fibrosis (Ishak 3-6), those without serologic evidence of prior exposure were vaccinated with either Havrix HAV, Engerix( HBV, or the TWINRIX HAV/HBV combination vaccine as appropriate, and response was defined as the development of anti-HAV or anti-HBV surface antibodies. Of the 162 eligible patients, the prevalence of prior exposure to HAV and HBV was 30 and 18%, respectively. Of the 84 patients vaccinated, 38% received Havrix, 14% Engerix, and 48% TWINRIX. The response to the HAV vaccine was 75% in those receiving Havrix compared to 78% receiving TWINRIX. In contrast, the response to HBV vaccination was 42% in patients receiving Engerix compared to 60% in those vaccinated with TWINRIX (difference 18.3%; OR 0.29; 95% CI: 0.57-7.79). The presence of diabetes was the only risk factor identified for reduced HBV response (P = 0.01). Responses to both HAV and HBV vaccines when administered alone or in combination were lower than expected in patients with HCV and advanced fibrosis, especially in those with diabetes. The observation that the decline in HBV vaccine response was somewhat lower when this was administered alone as opposed to the combination A/B vaccine suggests that the administration of a combination vaccine may enhance the vaccination response to HBV.
Weng, Hong-lei; Feng, De-chun; Radaeva, Svetlana; Kong, Xiao-ni; Wang, Lei; Liu, Yan; Li, Qi; Shen, Hong; Gao, Yun-peng; Müllenbach, Roman; Munker, Stefan; Huang, Tong; Chen, Jia-lin; Zimmer, Vincent; Lammert, Frank; Mertens, Peter R; Cai, Wei-min; Dooley, Steven; Gao, Bin
Proliferation of liver progenitor cells (LPCs) is associated with inflammation and fibrosis in chronic liver diseases. However, how inflammation and fibrosis affect LPCs remains obscure. We examined the role of interferon (IFN)-γ, an important pro-inflammatory and anti-fibrotic cytokine, in LPC expansion in HBV-infected patients and in mice challenged with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)- or choline-deficient, ethionine-supplemented (CDE) diet as well as in primary LPCs and LPC cell line. The CK19 staining scores correlated with inflammation and fibrosis grades in the livers from 110 HBV-infected patients. Nine-month IFN-γ treatment decreased LPC numbers, inflammation, and fibrosis in these HBV-infected patients. Similarly, a two-week IFN-γ treatment also decreased LPC activation in DDC-treated mice. Disruption of IFN-γ or its signaling components (e.g., IFNGR, STAT1, and IRF-1) increased LPC proliferation and liver fibrosis in DDC-fed mice. In contrast, deletion of IFN-γ did not increase, but rather slightly reduced LPC proliferation in CDE-fed mice. In vitro, IFN-γ attenuated proliferation of the LPC cell line BMOL and of primary LPCs from wild type mice, but not STAT1(-/-) or IRF-1(-/-) mice. Furthermore, co-culture assays suggest that IFN-γ can indirectly promote LPC proliferation via the activation of macrophages but attenuate it via the inhibition of hepatic stellate cells. IFN-γ inhibits LPC expansion via the direct inhibition of LPC proliferation and indirect attenuation of liver fibrosis in the DDC model, but it may also enhance LPC expansion via the promotion of inflammation in the CDE model; thereby playing dual roles in regulating LPC proliferation in vivo. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Kang, Lei; Pan, Jiaqian; Wu, Jiaofen; Hu, Jiali; Sun, Qian; Tang, Jing
Approximately 240 million people worldwide are chronically infected with hepatitis B virus (HBV), which represents a significant challenge to public health. The current goal in treating chronic HBV infection is to block progression of HBV-related liver injury and inflammation to end-stage liver diseases, including cirrhosis and hepatocellular carcinoma, because we are unable to eliminate chronic HBV infection. Available therapies for chronic HBV infection mainly include nucleos/tide analogues (NAs), non-NAs, and immunomodulatory agents. However, none of them is able to clear chronic HBV infection. Thus, a new generation of anti-HBV drugs is urgently needed. Progress has been made in the development and testing of new therapeutics against chronic HBV infection. This review aims to summarize the state of the art in new HBV drug research and development and to forecast research and development trends and directions in the near future. PMID:26389937
Guo, Jian-chun; Xiao, Li-na; Xun, Yun-hao
To study on the correlation between chronic asymptomatic HBV carriers (ASC) of yin asthenia constitution and genotypes of HLA-DRB1 and HLA DQA1 alleles. Totally 105 ASC were assigned to two groups according to their constitutions, i.e., the yin asthenia group (47 cases) and the non-yin asthenia group (58 cases). The genotypes of HLA-DRB1 and HLA DQA1 alleles were determined using PCR-SSP. The gene frequency of HLA-DRB1 * 09 allele and HLA-DQA1 * 0301 allele (being 12.1% and 19.1%) were obviously lower in the yin asthenia group than in the non-yin asthenia group (being 27.8% and 39.7%, P < 0.05). The gene frequency of HLA-DRB1 * 11 allele and HLA-DQA1 * 0501 allele were obviously higher in the yin asthenia group (being 12.1% and 28.7%) than in the non-yin asthenia group (4.3% and 9.5%), showing statistical difference (P < 0.05, P < 0.01). HLA-DRB1 * 09 allele and HLA-DQA1 * 0301 allele might be the molecular bases for non-yin asthenia patients with ASC. HLA-DRB1 * 11 allele and HLA-DQA1 * 0501 allele might be the molecular bases for yin asthenia patients with ASC.
Dumaidi, Kamal; Al-Jawabreh, Amer
Occult hepatitis B infection is the case with undetectable HBsAg, but positive for HBV DNA in liver tissue and/or serum. Occult hepatitis B infection among hemodialysis patients in Palestine has been understudied. In this study, 148 hemodialysis patients from 2 northern districts in Palestine, Jenin (89) and Tulkarem (59), were investigated for occult hepatitis B, HBV, HCV infections with related risk factors. ELISA and PCR were used for the detection of anti-HBc and viral DNA, respectively. The overall prevalence of occult hepatitis B infection among the study group was 12.5% (16/128). Occult hepatitis B infection is more prevalent among males with most cases (15/16) from Jenin District. About one-third (42/132) of the hemodialysis patients were anti-HBc positive. Approximately 27% of the hemodialysis patients were infected with HCV. Around 20% (28/140) were positive for HBV DNA, but only 8.2% (12/146) of the hemodialysis patients were positive for HBsAg. The comparison between hemodialysis patients with occult hepatitis B infection and those without occult hepatitis B infection for selected risk factors and parameters as liver Enzyme, age, sex, HCV infection, blood transfusion, kidney transplant, anti-HBc, and vaccination showed no statistical significance between both categories. Duration of hemodialysis significantly affected the rate of HCV infection. HCV is significantly higher in hemodialysis patients with both Diabetes mellitus and hypertension. The prevalence of occult hepatitis B infection among hemodialysis patients is high; requiring stringent control policies. HBsAg assay is insufficient test for accurate diagnosis of HBV infection among hemodialysis patients. © 2014 Wiley Periodicals, Inc.
Sampedro, Blanca; Hernández-López, Cándido; Ferrandiz, José Ramón; Illaro, Aitziber; Fábrega, Emilio; Cuadrado, Antonio; Iruzubieta, Paula; Menéndez, Susana; Cabezas, Joaquín; Crespo, Javier
Computerized physician order entry (CPOE) applications are widely used to prevent medical errors. In our center, a CPOE system has been in use since 2009 on both the inpatient and outpatient levels. A new and simple alert was introduced in the CPOE system to notify healthcare providers of the potential risk of viral reactivation when prescribing biological therapies, thereby facilitating the request for a serological profile (hepatitis B surface antigen [HBsAg], anti-HBc, and anti-HBs) in patients who have not had these tests. Between May 2012 and May 2013, a total of 1,076 patients undergoing biological treatment were included in the implementation of the CPOE in our hospital, resulting in the identification of 4 HBsAg-positive and 69 anti-HBc-positive/HBsAg-negative patients, two of them with positive viral loads. Since the implementation of this alert system, over 90% of patients who were prescribed a biological drug (BD) have undergone serological screening to detect hepatitis B virus (HBV) infection. The use of the alert system has increased the screening rate from less than 50% to 94% for HBsAg and from less than 30% to 85% for anti-HBc in patients for whom a BD is prescribed. Six patients received prophylactic antiviral therapy. No patient had HBV reactivation. This study demonstrates the feasibility of implementing a CPOE system that has allowed our hospital to increase the rate of HBV screening. Its use has facilitated the identification of patients at high risk for HBV reactivation and permitted physicians to prescribe prophylactic measures according to current guidelines. © 2014 by the American Association for the Study of Liver Diseases.
Liu, Miao; Du, Lingyao; He, Zhiliang; Yan, Libo; Shi, Ying; Shang, Jin
Aim. ERp57 is involved in virus induced endoplasmic reticulum stress (ERS) and plays an important role in tumorigenesis. This study aimed to find whether HBV infection altered ERp57 expression and whether ERp57 regulation was involved in hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) genesis. Materials and Methods. HBV-HCC tissues, chronic hepatitis B (CHB) liver tissues, and normal liver tissues were acquired. ERp57 expressions in these tissues were detected through immunohistochemistry (IHC). And ERp57 expression in liver cell line L02, HBV replicative liver cell line L02-pHBV4.1, and HCC cell lines were detected through western blot for verification. Then medical data on patients providing HCC tissues were collected and analyzed along with ERp57 expression. Results. Higher ERp57 expression was found in HCC and CHB tissues (p < 0.001). And HCC cell lines and L02-pHBV4.1 presented higher ERp57 expression as well. In patients, ERp57 expression showed significant differences between death and survival groups (p = 0.037). And cumulative survival in patients with higher ERp57 (score ⩾ 8.75) is significantly lower (p = 0.009). Conclusion. Our study found increased expression of ERp57 in HBV-HCC. Such altered expression could be related to HBV infection and high ERp57 expression may lead to poor prognosis of HBV-HCC patients. PMID:28373975
PHENYTOIN/SORAFENIB [VA Drug Interaction]; Liver Neoplasms; Carcinoma, Hepatocellular; Digestive System Neoplasms; Neoplasms by Site; Liver Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; DOXORUBICIN/TRASTUZUMAB [VA Drug Interaction]; HBV
Zhao, Ping-Wei; Shi, Xu; Li, Cong; Ayana, Desalegn Admassu; Niu, Jun-Qi; Feng, Jun-Yan; Wang, Juan; Jiang, Yan-Fang
This study aimed to investigate the potential effect of interleukin 33 (IL-33) on humoral responses to hepatitis B virus (HBV) and the possible mechanisms underlying the action of IL-33 in regulating follicular helper T (TFH) cells. The impact of IL-33 treatment on the levels of serum HBV DNA, HBsAg, HBeAg, HBsAb, and HBeAb, as well as the frequencies of CD4(+)CXCR5(+) TFH cells in wild-type HBV transgenic (HBV-Tg) mice and in a transwell coculture of HepG2.2.15 with IL-33-treated peripheral blood mononuclear cells (PBMCs) were determined. Furthermore, the gene transcription profiles in IL-33-treated TFH cells were determined by microarrays. IL-33 treatment significantly reduced the levels of serum HBV DNA, HBsAg, and HBeAg, but increased the levels of HBsAb and HBeAb in HBV-Tg mice, accompanied by increased frequency of splenic infiltrating CD4(+)CXCR5(+) TFH cells in HBV-Tg. Similarly, coculture of HepG2.2.15 cells with IL-33-treated PBMCs reduced the levels of HBV DNA, HBsAg, and HBeAg, but increased the levels of HBsAb and HBeAb. Microarray analyses indicated that IL-33 significantly modulated the transcription of many genes involved in regulating TFH activation and differentiation. Our findings suggest that IL-33 may activate TFH cells, promoting humoral responses to HBV during the pathogenic process.
Chantratita, Wasun; Song, Keum-Soo; Pongthanapisith, Viroj; Thongbaiphet, Nipa; Angkanavin, Kanokwan; Nimse, Satish Balasaheb; Sonawane, Mukesh Digambar; Kim, Taisun
A significant proportion of patients with chronic Hepatitis B infection require antiviral therapy during their life time. The Antiviral therapy with lamivudine or adefovir or telbivudine has shown to be a major risk factor for selection of resistance. Eighty percent of patients showed a development of lamivudine-resistant strains after five years of treatment with lamivudine alone. Adefovir and telbivudine inhibit HBV with very high efficacy and have moderate incidences of drug resistance. Entecavir and tenofovir have been shown to have a higher barrier to resistance with rates of less than 1.5% after five years of treatment. The rtA181V, rtM204V/I, rtN236T and, rtM250V are high prevalent mutations found in the drug-resistant HBV strains. Therefore, for accurate treatment of HBV-infected patients, it is important to discriminate the drug-resistant HBV strains by using simple and accurate detection method. In this study, we describe the HBV/4DR 9G test and its evaluation by using clinical samples and plasmid DNA standards with a range of HBV mutation sites. In tests with 384 plasmid DNA standards, the HBV/4DR 9G test showed higher than 95% sensitivity and 98% specificity. The HBV/4DR 9G test was compared with the INNO-LiPA HBV Multi DR test for detection of drug-resistant HBV strains only in clinical samples. The plasma samples were collected from patients suspected with HBV drug-resistant strain infection. The results of both tests were cross-checked with the HBV DNA sequence analysis. The HBV/4DR 9G test demonstrated a good agreement with the sequencing results as compared to the INNO-LiPA HBV Multi-DR test. These results indicate that the HBV/4DR 9G test can be a reliable, sensitive, and accurate diagnostic tool for the detection of drug-resistant genotypes of HBV in clinical specimens. HBV/4DR 9G test can genotype 4 drug resistant HBV strains in 1 PCR. The HBV/4DR 9G test will help to minimize the risk of HBV patients from liver cancer. Copyright © 2016
Khan, M R; Chowdhury, M S; Saha, M; Roknuzzaman, S M; Mahmuduzzaman, M; Miah, A R; Roy, P K; Raihan, M A; Rahman, K M
Hepatitis B virus (HBV) infection is a major public health problem in the world. About 30% of world population has serological evidence of HBV infection. The prevalence of chronic hepatitis B in Bangladesh is reported to be 7.8%. Several potentially effective agents with different mechanisms of action have entered clinical practice and adefovir dipivoxil is one of them. Studies on the efficacy of adefovir dipivoxil in Bangladeshi patients are lacking. This was a prospective study to find out the effect of one year adefovir therapy in patients with chronic hepatitis B virus infection who were HBeAg positive. Total number of patients included in this study was 68. Among them 53(77.94%) patients continued the therapy and completed follow up. At the end of one year of therapy, intention to treat analysis showed that the rate of response (HBeAg seroconversion and HBV DNA negative) was 37.73% which was comparable to the results obtained in other studies. There was major difference in the pre treatment serum ALT level between the responders and non-responders. Comparison of reduction of serum ALT level before treatment and after treatment showed that ALT level to be lower in both responder group and non responder group. Adefovir was effective in replicative HBV infection in Bangladeshi population. So we suggest that treatment can be started and subsequent follow up can be done in chronic HBV patients who are HBeAg positive without liver biopsy.
Xu, Zhen; Chen, Lu-biao; Cao, Hong; Shu, Xin; Xu, Qi-huan; Li, Gang; Xie, Qi-feng
To investigate the efficacy of the 96-week antiviral therapy with adefovir dipivoxil in patients with chronic hepatitis B. 80 patients with chronic hepatitis B received the antiviral therapy of adefovir dipivoxil (ADV, 10 mg/d). At the 12th week, 19 cases without early viral response (EVR, HBV DNA drop < 2 log10copies/ml) switched to the therapy of other nucleoside analogues. Aminotransferase (ALT) normalization, HBV DNA negative, HBeAg loss and HBeAg seroconvertion were accessed at the 96th week. At week 96, ALT normalization and HBV DNA negative in 61 patients with ADV therapy were 85.25% (52/61) and 95.08% (58/61); and HBeAg loss and HBeAg seroconvertion were 52.52% (17/33) and 42.42% (14/33) respectively. While for the other 19 patients switching to other nucleoside analogues, ALT normalization and HBV DNA negative came to 57.89% (11/19) and 68.42% (13/19). Both HBeAg loss and HBeAg seroconvertion were 58.33% (7/12). Long term ADV antiviral therapy is effective to inhibit HBV DNA replications and benefits patients with chronic hepatits B. Switching to another nucleoside analogue is an optimal alternative if there is no EVR at week 12 in ADV therapy.
Quarleri, J.; Moretti, F.; Bouzas, M.B.; Laufer, N.; Carrillo, M. Gómez; Giuliano, S. Fernández; Pérez, H.; Cahn, P.; Salomon, H.
Hepatitis B virus (HBV) genotypes were examined in HIV-infected patients with chronic and occult HBV infection. From a total population of 593 HIV-infected patients, 22 individuals (prevalence 3.7%) were found to be HBsAg while 72 (12.1%) were found to be anti-HBc alone. From them, 20 and 4 were HBV DNA positive, respectively. These last four patients are therefore considered to be HBV infected in an occult form. The genotypes could be determined in all 24 HBV-infected patients. HBV-A was the most common (20/24; 83.3%), followed by HBV-D (2/24; 8.3%) and HBV-F (1/24; 4.2%). The remaining sample exhibited mixed infection involving genotypes A and D as pure ones, thus also forming part of three intergenotypic recombinant forms exhibiting different mosaic S gene patterns. The sexual route of transmission was predominant among HBV genotype A-infected patients. Among the 24 HBV DNA-positive patients, point mutations related to lamivudine resistance were found in four strains. These viral strains showed a methionine-to-valine substitution at codon 204 (rtM204V) in association with an upstream B-domain change at rtL180M. Additionally, two of them exhibited the additional rtV173L mutation. The value of HBV molecular monitoring including both HBV viral genomic characterization and genotypic resistance profile in HIV-HBV-coinfected individuals is discussed. PMID:17506609
Ding, Feng; Yu, Hong-Gang; Li, Yan-Xia; Cui, Ning; Dai, Jin-Fen; Yu, Jie-Ping
The coexistence of hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs) in patients with hepatitis B virus (HBV) infection has been discovered and explained for several decades, but debate still exists. This study was to explore the relationship between this special serological pattern and mutations in S gene region. Fifteen patients with coexisting HBsAg and anti-HBs were selected as the experimental group, and 27 patients with HBsAg positive only were selected as the control group. The S gene region was amplified and sequenced. No significant differences were observed between the two groups with regard to age, gender, alanine aminotransferase level, HBsAg titer, genotype, and HBV DNA level. The patients from the two groups were infected with HBV of the genotype B and C. Compared with the control group, the experimental group showed a higher variability in amino acid within the N-terminal region and the MHR, especially the "a" determinant. The most frequent change in patients from the experimental group was located at positions s126. The coexistence of HBsAg and anti-HBs might be associated with the increased amino acid mutations in the "a" determinant. Further studies should be performed to determine the clinical implication of this serological pattern, including the binding of anti-HBs to HBsAg, escape from immune system, and efficacy of antiviral therapy.
Shen, Xiaokun; Fu, Binqing; Liu, Yanyan; Guo, Chuang; Ye, Ying; Sun, Rui; Li, Jiabin; Tian, Zhigang; Wei, Haiming
A pressing need exists for improved therapeutic options for chronic hepatitis B (CHB). Pegylated-interferon-alpha (Peg-IFN-α) achieves sustained off-treatment responses in many cases because of its direct anti-viral effects and regulation of the immune response. However, non-responsiveness to Peg-IFN-α is frequent, and the mechanism is poorly understood. In this study, we found that the frequency and absolute number of NKp30+ natural killer (NK) cells increased markedly, accompanied by enhanced CD107a and IFN-γ production, during Peg-IFN-α-2b monotherapy or combination therapy with adefovir dipivoxil in patients with CHB, especially in responders. The responders and non-responders differed in the frequency of polyfunctional IFN-γ+ CD107+ NK cells. In addition, the increase in NKp30+ NK cells was negatively correlated with the HBV viral load and plasma HBeAg. Moreover, it was found that IL-15 may contribute to the up-regulation of NKp30 on the NK cells, and this up-regulation was not induced in vitro by Peg-IFN-α-2b alone. However, in the non-responders, these NKp30+ NK cells were dysfunctional because of increased NKG2A expression, which partly explains the inactivation of NKp30+ NK cells and the reduced capacity of these cells to produce antiviral cytokines. These findings may provide a new mechanism to explain the variable efficacy of Peg-IFN-α-2b therapy. PMID:27941937
Su, Fu-Hsiung; Huang, Hsiao-Yun; Chang, Hong-Jer; Jeng, Jin-Ju; Liu, Yi-Hui; Chen, Chih-Dao
Prior to the introduction of universal hepatitis B virus (HBV) vaccination in Taiwan in 1984, 15-20% of the general population were chronic HBV carriers. We forecasted and quantified the declining HBV carrier rate 20 years subsequent to the implementation of universal HBV vaccination in Taiwan. At a Taiwanese university, 28,763 freshmen tested for serum HBsAg level were divided into ten age cohorts by date of birth, from July 1976 to June 1986 inclusive. Comparisons of HBsAg carrier rates according to gender were examined with the Z test. Regression methods and a time series model were applied to our sample to forecast trends in changes to the HBsAg carrier rate for the next five years. Regression analysis demonstrated a trend toward declining HBsAg-positive carrier rates. The HBsAg carrier rate for male students decreased from 16.8% (for those born between July 1976 and June 1977) to 2.2% (for those born between July 1985 and June 1986). The carrier rate for their female counterparts over the same period declined from 12.2% to 2.4%. The HBsAg carrier rate for male participants was significantly greater than that of their female counterparts for certain years during the test period. The results of time series analysis suggests the HBsAg carrier status rate will approach zero for students born after July 1987 (expected to enrol in the university in 2006). Our data demonstrate that in order for the HBV carrier rate to approximate zero, universal vaccination programs need to continue for at least 21 years.
A European multicientre study on the comparison of HBV viral loads between VERIS HBV assay and Roche COBAS(®) TAQMAN(®) HBV test, Abbott RealTime HBV assay, Siemens VERSANT HBV assay, and Qiagen artus HBV RG kit.
Braun, Patrick; Delgado, Rafael; Drago, Monica; Fanti, Diana; Fleury, Hervé; Izopet, Jacques; Lombardi, Alessandra; Marcos, MaAngeles; Sauné, Karine; O'Shea, Siobhan; Pérez-Rivilla, Alfredo; Ramble, John; Trimoulet, Pascale; Vila, Jordi; Whittaker, Duncan; Artus, Alain; Rhodes, Daniel
Hepatitis B viral load testing is essential to treatment and monitoring decisions in patients with chronic Hepatitis B. Beckman Coulter has developed the VERIS HBV Assay (Veris) for use on the fully automated DxN VERIS Molecular Diagnostics System.(1) OBJECTIVES: To evaluate the clinical performance of the Veris HBV Assay at multiple EU laboratories STUDY DESIGN: Method comparison was performed with a total of 344 plasma specimens from HBV infected patients tested with Veris and COBAS(®) TaqMan(®) HBV Test (Cobas), 207 specimens tested with Veris and RealTime HBV Assay (RealTime), 86 specimens tested with Veris and VERSANT(®) HBV Assay (Versant), and 74 specimens tested with Veris and artus(®) HBV RG PCR kit (artus). Bland-Altman analysis showed average bias of -0.46 log10 IU/mL between Veris and Cobas, -0.46 log10IU/mL between Veris and RealTime, -0.36 log10IU/mL between Veris and Versant, and -0.12 log10IU/mL between Veris and artus. Bias was consistent across the assay range. Patient monitoring results using Veris demonstrated similar viral load trends over time to Cobas, RealTime, and artus. The VERIS HBV Assay demonstrated comparable clinical performance, with varying degrees of negative bias, compared to other currently marketed assays for HBV DNA monitoring. This negative bias should be taken into consideration if switching monitoring methods to Veris. Copyright © 2017 Elsevier B.V. All rights reserved.
Gane, Edward J
Although current oral antivirals can maintain viral suppression and reduce the risk of liver-related complications, lifelong therapy is associated with high cost, risk of breakthrough and potential toxicity. There is a need to develop a finite course of treatment which can provide sustained off-treatment virological and clinical response. The likely marker of such a clinical HBV CURE would be HBsAg clearance, but in addition cccDNA elimination would be required to prevent future reactivation (ie complete HBV cure). Chronic HBV infection is characterised by high viral and antigen burden and inadequate host immune responses, both of which will need to be overcome to achieve HBV CURE. Innovative approaches to restore innate and adaptive immune responses against HBV currently in clinical development include therapeutic vaccines, TLR-7 and TLR-8 agonists. In future, strategies to reverse T-cell exhaustion such as checkpoint inhibitors may be feasible. Currently, the only antivirals in clinical use are the HBV polymerase inhibitors. However, many other steps of HBV virion life cycle can be targeted by small molecules, including inhibitors of HBV entry, nucleocapsid formation and virion assembly and release. siRNAs could inhibit many different steps by blocking multiple HBV transcripts. But, the ultimate goal will be to successfully eradicate or silence cccDNA. It is likely that successful HBV cure will require combination of immunomodulatory, antiviral and cccDNA silencing strategies. Efficacy, safety, route of administration and cost will ultimately determine the impact of these new regimens on the burden of HBV. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Shih, Yao-Ming; Sun, Cheng-Pu; Chou, Hui-Hsien; Wu, Tzu-Hui; Chen, Chun-Chi; Wu, Ping-Yi; Enya Chen, Yu-Chen; Bissig, Karl-Dimiter; Tao, Mi-Hua
Selection of escape mutants with mutations within the target sequence could abolish the antiviral RNA interference activity. Here, we investigated the impact of a pre-existing shRNA-resistant HBV variant on the efficacy of shRNA therapy. We previously identified a highly potent shRNA, S1, which, when delivered by an adeno-associated viral vector, effectively inhibits HBV replication in HBV transgenic mice. We applied the “PICKY” software to systemically screen the HBV genome, then used hydrodynamic transfection and HBV transgenic mice to identify additional six highly potent shRNAs. Human liver chimeric mice were infected with a mixture of wild-type and T472C HBV, a S1-resistant HBV variant, and then treated with a single or combined shRNAs. The presence of T472C mutant compromised the therapeutic efficacy of S1 and resulted in replacement of serum wild-type HBV by T472C HBV. In contrast, combinatorial therapy using S1 and P28, one of six potent shRNAs, markedly reduced titers for both wild-type and T472C HBV. Interestingly, treatment with P28 alone led to the emergence of escape mutants with mutations in the P28 target region. Our results demonstrate that combinatorial RNAi therapy can minimize the escape of resistant viral mutants in chronic HBV patients. PMID:26482836
Shih, Yao-Ming; Sun, Cheng-Pu; Chou, Hui-Hsien; Wu, Tzu-Hui; Chen, Chun-Chi; Wu, Ping-Yi; Enya Chen, Yu-Chen; Bissig, Karl-Dimiter; Tao, Mi-Hua
Selection of escape mutants with mutations within the target sequence could abolish the antiviral RNA interference activity. Here, we investigated the impact of a pre-existing shRNA-resistant HBV variant on the efficacy of shRNA therapy. We previously identified a highly potent shRNA, S1, which, when delivered by an adeno-associated viral vector, effectively inhibits HBV replication in HBV transgenic mice. We applied the "PICKY" software to systemically screen the HBV genome, then used hydrodynamic transfection and HBV transgenic mice to identify additional six highly potent shRNAs. Human liver chimeric mice were infected with a mixture of wild-type and T472C HBV, a S1-resistant HBV variant, and then treated with a single or combined shRNAs. The presence of T472C mutant compromised the therapeutic efficacy of S1 and resulted in replacement of serum wild-type HBV by T472C HBV. In contrast, combinatorial therapy using S1 and P28, one of six potent shRNAs, markedly reduced titers for both wild-type and T472C HBV. Interestingly, treatment with P28 alone led to the emergence of escape mutants with mutations in the P28 target region. Our results demonstrate that combinatorial RNAi therapy can minimize the escape of resistant viral mutants in chronic HBV patients.
Yu, Xuelian; Zhang, Jing; Hong, Liang; Wang, Jiayu; Yuan, Zhengan; Zhang, Xi; Ghildyal, Reena
Human parvovirus 4 (PARV4) has been detected in blood and diverse tissues samples from HIV/AIDS patients who are injecting drug users. Although B19 virus, the best characterized human parvovirus, has been shown to co-infect patients with hepatitis B or hepatitis C virus (HBV, HCV) infection, the association of PARV4 with HBV or HCV infections is still unknown.The aim of this study was to characterise the association of viruses belonging to PARV4 genotype 1 and 2 with chronic HBV and HCV infection in Shanghai.Serum samples of healthy controls, HCV infected subjects and HBV infected subjects were retrieved from Shanghai Center for Disease Control and Prevention (SCDC) Sample Bank. Parvovirus-specific nested-PCR was performed and results confirmed by sequencing. Sequences were compared with reference sequences obtained from Genbank to derive phylogeny trees.The frequency of parvovirus molecular detection was 16-22%, 33% and 41% in healthy controls, HCV infected and HBV infected subjects respectively, with PARV4 being the only parvovirus detected. HCV infected and HBV infected subjects had a significantly higher PARV4 prevalence than the healthy population. No statistical difference was found in PARV4 prevalence between HBV or HCV infected subjects. PARV4 sequence divergence within study groups was similar in healthy subjects, HBV or HCV infected subjects.Our data clearly demonstrate that PARV4 infection is strongly associated with HCV and HBV infection in Shanghai but may not cause increased disease severity.
Yang, Yinli; Han, Qiuju; Hou, Zhaohua; Zhang, Cai; Tian, Zhigang; Zhang, Jian
Evidence suggests that exosomes can transfer genetic material between cells. However, their roles in hepatitis B virus (HBV) infection remain unclear. Here, we report that exosomes present in the sera of chronic hepatitis B (CHB) patients contained both HBV nucleic acids and HBV proteins, and transferred HBV to hepatocytes in an active manner. Notably, HBV nucleic acids were detected in natural killer (NK) cells from both CHB patients and healthy donors after exposure to HBV-positive exosomes. Through real-time fluorescence microscopy and flow cytometry, 1,1'-dioctadecyl-3,3,3',3',-tetramethylindodicarbocyanine, 4-chlorobenzenesulfnate salt (DiD)-labeled exosomes were observed to interact with NK cells and to be taken up by NK cells, which was enhanced by transforming growth factor-β treatment. Furthermore, HBV-positive exosomes impaired NK-cell functions, including interferon (IFN)-γ production, cytolytic activity, NK-cell proliferation and survival, as well as the responsiveness of the cells to poly (I:C) stimulation. HBV infection suppressed the expression of pattern-recognition receptors, especially retinoic acid inducible gene I (RIG-I), on NK cells, resulting in the dampening of the nuclear factor κB(NF-κB) and p38 mitogen-activated protein kinase pathways. Our results highlight a previously unappreciated role of exosomes in HBV transmission and NK-cell dysfunction during CHB infection. PMID:27238466
Wang, Cheng; Zhu, Zi-Man; Liu, Cheng-Li; He, Xiao-Jun; Feng, Xiao-Bin; Zhang, Lin; Dong, Jia-Hong; Zhang I, Hong-Yi
It was necessary to assess the relationship between Yes-associated protein (YAP) and some clinical features of hepatocellular carcinoma (HCC), especially hepatitis B virus (HBV) correlation factors as they relate to tumorigenesis. A tissue microarray including 84 HCC samples was retrospectively analyzed by immunohistochemistry. This study showed that YAP expression was associated with HCC differentiation and the patient age at diagnosis of HCC. The mean age at diagnosis of YAP(+) HCC patients was 46.19 ± 9.45 years old, which is youn- ger than 51.40 ± 12.51 years old found for YAP(-) HCC patients (< 0.048). There was no significant correlation between YAP expression and HBV correlation factors (HBsAg, HBV DNA, and the duration of hepatitis B infec- tion). YAP(+) HCC patients had a younger mean age at diagnosis and more poor-differentiation charac- teristics of HCC. However, there were no independent HBV correlation factors.
Ramirez, Jonathan C; Ackerman, Kimberly; Strain, Sasha C; Ahmed, Syed T; de Los Santos, Mario J; Sears, Dawn
Vaccinations against hepatitis A virus (HAV) and hepatitis B virus (HBV) are recommended for patients with chronic liver disease (CLD), yet implementation of these recommendations is lacking. This study reviewed HAV and HBV antibody testing and vaccination status of patients with CLD. In 2008, we began using pre-printed liver order sets, which included vaccination options. We compared Scott & White liver clinic CLD patient records from 2005 (238) with patient records from 2008 (792). Screening rates for immunity and vaccination rates of those lacking immunity were calculated. In 2005, 66% of CLD patients were screened for HAV immunity. In 2008, 56% of CLD patients were screened. The HAV vaccination completion rate was 37% in 2005, while in 2008, the rate was 46%. In 2005, 66% of CLD patients were screened for HBV immunity; in 2008, 56 % CLD patients were screened. The HBV vaccination completion rate was 26% in 2005 compared with 36% in 2008. Although there was a lower percentage of screening in 2008, the overall number of patients tripled between 2005 and 2008. There was a significant increase in the total number of patients screened and vaccinated in 2008. Some physicians may have vaccinated their patients without checking for immunity. In January 2008, we implemented pre-printed order sets with checkboxes to help remind providers to order labs to screen for immunity against HAV and HBV and to order vaccinations for those who lacked immunity. The use of these sets may have aided in the increase of vaccination completion rates.
Baha, Warda; Ennaji, My Mustapha; Lazar, Fatiha; Melloul, Marouane; El Fahime, Elmostafa; El Malki, Abdelouahad; Bennani, Abdelouaheb
The study of hepatitis B virus (HBV) genomic heterogeneity has become a major issue in investigations aimed at understanding the relationship between HBV mutants and the wide spectrum of clinical and pathological conditions associated with HBV infection. The objective of the current study was to find out the pattern of HBV genotypes circulating in Morocco and to investigate the precore (PC) and basal core promoter (BCP) mutants' status in Moroccan chronic hepatitis B patients. Viral genotypes were determined in 221 chronic carriers using INNO-LiPA HBV assay and hemi-nested PCR. Phylogenetic analysis was performed in 70 samples, and multiplex PCR method was used to confirm some genotyping results. PC and CP mutants were determined using Inno-Lipa. All isolates were successfully genotyped. The genotype distribution was D in 90.45% of cases, A (5.9%), E (1 case), and mixed genotypes (5 A/D and 2 D/F) in 3.17% patients. HBV carried in the HBV/D samples could be assigned to D7 (63.3%), D1 (32.7%) and 2% of strains to each D4 and D5, all HBV/A belonged to A2 subgenotype and HBV/E strain could not be sub-genotyped. In 70 studied strains, HBV mutants were detected in 88.6% of cases; PC mutants were detected in (40%) of patients and 21.5% present a mixture of wild type and G1896A mutation. BCP mutants were observed in 65.7% of cases, 22.9% were found to have the T1762/1764A double mutation, 18.6% had A1762/1764T mutation and 22.9% of patients showed the A1762T/G1764A double mutation with either A1762T/G1764T mutation. Co-infection by PC and BCP mutants was detected in 52.9% of cases. Movement from place to place most likely shapes the observed genotype distribution and consequent prevalence of genotypes other than A2 or D7 in this population. High circulation of PC and BCP mutants is common in chronic hepatitis B infection in Morocco.
Spaziante, Martina; Biliotti, Elisa; Grieco, Stefania; Palazzo, Donatella; Esvan, Rozenn; Taliani, Gloria
Hepatitis B (HBV) virus infection is one of the most important causes of liver disease in patients with end-stage renal failure on hemodialysis. The natural history of chronic HBV infection acquired in childhood starts with an immune tolerant phase, followed by an immune clearance phase that may lead to the inactive carrier state or the development of chronic liver disease. Information on antiviral therapy administered very early during the immune clearance phase are lacking and no data exist on the treatment of early immune activation in the hemodialysis setting. This report describes the case of a patient affected by end-stage renal failure and HBeAg-positive chronic HBV virus infection treated very early during the immune clearance phase of HBV infection with an adjusted-dose of nucleoside analogue entecavir. The patient achieved a very rapid HBV-DNA undetectability, anti-HBe, and anti-HBs seroconversion. This is the first report of antiviral therapy with entecavir started during the immune reactive phase of HBV infection in a patient on hemodialysis and it suggests that antiviral treatment can enhance the effects of host immune activation resulting in biochemical, serological, and viral response, even in end-stage renal failure patients with partial immunodeficiency. Antiviral therapy with entecavir in the setting of hemodialysis was safe and well tolerated.
Tjwa, Eric T T L; van Oord, Gertine W; Hegmans, Joost P; Janssen, Harry L A; Woltman, Andrea M
Natural killer (NK) cells play a major role in anti-viral immunity as first line defense and regulation of virus-specific T cell responses. This study aimed to investigate phenotype and function of NK cells in patients with chronic hepatitis B virus (HBV) infection and to study the effect of anti-viral therapy. Peripheral blood NK cells from 40 chronic HBV patients were compared to NK cells of 25 healthy controls. The effect of entecavir-induced viral load reduction on NK cell phenotype and function was investigated in 15 chronic HBV patients. NK cell numbers and subset distribution did not differ between HBV patients and normal subjects. In chronic HBV patients, the cytotoxic capacity was retained, but NK cell activation and subsequent IFNγ and TNFα production, especially of the CD56(dim) subset, were strongly hampered. This functional dichotomy was paralleled by an altered activation state, elevated expression of NKG2A, and downregulated expression of CD16 and NKp30, which correlated with serum HBV-DNA load. Anti-viral therapy partially restored NK cell phenotype, as shown by NKG2A downregulation. Moreover, viral replication inhibition improved IFNγ production as a result of an increased ability of CD56(dim) NK cells to become activated de novo. This improved NK cell activation and function which correlated with therapy-induced reduction in serum ALT levels, but not HBV-DNA load. The specific defect in CD56(dim) NK cell activation and the reduced capacity to produce anti-viral and Th1-skewing cytokines may play a role in HBV persistence. Restoration of this NK cell cytokine-producing capacity, as achieved by viral load reduction, could therefore contribute to definite clearance of the virus. Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Montineri, Arturo; Nigro, Luciano; La Rosa, Rosario; Iacobello, Carmelo; Larocca, Licia; Cappello, Elisa; Fiumara, Paolo Fabio; Di Raimondo, Francesco; Fatuzzo, Filippo
In onco-haematological patients inactive or occult HBV infection may be reactivated as a result of disease-related immuno-suppression and/or chemotherapy with rituximab. This study reports the clinical features of five patients affected by onco-haematological disorders who experienced hepatitis B reactivation. From 2005 to 2010, five onco-haematological patients with hepatitis B reactivation were admitted to the department of Infectious Diseases, Ferrarotto Hospital, Catania, Italy. At the time of onco-haematological disease diagnosis, 3 patients were HBcAb positive; 1 HBsAb and HBcAb positive; and 1 HBsAg positive, HBV DNA negative. None of the patients received hepatitis B prophylaxis. Reactivation was observed following chemotherapy. One patient was treated with lamivudine, 2 with tenofovir and 2 with telbivudine. Following treatment all patients achieved undetectable HBV DNA and normalization of transaminases. Three patients, those treated with lamivudine and tenofovir, cleared HBsAg and developed protective titres of HBsAb. The remaining patients, who were treated with telbivudine, were HBV DNA negative and HBsAg positive one at 27 months and the other at 5 months of therapy. Treatment thus continued in these patients. HBV reactivation can be a severe complication in onco-haematological patients undergoing chemotherapy with rituximab. In our experience all nucleos(t)ide analogues were safe and effective. Three patients seroconverted to HBsAb. This may be as a result of the antivirals enhancing the immune response to HBV. A similar role may also be played by immune recovery following the withdrawal of immune-suppressive treatment. This report confirms the importance of anti-viral prophylaxis in patients with a high risk of HBV reactivation. Copyright © 2011 Elsevier B.V. All rights reserved.
Wu, Shaoxu; Geng, Qirong; Huang, Huiqiang; Lin, Tongyu; Jiang, Wenqi; Xia, Zhongjun; Duan, Huaxin; Rao, Huilan; Yao, Mengfei; Hu, Liyang
Prophylactic antiviral therapy is essential for lymphoma patients with high baseline HBV DNA who undergo cytotoxic chemotherapy. However, there are limited data on the optimal options. The present study was designed to compare the efficacy of prophylactic lamivudine (LAM) with lamivudine plus adefovir dipivoxil (LAM+ADV) in preventing hepatitis B virus (HBV) reactivation in lymphoma with, pre-chemotherapy HBV DNA load ≥2000 IU/ml. We retrospectively analyzed the medical records of 86 lymphoma patients with baseline HBV DNA load ≥2000 IU/ml during chemotherapy and received LAM or LAM+ADV as prophylaxis between January 1, 2008 and November 30, 2014 at Sun Yat-sen University Cancer Center, China. Sixty-five patients received LAM and 21 received LAM+ADV. The rate was significantly lower in the LAM+ADV group compared with the LAM group for HBV reactivation (23.8% vs 55.4%; p = 0.012), while no difference was observed between the two groups in patients for HBV-related hepatitis (21.3% vs 33.3%; p = 0.349), and chemotherapy disruption (10.9% vs 19.0%; p = 0.337). In a multivariate analysis of factors associated with HBV reactivation in these patients, LAM+ADV treatment and HBeAg negative were the independent protective factors. Therefore, LAM+ADV should be considered for antiviral prophylaxis in lymphoma patients with pre-chemotherapy HBV DNA load ≥2000 IU/ml. Further study is warranted to confirm these findings. PMID:27711135
Kurihara, Takeshi; Fukuhara, Takasuke; Ono, Chikako; Yamamoto, Satomi; Uemura, Kentaro; Okamoto, Toru; Sugiyama, Masaya; Motooka, Daisuke; Nakamura, Shota; Ikawa, Masato; Mizokami, Masashi; Maehara, Yoshihiko; Matsuura, Yoshiharu
Complete removal of hepatitis B virus (HBV) DNA from nuclei is difficult by the current therapies. Recent reports have shown that a novel genome-editing tool using Cas9 with a single-guide RNA (sgRNA) system can cleave the HBV genome in vitro and in vivo. However, induction of a double-strand break (DSB) on the targeted genome by Cas9 risks undesirable off-target cleavage on the host genome. Nickase-Cas9 cleaves a single strand of DNA, and thereby two sgRNAs are required for inducing DSBs. To avoid Cas9-induced off-target mutagenesis, we examined the effects of the expressions of nickase-Cas9 and nuclease dead Cas9 (d-Cas9) with sgRNAs on HBV replication. The expression of nickase-Cas9 with a pair of sgRNAs cleaved the target HBV genome and suppressed the viral-protein expression and HBV replication in vitro. Moreover, nickase-Cas9 with the sgRNA pair cleaved the targeted HBV genome in mouse liver. Interestingly, d-Cas9 expression with the sgRNAs also suppressed HBV replication in vitro without cleaving the HBV genome. These results suggest the possible use of nickase-Cas9 and d-Cas9 with a pair of sgRNAs for eliminating HBV DNA from the livers of chronic hepatitis B patients with low risk of undesirable off-target mutation on the host genome.
Hoan, Nghiem Xuan; Van Tong, Hoang; Giang, Dao Phuong; Cuong, Bui Khac; Toan, Nguyen Linh; Wedemeyer, Heiner; Bock, C Thomas; Kremsner, Peter G; Song, Le Huu; Velavan, Thirumalaisamy P
The clinical manifestations of hepatitis B viral infection (HBV) include chronic hepatitis B (CHB), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The contribution of negative regulator suppressor of cytokine signaling-3 (SOCS3) promoter variants in HBV disease and SOCS3 hypermethylation in tumor tissues were investigated. The SOCS3 promoter region was screened for polymorphisms in 878 HBV patients and in 272 healthy individuals. SOCS3 promoter methylation was examined by bisulfite sequencing. SOCS3 mRNA expression was quantified in 37 tumor and adjacent non-tumor liver tissue specimens. The minor allele rs12953258A was associated with increased susceptibility to HBV infection (OR=1.3, 95%CI=1.1-1.6, adjusted P=0.03). The minor allele rs111033850C and rs12953258A were observed in increased frequencies in HCC and LC patients compared to CHB patients (HCC: OR=1.7, 95%CI=1.1-2.9, adjusted P=0.046; LC: OR=1.4, 95%CI=1.1-1.9, adjusted P=0.017, respectively). HBV patients with rs111033850CC major genotype had decreased viral load (P=0.034), whereas the rs12953258AA major genotype contributed towards increased viral load (P=0.029). Tumor tissues revealed increased hypermethylation compared to adjacent non-tumor tissues (OR=5.4; 95%CI= 1.9-17.1; P=0.001). Increased SOCS3 expression was observed in HBV infested tumor tissues than non-HBV related tumor tissues (P=0.0048). SOCS3 promoter hypermethylation was associated with relatively low mRNA expression in tumor tissues (P=0.0023). In conclusion, SOCS3 promoter variants are associated with HBV susceptibility and SOCS3 hypermethylation stimulates HCC development.
Viganò, Mauro; Brocchieri, Alessandra; Spinetti, Angiola; Zaltron, Serena; Mangia, Giampaolo; Facchetti, Floriana; Fugazza, Alessandro; Castelli, Francesco; Colombo, Massimo; Lampertico, Pietro
Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor widely used to treat patients with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infection. Despite the excellent safety records of this regimen, a few cases of acute renal failure and Fanconi syndrome have been reported among HIV patients exposed to TDF. In the HBV monoinfection scenario, only two cases of TDF-associated Fanconi syndrome have been reported thus far. Here, we describe two additional patients with chronic hepatitis B (CHB) who developed a TDF-induced Fanconi syndrome that reverted after TDF withdrawal and had viral replication fully suppressed upon switching to entecavir (ETV). Though the overall risk of TDF associated severe renal toxicity in HBV patients appears to be negligible, both glomerular and tubular function should be monitored in patients exposed to TDF, especially when other renal risk factors or a history of previous exposure to adefovir dipivoxil (ADV) are present.
Jang, Jae Young; Park, Eui Ju
Occult HBV infection is defined as the presence of HBV DNA in the liver (with or without detectable or undetectable HBV DNA in the serum) of individuals testing negative for HBsAg. Studies on occult HBV infection in hepatitis C patients have reported highly variable prevalence, because the prevalence of occult HBV infection varies depending on the hepatitis B risk factors and methodological approaches. The most reliable diagnostic approach for detecting occult HBV detection is through examination of liver DNA extracts. HCV has been suspected to strongly suppress HBV replication up to the point where it may be directly responsible for occult HBV infection development. However, more data are needed to arrive at a definitive conclusion regarding the role of HCV in inducing occult HBV infection. Occult HBV infection in chronic hepatitis C patients is a complex biological entity with possible relevant clinical implications. Influence of occult HBV infection on the clinical outcomes of chronic hepatitis C may be considered negative. However, recent studies have shown that occult HBV infection could be associated with the development of hepatocellular carcinoma and contribute to the worsening of the course of chronic liver disease over time in chronic hepatitis C patients. Nevertheless, the possible role of occult HBV infection in chronic hepatitis C is still unresolved and no firm conclusion has been made up until now. It still remains unclear how occult HBV infection affects the treatment of chronic hepatitis C. Therefore, in order to resolve current controversies and understand the pathogenic role and clinical impacts of occult HBV infection in chronic hepatitis C patients, well-designed clinical studies are needed.
Chambal, Lúcia Mabalane; Samo Gudo, Eduardo; Carimo, Awa; Corte Real, Rita; Mabunda, Nédio; Maueia, Cremildo; Vubil, Adolfo; Zicai, Ana Flora; Bhatt, Nilesh; Antunes, Francisco
HIV/ HBV coinfected patients are at high risk of developing chronic HBV infection, liver cirrhosis and hepatocellular carcinoma. In Mozambique, where HIV prevalence is one of the highest in the world, HIV-infected patients are scarcely characterized in terms of HBV coinfection and 3TC-resistance mutations profile. To characterize ART-naïve HIV-infected adults, with and without HBV coinfection, a cross-sectional study was conducted between May and November 2012 in two health centers from Maputo city, Mozambique. Subjects were consecutively enrolled in the study and, then, tested for hepatitis B surface antigen (HBsAg). Moreover, CD4+ T cells count, HBV DNA in plasma, HBV genotyping and 3TC-resistance mutations profile of HBV were assessed in HIV/HBV coinfected patients. In total, 518 patients were enrolled in the study. The median age was 33 years old and 66.8% were women. The median CD4+ T cells count was 361 cells/mm3 and 47 (9.1%) were coinfected with HBV. Out of 46 coinfected patients, 24 (55.2%) had HBV DNA ≥ 20 - < 20 000 and 12 (26.1%) had HBV-DNA ≥20 000. APRI > 2.0 was reported in 4.3% of coinfected and 1.7% of monoinfected patients (p = 0.228), while FIB-4 > 3.25 was reported in 4.4% of coinfected and 1.3% of monoinfected patients (p = 0.112). Genotype A was the most frequent, identified in 25/27 (92.6%) patients, whereas genotype E was present in 2/27 (7.4%) patients. No patient had 3TC-resistance mutations. This study showed that HBV coinfection was prevalent among ART-naïve HIV-infected adults in Mozambique. Overall, these data highlight the importance of screening HBV coinfection as an integrated measure of HIV routine care to improve health conditions and treatment of HIV/HBV coinfected patients.
Ziaee, Masood; Namaei, Mohammad Hassan; Azarkar, Ghodseh
Background and Objective: Blood-borne infections, such as the HIV virus and hepatitis B and C, are major problems in patients receiving blood products. Here we examined the prevalence of HTLV-1, HCV, HBV, and HIV in hemophilic patients. Methods: A cross-sectional study on 108 hemophilic patients (101 males and 7 females) involved detection of HBV, HCV, HIV and HTLV-1 infections using immunoassays for HBsAg, hepatitis B core antibodies (anti-HBc), hepatitis C antibodies (anti-HCV), HIV antibodies (anti-HIV) and Anti-HTLV-1. Real-time PCR was used to measure HCV RNA, and HCV genotyping was performed by direct sequencing of the 5’ noncoding region. Results: Hemophilia A was reported in 93 (86%) patients with severe symptoms in 8 cases. The seroprevalence of anti-HCV and anti-HTLV-1 antibodies was 20% and 3% respectively. One patient with severe hemophilia had a HCV/HTLV-1 co-infection. HCV-RNA was detected in 82% of patients. In terms of genotyping prevalence was 56% HCV genotype 3a, 39% HCV genotype 1a, and 6% HCV genotype2. Anti HIV and HBsAg were not detected in any patient. HTLV1 prevalence was higher, HCV lower in South Khorasan than other regions in Iran or elsewhere. Conclusion: Management of transfusion of blood and blood products should account for the underlying prevalence of infectious agents. PMID:26649023
Yim, Hyung Joon; Lok, Anna Suk-Fong
Remarkable progress has been made in our understanding of the natural history of chronic hepatitis B virus (HBV) infection in the past 25 years. Availability of sensitive HBV DNA assays and application of sophisticated immunological techniques led to the recognition that HBV replication persists throughout the course of chronic HBV infection, and host immune response plays a pivotal role in HBV-related liver disease. Knowledge of the HBV genome organization and replication cycle led to the unraveling of HBV genotypes and molecular variants, which contribute to the heterogeneity in outcome of chronic HBV infection. The natural course of chronic HBV infection is now perceived as consisting of 4 phases: immune tolerance, immune clearance [hepatitis B e antigen (HBeAg)-positive chronic hepatitis], inactive carrier state, and reactivation (HBeAg-negative chronic hepatitis B). Understanding the dynamic nature of chronic HBV infection is crucial in the management of HBV carriers and underscores the need for long-term monitoring. Accumulating evidence indicates that antiviral therapy can prevent progression of HBV-related liver disease, particularly among patients with sustained response. Newer antiviral therapies with improved efficacy and decreased risk of resistance may lead to a complete revision of the chapter on the natural history of chronic HBV infection on the occasion of the golden jubilee of Hepatology.
Antiviral therapies with nucleotide analogues (NA) is crucial in the treatment of chronic hepatitis B as it substantially protects patients from the complications of the disease . However in most of the available NA therapies, resistance emerges in the patients' HBV populations. Therefore, detection of antiviral resistance as early as possible by means of genotypically monitoring the patients' HBV pool during NA therapy is critical to manage treatment regime. In this research study we have investigated the sensitivity and specificity of the terminal restriction fragment length polymorphism (T-RFLP) method in detecting HBV subpopulations carrying antiviral resistance mutations. For this aim, differentiation of mutant strains from wild type strains was demonstrated by PCR-RFLP method. With using recombinant plasmids containing mutant and wild type HBV genomes, we constructed artificial HBV genome populations in order to determine the sensitivity of PCR-T-RFLP method in detecting antiviral resistant minor HBV populations. Finally by comparing with the DNA sequencing method, we demonstrated the specificity of T-RFLP method in genotyping HBV populations. As a result we showed that T-RFLP is able to detect HBV subpopulations representing as low as 1 % of the whole viral population. Additionally T-RFLP showed 100 % concordance with the DNA sequencing method in genotyping HBV populations. As a conclusion, considering the other genotyping methods used in evaluating HBV populations, T-RFLP showed high sensitivity and specificity profiles in detecting antiviral resistant HBV subpopulations. Therefore T-RFLP method can be easily employed in genotypic evaluation of patients' HBV populations during the course of antiviral treatment.
Tashiro, Ryosuke; Ogawa, Yoshikazu; Tominaga, Teiji
Reactivation of the hepatitis B virus (HBV) is a risk in the 350 million HBV carriers worldwide. HBV reactivation may cause hepatocellular carcinoma, cirrhosis, and fulminant hepatitis, and HBV reactivation accompanied with malignant tumor and/or chemotherapy is a critical problem for patients with chronic HBV infection. Multiple risk factors causing an immunosuppressive state can also induce HBV reactivation.We present a case of HBV reactivation during an immunosuppressive state caused by Cushing disease and physical and psychological stress after a disaster. A 47-year-old Japanese woman was an inactive HBV carrier until the Great East Japan Earthquake occurred and follow-up was discontinued. One year after the earthquake she had intractable hypertension, and her visual acuity gradually worsened. Head magnetic resonance imaging showed a sellar tumor compressing the optic chiasm, and hepatic dysfunction with HBV reactivation was identified. Endocrinologic examination established the diagnosis as Cushing disease. After normalization of hepatic dysfunction with antiviral therapy, transsphenoidal tumor removal was performed that resulted in subtotal removal except the right cavernous portion. Steroid hormone supplementation was discontinued after 3 days of administration, and gamma knife therapy was performed for the residual tumor. Eighteen months after the operation, adrenocorticotropic hormone and cortisol values returned to normal. The patient has been free from tumor regrowth and HBV reactivation throughout the postoperative course.Accomplishment of normalization with intrinsic steroid value with minimization of steroid supplementation should be established. Precise operative procedures and careful treatment planning are essential to avoid HBV reactivation in patients with this threatening condition. Georg Thieme Verlag KG Stuttgart · New York.
Sagnelli, Evangelista; Taliani, Gloria; Castelli, Francesco; Bartolozzi, Dario; Cacopardo, Bruno; Armignacco, Orlando; Scotto, Gaetano; Coppola, Nicola; Stroffolini, Tommaso; Sagnelli, Caterina
The aims of the study were to estimate the clinical impact of HBV infection in pregnant immigrants and their family members and to identify a useful approach to managing the healthcare of HBsAg-positive immigrants. Included in this study were 143 HBsAg-positive pregnant immigrants of the 1,970 from countries with intermediate/high HBV endemicity who delivered in 8 Italian hospitals in 2012-2013. In addition, 172 family members of 96 HBsAg-positive pregnant immigrants were tested for serum HBsAg. The median age of the 143 HBsAg-positive pregnant immigrants was 31.0±12.1 years and the length of stay in Italy 5.0±4.1 years; 56.5% were unaware of their HBsAg positivity. HBV DNA was detected in 74.5% of the pregnant immigrants, i.e., 94.3% from Eastern Europe, 72.2% from East Asia and 58.1% from Sub-Saharan Africa. HBV DNA ≥2000 IU/mL was detected in 47.8% of pregnant immigrants, associated with ALT ≥1.5 times the upper normal value in 15% of cases. Anti-HDV was detected in 10% of cases. HBsAg was detected in 31.3% of the 172 family members. All HBsAg-positive immigrants received counseling on HBV infection and its prevention, and underwent a complete clinical evaluation. The findings validate the approach used for the healthcare management of the HBsAg-positive immigrant population.
Douglas, Sara L.; Daly, Barbara J.; Kelley, Carol Genet; O’Toole, Elizabeth; Montenegro, Hugo
Background Chronically critically ill patients often have high costs of care and poor outcomes and thus might benefit from a disease management program. Objectives To evaluate how adding a disease management program to the usual care system affects outcomes after discharge from the hospital (mortality, health-related quality of life, resource use) in chronically critically ill patients. Methods In a prospective experimental design, 335 intensive care patients who received more than 3 days of mechanical ventilation at a university medical center were recruited. For 8 weeks after discharge, advanced practice nurses provided an intervention that focused on case management and interdisciplinary communication to patients in the experimental group. Results A total of 74.0% of the patients survived and completed the study. Significant predictors of death were age (P = .001), duration of mechanical ventilation (P = .001), and history of diabetes (P = .04). The disease management program did not have a significant impact on health-related quality of life; however, a greater percentage of patients in the experimental group than in the control group had “improved” physical health-related quality of life at the end of the intervention period (P = .02). The only significant effect of the intervention was a reduction in the number of days of hospital readmission and thus a reduction in charges associated with readmission. Conclusion The intervention was not associated with significant changes in any outcomes other than duration of readmission, but the supportive care coordination program could be provided without increasing overall charges. PMID:17724242
Huang, Ju; Cui, Jun
Background: The 13C urea breath test (13C-UBT) is the gold standard for detecting Helicobacter pylori infection. H. pylori pathogenesis in patients with hepatitis B virus (HBV) and related diseases remains obscure. We used 13C-UBT to detect H. pylori infection in patients with chronic HBV infection, HBV-related cirrhosis, HBV-related hepatic carcinoma, and other chronic hepatic diseases. Methods: A total of 131 patients with chronic hepatitis B (HB), 179 with HBV-related cirrhosis, 103 with HBV-related hepatic carcinoma, 45 with HBV-negative hepatic carcinoma, and 150 controls were tested for H. pylori infection using 13C-UBT. We compared H. pylori infection rate, liver function, complications of chronic hepatic disease, serum HBV-DNA, serum alpha-fetoprotein (AFP), and portal hypertensive gastropathy (PHG) incidence among groups. Results: HBV-related cirrhosis was associated with the highest H. pylori infection rate (79.3%). H. pylori infection rate in chronic HB was significantly higher than in the HBV-negative hepatic carcinoma and control groups (P < 0.001). H. pylori infection rate in patients with HBV-DNA ≥103 copies/ml was significantly higher than in those with HBV-DNA <103 copies/ml (76.8% vs. 52.4%, P < 0.001). Prothrombin time (21.3 ± 3.5 s vs. 18.8 ± 4.3 s), total bilirubin (47.3±12.3 μmol/L vs. 26.6 ±7.9 μmol/L), aspartate aminotransferase (184.5 ± 37.6 U/L vs. 98.4 ± 23.5 U/L), blood ammonia (93.4 ± 43.6 μmol/L vs. 35.5 ± 11.7 μmol/L), and AFP (203.4 ± 62.6 μg/L vs. 113.2 ± 45.8 μg/L) in the 13C-UBT-positive group were significantly higher than in the 13C-UBT-negative group (P < 0.01). The incidence rates of esophageal fundus variceal bleeding (25.4% vs. 16.0%), ascites (28.9% vs. 17.8%), and hepatic encephalopathy (24.8% vs. 13.4%) in the 13C-UBT-positive group were significantly higher than in the 13C-UBT-negative group (P < 0.01). The percentages of patients with liver function in Child-Pugh Grade C (29.6% vs. 8.1%) and PHG (43
Zidi, I; Laaribi, A B; Bortolotti, D; Belhadj, M; Mehri, A; Yahia, H B; Babay, W; Chaouch, H; Zidi, N; Letaief, A; Yacoub, S; Boukadida, J; Di Luca, D; Hannachi, N; Rizzo, R
Chronic hepatitis B virus (HBV) infection occurs in association to a deregulation of immune system. Human leukocyte antigen E (HLA-E) is an immune-tolerant nonclassical HLA class I molecule that could be involved in HBV progression. To measure soluble (s) HLA-E in patients with chronic HBV hepatitis (CHB). We tested the potential association of HLA-E*01:01/01:03 A > G gene polymorphism to CHB. Our cohort consisted of 93 Tunisian CHB patients (stratified in CHB with high HBV DNA levels and CHB with low HBV DNA levels) and 245 healthy donors. Plasma sHLA-E was determined using enzyme-linked immunosorbent assay (ELISA). Genotyping was performed using polymerase chain reaction sequence-specific primer. No association between HLA-E*01:01/01:03 A > G polymorphism and HBV DNA levels in CHB patients was found. G/G genotype is less frequent in CHB patients without significance. sHLA-E is significantly enhanced in CHB patients compared with healthy controls (P = 0.0017). Stratification according to HBV DNA levels showed that CHB patients with low HBV DNA levels have higher sHLA-E levels compared with CHB patients with high HBV DNA levels. CHB patients with G/G genotype have enhanced sHLA-E levels compared with other genotypes (P = 0.037). This significant difference is maintained only for CHB women concerning G/G genotypes (P = 0.042). Finally, we reported enhanced sHLA-E in CHB patients with advanced stages of fibrosis (P = 0.032). We demonstrate, for the first time, the association of sHLA-E to CHB. Owing to the positive correlation of HLA-E*01:01/01:03 A > G polymorphism and the association of sHLA-E to advanced fibrosis stages, HLA-E could be a powerful predictor for CHB progression. Further investigations will be required to substantiate HLA-E role as a putative clinical biomarker of CHB.
Wang, Jing-Hui; Huang, Ling; Wang, Deng-yu; Zhao, Ling; Zhao, Guo-ping; Wang, Ying
High rate of viral replication and lacking of proofreading activity in hepatitis B virus (HBV) polymerase lead to the generation of mutations in HBV virus. Mutations in the reverse transcriptase (RT) region of HBV polymerase are demonstrated to be strongly associated with drug resistance during antiviral treatment. However, the presence of mutations as well as its clinical significance in treatment-naïve hepatitis patients (defined as pre-existing mutations) need to be further investigated. In the present study, a total of 168 serum samples from treatment-naive chronic hepatitis B (CHB) patients were collected, and the RT region of HBV polymerase was sequenced. The results showed that pre-existing mutations in the RT region of HBV polymerase were detected in 43 of 168 (25.6%) treatment-naive CHB patients within which there were no well-characterized primary nucleotide analogs (NAs) resistance sites. Three dominant sites at rt191, rt207 and rt226 were found mutant in 7(16.28%), 8(18.60%), and 14(32.56%) samples respectively among these 43 patients. No significant correlation was found between pre-existing mutations and gender, age, HBV genotype, ALT, HBeAg or HBV DNA loads. However, patients with pre-existing RT mutations under HBeAg sero-negative status exhibited decreased HBV DNA loads, which contributed to the decreased HBV DNA loads in the total HBeAg sero-negative patients. The above investigation indicated that there was a prevalence of pre-existing mutations in RT region of HBV polymerase which might affect the serum HBV DNA level in treatment-naive CHB patients. Its effects on the occurrence of NAs resistance and the prognosis after treatment need to be further investigated. PMID:25821965
Coppola, Nicola; Onorato, Lorenzo; Iodice, Valentina; Starace, Mario; Minichini, Carmine; Farella, Nunzia; Liorre, Giulia; Filippini, Pietro; Sagnelli, Evangelista; de Stefano, Giorgio
Aim To evaluate the virological and clinical characteristics of occult HBV infection (OBI) in 68 consecutive HBsAg-negative patients with biopsy-proven cirrhosis and HCC. Methods HBV DNA was sought and sequenced in plasma, HCC tissue and non-HCC liver tissue by PCRs using primers for HBV core, surface and x regions. OBI was identified by the presence of HBV DNA in at least two different PCRs. Results OBI was detected in HCC tissue of 13 (20%) patients and in non-HCC liver tissue of 3 of these 13. OBI was detected in HCC tissue of 54.5% of 11 anti-HBs- negative/anti-HBc-positive patients, in 29.4% of 17 anti-HBs/anti-HBc-positive and in 5% of 40 anti-HBs/anti-HBc-negative (p < 0.0005). The 13 patients with OBI in HCC tissue more frequently than the 55 without showed Child-B or -C cirrhosis (53.9% vs. 5.5%, p < 0.0001) and BCLC-B or -C stages (46.1% vs. 1.8%, p < 0.0001). The pre-S1, pre-S2 and S region sequences in HCC tissue showed amino acid (AA) substitutions (F19L, P24L, S59F, T131I, Q129H) and deletions (in positions 4,8, 17 and 86) in the S region, AA substitutions (T40S, P124K, L54P, G76A, N222T and I273L) in pre-S1 region and AA substitutions in pre-S2 region (P41H and P66L). In the 3 patients showing OBI also in non-HCC liver tissue the S, pre-S1 and pre-S2 sequencing displayed patterns of mutations different. Conclusions The study showed a significant correlation between OBI and the severity of liver damage, several patterns of mutations in the S, pre-S1 and pre-S2 regions in HCC tissue, some at their first description. PMID:27486882
Rivero-Juárez, Antonio; Camacho, Angela; Merchante, Nicolás; Pérez-Camacho, Inés; Macias, Juan; Ortiz-Garcia, Carmen; Cifuentes, Celia; Torre-Cisneros, Julián; Peña, José; Pineda, Juan A; Rivero, Antonio
Several studies have reported that a significant number of HIV patients not co-infected with HCV/HBV develop liver damage of uncertain origin (LDUO). The objective of our study was to evaluate the incidence of and risk factors for the development of LDUO in HIV infected patients not co-infected with HCV/HBV. Prospective longitudinal study that included HIV-infected patients free of previous liver damage and viral hepatitis B or C co-infections. Patients were followed up at 6-monthly intervals. Liver stiffness was measured at each visit. Abnormal liver stiffness (ALS) was defined as a liver stiffness value greater than 7.2 kPa at two consecutive measurements. For patients who developed ALS, a protocol was followed to diagnose the cause of liver damage. Those patients who could not be diagnosed with any specific cause of liver disease were diagnosed as LDUO and liver biopsy was proposed. 210 patients matched the inclusion criteria and were included. 198 patients completed the study. After a median (Q1-Q3) follow-up of 18 (IQR 12-26) months, 21 patients (10.6%) developed ALS. Of these, fifteen patients were diagnosed as LDUO. The incidence of LDUO was 7.64 cases/100 patient-years. Histological studies were performed on ten (66.6%) patients and all showed liver steatosis. A higher HOMA-IR value and body mass index were independently associated with the development of LDUO. We found a high incidence of LDUO in HIV-infected patients associated with metabolic risk factors. The leading cause of LDUO in our study was non-alcoholic fatty liver disease.
Wu, Tao; Zheng, Xiaojiao; Yang, Ming; Zhao, Aihua; Li, Meng; Chen, Tianlu; Panee, Jun; Jia, Wei; Ji, Guang
The incidences of chronic hepatitis B (CHB), Hepatitis B virus (HBV)-associated cirrhosis and HBV-associated carcinoma are high and increasing. This study was designed to evaluate serum lipid metabolite changes that are associated with the progression from CHB to HBV-associated cirrhosis and ultimately to HBV-associated HCC. A targeted metabolomic assay was performed in fasting sera from 136 CHB patients, 104 HBV-associated cirrhosis, and 95 HBV-associated HCC using ultra-performance liquid chromatography triple quadrupole mass spectrometry. A total of 140 metabolites were identified. Clear separations between each two groups were obtained using the partial least squares discriminate analysis of 9 lipid metabolites. Progressively lower levels of long-chain lysophosphatidylcholines (lysoPC a C18:2, lysoPC a C20:3, lysoPC a C20:4) were observed from CHB to cirrhosis to carcinoma; lower levels of lysoPC a C20:4 were found in patients with higher model for end-stage liver disease in the same disease group; and lysoPC a C20:3 levels were lower in Child-Pugh Class C than in Class A and Class B in HBV-associated cirrhosis and HBV-associated HCC groups. The octadecadienyl carnitine level was higher in HBV-associated cirrhosis group than in other two groups. Serum levels of selected long-chain lysoPCs are promising markers for the progression of HBV-associated liver diseases. PMID:28198443
Hawkins, Claudia; Christian, Beatrice; Fabian, Emanuel; Macha, Irene; Gawile, Cecilia; Mpangala, Shida; Ulenga, Nzovu; Thio, Chloe L; Rose Ammerman, Lauren; Mugusi, Ferdinand; Fawzi, Wafaie; Green, Richard; Murphy, Robert
In sub-Saharan Africa, the burden of liver disease associated with chronic hepatitis B (HBV) and HIV is unknown. We characterized liver disease using aspartate aminotransferase-to-platelet ratio index (APRI) and FIB-4 in patients with HIV, HBV, and HIV/HBV co-infection in Tanzania. Using a cross sectional design, we compared the prevalence of liver fibrosis in treatment-naive HIV mono-infected, HBV mono-infected, and HIV/HBV co-infected adults enrolled at Management and Development for Health (MDH)-supported HIV treatment clinics in Dar es Salaam, Tanzania. Risk factors associated with significant fibrosis (APRI>0.5 and FIB-4 >1.45) were examined. 267 HIV-infected, 165 HBV-infected and 63 HIV/HBV co-infected patients were analyzed [44% male, median age 37 (IQR 14), BMI 23 (7)]. APRI and FIB-4 were strongly correlated (r = 0.78, p = < .001, R2 0.61). Overall median APRI scores were low [HIV/HBV [0.36 (IQR 0.4)], HIV [0.23 (0.17)], HBV [0.29 (0.15)] (p <0.01)]. In multivariate analyses, HIV/HBV co-infection was associated with APRI >0.5 [HIV/HBV vs. HIV: OR 3.78 (95% CI 1.91, 7.50)], [HIV/HBV vs. HBV: OR 2.61 (1.26, 5.44)]. HIV RNA per 1 log10 copies/ml increase [OR 1.53 (95% CI 1.04, 2.26)] and HBV DNA per 1 log10 copies/ml increase [OR 1.36 (1.15, 1.62)] were independently associated with APRI >0.5 in HIV-infected and HBV-infected patients, respectively. HIV/HBV co-infection is an important risk factor for significant fibrosis. Higher levels of circulating HIV and HBV virus may play a direct role in liver fibrogenesis. Prompt diagnosis and aggressive monitoring of liver disease in HIV/HBV co-infection is warranted.
Dong, Jie; Yang, Xiao-Fei; Wang, Lin-Xu; Wei, Xin; Wang, An-Hui; Hao, Chun-Qiu; Shen, Huan-Jun; Huang, Chang-Xing; Zhang, Ye; Lian, Jian-Qi
T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3) was up-regulated on viral specific T cells and contributed to T cells exhaustion during chronic hepatitis B virus (HBV) infection. However, modulation of Tim-3 expression was still not fully elucidated. To evaluate the potential viral and inflammatory factors involved in the inductor of Tim-3 expression on T cells, 76 patients with chronic HBV infection (including 40 chronic hepatitis B [CHB] and 36 asymptomatic HBV carriers [AsC]) and 40 of normal controls (NCs) were enrolled in this study. Tim-3 expressions on CD4+ and CD8+ T cells were assessed in response to HBV-encoding antigens, HBV peptide pools, and common γ-chain (γc) cytokines stimulation by flow cytometry. HBV peptides and anti-CD3/CD28 directly induced Tim-3 expression on T cells. γc cytokines also drive Tim-3 up-regulations on both CD4+ and CD8+ T cells in patients with chronic HBV infection. However, γc cytokines did not enhance the Tim-3 inductions by either anti-CD3/CD28 or HBV peptides stimulation. Furthermore, γc cytokines-mediated Tim-3 induction could not be abrogated by γc cytokine receptor-neutralizing antibodies. The current results suggested that elevation of Tim-3 expression on T cells could be regulated by both antigen-dependent and -independent manner in patients with chronic HBV infection. The role of γc cytokines in modulation of inhibitory pathway might be evaluated as immunotherapies in humans. PMID:28401068
Liu, Yong; Zhang, Le; Zhou, Jin-Yong; Pan, Jinshun; Hu, Wei; Zhou, Yi-Hua
Coexistence of hepatitis B surface antigen (HBsAg) and antibody against HBsAg (anti-HBs) comprises an atypical serological profile in patients with chronic hepatitis B virus (HBV) infection. In this study, in total 94 patients with coexisting HBsAg and anti-HBs and 94 age- and sex-matched patients with positive HBsAg were characterized by quantitatively measuring HBsAg and HBV DNA, sequencing large S genes, and observing clinical features. Compared with common hepatitis B patients, the patients with coexisting HBsAg and anti-HBs had lower HBsAg and HBV DNA levels. These two groups had similar rate of pre-S deletion mutations. However, in patients with coexisting HBsAg and anti-HBs, more amino acid substitutions in the a determinant of S gene were observed in HBV genotype C, but not in genotype B. Fourteen patients with coexisting HBsAg and anti-HBs were followed up for an average of 15.5 months. There were no significant changes in the levels of HBsAg, anti-HBs, HBV DNA and ALT over the follow-up period. Compared with the baseline sequences, amino acid substitutions in the MHR of HBsAg occurred in 14.3% (2/14) patients. In conclusion, coexistence of HBsAg and anti-HBs may be associated with higher frequency of mutations in the a determinant of HBV genotype C.
Al-Qahtani, A A; Al-Anazi, M R; Nazir, N; Wani, K; Abdo, A A; Sanai, F M; Khan, M Q; Al-Ashgar, H I; Albenmousa, A; Al-Hamoudi, W K; Alswat, K A; Al-Ahdal, M N
The aim of this study was to evaluate the association of 10 SNPs in different microRNAs (miRNAs) with susceptibility to hepatitis B virus (HBV) infection, HBV clearance, persistence of chronic HBV infection, and progression to liver cirrhosis and hepatocellular carcinoma (HCC). Patients were categorized into the following groups: inactive HBV carrier, active HBV carrier, HBV-cleared subject and cirrhosis+HCC. Samples were analysed for 10 SNPs in microRNAs using either PCR-based genotyping or the TaqMan assay. We found that rs1358379 was associated with susceptibility to HBV infection, HBV clearance, persistent chronic HBV infection and liver cirrhosis+HCC. In addition, we found that rs2292832 and rs11614913 were associated with risk of HBV infection, viral clearance and cirrhosis+HCC, whereas rs2910164 was associated with proneness to HBV infection, and ability to clear the virus. There was evidence of associations between rs6505162 and HBV clearance and the development of liver disease, whereas a single association was found between rs2289030 and HBV clearance. Similarly, rs7372209 and rs4919510 were specifically associated with the development of HBV-induced liver complications. SNPs in miRNAs affect the susceptibility, clearance and progression of HBV infection in Saudi Arabian patients. We found, using Gene Ontology or pathway analyses, that these genes may contribute to the pathophysiology of HBV infection and related liver complications. However, differences in the association of examined SNPs with various clinical stages indicate variations in the respective functional roles of these polymorphisms and their miRNAs, and thus, further investigation to fully explore their therapeutic potential is warranted. © 2017 The Authors Journal of Viral Hepatitis Published by John Wiley & Sons Ltd.
Castelain, Sandrine; Descamps, Véronique; Brochot, Etienne; Helle, François; Duverlie, Gilles; Nguyen-Khac, Eric; François, Catherine
The progression of liver disease in hepatitis B virus (HBV) infection is fostered by active virus replication. Mutations in the basal core promoter (BCP) and precore (PC) regions of the HBV genome are known to have an impact on viral replication. The aim of the present study was to assess the correlation of mutation profiles in the BCP and PC regions with the viral load in HBeAg-negative chronically infected patients. The HBV genotype, BCP/PC mutations, serum HBV DNA levels, and associated serological markers were analyzed in 92 HBeAg-negative chronically infected patients. Sequence analysis of the BCP and PC regions revealed variability of 19% and 24.1%, respectively. This variability was primarily associated with five critical positions (1753, 1762, 1764, 1896 and 1899). An elevated HBV viral load (>20,000 IU/ml) was classically correlated with F2-F4 liver fibrosis, elevated serum alanine aminotransferase levels, 1762/1764 and 1753 combination mutations, and surprisingly, with an 1858T-1896G double mutation that impairs base pairing at the base of the bulge in the ε encapsidation signal. An analysis of covariance confirmed the independent nature of the relationship between the 1858T-1896G double mutation and the HBV viral load. In conclusion, independently of conventional parameters, this study demonstrates that a high serum HBV DNA level was also associated with PC 1858-1896 mutations. These BCP/PC mutations may have important clinical implications as predictive factors for HBV DNA increase.
Lin, Ching-Chung; Bair, Ming-Jong; Chen, Chih-Jen; Lee, Keng-Han; Chen, Ming-Jen; Liu, Chia-Yuan; Chang, Chen-Wang; Hu, Kuang-Chun; Liou, Tai-Cherng; Lin, Shee-Chan; Wang, Horng-Yuan; Chu, Cheng-Hsin; Shih, Shou-Chuan; Wang, Tsang-En
Lamivudine, telbivudine, and entecavir are the first-line drugs covered by the Taiwan National Health Insurance as 3-year treatments for patients with chronic hepatitis B virus (HBV), but the optimal treatment duration of each remains unclear. We aimed to detect HBV treatment-cessation durability, and compare the predictors in patients with and without clinical relapse. In this retrospective cohort study, 210 patients with chronic HBV who tested hepatitis B e-antigen positive or hepatitis B e-antigen negative were treated for 3 years with a nucleos(t)ide analogue. Of these, 102 patients continued therapy after 3 years, while 88 patients stopped treatment and were followed for 1 year due to financial difficulties. Efficacy was assessed in terms of alanine aminotransferase (ALT) level normalization, HBV DNA clearance, virus breakthrough, clinical relapse, and liver decompensation. The durability predictors were evaluated by host factors, HBV DNA, and drug differences. Eighty patients (14 on lamivudine, 19 on telbivudine, and 47 on entecavir) were recruited. There was no difference in clinical-relapse rate among lamivudine, telbivudine, and entecavir (35.7% vs. 36.8% vs. 31.9%, respectively; p = 0.916), and liver decompensated hepatitis was absent. In baseline clinical characteristics, there were no differences between the clinical-relapse and nonrelapse groups in age, sex, cirrhosis, prior treatment, HBV DNA, pretreatment ALT, or hepatitis B e-antigen (HBeAg). The mean 3(rd) year serum ALT level differed significantly between clinical-relapse and nonrelapse patients (37.5 U/L vs. 27.7 U/L, respectively; p = 0.044). The 3-year nucleos(t)ide analogue off-treatment in patients with chronic HBV delivered according to the Taiwan National Health Insurance guidelines had an overall 33.8% 1-year clinical-relapse rate without any decompensated hepatitis flare-ups.
Huang, Xiangyan; Ma, Chenyun; Zhang, Qiang; Shi, Qingfen; Huang, Tao; Liu, Chao; Li, Jie; Hollinger, F Blaine
This study was designed to detect mutations that occur within the "a" determinant in the S gene of the hepatitis B virus (HBV) in patients with occult hepatitis B (OHB), and to analyze the influence of these mutations on expression and reactivity of the hepatitis B surface antigen (HBsAg). Twenty-three certified OHB samples were compared to 32 HBsAg positive samples from patients with chronic hepatitis B. The median HBV DNA levels in the OHB group were significantly lower than those in the control group (P < 0.0001). Mutations within the "a" determinant were analyzed by gene amplification and sequencing. This revealed mixed infections in which clones within a sample displayed either different mutations or mutations in association with clones that exhibited wild type amino acid patterns. Sequencing analysis also showed a significant difference between the proportions of amino acid mutations observed in the OHB and control groups. Seven recombinant S (rS) proteins with corresponding OHB mutations and three wild type alleles were expressed and purified in the Pichia pastoris expression system to preserve conformational attributes, and their reactivity analyzed using six commercial HBsAg assays. The OHB sera were HBsAg nonreactive while the rS proteins with corresponding OHB mutations were universally reactive. Thus, we postulate that the reduced binding affinity between mutated HBsAg and its antibody may not be as important in defining OHB as is the effect of specific mutations in the preS/S region of the genome that affect the synthesis and secretion of the S protein and/or the virion. © 2017 Wiley Periodicals, Inc.
Fuster, Francisco; Vargas, Jose Ignacio; Jensen, Daniela; Sarmiento, Valeska; Acuña, Pedro; Peirano, Felipe; Fuster, Felipe; Arab, Juan Pablo; Martínez, Felipe
Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) share transmission mechanisms and thus coinfection is frequent. Active immunization against HBV is essential in HIV patients. Reports using standard and reinforced HBV vaccination schedules vary widely in seroconversion rates depending on the characteristics of the included patients. Regional data concerning HBV vaccination in HIV patients are scarce. We aim to determine the serological response to HBV vaccination using standard schedule in HIV-positive patients and to evaluate characteristics that predict seroconversion. We performed a single centre prospective study of HBV vaccination with standard schedule in HIV-positive patients. Adults with negative markers of HBV infection were included between November 2012 and December 2014. Anti-HBs titres were measured 4-8 weeks after completion of vaccination schedule. Clinical, laboratory values and HIV characteristics were analyzed to determine their association with seroconversion and adherence to the HBV vaccination schedule. The study included 245 HIV-positive patients, 68.9% were male and the mean age was 42.1 years. A total of 80.7% of the patients had undetectable HIV viral loads, 86.1% had CD4 counts >200, and 94.7% were on HAART. The response to vaccination was positive in 62% (95% CI, 56-68%) and mean anti-HBs titres of 646 IU/ml. 85.5% of the responders had anti-HBs titres >100 IU/ml. An age less than 45 years, no tobacco use and a CD4/CD8 ratio >0.4 were associated with seroconversion in multivariate analysis. The seroconversion rates were 86% in the subgroup of patients who met these criteria. A total of 97.9% of the study population completed the vaccination schedule. The CD4/CD8 ratio was the primary factor associated with positive serological conversion in the multivariate analysis. The seroconversion rates were higher in a selected group of patients who were particularly suitable for the use of the standard HBV vaccination schedule
Rui, Shaozhen; Yan, Jun; Zhang, Hui; Wang, Zhengfeng; Zhou, Wence
Liver resection may be beneficial in intermediate-stage hepatocellular carcinoma (HCC), though the benefit of postoperative anti-hepatitis B virus (HBV) therapy in these patients remains unclear. In this study, we sought to evaluate the efficacy of postoperative anti-HBV for intermediate-stage HCC patients who underwent radical liver resection.According to inclusion and exclusion criteria, this study enrolled 202 HCC patients who underwent liver resection and had a high HBV-DNA load. The patients were divided into 2 groups on the basis of postoperative anti-HBV therapy: group A included patients undergoing postoperative anti-HBV therapy, whereas group B patients did not receive any postoperative anti-HBV therapy. Factors including baseline demographics, tumor characteristics, overall long-term survival, tumor-free survival, and tumor recurrence rate were compared between the 2 groups. Moreover, univariate and multivariate analyses were used to identify risk factors of HCC recurrence.Baseline demographics and tumor characteristics were comparable between the groups. The 1-, 3-, and 5-year overall survival rates in group A were 91.3%, 80.9%, and 66.1%, respectively, values that were significantly increased compared with group B (91.7%, 60.7%, and 52.4%, respectively, P = .019). Group A patients also exhibited enhanced 1-, 3-, and 5-year tumor-free survival compared with group B patients (87.0%, 67.0%, and 62.6%, respectively, in group A; 82.1%, 50.0%, and 42.9% in group B, P = .002). In addition, the tumor recurrence rate in group B was significantly increased compared with group A (P < .01). Univariate and multivariate analyses indicated lack of postoperative anti-HBV therapy [hazard ratio (HR) = 0.882; 95% confidence interval (CI), 0.712-0.938; P = .042] to be a predictor of tumor recurrence.For intermediate-stage [Barcelona Clinic Liver Cancer (BCLC) stage B] HCC with a high HBV-DNA load, postoperative anti-HBV therapy after curative resection
Tang, Shengli; Yuan, Yufeng; He, Yueming; Pan, Dingyu; Zhang, Yongxi; Liu, Yuanyuan; Liu, Quanyan; Zhang, Zhonglin; Liu, Zhisu
As a multifunctional cytokine, interleukin-6 (IL-6) plays a key role in chronic inflammation as well as tumor growth and progression of hepatitis B virus (HBV) infection. Recent studies have implicated that single nucleotide polymorphism (SNP) -572C>G (rs1800796) located within the promoter region of IL-6 gene was associated with susceptibility to several diseases. Here, a case-control study was undertaken to investigate the association between this polymorphism and HBV-related hepatocellular carcinoma (HCC) susceptibility in a Chinese Han population. A total of 900 patients with chronic HBV infection, including 505 HBV-related HCC patients and 395 HBV infected patients without HCC were enrolled, and rs1800796 polymorphism was genotyped by the TaqMan method and DNA sequencing technology. The results indicated no significant association between rs1800796 polymorphism and the risk of HBV-related HCC in all subjects; however, a significant difference was identified in male subjects. Under the dominant model, male subjects with the G allele (CG/GG) have higher susceptibility to HBV-related HCC than those with CC genotype after adjusting confounding factors (P=0.012, odds ratio [OR] 1.68, 95% confidence interval [95% CI] 1.15-2.42). Our results suggested that rs1800796 polymorphism of IL-6 gene was associated with susceptibility to HBV-related HCC in a male Chinese Han population.
Mozer-Lisewska, Iwona; Kowala-Piaskowska, Arleta; Mania, Anna; Jenek, Renata; Samara, Husam; Kaczmarek, Elżbieta; Sikora, Jan; Służewski, Wojciech; Zeromski, Jan
Pattern recognition receptors (PRRs) constitute a pivotal arm of innate immunity. Their distribution is widespread and not limited to cells of the immune system. Following our previous findings concerning the expression of Toll-like receptors (TLRs) 2, 3 and 4 in chronic viral hepatitis C of children, we wished to search for other PRRs, including other TLRs, NOD-like receptors (NLRs) and RIG-1-like helicase receptors (RLR) in infected hepatocytes. Liver biopsy fragments from ten children with chronic hepatitis B and C were used and two others in which hepatotropic virus infection was excluded. Frozen sections of liver samples were subjected to ABC immunohistochemistry (IHC) following incubation with a set of antibodies. Results of IHC findings were screened for correlation with clinical/laboratory data of patients. It was found that several PRRs could be shown in affected hepatocytes, but the incidence was higher in hepatitis C than in B. In hepatitis C, TLR1, 2, 4, NALP and RIG-1 helicase showed the most marked expression. In hepatitis B, TLR1, 3, 9, NOD1 and NALP expression were the most conspicuous. Expression PRRs in liver from hepatitis of unknown origin was much lower. It was also the case in cytospins from human hepatoma cell line. Several correlations between PRRs expression and clinical findings in patients could be shown by statistical exploration. In conclusion, this data suggests some role for PRRs in the pathogenesis of chronic viral hepatitis.
Huang, Hai; Zhou, Wei; Zhu, Haiyan; Zhou, Pei; Shi, Xunlong
Although current antiviral treatments (nucleoside analogs, NAs) for chronic hepatitis B virus (HBV) infection are effective in suppressing HBV-DNA replication, their clinical outcomes can be compromised by the increasing drug resistance and the inefficiency in promoting HBsAg/HBeAg seroconversion. In this study, we will explore possible effects and mechanism of a natural product baicalin (BA) with the anti-HBV efficacy of entecavir (ETV), a first-line anti-HBV drug, in HBV-DNA, HBsAg/HBeAg seroconversion and drug-resistance. The co-effects of BA and ETV were conducted in wild-type/NA-resistance mutant HBV cell lines and DHBV-infected duckling models. HBV-DNA/RNAs, HBsAg/HBeAg, host factors (hepatocyte nuclear factors) were explored for possible anti-HBV mechanism. BA could significantly enhance and reduced HBsAg and HBeAg in hepG2.2.15, a wild-type HBV cell line. Co-treatment of BA and ETV had a more dramatic effect in NA-resistant HBV(rtM204V/rtLl80M) transfected hepG2 cells. Our study further revealed that BA mainly inhibited the production of HBV RNAs (3.5, 2.4, 2.1kb), the templates for viral proteins and HBV-DNA synthesis. BA blocked HBV RNAs transcription possibly by down-regulating transcription and expression of HBV replication dependent hepatocyte nuclear factors (HNF1α and HNF4α). Thus, BA may benefit the anti-HBV therapy via inhibiting HBV viral RNAs. Copyright © 2017 Elsevier Inc. All rights reserved.
Jaroszewicz, Jerzy; Calle Serrano, Beatriz; Wursthorn, Karsten; Deterding, Katja; Schlue, Jerome; Raupach, Regina; Flisiak, Robert; Bock, C-Thomas; Manns, Michael P; Wedemeyer, Heiner; Cornberg, Markus
The quantifiable level of HBsAg has been suggested as a predictor of treatment response in chronic hepatitis B. However, there is limited information on HBsAg levels considering the dynamic natural course of HBV-infection. This study aimed to determine HBsAg levels in the different phases of HBV-infection in European HBsAg-positive patients. 226 HBV-monoinfected patients, not undergoing antiviral therapy, were analyzed in a cross-sectional study. Patients were categorized according to the phase of HBV-infection: HBeAg(+) immune tolerance phase (IT, n=30), immune clearance phase (IC, n=48), HBeAg(-) low-replicative phase (LR, n=68), HBeAg(-) hepatitis (ENH, n=68), and acute hepatitis B (n=12). HBsAg was quantified and correlated with HBV-DNA, HBV-genotypes and clinical parameters. In addition, 30 LR-patients were followed longitudinally. HBsAg levels were higher in IT-patients and IC-patients compared to LR-patients and ENH-patients (4.96/4.37/3.09/3.87-log(10)IU/ml, p<0.001). HBsAg showed a strong correlation with HBV-DNA during acute hepatitis B (R=0.79, p<0.01). Correlation of HBsAg and HBV-DNA was weak or missing when analyzing different phases of persistent HBV-infection separately. However, associations between HBsAg and HBV-DNA were observed in patients infected with HBV-genotype D but not with HBV-genotype A. LR-patients with HBV-reactivation during follow-up (increase of HBV-DNA >2000IU/ml) showed >3-fold higher baseline HBsAg levels with a NPV of 95% for an HBsAg cut-off of 3500IU/ml. HBsAg levels show significant differences during the natural course of HBV-infection and between HBV-genotypes. These findings may have important implications for understanding the natural history of HBV-infection and for using quantitative HBsAg as a diagnostic tool, i.e. as a marker for predicting HBV-reactivation.
Kim, Jong Hun; Psevdos, George; Sharp, Victoria
A retrospective review of 4,721 human immunodeficiency virus (HIV)-infected patients, followed at St. Luke's Roosevelt Hospital Center, New York City, was conducted from January 1, 2005 to December 31, 2009. HIV-Hepatitis B virus (HBV) co-infection rate was 218/4,721, 4.6%. Among co-infected patients, 19 patients (19/218, 8.7%) died; 13 patients (13/19, 68.4%) died from non-acquired immune deficiency syndrome (AIDS) defining including 2 patients with liver failure. More non-survivors (5 patients, 5/19, 26.3%) had liver cirrhosis than those who survived (8 patients, 8/199, 4.0%; P = 0.002). There were more patients with positive HBV e antigen (HBeAg) among non-survivors, (12 patients, 12/19, 63.2%) than among survivors (74 patients, 74/199, 37.2%; P = 0.047). HIV-HBV co-infection is associated with increased overall mortality. Therefore, use of dual active antiretrovirals, particularly, tenofovir (TDF) based regimen for optimal suppression of HIV-HBV and immune restoration with prevention of high risk behaviors may contribute to improved outcomes.
Ito, H; Ando, T; Nakamura, M; Ishida, H; Kanbe, A; Kobiyama, K; Yamamoto, T; Ishii, K J; Hara, A; Seishima, M; Ishikawa, T
A persistent hepatitis B virus (HBV) infection is characterized by a lack of or a weak immune response to HBV, which may be reflective of tolerance to HBV. Efficient induction of HBV-specific immune response leads to the clearance of HBV in patients with a chronic HBV infection. CpG oligodeoxynucleotides (ODN) has a powerful adjuvant effect in HBV vaccination. A recent report demonstrated that the immunization by B/K CpG ODN (K3) wrapped by the nonagonistic Dectin-1 ligand, schizophyllan (SPG), namely K3-SPG, was more effective in the induction of antigen-specific immune response than that by K3. In this study, we examined the efficacy of K3-SPG as a HBV vaccine adjuvant. Wild-type (WT) mice and HBV transgenic (HBV-Tg) mice were subcutaneously immunized with hepatitis B surface antigen (HBsAg) alone, HBsAg and K3, or HBsAg and K3-SPG. The vaccination with HBsAg and K3-SPG significantly enhanced humoral and cellular immune response to HBV antigen compared to the other vaccinations in WT and HBV-Tg mice. K3-SPG induced the accumulation of dendritic cells (DCs) into draining lymph node and the activation of DCs. The expression of cytokines and chemokines related to Th1 and Th2 responses was upregulated after the vaccination including with K3-SPG. In conclusion, these results indicated that the vaccination using K3-SPG may overcome tolerance even in patients with chronic HBV infection. © 2016 John Wiley & Sons Ltd.
Dusséaux, Mathilde; Masse-Ranson, Guillemette; Darche, Sylvie; Ahodantin, James; Li, Yan; Fiquet, Oriane; Beaumont, Elodie; Moreau, Pierrick; Rivière, Lise; Neuveut, Christine; Soussan, Patrick; Roingeard, Philippe; Kremsdorf, Dina; Di Santo, James P; Strick-Marchand, Helene
recapitulates some of the immunopathology observed in patients with chronic infection. Inoculation with different viral loads led to different immune responses and levels of virus control. We found HBV to infect liver progenitor cells, which could be involved in hepatocellular carcinogenesis. This is an important new system to study anti-HBV immune responses and screen for combination therapies against hepatotropic viruses. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.
Wang, H; Hu, J; Zhu, K
To evaluate the role of apoptosis mediated by Fas/FasL in the liver of hepatitis B and the expression status of Fas, FasL, and HBV antigens. We studied the expression of Fas antigen, Fas-ligand (FasL) and hepatitis B virus(HBV) antigens(HBsAg and HBcAg) in the livers of 62 patients with hepatitis B using immunohistochemistry ABC method. Six normal liver samples were used as control. Hepatocytes in normal liver had no Fas/FasL expression, but in the cases of hepatitis B, Fas was expressed mainly in the cytoplasm in 58 cases(93.5%); FasL was observed in infiltrating mononuclear cells and in the cytoplasm of hepatocytes in 37 cases (59.7%). The expressions of Fas/FasL were closely related to the liver histological inflammation degrees. The apoptosis mediated by Fas/FasL may play an important role in the hepatocellular injury in hepatitis B. No correlation was found between the degrees of Fas/FasL expression and the presence of HBsAg and HBcAg in the liver.
Woynarowski, Marek; Cielecka-Kuszyk, Joanna; Kałużyński, Andrzej; Omulecka, Aleksandra; Sobaniec-Łotowska, Maria; Stolarczyk, Julian; Szczepański, Wojciech
AIM: To our knowledge, the inter-observer variability of the liver biopsy findings in HBV-infected children have not been studied as yet. Hence, we aimed to compare different pathologist’s assessment of grading and staging in liver biopsies obtained from children prior to interferon treatment. METHODS: We collected 920 biopsies from 11 medical centers. The biopsies were independently reviewed by 6 pathologists from academic centers who assessed Batts-Ludwig score for grading and staging. Satisfactory agreement among observers was defined as at least 60% of observers having the same opinion. Satisfactory dispersion between maximal and minimal score for the same biopsy specimen was defined as a maximum 1 point. RESULTS: Satisfactory inter-observer agreement for grading was obtained in 51.6% and for staging in 75.7% of biopsies. Satisfactory dispersion for grading scores was observed in 44.5% and for staging in 72.7% of cases. CONCLUSION: Our study demonstrates that: (1) pathologists differ in their assessment of grading and staging of liver biopsies; (2) inter-observer variability for staging is lower than that for grading; and (3) regardless of the inter-observer variability of assessments, the majority of children with chronic HBV infection have mild to moderate inflammation and mild to moderate fibrosis. PMID:16586539
Woynarowski, Marek; Cielecka-Kuszyk, Joanna; Kałuzyński, Andrzej; Omulecka, Aleksandra; Sobaniec-Łotowska, Maria; Stolarczyk, Julian; Szczepański, Wojciech
To our knowledge, the inter-observer variability of the liver biopsy findings in HBV-infected children have not been studied as yet. Hence, we aimed to compare different pathologist's assessment of grading and staging in liver biopsies obtained from children prior to interferon treatment. We collected 920 biopsies from 11 medical centers. The biopsies were independently reviewed by 6 pathologists from academic centers who assessed Batts-Ludwig score for grading and staging. Satisfactory agreement among observers was defined as at least 60% of observers having the same opinion. Satisfactory dispersion between maximal and minimal score for the same biopsy specimen was defined as a maximum 1 point. Satisfactory inter-observer agreement for grading was obtained in 51.6% and for staging in 75.7% of biopsies. Satisfactory dispersion for grading scores was observed in 44.5% and for staging in 72.7% of cases. Our study demonstrates that: (1) pathologists differ in their assessment of grading and staging of liver biopsies; (2) inter-observer variability for staging is lower than that for grading; and (3) regardless of the inter-observer variability of assessments, the majority of children with chronic HBV infection have mild to moderate inflammation and mild to moderate fibrosis.
Every practice has patients who are chronically late. This wrecks havoc with your schedule and makes you less productive. Patients can be trained to respect your time and arrive in the office on time. This article discusses several approaches to managing the chronically late patient.
Kim, Min; Kim, Seul Young; Rou, Woo Sun; Hwang, Se Woong; Lee, Byung Seok
Despite sexual function making an important contribution to the quality of life, data on erectile function are relatively scant in patients with chronic liver disease. We evaluated the prevalence of and risk factors for erectile dysfunction (ED) in patients with liver disease related to hepatitis B, especially among those with chronic hepatitis B (CHB) or early-stage cirrhosis. In total, 69 patients (35 with CHB and 34 with hepatitis-B-related liver cirrhosis [HBV-LC]) aged 40-59 years were analyzed. Child-Pugh classes of A and B were present in 30 (88.2%) and 4 (11.8%) of the patients with HBV-LC, respectively. The erectile function of the patients was evaluated using the Korean version of IIEF-5. The prevalence of any ED was 24.6% for all patients, and 8.6% and 41.2% for those with CHB and HBV-LC, respectively (P=0.002). While there was only one (2.9%) CHB patient for each stage of ED, mild, moderate, and severe ED stages were seen in three (8.8%), one (2.9%), and ten (29.4%) of the HBV-LC patients, respectively. Multiple regression analysis identified the type of liver disease (P=0.010), hypertension (P=0.022), score on the Beck Depression Inventory (P =0.044), and the serum albumin level (P=0.014) as significant independent factors for the presence of ED. The prevalence of ED was significantly higher in patients with early-stage HBV-LC than in those with CHB. Therefore, screening male patients with early viral cirrhosis for ED and providing appropriate support are needed, especially when the cirrhosis is accompanied by hypertension, depression, or a depressed level of serum albumin.
Zheng, Zuci; Wang, Qiwen; Weng, Cuncheng; Lin, Xueliang; Lin, Yao; Feng, Shangyuan
An optical method of surface-enhanced Raman spectroscopy (SERS) was developed for non-invasive detection of hepatitis B surface virus (HBV). Hepatitis B virus surface antigen (HBsAg) is an established serological marker that is routinely used for the diagnosis of acute or chronic hepatitis B virus(HBV) infection. Utilizing SERS to analyze blood serum for detecting HBV has not been reported in previous literature. SERS measurements were performed on two groups of serum samples: one group for 50 HBV patients and the other group for 50 healthy volunteers. Blood serum samples are collected from healthy control subjects and patients diagnosed with HBV. Furthermore, principal components analysis (PCA) combined with linear discriminant analysis (LDA) were employed to differentiate HBV patients from healthy volunteer and achieved sensitivity of 80.0% and specificity of 74.0%. This exploratory work demonstrates that SERS serum analysis combined with PCA-LDA has tremendous potential for the non-invasive detection of HBV.
Zhao, Weidong; Zhou, Xian; Zhao, Gan; Lin, Qing; Wang, Xianzheng; Yu, Xueping; Wang, Bin
Adjuvants are considered a necessary component for HBV therapeutic vaccines but few are licensed in clinical practice due to concerns about safety or efficiency. In our recent study, we established that a combination protocol of 3-day pretreatments with GM-CSF before a vaccination (3 × GM-CSF+VACCINE) into the same injection site could break immune tolerance and cause over 90% reduction of HBsAg level in the HBsAg transgenic mouse model. Herein, we further investigated the therapeutic potential of the combination in AAV8-1.3HBV-infected mice. After four vaccinations, both serum HBeAg and HBsAg were cleared and there was a 95% reduction of HBV-positive hepatocytes, in addition to the presence of large number of infiltrating CD8+ T cells in the livers. Mechanistically, the HBV-specific T-cell responses were elicited via a 3 × GM-CSF+VACCINE-induced conversion of CCR2-dependent CD11b+ Ly6Chi monocytes into CD11b+CD11c+ DCs. Experimental depletion of Ly6Chi monocytes resulted in a defective HBV-specific immune response thereby abrogating HBV eradication. This vaccination strategy could lead to development of an effective therapeutic protocol against chronic HBV in infected patients.
Tajik, Zahra; Keyvani, Hossein; Bokharaei-Salim, Farah; Zolfaghari, Mohammad Reza; Fakhim, Shahin; Keshvari, Maryam; Alavian, Seyed Moayed
Background: Covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) is a marker of HBV replication in the liver of patients infected with HBV. Objectives: This study aimed to investigate the association between the presence of cccDNA in the plasma samples of Iranian treatment-naive patients with chronic hepatitis B infection and HBV viral load and HBsAg levels. Patients and Methods: From April 2012 to May 2015, 106 treatment-naive patients with chronic hepatitis B infection were enrolled in this cross-sectional study. The HBsAg titer was measured by the Roche HBsAg II assay on the Cobas e411 system, and HBV DNA quantitation was performed using the COBAS TaqMan 48 kit. Real-time polymerase chain reaction was performed for the detection of HBV cccDNA. Results: The mean (SD) age of the patients was 41.1 ± 12.4 years (range, 20 - 62 years). From a total of 106 study participants, 67 (63.2%) were males. The HBV cccDNA was detected in plasma specimens in 19 (17.9%) out of the total 106 patients, and a significant relationship was found between the presence of cccDNA in plasma sample of males (23.9%) and females (7.7%) (P = 0.039). Also, a significant correlation was found between the presence of cccDNA in plasma sample of the patients and HBV viral load level (P < 0.0001) and HBsAg titer (P = 0.0043). Conclusions: This study showed that cccDNA can be detected in the plasma specimen of 17.9% of Iranian treatment-naive patients with chronic hepatitis B infection. Therefore, designing prospective studies focusing on the detection of cccDNA in these patients would provide more information. PMID:26504471
Background Liver dominates the production and secretion of apolipoprotein B (apoB) and evidence shows that liver malfunction induced by hepatitis B virus (HBV) infection could lead to apolipoprotein metabolism disorders. The present study was undertaken to assess the effects of HBV on apoB expression. Methods Clinical examination: serum apoB levels in patients with chronic HBV infection and in healthy individuals were measured by immunoturbidimetry using biochemical analyzer Olympus 5400. Cell study: mRNA and protein expression levels of apoB in HepG2 and HepG2.2.15 cells were measured by RT-PCR and Western blot. Alternatively, HBV infectious clone pHBV1.3 or control plasmid pBlue-ks were tranfected into HepG2 cells, and mRNA and protein expression levels of apoB, as well as the microsomal triglyceride transfer protein (MTP) in tranfected HepG2 cells were also measured by RT-PCR and western blot. Results Serum apoB level was much lower in chronic HBV patients as compared to healthy individuals (P < 0.05). Expression of apoB mRNA and protein was lower in HepG2.2.15 cells than in HepG2 cells. Similarly, expression of apoB mRNA and protein was lower in pHBV1.3 transfected HepG2 cells than in pBlue-ks transfected HepG2 cells. Expression of MTP mRNA and protein in pHBV1.3 transfected HepG2 cells was reduced in a dose-dependent fashion. Conclusion HBV infection plays an inhibitory effect on apoB expression. PMID:22074108
Revill, Peter; Testoni, Barbara; Locarnini, Stephen; Zoulim, Fabien
Chronic HBV infection results in >1 million deaths per year from cirrhosis and liver cancer. No known cure for chronic HBV exists, due in part to the continued presence of transcriptionally active DNA in the nucleus that is not directly targeted by current antiviral therapies. A coordinated approach is urgently needed to advance an HBV cure worldwide, such as those established in the HIV field. We propose the establishment of an International Coalition to Eliminate Hepatitis B Virus (ICE-HBV) to facilitate the formation of international working groups on HBV virology, immunology, innovative tools and clinical trials: to promote awareness and education as well as to drive changes in government policy and ensure funds are channelled to HBV cure research and drug development. With the ICE-HBV in place, it should be possible to enable a HBV cure within the next decade.
Fu, Xiaochun; Chen, Jing; Chen, Huijuan; Lin, Jinpiao; Xun, Zhen; Li, Shiqi; Liu, Can; Zeng, Yongbin; Chen, Tianbin; Yang, Bin; Ou, Qishui
The mechanism for the co-existence of hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs) in chronic HBV infected patients remains controversial. This study aimed to explore the role of HBV S gene mutation and anti-HBs subtype-nonspecificity in patients with simultaneous HBsAg/anti-HBs positivity. Chronic HBV infections with (n = 145, group I) and without (n = 141, group II) anti-HBs were included. The S gene was amplified and sequenced. The neutralization experiment was used in group I patients' sera to determine the specificity of anti-HBs. Additionally, the HBV vaccinated persons' sera were used to estimate the neutralize capacity of anti-HBs against HBsAg in group I patients. Results showed that 2.63% (145/5513) chronic HBV infected patients had positive results for anti-HBs. HBsAg amino acid (aa) substitution rate in 35 patients of group I was significantly higher than that in 58 patients of group II (1.89% vs 0.95%, P < 0.05), especially within "a" determinant (4.05% vs 1.22%, P < 0.05). In group I patients, anti-HBs in (74.29%, 26/35) patients was not directed to the subtypes of the co-existing HBsAg. Besides, some HBsAg variations in group I patients, sG145R mutation, inserted mutations, and continuous aa mutations within the major hydrophilic region (MHR), decreased the neutralized capacity of anti-HBs from HBV vaccinated persons. In conclusion, both of HBsAg mutation and anti-HBs subtype-nonspecificity contributed to the co-existence of HBsAg and anti-HBs in chronic HBV infection. HBV vaccine recipients may still have a risk of HBV infection when exposure to patients with simultaneous HBsAg/anti-HBs positivity.
De Francesco, Maria Antonia; Gargiulo, Franco; Spinetti, Angiola; Zaltron, Serena; Giagulli, Cinzia; Caccuri, Francesca; Castelli, Francesco; Caruso, Arnaldo
Little is known about the optimal management of patients with chronic hepatitis B (CHB) who develop drug resistance. The aim of this study was to investigate the effectiveness of different drug regimens in chronically HBV-infected patients. HBV viral load was determined using a bDNA assay and the substitutions in HBV-DNA were studied by polymerase sequencing test. The study involved 38 patients who experienced a therapeutic failure to lamivudine (LAM). The sequential treatments used were: LAM + adefovir (ADV), LAM + tenofovir (TDF), entecavir (ETV) monotherapy, ADV monotherapy and TDF monotherapy. Similar activity against HBV replication was observed with all drug regimens. Of the patients treated with LAM, 44% developed resistance mutations. The rt M204I mutation was observed more frequently. Sequential ADV add-on LAM and TDF therapy induced the appearance of resistance in 3/18 (16.6%) and in 1/8 (5.5%) treated patients, respectively. Genotype D was the most prevalent (78.9%), followed by genotype A (13%), genotype E (5.2%) and genotype C (2.6%). Our study showed that baseline serum HBV DNA is an important predictor of virologic response and that virologic breakthrough is significantly associated with the insurgence of genotypic resistance.
Hussain, Munira; Soldevila-Pico, Consuelo; Emre, Sukru; Luketic, Velimir; Lok, Anna S F
Previous studies reported that hepatitis B virus (HBV) deoxyribonucleic acid (DNA) can be detected in livers of patients who received transplants for hepatitis B despite the absence of serological markers of HBV recurrence. Quantification of HBV DNA was not performed and presence of covalently closed circular (ccc) DNA was not analyzed in most studies. We aimed to quantify total and ccc HBV DNA in explant liver and post-orthotopic liver transplantation (OLT) biopsies and to correlate the values with HBV recurrence post-OLT. Frozen liver tissue from 34 patients (9 with explant liver only, 9 with explant liver and post-OLT liver biopsies, and 16 with post-OLT biopsies only) in the National Institutes of Health HBV-OLT study was examined using real-time polymerase chain reaction (PCR). Among the 18 patients with explant liver, 7 were hepatitis B e antigen (HBeAg)-positive, 8 had detectable serum HBV DNA, and 10 received antiviral therapy prior to OLT. Total and ccc HBV DNA was detected in explant livers of 17 and 16 patients, respectively. Of the 10 patients who received antiviral therapy pre-OLT, serum HBV DNA was undetectable in 8 at transplantation but 7 had detectable total and ccc HBV DNA in their explant liver. Of the 25 patients with post-OLT biopsies, total HBV DNA was detected in 83% and ccc DNA in 17% of 47 biopsies, although only 2 patients had HBV recurrence. In conclusion, total and ccc HBV DNA could be detected in explant livers of most patients despite antiviral therapy pre-OLT. Total but not ccc HBV DNA could be detected in post-OLT liver biopsies of most patients despite undetectable serum HBV DNA and hepatitis B surface antigen (HBsAg). Our findings suggest that occult HBV reinfection occurs in most HBV patients after OLT and continued administration of appropriate prophylactic therapy is important in preventing overt HBV recurrence. Copyright (c) 2007 AASLD.
Ito, Kiyoaki; Yotsuyanagi, Hiroshi; Sugiyama, Masaya; Yatsuhashi, Hiroshi; Karino, Yoshiyasu; Takikawa, Yasuhiro; Saito, Takafumi; Arase, Yasuji; Imazeki, Fumio; Kurosaki, Masayuki; Umemura, Takeji; Ichida, Takafumi; Toyoda, Hidenori; Yoneda, Masashi; Tanaka, Yasuhito; Mita, Eiji; Yamamoto, Kazuhide; Michitaka, Kojiro; Maeshiro, Tatsuji; Tanuma, Junko; Korenaga, Masaaki; Murata, Kazumoto; Masaki, Naohiko; Koike, Kazuhiko; Mizokami, Masashi
The prevalence of sexually transmitted acute infections of the genotype A hepatitis B virus (HBV) has been increasing in Japan. Genotype A HBV is associated with an increased risk of HBV progression to chronic infection after acute hepatitis B (AHB) in adults. A nationwide survey was conducted to evaluate the geographic distribution, clinical, and virologic characteristics of genotype A AHB and chronic hepatitis B (CHB) in Japan. Five hundred seventy AHB patients were recruited between 2005 and 2010, and 3682 CHB patients were recruited between 2010 and 2011. HBV genotypes were determined for 552 and 3619 AHB and CHB patients, respectively. Clinical characteristics were compared among different genotypes in AHB and CHB patients. Genomic characteristics of HBV genotype A were examined by molecular evolutionary analysis. Hepatitis B virus genotype A was the predominant genotype for AHB between 2005 and 2010. Phylogenetic analysis showed that all strains in the AHB patients with genotype A were classified into subtype Ae. Among CHB patients, the occurrence of genotype A was 4.1%, and genotype A was spreading in young adults. In genotype A CHB patients, early stage liver diseases were predominant, although liver diseases progressed to cirrhosis or hepatocellular carcinoma in some patients. The distribution of HBV genotypes is quite different between AHB and CHB in Japanese patients. Genotype A infection is spreading in young adults of Japanese CHB patients. Sequences derived from Japanese AHB patients were identical to or closely resembled the sequences derived from other Japanese AHB patients. © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.
Moreno, S; García-Samaniego, J; Moreno, A; Ortega, E; Pineda, J A; del Romero, J; Tural, C; von Wichmann, M A; Berenguer, J; Castro, A; Espacio, R
The measurement of fibrosis stage critically affects the identification of the progression of liver disease, the establishment of a prognosis and therapeutic decision making. Liver biopsy has been the single, most useful method to determine the degree of liver fibrosis (LF), but with recognized limitations, mainly associated with its invasiveness. In recent years, alternative noninvasive methods have been developed, including imaging methods, such as transient elastometry, and assays based on serum biomarkers. This article reviews the available studies evaluating the value of various noninvasive methods for the assessment of LF in patients with HIV-infection and HBV/HCV co-infection, and makes recommendations on how to best use and combine them in clinical practice.
Background Chronic HCV infection combined with occult hepatitis B infection has been associated with liver enzymes flare, advanced hepatic fibrosis and cirrhosis, poor response to standard interferon-α, and increased risk of HCC. This study aimed to elucidate the prevalence of occult hepatitis B infection in Egyptian chronic HCV patients, and to clarify its role in non-response of those patients to pegylated interferon/ribavirin therapy. This study enrolled 155 consecutive chronic HCV patients under pegylated interferon/ribavirin therapy. All patients were exposed to clinical assessment, biochemical, histological and virological examinations. HBV parameters (HBV DNA, anti-HBc, anti-HBs) and patients' response status to the combination therapy were determined. Results In this study, occult hepatitis B infection occurs in 3.9% of Egyptian chronic HCV patients; tends to affect younger age patients, associated with higher base line HCV viral load, less hepatic fibrosis than monoinfected patients. This occult hepatitis B infection is not a statistically significant cause of non-response to pegylated interferon/ribavirin therapy. Anti-HBs was not associated with any biochemical, histological or virological abnormalities in those patients, contrary to low response rate to therapy and higher HCV viral load that was observed with anti-HBc. Conclusions Detection of HBV DNA in HBsAg negative chronic HCV patients plays a non significant role in non-response of Egyptian patients to pegylated interferon/ribavirin therapy. PMID:21083926
Mendes-Correa, Maria Cassia; Pinho, João R R; Gomes-Gouvea, Michele S; da Silva, Adriana C; Guastini, Cristina F; Martins, Luiz G; Leite, Andréa G; Silva, Mariliza H; Gianini, Reinaldo J; Uip, David E
HBV-HIV co-infection is associated with an increased liver-related morbidity and mortality. However, little is known about the natural history of chronic hepatitis B in HIV-infected individuals under highly active antiretroviral therapy (HAART) receiving at least one of the two drugs that also affect HBV (TDF and LAM). Information about HBeAg status and HBV viremia in HIV/HBV co-infected patients is scarce. The objective of this study was to search for clinical and virological variables associated with HBeAg status and HBV viremia in patients of an HIV/HBV co-infected cohort. A retrospective cross-sectional study was performed, of HBsAg-positive HIV-infected patients in treatment between 1994 and 2007 in two AIDS outpatient clinics located in the São Paulo metropolitan area, Brazil. The baseline data were age, sex, CD4 T+ cell count, ALT level, HIV and HBV viral load, HBV genotype, and duration of antiretroviral use. The variables associated to HBeAg status and HBV viremia were assessed using logistic regression. A total of 86 HBsAg patients were included in the study. Of these, 48 (56%) were using combination therapy that included lamivudine (LAM) and tenofovir (TDF), 31 (36%) were using LAM monotherapy, and 7 patients had no previous use of either one. Duration of use of TDF and LAM varied from 4 to 21 and 7 to 144 months, respectively. A total of 42 (48.9%) patients were HBeAg positive and 44 (51.1%) were HBeAg negative. The multivariate analysis revealed that the use of TDF for longer than 12 months was associated with undetectable HBV DNA viral load (serum HBV DNA level < 60 UI/ml) (p = 0.047). HBeAg positivity was associated with HBV DNA > 60 UI/ml (p = 0.001) and ALT levels above normality (p = 0.038). Prolonged use of TDF containing HAART is associated with undetectable HBV DNA viral load. HBeAg positivity is associated with HBV viremia and increased ALT levels.
Background HBV-HIV co-infection is associated with an increased liver-related morbidity and mortality. However, little is known about the natural history of chronic hepatitis B in HIV-infected individuals under highly active antiretroviral therapy (HAART) receiving at least one of the two drugs that also affect HBV (TDF and LAM). Information about HBeAg status and HBV viremia in HIV/HBV co-infected patients is scarce. The objective of this study was to search for clinical and virological variables associated with HBeAg status and HBV viremia in patients of an HIV/HBV co-infected cohort. Methods A retrospective cross-sectional study was performed, of HBsAg-positive HIV-infected patients in treatment between 1994 and 2007 in two AIDS outpatient clinics located in the São Paulo metropolitan area, Brazil. The baseline data were age, sex, CD4 T+ cell count, ALT level, HIV and HBV viral load, HBV genotype, and duration of antiretroviral use. The variables associated to HBeAg status and HBV viremia were assessed using logistic regression. Results A total of 86 HBsAg patients were included in the study. Of these, 48 (56%) were using combination therapy that included lamivudine (LAM) and tenofovir (TDF), 31 (36%) were using LAM monotherapy, and 7 patients had no previous use of either one. Duration of use of TDF and LAM varied from 4 to 21 and 7 to 144 months, respectively. A total of 42 (48. 9%) patients were HBeAg positive and 44 (51. 1%) were HBeAg negative. The multivariate analysis revealed that the use of TDF for longer than 12 months was associated with undetectable HBV DNA viral load (serum HBV DNA level < 60 UI/ml) (p = 0. 047). HBeAg positivity was associated with HBV DNA > 60 UI/ml (p = 0. 001) and ALT levels above normality (p = 0. 038). Conclusion Prolonged use of TDF containing HAART is associated with undetectable HBV DNA viral load. HBeAg positivity is associated with HBV viremia and increased ALT levels. PMID:21933423
Ye, Lei; Kan, Fangming; Yan, Tao; Cao, Jiaqi; Zhang, Leiliang; Wu, Zhijian; Li, Wuping
The hepatitis B virus (HBV) causes acute and chronic liver infection, which may lead to liver cirrhosis and hepatocellular carcinoma. Current treatments including interferons and nucleotide analogs, have limited therapeutic effects, underscoring the need to identify effective therapeutic options to inhibit HBV replication and prevent complications. Previous animal models mimicking chronic HBV infection do not faithfully reflect disease progression in humans. Here, we used our established HBV-persistent mouse line with liver fibrosis to evaluate the efficacy of novel therapies. The combination of two short hairpin RNAs (dual-shRNA) against different coding regions of HBV delivered by a self-complementary AAV vector showed better antiviral effects than single shRNA both in vitro and in HBV-persistent mice. The dual-shRNA also exhibited stronger antifibrotic activity in vivo. Vector carrying shRNA against TGF-β, though did not inhibit HBV replication alone, enhanced the antiviral and antifibrotic activities of single and dual HBV shRNAs. Co-administration of TGF-β shRNA and HBV dual-shRNA decreased HBV DNA, HBV RNA, HBsAg, HBeAg, and liver fibrosis markers in serum and tissues, and improved liver morphology more effectively than single treatments. Our results suggest that the combination of shRNAs against HBV and TGF-β could be developed into a viable treatment for human HBV infection.
de la Torre, A N; Castaneda, I; Ahmad, M; Ekholy, N; Tham, N; Herrera, I B; Beaty, P; Malapero, R J; Ayoub, F; Slim, J; Johnson, M B
Intravenous drug use and sexual practices account for 60% of hepatitis C (HCV) and B (HBV) infection. Disclosing these activities can be embarrassing and reduce risk reporting, blood testing and diagnosis. In diagnosed patients, linkage to care remains a challenge. Audio-computer-assisted survey interview (Audio-CASI) was used to guide HCV and HBV infection testing in urban clinics. Risk reporting, blood testing and serology results were compared to historical controls. A patient navigator (PN) followed up blood test results and provided patients with positive serology linkage to care (LTC). Of 1932 patients surveyed, 574 (30%) were at risk for chronic viral hepatitis. A total of 254 (44.3%) patients were tested, 34 (13.5%) had serology warranting treatment evaluation, and 64% required HBV vaccination. Of 16 patients with infection, seven HCV and three HBV patients started treatment following patient LTC. Of 146 HBV-naïve patients, 70 completed vaccination. About 75% and 49% of HCV antibody and HBV surface antigen-positive patients were born between 1945 and 1965. Subsequently, automated HCV testing of patients born between 1945 and 1965 was built into our hospital electronic medical records. Average monthly HCV antibody testing increased from 245 (January-June) to 1187 (July-October). Patient navigator directed LTC for HCV antibody-positive patients was 61.6%. In conclusion, audio-CASI can identify patients at risk for HCV or HBV infection and those in need of HBV vaccination in urban medical clinics. Although blood testing once a patient is identified at risk for infection needs to increase, a PN is useful to provide LTC of newly diagnosed patients. © 2017 John Wiley & Sons Ltd.
Liu, Mei; Li, Lu; Zheng, Su-Jun; Zhao, Jing; Ungvari, Gabor S; Hall, Brian J; Duan, Zhong-Ping; Xiang, Yu-Tao
There are no data about the frequency of major depression in patients with liver disease related to Hepatitis B virus (HBV) in China. This study examined the prevalence of major depression and its clinical correlates and association with quality of life (QOL) in patients with HBV-related liver diseases. Altogether 634 patients with HBV-related liver diseases met study entry criteria and completed the survey. The diagnosis of major depression was established with the Mini International Neuropsychiatric Interview (MINI). Socio-demographic and clinical characteristics, Global Assessment of Functioning (GAF) and QOL were measured. The prevalence of major depression was 6.4%. Multivariable logistic regression analyses revealed that insomnia (P=0.01, OR=5.5, 95%CI=1.4-21.6) and global functioning (P<0.001, OR=0.6, 95% CI=0.5-0.7) were independently associated with major depression. Major depression was associated with both poor physical (F (1, 634)=4.0, P=0.04) and mental QOL (F (1, 634)=26.2, P<0.001). Given the negative impact of depression on patients' QOL, more attempts should be made to identify and treat it in HBV-related diseases. Copyright © 2017. Published by Elsevier Inc.
Kalyanaraman, Narayanan; Thayumanavan, Lakshmikanthan; Jayalakshmi, Mariakuttikan
The antiviral action of natural killer (NK) cells is regulated by a wide repertoire of germ-line encoded membrane receptors which recognize the expression of certain self-molecules on target cells. Among the receptors, killer cell immunoglobulinlike receptor (KIR) which recognizes the expression of human leukocyte antigen (HLA) class I has a predominant role in regulating the effector functions of NK cells, particularly in viral infections.We studied a total of 128 hepatitis B virus (HBV) patients (15 acute, 43 asymptomatic, 27 chronic and 43 with other liver diseases) while attending the Department of Medical Gastroenterology, Government Rajaji Hospital, Madurai, India, and 128 ethnic matched control to find the association between the KIR : HLA genes and differential manifestations of HBV. KIR and its ligand HLA polymorphism were identified by DNAPCR methods. The activatory receptor KIR-2DS1 was significantly elevated in various disease categories, namely asymptomatic, chronic and other HBV, except acute HBV infection. Whereas, KIR 2DS3 in acute and chronic patients and KIR 2DS5 and 3DS1 in asymptomatic individuals. Among various KIR-HLA combinations, homozygous 2DS2:C1 and individuals with 3DSI:BW4 (OR = 3.23, CI = 1.55-6.7, Pc = 0.02) are associated with HBV asymptomatism, while most of the two domain inhibitory receptors with their ligands showed significant risk in other liver diseases. Further, KIR3DL1 : HLA Bw4Iso80 (OR = 3.89, 95% CI = 1.58-9.55, Pc = 0.004) is related with higher risk for asymptomatic infection when compared with chronic HBV. Thus, the select KIR : HLA alleles and combinations seem to direct the NK cell activities and immune response in different directions resulting in varied symptoms and manifestations in the subgroups of HBV-infected patients studied.
Rijckborst, Vincent; Hansen, Bettina E; Ferenci, Peter; Brunetto, Maurizia R; Tabak, Fehmi; Cakaloglu, Yilmaz; Lanza, A Galeota; Messina, Vincenzo; Iannacone, Claudio; Massetto, Benedetta; Regep, Loredana; Colombo, Massimo; Janssen, Harry L A; Lampertico, Pietro
It was recently demonstrated that none of the hepatitis B e antigen (HBeAg)-negative patients without any serum hepatitis B surface antigen (HBsAg) decline and with <2log hepatitis B virus (HBV) DNA decline at week 12 of a 48-week peginterferon alfa-2a (PEG-IFN) treatment course achieved a sustained response (SR). We aimed at validating this stopping rule in two independent trials. HBeAg-negative patients receiving 48 or 96 weeks of PEG-IFN in the phase III registration trial (N=85) and PegBeLiver study (N=75) were stratified according to the presence of any HBsAg decline and/or 2log HBV DNA decline at week 12. SR was defined as HBV DNA <2000IU/ml and normal alanine aminotransferase 24 weeks after treatment. The original PARC trial included 102 patients (genotype A/D/other: 14/81/7), 25 (25%) had an SR. The validation dataset consisted of 160 patients (genotype A/B/C/D/other: 10/18/34/91/7), 57 (36%) achieved an SR. The stopping rule performed well across the two studies (p=0.001) and its negative predictive value [NPV] was 95% in the validation dataset harbouring genotypes A-D. Its performance was best for genotype D. Moreover, among the 34 patients treated for 96 weeks, none of the 7 (21%) without HBsAg decline and with <2log HBV DNA decline at week 12 achieved an SR (NPV 100%). We confirmed in two independent studies that the combination of HBsAg and HBV DNA levels at week 12 identifies HBeAg-negative patients with a very low chance of SR to either 48 or 96 weeks of PEG-IFN therapy. Copyright Â© 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Detection of Hepatitis B Virus (HBV) Genomes and HBV Drug Resistant Variants by Deep Sequencing Analysis of HBV Genomes in Immune Cell Subsets of HBV Mono-Infected and/or Human Immunodeficiency Virus Type-1 (HIV-1) and HBV Co-Infected Individuals
Lee, Z.; Nishikawa, S.; Gao, S.; Eksteen, J. B.; Czub, M.; Gill, M. J.; Osiowy, C.; van der Meer, F.; van Marle, G.; Coffin, C. S.
The hepatitis B virus (HBV) and the human immunodeficiency virus type 1 (HIV-1) can infect cells of the lymphatic system. It is unknown whether HIV-1 co-infection impacts infection of peripheral blood mononuclear cell (PBMC) subsets by the HBV. Aims To compare the detection of HBV genomes and HBV sequences in unsorted PBMCs and subsets (i.e., CD4+ T, CD8+ T, CD14+ monocytes, CD19+ B, CD56+ NK cells) in HBV mono-infected vs. HBV/HIV-1 co-infected individuals. Methods Total PBMC and subsets isolated from 14 HBV mono-infected (4/14 before and after anti-HBV therapy) and 6 HBV/HIV-1 co-infected individuals (5/6 consistently on dual active anti-HBV/HIV therapy) were tested for HBV genomes, including replication indicative HBV covalently closed circular (ccc)-DNA, by nested PCR/nucleic hybridization and/or quantitative PCR. In CD4+, and/or CD56+ subsets from two HBV monoinfected cases, the HBV polymerase/overlapping surface region was analyzed by next generation sequencing. Results All analyzed whole PBMC from HBV monoinfected and HBV/HIV coinfected individuals were HBV genome positive. Similarly, HBV DNA was detected in all target PBMC subsets regardless of antiviral therapy, but was absent from the CD4+ T cell subset from all HBV/HIV-1 positive cases (P<0.04). In the CD4+ and CD56+ subset of 2 HBV monoinfected cases on tenofovir therapy, mutations at residues associated with drug resistance and/or immune escape (i.e., G145R) were detected in a minor percentage of the population. Summary HBV genomes and drug resistant variants were detectable in PBMC subsets from HBV mono-infected individuals. The HBV replicates in PBMC subsets of HBV/HIV-1 patients except the CD4+ T cell subpopulation. PMID:26390290
Guo, Tao; He, Yukun; Ma, Weijie; Liu, Zhisu
Aims. To understand the feasibility and efficacy of treatment with SAMe in patients with hepatitis B-related HCC with different Barcelona Clinic Liver Cancer (BCLC) stages. Methods. We retrospectively enrolled 697 patients with BCLC early-stage (stages 0-A) and advanced-stage (stages B-C) HCC who underwent SAMe therapy (354 cases) or no SAMe therapy (343 cases). The baseline characteristics, postoperative recoveries, and 24-month overall survival rates of the patients in the 2 groups were compared. Cox regression model analysis was performed to confirm the independent variables influencing the survival rate. Results. For patients in the early-stage (BCLC stages A1–A4) group, little benefit of SAMe therapy was observed. For advanced-stage (BCLC B-C) patients, SAMe therapy reduced alanine aminotransferase (ALT) and aspartate transaminase (AST) levels and effectively delayed the recurrence time and enhanced the 24-month survival rate. Cox regression model analysis in the advanced-stage group revealed that treatment with SAMe, preoperative viral load, and Child-Pugh grade were independent variables influencing survival time. Conclusion. SAMe therapy exhibited protective and therapeutic efficacy for BCLC advanced-stage HBV-related HCC patients. And the efficacy of SAMe therapy should be further explored in randomized prospective clinical trials. PMID:28003820
Liao, Xiwen; Han, Chuangye; Qin, Wei; Liu, Xiaoguang; Yu, Long; Zhu, Guangzhi; Yu, Tingdong; Lu, Sicong; Su, Hao; Liu, Zhen; Chen, Zhiwei; Yang, Chengkun; Huang, Ketuan; Liu, Zhengtao; Liang, Yu; Huang, Jianlu; Dong, Jiahong; Li, Lequn; Qin, Xue; Ye, Xinping; Xiao, Kaiyin; Peng, Minhao; Peng, Tao
Polymorphisms in the phospholipase C epsilon (PLCE) 1 gene play a crucial role in the development and progression of several types of cancer. The present study investigated the prognostic significance of PLCE1 gene polymorphisms and expression combined with serum α-fetoprotein (AFP) level in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Single nucleotide polymorphisms were genotyped by sequencing DNA isolated from surgically resected tumor samples of 421 HBV-related HCC patients, and expression profiles were generated based on the GSE14520 dataset. A joint-effects analysis of PLCE1 haplotypes (Ars2274223Crs3765524; Grs2274223Trs3765524) with AFP level stratified at 20 ng/ml showed a significant association with overall survival(OS) of HBV-related HCC patients(log-rank P=0.0003). Patients with AC and GT haplotypes with AFP level ≥ 20 ng/ml had an increased risk of death as compared to those with the AC haplotype and AFP level < 20 ng/ml (adjusted P=0.029 and 0.041, respectively). Patients with the GT haplotype and AFP level < 20 ng/ml also had an increased risk of death, although with a non-significant P value (adjusted P=0.092). Joint-effects analysis of PLCE1 mRNA expression with serum AFP level stratified at 300 ng/ml was significantly associated with HBV-related HCC recurrence and OS. Our results demonstrate that PLCE1 haplotypes (including rs2274223 and rs3765524) and expression combined with serum AFP level may predict postoperative outcome of HBV-related HCC patients.
Wong, Robert J; Campbell, Brendan; Liu, Benny; Baden, Rachel; Bhuket, Taft
Sub-optimal screening for chronic hepatitis C virus (HCV) and chronic hepatitis B virus (HBV) among high risk groups delays diagnosis and treatment. We aimed to evaluate overall rates of HCV and HBV screening and patient knowledge of their testing result. Adults age ≥18 years undergoing elective outpatient endoscopy at a large, urban safety-net hospital from July 2015 to July 2016 were prospectively evaluated to determine rates of HCV and HBV testing, the results of those completed tests, and patient knowledge of test results among high risk individuals (as determined by U.S. Preventative Services Task Force). Among 1125 patients (52.3% male, 70.4% foreign-born), 66.5% were high risk for chronic HCV; only 30.9% received prior testing. 14.7% had positive chronic HCV infection. Patients born in the 1945-1965 cohort were more likely to have received prior HCV testing compared to those born outside of this cohort (32.7 vs. 16.9%, p = 0.01). Among patients who received HCV screening, 29.3% were aware of test results. Overall, 61.6% were high risk for chronic HBV; only 25.1% received prior testing. 4.1% were positive for chronic HBV. Compared to Caucasians, Asians (19.0 vs. 44.4%, p < 0.001) and Hispanics (20.0 vs. 44.4%, p < 0.001) were less likely to have previous HBV testing. Among patients who received prior HBV screening, 18.4% were aware of test results. Less than one-third of high risk patients received HCV and HBV screening among an ethnically diverse safety-net population. Equally low rates of patient knowledge of testing results were observed.
ZHOU, DONGSHENG; LIANG, JIANZHONG; XU, LI; HE, FENGYING; ZHOU, ZHONGGUO; ZHANG, YAOJUN; CHEN, MINSHAN
The derived neutrophil to lymphocyte ratio (dNLR) has been proposed as an easily determinable prognostic factor for cancer patients, but the prognostic significance of the dNLR in hepatocellular carcinoma (HCC) has not been investigated. The present study aimed to validate the prognostic power of the NLR and dNLR in HCC patients undergoing transarterial chemoembolization (TACE). The data of 279 consecutive patients who underwent TACE for unresectable HBV-associated HCC between September 2009 and November 2011 at the Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center (Guangzhou, China) were retrieved from a prospective database. The cut-off values for the NLR and dNLR were determined by receiver operating characteristic (ROC) analysis. The association between the NLR and dNLR and the clinicopathological characteristics and overall survival (OS) rates and times of patients was analyzed. The area under the curve (AUC) was calculated to evaluate the discriminatory ability of the NLR and dNLR. The median follow-up period was 446 days, the 1, 2 and 3-year OS rates were 38.8, 18.5 and 11.1% respectively, and the median OS time was 264 days. The cut-off values were determined as 2.6 and 1.8 for the NLR and dNLR, respectively. The NLR and dNLR were each associated with patient age, presence of vascular invasion, tumor size, AST level and ALP level. Multivariate analysis showed that the NLR, dNLR, ALT level and AFP level were independent prognostic factors for OS. An elevated NLR or dNLR was associated with a poor prognosis (P=0.001 and P=0.002, respectively). The prognostic power of NLR [AUC=0.539; 95% confidence interval (CI), 0.423–0.656] and dNLR (AUC=0.522; 95% CI, 0.406–0.638) was similar. Elevated dNLR predicted poor prognosis for patients with HBV-associated HCC undergoing TACE, with similar prognostic power to NLR. The dNLR may be used as an alternative to the NLR, as it is easily available and inexpensive. PMID:27123051
Fontenele, Andrea Martins Melo; Gainer, Juliana Braga Furtado; da Silva E Silva, Daniel Viana; Cruz Santos, Max Diego; Salgado, João Victor; Salgado Filho, Natalino; Ferreira, Adalgisa Sousa Paiva
Occult hepatitis B (OHB) is characterized by the presence of HBV-DNA in the absence of HBsAg in the serum of patients. Hemodialysis patients are at high risk for hepatitis B virus and there are few data on the prevalence of OHB in this population, mainly in Brazil. Thus, the aim of this study was to determine the prevalence of OHB in patients undergoing hemodialysis. A cross-sectional study was performed, including 301 patients on chronic hemodialysis at two dialysis centers in São Luís (Maranhão), northeast Brazil. Serological tests were performed for HBsAg, anti-HBc, anti-HBs, and anti-HCV using enzyme immunoassays (ELISA); HBV-DNA and HCV-RNA were studied by real-time PCR. The mean age was 49 ± 15 years, and 128 (42%) were female. Serological tests confirmed that all samples were HBsAg negative. Anti-HBc was positive in 114 (38%) patients, anti-HBc and anti-HBs were simultaneously positive in 104 (35%), and anti-HBc alone was positive in 10 (3%). Tests were negative for anti-HBc and anti-HBs in 55 patients (18%). Anti-HBs was the only positive marker in 132 (44%) patients. Anti-HCV was positive in 15 (5%) patients with HCV-RNA present in 14 of them (93%). HBV-DNA was positive in seven cases (2.3%). There was no association of HBV-DNA with age, gender, time on dialysis, previous kidney transplant, or HBV serological pattern, but there was a positive correlation with the presence of anti-HCV (P < 0.001). OHB in chronic renal failure patients on hemodialysis appears to be a relevant finding, suggesting that studying HBV-DNA in this population using sensitive molecular tests should be a recommended course of action, especially in candidates for renal transplant.
Harada, Keisuke; Nishitsuji, Hironori; Ujino, Saneyuki; Shimotohno, Kunitada
Antiviral therapies for chronic hepatitis B virus (HBV) infection that are currently applicable for clinical use are limited to nucleos(t)ide analogs targeting HBV polymerase activity and pegylated interferon alpha (PEG-IFN). Towards establishing an effective therapy for HBV related diseases, it is important to develop a new anti-HBV agent that suppresses and eradicates HBV. This study used recombinant HBV encoding NanoLuc to screen anti-HBV compounds from 1827 US Food and Drug Administration approved compounds and identified several compounds that suppressed HBV infection. Among them, KX2-391, a non-ATP-competitive inhibitor of SRC kinase and tubulin polymerization, was identified as a lead candidate for an anti-HBV drug. Treatment of sodium taurocholate cotransporting polypeptide (NTCP) transduced-HepG2 (HepG2-NTCP) or primary human hepatocytes with KX2-391 suppressed HBV replication in a dose-dependent manner. The anti-HBV activity of KX2-391 appeared not to depend on SRC kinase activity because siRNA for SRC mRNA did not impair the HBV infection/replication. The anti-HBV activity of KX2-391 depended on the inhibitory effect of tubulin polymerization similar to other tubulin polymerization inhibitors, some of which were shown to inhibit HBV replication. KX2-391 inhibited HBV transcription driven by a HBV precore promoter in an HBV X protein-independent manner but did not inhibit the activity of HBV-S1, -S2, -X or cytomegalovirus promoters. Treatment with KX2-391 reduced the expression of several various factors including hepatocyte nuclear factor-4a. Copyright © 2017 Elsevier B.V. All rights reserved.
Chen, En-Qiang; Wang, Meng-Lan; Zhang, Dong-Mei; Shi, Ying; Wu, Do-Bo; Yan, Li-Bo; Du, Ling-Yao; Zhou, Ling-Yun; Tang, Hong
Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a life-threatening condition, and the lipid metabolism disorder is common in the development of this disease. This prospective observational study aimed to define the characteristics of plasma apolipoprotein A-V (apoA-V) in long-term outcome prediction of HBV-ACLF, and a total of 330 HBV-ACLF patients were included and followed for more than 12 months. In this cohort, the 4-week, 12-week, 24-week and 48-week cumulative mortality of HBV-ACLF was 18.2%(60/330), 50.9%(168/330), 59.7%(197/330) and 63.3%(209/330), respectively. As compared to survivors, the non-survivors had significantly lower concentrations of plasma apoA-V on admission. Plasma apoA-V concentrations were positively correlated with prothrombin time activity (PTA), and negatively correlated with interleukin-10, tumor necrosis factor-α, and iMELD scores. Though plasma apoA-V, PTA, total bilirubin(TBil) and blood urea nitrogen(BUN) were all independent factors to predict one-year outcomes of HBV-ACLF, plasma apoA-V had the highest prediction accuracy. And its optimal cutoff value for one-year survival prediction was 480.00 ng/mL, which had a positive predictive value of 84.68% and a negative predictive value of 92.23%. In summary, plasma apoA-V decreases significantly in non-survivors of HBV-ACLF, and it may be regarded as a new predictive marker for the prognosis of patients with HBV-ACLF. PMID:28358016
Singla, Bhupesh; Chakraborti, Anuradha; Sharma, Bal Krishan; Kapil, Shweta; Chawla, Yogesh K; Arora, Sunil K; Das, Ashim; Dhiman, Radha K; Duseja, Ajay
Mutations in the reverse transcriptase (RT) region of the hepatitis B virus (HBV) genome lead to decreased susceptibility to nucleos(t)ide analogs approved for treatment of HBV infection. The aim of this study was to detect and analyze pre-existing HBV RT mutations in treatment naïve patients with chronic hepatitis B. Seventy one chronic HBV treatment naïve patients were enrolled from January 2009 to June 2011. HBV RT sequence analysis was done by using direct bidirectional sequencing of semi-nested PCR products. HBV genotypes were determined by multiplex PCR. Genotype D was found in 64 patients (90.1%) followed by genotype C and A which were present in 5 (7.0%) and 2 (2.8%) patients respectively. The results of the RT sequence analysis showed mutations in 34 (47.9%) patients. The rtH248N mutation was the most common mutation, accounting for 47.1% patients. Other common mutations included rtD263E/S, rtM129L, rtF122L/V/I, rtS135Y/H, rtQ149K, rtL91I, rtH126R, rtC256S/G, rtY257W, rtS259T and rtE271D, which were present in 26.5% (9/34), 29.4% (10/34), 20.6% (7/34), 20.6% (7/34), 20.6% (7/34), 17.6% (6/34), 14.7% (5/34), 14.7% (5/34), 11.8% (4/34), 11.8% (4/34) and 11.8% (4/34) patients respectively. The known primary drug resistance mutations were found in 3 (8.8%) patients. The present study shows the presence of RT amino acid substitutions in treatment-naïve patients with chronic hepatitis B, which may decrease susceptibility to available oral antiviral drugs. On the basis of the finding of this study, genotypic testing is recommended before the start of therapy in naïve patients, so that suitable antiviral drugs can be prescribed.
Bura, Maciej; Mozer-Lisewska, Iwona
Chronic hepatitis B and C are among most important problems in contemporary hepatology. Natural history of the disease can be changed as a result of superinfection with other primary hepatotropic viruses. Clinical consequences of such events are uncommon subjects of clinical reports. Acute viral hepatitis occurring in HBV- or HCV-infected patients can result in severe exacerbation of liver disease, including acute liver failure; sometimes progression of liver disease toward liver cirrhosis is observed; HBV and/or HCV clearance is also possible. Because of potentially severe outcomes of superinfections, prevention of such events based on vaccinations and education about the risk related with additional infections should be implemented in the management of patients with chronic viral hepatitis B and C.
Rostey, Renato Roberto Liberato; Souto, Francisco José Dutra
BACKGROUND Extrahepatic manifestations are seen in association with chronic infection by hepatitis B or C virus including cutaneous disorders. The frequency of these findings seems to vary among different places and reports. There is a lack of information about this issue in Brazil. OBJECTIVES To estimate the prevalence of cutaneous findings affecting HBV or HCV carriers from a reference outpatient unit in Mato Grosso. METHODS A cross-sectional observational study. RESULTS 108 patients were studied. 88.9% presented some cutaneous findings but must of them were nonrelated to chronic viral infection. Four patients had cutaneous or autoimmune syndromes that may be HBV or HCV related. CONCLUSION In our study we found no statistical association between viral hepatitis and skin diseases. PMID:26734863
Clark, Daniel N; Hu, Jianming
Infection with HBV is common worldwide, with over 350 million chronic carriers. Chronic HBV infection is associated with cirrhosis and hepatocellular carcinoma. All currently available oral antivirals are directed against the HBV polymerase enzyme, a reverse transcriptase. HBV polymerase contains several important domains and motifs which define its functions and reveal ways to further target it. This enzyme executes many functions required for the HBV replication cycle, including viral RNA binding, RNA packaging, protein priming, template switching, DNA synthesis and RNA degradation. In addition, HBV polymerase must interact with host proteins for its functions. Future therapeutics may inhibit not only the DNA synthesis steps which are carried out by the reverse transcriptase domain (as all current antivirals do) but other domains, functions and interactions which are essential to the HBV replication cycle. PMID:25893003
ABSTRACT Chronic infection with hepatitis B virus (HBV) is a risk factor for developing liver diseases such as hepatocellular carcinoma (HCC). HBx is a multifunctional protein encoded by the HBV genome; HBx stimulates HBV replication and is thought to play an important role in the development of HBV-associated HCC. HBx can activate the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway in some cell lines; however, whether HBx regulates PI3K/AKT signaling in normal hepatocytes has not been evaluated. In studies described here, we assessed HBx activation of PI3K/AKT signaling in an ex vivo model of cultured primary hepatocytes and determined how this HBx activity affects HBV replication. We report that HBx activates AKT in primary hepatocytes and that the activation of AKT decreases HBV replication and HBV mRNA and core protein levels. We show that the transcription factor hepatocyte nuclear factor 4α (HNF4α) is a target of HBx-regulated AKT, and we link HNF4α to HBx-regulated AKT modulation of HBV transcription and replication. Although we and others have shown that HBx stimulates and is likely required for HBV replication, we now report that HBx also activates signals that can diminish the overall level of HBV replication. While this may seem counterintuitive, we show that an important effect of HBx activation of AKT is inhibition of apoptosis. Consequently, our studies suggest that HBx balances HBV replication and cell survival by stimulating signaling pathways that enhance hepatocyte survival at the expense of higher levels of HBV replication. IMPORTANCE Chronic hepatitis B virus (HBV) infection is a common cause of the development of liver cancer. Regulation of cell signaling pathways by the HBV HBx protein is thought to influence the development of HBV-associated liver cancer. HBx stimulates, and may be essential for, HBV replication. We show that HBx activates AKT in hepatocytes to reduce HBV replication. While this seems contradictory to an
Lampertico, Pietro; Invernizzi, Federica; Viganò, Mauro; Loglio, Alessandro; Mangia, Giampaolo; Facchetti, Floriana; Primignani, Massimo; Jovani, Manol; Iavarone, Massimo; Fraquelli, Mirella; Casazza, Giovanni; de Franchis, Roberto; Colombo, Massimo
Esophageal varices (EV) are a marker of disease severity in compensated cirrhosis due to hepatitis B virus (HBV) which predicts also the risk of hepatocellular carcinoma (HCC), clinical decompensation and anticipated liver related death. The dynamics and prognostic significance of EV in patients under long-term HBV suppression by nucleos(t)ide analogs (NUC), are poorly known. A standardized protocol (Baveno) including 414 upper gastrointestinal (GI) endoscopies was applied to 107 HBeAg-negative compensated cirrhotic patients (93% Child-Pugh A) during a median of 12 (range 2 to 17) years of NUC therapy. Patients who initially started on lamivudine (LMV) and then developed resistance (LMV-R), were rescued by early administration of adefovir, or were switched to tenofovir. Surveillance included serum HBV DNA every three months and abdominal ultrasound every six months. Twenty-seven patients had baseline F1 EV which regressed in 18, remained unchanged in eight and progressed in one patient; the 12-year cumulative incidence of EV regression was 83% (95% CI: 52-92%). De novo F1/F2 EV developed in 6/80 patients with a 12-year cumulative incidence of 10% (95% CI: 5-20%). Six of seven patients with de novo varices or progression of pre-existing varices had either a clinical breakthrough due to LMV-R and/or developed a HCC. No bleedings from ruptured EV occurred, 12 patients died (9 HCC) and 15 were transplanted (13 HCC): the 12-year cumulative incidence of HCC and overall survival was 33% (95% CI: 24-42%) and 76% (95% CI: 67-83%), respectively. Long-term pharmacological suppression of HBV in HBeAg-seronegative patients with compensated cirrhosis leads to a significant regression of pre-existing EV accompanied by a negligible risk of developing de novo EV. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Chen, Miao; Zhuang, Junling; Zhou, Daobin; Xu, Ying; Zhao, Yongqiang; Wang, Shujie; Zhang, Wei; Duan, Minghui; Zhu, Tienan; Li, Jian; Cai, Huacong; Cao, Xinxin; Han, Bing
The influence of chronic hepatitis B virus (HBV) infection on the efficacy of intensive immunosuppressive treatment (IST) of severe aplastic anaemia (SAA) patients remains unclear. Previous reports on this topic have been mostly case reports or have had a relatively short follow-up. Eight SAA patients carrying chronic HBV infection and 24 matched patients without HBV at a ratio of 1:3 were included in this retrospective analysis. The patients were treated with anti-thymocyte globulin (ATG) and cyclosporine A. Entecavir was or was not administered throughout the IST course to patients with positive or negative HBV-DNA results, respectively. No evident HBV reactivation developed. The overall response was 87.5% by 12 months, and the recurrence rate was 12.5%. There were no significant differences in overall response, overall survival and event-free survival between groups. Entecavir can effectively prevent reactivation of HBV in SAA patients with positive HBV-DNA who received intensive IST. Regular surveillance may be sufficient for HBV-DNA negative patients who should receive antiviral drugs immediately when their HBV-DNA status changes from negative to positive. The prognosis of SAA patients with chronic HBV infection after intensive IST treatment is not worse than those without HBV infection.
Xia, Chunxiang; Liu, Wenwu; Zeng, Dongxiao; Zhu, Liyao; Sun, Xiaoli; Sun, Xuejun
To investigate effects of hydrogen-rich water (HRW) on oxidative stress, liver function and HBV DNA in patients with chronic hepatitis B (CHB). Sixty patients with CHB were randomly assigned into routine treatment group or hydrogen treatment group in which patients received routine treatment alone or additional oral HRW (1200-1800 mL/day, twice daily), respectively, for 6 consecutive weeks. Serum oxidative stress, liver function, and HBV DNA level were detected before and after treatment. Thirty healthy subjects served as controls. When compared with controls, oxidative stress was obvious in CHB patients, and the liver function also significantly impaired. After treatment, the oxidative stress remained unchanged in routine treatment group, but markedly improved in hydrogen treatment group. The liver function was improved significantly and the HBV DNA reduced markedly after corresponding treatments. Although a significant difference was noted in the oxidative stress between two groups after treatment, the liver function and HBV DNA level were comparable after treatment and both had improved tendencies. HRW significantly attenuates oxidative stress in CHB patients, but further study with long-term treatment is required to confirm the effect of HRW on liver function and HBV DNA level. © 2013 Wiley Periodicals, Inc.
Yao, Guangbi; Cui, Zhenyu; Wang, Baoen; Yao, Jilu; Zeng, Minde
To evaluate the long-term efficacy and safety of lamivudine therapy for the treatment of chronic hepatitis B and the clinical influence of emergence of tyrosine methionine aspartic acid (YMDD) motif mutation of hepatitis B virus (HBV). This multicenter, double-blind, randomized, placebo controlled trial began in 1996. A total of 429 patients with HBsAg, HBeAg and HBV CNA positives were enrolled. They were randomized to receive either lamivudine 100 mg daily (n = 322) or placebo (n = 107) on 3 : 1 ratio for the first 12 weeks. Thereafter all patients were offered open label lamivudine treatment and assessed every 4 weeks for a total of 104 weeks. After 1 year treatment 72.7% patients (285/392) had a sustained serum HBV DNA response. HBV DNA continued to be substantially suppressed at the second year, except in patients with the emergence of YMDD mutation whose mean HBV DNA levels increased to 86 Meq/ml (bDNA assay) but were much more lower than that of pre-treatment baseline level. lamivudine therapy resulted in increased HBeAg loss and HBeAg/anti-HBe seroconversion, which were correlated with both baseline alanine transaminase (ALT) levels and also with duration of lamivudine treatment. HBeAg loss was achieved in 26.8% of patients with ALT > 1-fold upper limit of normal at 2 yeas and in 35.6% and 55.6% of patients with ALT > 2-fold upper limit of normal and ALT > 5-fold upper limit of normal, respectively. For HBeAg seroconversion, these figures were 17.4%, 22.2%, and 33.3% respectively. By the end of 2 years, ALT levels were remained in normal ranges in 50.3% whose ALT were abnormal before treatment, and in 83% whose ALT were mormal before treatment. YMDD mutation were developed in 49.7% of the patients. Their serum HBV DNA levels were slightly increased to bDNA median level 86 Meq/ml and 15% of the patients they were ALT exceeded baseline levels. Four patients clinically flared-up and recovered after stop treatment. The adverse drug reactions (ADRs) of lamivudine
THIO, Chloe L.; SMEATON, Laura; HOLLABAUGH, Kimberly; SAULYNAS, Melissa; HWANG, Hyon; SARAVANAN, Shanmugam; KULKARNI, Smita; HAKIM, James; NYIRENDA, Mulinda; IQBAL, Hussain Syed; LALLOO, Umesh G.; CAMPBELL, Thomas B.; LOCKMAN, Shahin; CURRIER, Judith S.
Objectives To explore factors associated with short and long-term HBV DNA suppression in a multinational cohort of HIV-HBV co-infected subjects receiving HBV-active antiretrovirals. Methods 115 HIV-HBV co-infected subjects participating in one of two global ACTG randomized clinical trials of different antiretroviral regimens received either HBV-monotherapy with either lamivudine or emtricitabine (N=56) or HBV-dual therapy with TDF plus lamivudine or emtricitabine (N=59). Associations of pre-treatment characteristics with the primary (HBV DNA <200 IU/ml at 24 weeks) and longitudinal outcomes through 144 weeks were explored using logistic regression. HBV drug-resistance mutations were determined by pol sequencing in those with viral rebound. Results The proportion with HBV DNA<200 IU/ml was 60% (95% CI 50%–69%) at 24 weeks and 79% (95% CI 69%–88%) at 144 weeks. Pre-treatment factors associated with the primary outcome were HBV DNA, CD4 T-cell count, and AST, but only pre-treatment HBV DNA remained associated with long-term suppression (P<0.0001). HBV therapy group was not significantly associated with the primary outcome at 24 weeks; however, longitudinally, a greater proportion in the dual therapy group achieved HBV DNA<200 IU/mL (P=0.007). A higher proportion of hepatitis B e antigen negative subjects (n=57) achieved HBV DNA <200 IU/ml at any point, regardless of therapy group. All 12 subjects with emergence of lamivudine-resistant mutants were in the monotherapy group. Conclusions TDF-based dual HBV-active antiretroviral therapy is preferred to treat HIV-HBV co-infected patients. In resource-limited settings where TDF may not be universally available, lamivudine or emtricitabine HBV-monotherapy is a reasonable option in patients with low HBV replication. PMID:26035319
Schmilovitz-Weiss, H; Tovar, A; Halpern, M; Sulkes, J; Braun, M; Rotman, Y; Tur-Kaspa, R; Ben-Ari, Z
The mechanism underlying disease progression in hepatitis B virus (HBV) infection is unknown. Immunoglobulins stimulate the proliferative activity of rat hepatic stellate cells in vitro. A strong association was found between serum immunoglobulin levels and hepatic fibrosis in patients with hepatitis C virus infection. Our objective was to determine if the same index could also be used in patients with chronic HBV infection. The records of 100 patients with biochemical, serological, virological and histological evidence of chronic HBV infection were reviewed for background factors and serum globulin and immunoglobulin levels. Mean (+/-SD) patient age was 44.0 +/- 14.7 years; 80 (80%) were male. Of the factors found to be significant on univariate analysis, the only significant predictors of severe hepatic fibrosis (stage > or = 2) on multivariate analysis were serum globulin level [odds ratio (OR) 5.97, 95% confidence intervals (CI) 1.82-19.53, P = 0.0004], platelet count (OR 0.98, CI 0.97-0.99, P = 0.001), and immunoglobulin G (IgG) level (OR 1.003, CI 1.000-1.007, P < 0.042) but not IgA, alkaline phosphatase, albumin or international normalized ratio. For each increase of 0.33 mg/dL in serum globulin, there was a 0.5 point increase in the stage of hepatic fibrosis. There appears to be a strong association between levels of serum globulin and IgG and extent of hepatic fibrosis in patients with chronic HBV infection. They can serve as noninvasive markers of hepatic fibrosis and, if confirmed, have important implications for the management of patients with chronic HBV infection.
Yeh, Chih-Ching; Wang, Wen-Chang; Wu, Chien-Sheng; Sung, Fung-Chang; Su, Chien-Tien; Shieh, Ying-Hua; Chang, Shih-Ni; Su, Fu-Hsiung
Objective The association between Sjögren’s syndrome (SS) and chronic hepatitis virus infection is inconclusive. Hepatitis B (HBV) and hepatitis C virus (HCV) infections are highly prevalent in Taiwan. We used a population-based case-control study to evaluate the associations between SS and HBV and HCV infections. Materials and Methods We identified 9,629 SS patients without other concomitant autoimmune diseases and 38,516 sex- and age-matched controls without SS from the Taiwan National Health Insurance claims data between 2000 and 2011. We utilized multivariate logistic regression to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) of the associations between SS and HBV and HCV infections. Sex- and age-specific (<55 and ≥55 years) risks of SS were evaluated. Results The risk of SS was higher in patients with HCV than in those without chronic viral hepatitis (OR = 2.49, 95% CI = 2.16–2.86). Conversely, HBV infection was not associated with SS (OR = 1.10, 95% CI = 0.98–1.24). Younger HCV patients were at a higher risk for SS (<55 years: OR = 3.37, 95% CI = 2.62–4.35; ≥55 years: OR = 2.20, 95% CI = 1.84–2.62). Men with HCV were at a greater risk for SS (women: OR = 2.26, 95% CI = 1.94–2.63; men: OR = 4.22, 95% CI = 2.90–6.16). Only men with chronic HBV exhibited a higher risk of SS (OR = 1.61, 95% CI = 1.21–2.14). Conclusion HCV infection was associated with SS; however, HBV only associated with SS in men. PMID:27560377
Rao, Sirish C; Ashraf, Imran; Mir, Fazia; Samiullah, Sami; Ibdah, Jamal A; Tahan, Veysel
BACKGROUND Hepatitis B virus (HBV) has been reported as a coinfection with hepatitis C virus (HCV), hepatitis D virus (HDV), cytomegalovirus (CMV), and human immunodeficiency virus (HIV). CASE REPORT A 34-year-old female presented to our clinic with epigastric pain and severe acute hepatitis manifested as jaundice associated with hyperbilirubinemia, elevated transaminases, and coagulopathy. The patient was diagnosed with acute HBV with Epstein-Barr virus (EBV) coinfection leading to subsequent chronic hepatitis B. CONCLUSIONS To our knowledge, this patient case is the first reported case of HBV and EBV coinfection reported in the literature. HBV and EBV coinfection may cause severe acute hepatitis with HBV chronicity.
Background HBV-X protein is associated with the pathogenesis of HBV related diseases, specially in hepatocellular carcinomas of chronic patients. Genetic variability of the X gene includes genotypic specific variations and mutations emerging during chronic infection. Its coding sequence overlaps important regions for virus replication, including the basal core promoter. Differences in the X gene may have implications in biological functions of the protein and thus, affect the evolution of the disease. There are controversial results about the consequences of mutations in this region and their relationship with pathogenesis. The purpose of this work was to describe the diversity of HBV-X gene in chronic hepatitis patients infected with different genotypes, according to liver disease. Methods HBV-X gene was sequenced from chronic hepatitis B patient samples, analyzed by phylogeny and genotyped. Nucleotide and aminoacid diversity was determined calculating intragenetic distances. Mutations at 127, 130 and 131 aminoacids were considered in relation to liver disease. Results The most prevalent genotype detected in this cohort was F (F1 and F4), followed by D and A. Most of the samples corresponding to genotypes A and F1 were HBeAg(+) and for genotypes D and F4, HBeAg(−) samples were represented in a higher percentage. Intragenetic distance values were higher in HBeAg(−) than in positive samples for all genotypes, and lower in overlapped regions, compared to single codification ones. Nucleotide and aminoacid diversities were higher in HBeAg(−), than in HBeAg(+) samples. Conclusions Independently of the infecting genotypes, mutations at any of 127, 130 and/or 131 aminoacid positions and HBeAg(−) status were associated with mild liver disease in this cohort. PMID:22769058
Godon, O; Fontaine, H; Kahi, S; Meritet, Jf; Scott-Algara, D; Pol, S; Michel, Ml; Bourgine, M
A substudy of a phase I/II, prospective, multicenter clinical trial was carried out to investigate the potential benefit of therapeutic vaccination on hepatitis B e antigen-negative patients with chronic hepatitis B (CHB), treated efficiently with analogues. Patients were randomized in 2 arms, one receiving a hepatitis B virus (HBV) envelope DNA vaccine, and one without vaccination. At baseline, HBV-specific interferon (IFN)-γ-producing T cells were detected in both groups after in vitro expansion of peripheral blood mononuclear cells. Vaccine-specific responses remained stable in the vaccine group, whereas in the control group the percentage of patients with HBV-specific IFN-γ-producing T cells decreased over time. The vaccine-specific cytokine-producing T cells were mostly polyfunctional CD4(+) T cells, and the proportion of triple cytokine-producer T cells was boosted after DNA injections. However, these T-cell responses did not impact on HBV reactivation after stopping analogue treatment. Importantly, before cessation of treatment serum hepatitis B surface antigen (HBsAg) titers were significantly associated with DNA or HBsAg clearance. Therapeutic vaccination in CHB patients with persistent suppression of HBV replication led to the persistence of T-cell responses, but further improvements should be searched for to control infection after treatment discontinuation.
Sun, Hsin-Yun; Sheng, Wang-Huei; Tsai, Mao-Song; Lee, Kuan-Yeh; Chang, Sui-Yuan; Hung, Chien-Ching
Hepatitis B virus (HBV) infection is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide. Due to the shared modes of transmission, coinfection with HBV and human immunodeficiency virus (HIV) is not uncommon. It is estimated that 10% of HIV-infected patients worldwide are coinfected with HBV. In areas where an HBV vaccination program is implemented, the HBV seroprevalence has declined significantly. In HIV/HBV-coinfected patients, HBV coinfection accelerates immunologic and clinical progression of HIV infection and increases the risk of hepatotoxicity when combination antiretroviral therapy (cART) is initiated, while HIV infection increases the risk of hepatitis events, cirrhosis, and end-stage liver disease related to chronic HBV infection. With the advances in antiviral therapy, concurrent, successful long-term suppression of HIV and HBV replication can be achieved in the cART era. To reduce the disease burden of HBV infection among HIV-infected patients, adoption of safe sex practices, avoidance of sharing needles and diluent, HBV vaccination and use of cART containing tenofovir disoproxil fumarate plus emtricitabine or lamivudine are the most effective approaches. However, due to HIV-related immunosuppression, using increased doses of HBV vaccine and novel approaches to HBV vaccination are needed to improve the immunogenicity of HBV vaccine among HIV-infected patients. PMID:25356024
Wandeler, Gilles; Mulenga, Lloyd; Vinikoor, Michael J; Kovari, Helen; Battegay, Manuel; Calmy, Alexandra; Cavassini, Matthias; Bernasconi, Enos; Schmid, Patrick; Bolton-Moore, Carolyn; Sinkala, Edford; Chi, Benjamin H; Egger, Matthias; Rauch, Andri
To examine the association between hepatitis B virus (HBV) infection and liver fibrosis in HIV-infected patients in Zambia and Switzerland. HIV-infected adults starting antiretroviral therapy in two clinics in Zambia and Switzerland were included. Liver fibrosis was evaluated using the aspartate aminotransferase-to-platelet-ratio index (APRI), with a ratio >1.5 defining significant fibrosis and a ratio >2.0 indicating cirrhosis. The association between hepatitis B surface antigen (HBsAg) positivity, HBV replication, and liver fibrosis was examined using logistic regression. In Zambia, 96 (13.0%) of 739 patients were HBsAg-positive compared to 93 (4.5%) of 2058 in Switzerland. HBsAg-positive patients were more likely to have significant liver fibrosis than HBsAg-negative ones: the adjusted odds ratio (aOR) was 3.25 (95% confidence interval (CI) 1.44-7.33) in Zambia and 2.50 (95% CI 1.19-5.25) in Switzerland. Patients with a high HBV viral load (≥20000 IU/ml) were more likely to have significant liver fibrosis compared to HBsAg-negative patients or patients with an undetectable viral load: aOR 3.85 (95% CI 1.29-11.44) in Zambia and 4.20 (95% CI 1.64-10.76) in Switzerland. In both settings, male sex was a strong risk factor for significant liver fibrosis. Despite the differences in HBV natural history between Sub-Saharan Africa and Europe, the degree of liver fibrosis and the association with important risk factors were similar. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.
Lv, W; Yan, F; Zeng, M; Zhang, J; Yuan, Y; Ma, J
To assess hepatic iron deposition quantitatively in patients with chronic hepatitis B (HBV) infection, using abdominal susceptibility-weighted magnetic resonance imaging (SWI). Patients with HBV infection and healthy controls underwent abdominal SWI and were assessed for serum iron markers. Phase values were measured and five grades of hepatic iron deposition were described by SWI. Patients with HBV infection (n = 327) and healthy controls (n = 50) were prospectively enrolled. In total, 77 (25.4%) patients with HBV infection had hepatic iron deposition as determined by SWI. Phase values were significantly different between patients with hepatic iron deposition compared with patients without hepatic iron deposition or controls, and were significantly different across different grades of hepatic iron deposition. Serum iron, ferritin, transferrin and transferrin saturation were significantly higher in patients with, versus those without, hepatic iron deposition. Only serum ferritin was significantly different across different grades of hepatic iron deposition, and there was a low inverse correlation between serum ferritin and phase values. Compared with serum iron markers, abdominal SWI may represent a powerful tool to assess hepatic iron deposition quantitatively in patients with chronic HBV infection.
Khan, Fawad; Akbar, Haji; Idrees, Muhammad; Khan, Hayat; Shahzad, Khuram; Kayani, Mahmood A
Hepatitis B is an important public health problem in the Pakistani population and is the major cause of chronic hepatitis, cirrhosis, fibrosis and hepatocellular carcinoma. High prevalence of HBV infections has been observed especially in areas of low economic status. In spite of effective immunization programs, no significant change has been observed in the epidemiology of HBV in the rural areas of Pakistan (~67.5% of the total population) mainly due to lack of interest from government authorities and poor hygienic measures. The current study was aimed at estimating the prevalence and risk factors associated with HBV infection within internally displaced persons (IDPs) due to war against terrorism in the Malakand Division of Northern Pakistan. Blood samples from 950 IDPs suspected with HBV infection (including both males and females) were collected and processed with commercial ELISA kits for HBsAg, Anti HBs, HBeAg, Anti HBe antibodies. The samples positive by ELISA were confirmed for HBV DNA by real-time PCR analysis. The overall prevalence of HBV observed was 21.05% of which 78.5% were males and 21.5% were females. Most confirmed HBV patients belong to the Malakand and Dir (lower) district. High-risk of infection was found in the older subjects 29.13% (46-60 years), while a lower incidence (11.97%) was observed in children aged <15 years. Lack of awareness, socioecomic conditions, sexual activities and sharing of razor blades, syringes and tattooing needles were the most common risk factors of HBV infection observed during the cohort of patients. The present study, revealed for the first time a high degree of prevalence of HBV infection in rural areas of Northern Pakistan. The noticed prevalence is gender- and age-dependent that might be due to their high exposures to the common risk factors. To avoid the transmission of HBV infection proper awareness about the possible risk factors and extension of immunization to the rural areas are recommended.
Tang, Zilin; Li, Xiaodong; Wu, Shunquan; Liu, Yan; Qiao, Yan; Xu, Dongping; Li, Jin
Hepatitis B surface antigen (HBsAg)-negative/hepatitis B core antibody (HBcAb)-positive patients with undetectable serum hepatitis B virus (HBV) DNA have experienced and resolved hepatitis B virus (HBV) infection. Lymphoma patients with resolved HBV infection have high risk of HBV reactivation when treated with robust immunosuppressive agents, but the reported rate varies extensively between different studies. This study aims to estimate the risk of HBV reactivation in HBsAg-negative/HBcAb-positive patients receiving rituximab-containing chemotherapy for lymphoma. Databases were searched for papers published in English until 8 August 2016. The pooled risk of HBV reactivation was estimated using a random-effects model. Data from 15 studies were retrieved, including a total of 1312 HBsAg-negative/HBcAb-positive lymphoma patients treated with rituximab-containing chemotherapy. The results revealed HBV reactivation rate of 9.0 % [95 % confidence interval (CI) 0.05-0.15]. In subgroup analysis, the reactivation rates for prospective and retrospective studies were 17 % (I (2) = 87.3 %; 95 % 0.08-0.39, p < 0.001) and 7 % (I (2) = 43.1 %; 95 % CI 0.05-0.11, p = 0.07), respectively. This meta-analysis confirms a measurable and potentially substantial risk of HBV reactivation in HBsAg-negative/HBcAb-positive patients with rituximab treatment for lymphoma. Prophylactic use of anti-HBV agents should be seriously considered for such patients.
Motamedifar, Mohammad; Taheri, Mohammad; Lankarani, Kamran Bagheri; Gholami, Mina; Lari, Mahmood Amini; Faramarzi, Hossein; Sarvari, Jamal
Evidence has shown that liver disease caused by hepatitis viruses can be more aggressive and severe in HIV infected subjects. Therefore, the present cross-sectional study aimed to evaluate the seroprevalence of HDV infection among HIV/HBV co-infected clients in Shiraz, southwest Iran. In this study, 178 patients co-infected with HBV and HIV individuals were enrolled. The diagnosis of HIV infection was documented based on serological assays. The demographic and complementary data were collected by a questionnaire. HBsAg and HDV Ab were detected by commercial quantitative enzyme linked immunosorbent assay kits according to the manufacturer’s instructions. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were also measured. The mean age of the participants was 37.4±7.4 years (range 22-63). 175 (98.4 %) patients were male and 3 (1.6 %) were female. Among 178 patients co-infected with HIV/HBV, 35 cases (19.7%, 95% CI: 14%-25%) were anti-HDV positive and 143 (80.3%) were negative for anti-HDV. HDV exposure in HIV/HBV co-infected patients was associated with blood transfusion (P=0.002, OR: 14.3) and prison history (P=0.01, OR: 2.31) but not with age, marital status, unsafe sex contact, and injection drug abuse. Our data showed a relatively high prevalence of HDV infection in HIV infected population in Shiraz, Iran. The high frequency of HDV Ab in patients with blood transfusion and prison history reveals that HDV transmission occurs more frequently in the parental route than sexual contacts; therefore, blood screening for HDV diagnosis in the high-risk group is recommended. PMID:26379352
Tan, Guolei; Zhao, Wei; Liu, Xinyu; Wang, Jianfang; Wu, Yinwei
Persistent hepatitis B virus (HBV) infection is associated with particular deficiencies in the host immune system. To gain insight into the role of lymphocyte subsets involved in viral clearance and hepatic injury. The immunophenotype of peripheral blood and biopsied liver tissues in hepatitis B patients were examined. Among lymphocyte subsets analyzed, CD45RA+CD62L+ subsets were significantly lower in HBV-infected livers than in healthy controls. Intrahepatic naive lymphocytes was negatively correlated with serum viral load (r =-0.47, p<0.05) and liver injury measured by serum alanine aminotransferase (ALT) (r=-0.36, p<0.05). Serum HBV DNA was also negatively associated with intrahepatic CD8+CD95+ (r=-0.49, p<0.01), circulating CD4+HLA-DR+ (r=-0.43, p<0.05) and circulating CD3+CD(16+56)+ (r =-0.35, p<0.05). CD3+CD8+ subsets were positively correlated with serum ALT and HBV DNA (r=0.56, 0.74, p<0.01), respectively. These data suggest a key role for the exhaustion of intrahepatic naive lymphocyte reservoir in the development of a weak antiviral immune response and the inability to control viral replication in chronic hepatitis B patients. While cellular immunity is critical to clear the viral load, over-activated cytotoxic lymphocytes may also be involved in hepatic injury.
Prestileo, Tullio; Di Lorenzo, Francesco; Sanfilippo, Adriana; Imburgia, Claudia; Cabibbo, Giuseppe; Corrao, Salvatore
Among HIV-infected patients worldwide, 2-4 million are chronically infected with HBV. We report a 15-year, real-life story of a patient with HBV-HIV coinfection, who developed HCC despite high treatment adherence and complete viral suppression. The aim of our report is to alert the infectious diseases community to monitor the possible development of HCC regardless of high treatment adherence and complete viral suppression.
Tajiri, Kazuto; Shimizu, Yukihiro
About 250 to 350 million people worldwide are chronically infected with hepatitis B virus (HBV), and about 700000 patients per year die of HBV-related cirrhosis or hepatocellular carcinoma (HCC). Several anti-viral agents, such as interferon and nucleos(t)ide analogues (NAs), have been used to treat this disease. NAs especially have been shown to strongly suppress HBV replication, slowing the progression to cirrhosis and the development of HCC. However, reactivation of HBV replication often occurs after cessation of treatment, because NAs alone cannot completely remove covalently-closed circular DNA (cccDNA), the template of HBV replication, from the nuclei of hepatocytes. Anti-HBV immune responses, in conjunction with interferon-γ and tumor necrosis factor-α, were found to eliminate cccDNA, but complete eradication of cccDNA by immune response alone is difficult, as shown in patients who recover from acute HBV infection but often show long-term persistence of small amounts of HBV-DNA in the blood. Several new drugs interfering with the life cycle of HBV in hepatocytes have been developed, with drugs targeting cccDNA theoretically the most effective for radical cure of chronic HBV infection. However, the safety of these drugs should be extensively examined before application to patients, and combinations of several approaches may be necessary for radical cure of chronic HBV infection.
Li, Xiaosong; Zhu, Junke; Lai, Guoqi; Yan, Lei; Hu, Jieli; Chen, Juan; Tang, Ni; Huang, Ailong
Studies on molecular mechanisms of the persist infection of hepatitis B virus have been hampered by a lack of a robust animal model. We successfully established a simple, versatile, and reproducible HBV persist infection model in vitro and in vivo with the circularized HBV DNA. The cells and mice were transfected or injected with circularized HBV DNA and pAAV/HBV1.2, respectively. At the indicated time, the cells, supernatants, serum samples, and liver tissues were collected for virological and serological detection. Both in vitro and in vivo, the circularized HBV DNA and pAAV/HBV1.2 could replicate and transcribe efficiently, but the infection effect of the former was superior to the latter (p < 0.05). The injection of circularized HBV genome DNA into the mice robustly supported HBV infection and approximately 80% of HBV infected mice established persistent infection for at least 10 weeks. This study demonstrated that the infection efficiency and replication ability of the circularized structure of HBV DNA overmatched that of the expression plasmid containing the linear structure of HBV DNA in vitro and in vivo. Meanwhile, this research results could provide useful tools and methodology for further study of pathogenic mechanisms and potential antiviral treatments of human chronic HBV infection in vitro and in vivo. PMID:25751726
Ahn, Jem Ma; Sinn, Dong Hyun; Gwak, Geum-Youn; Paik, Yong-Han; Choi, Moon Seok; Lee, Joon Hyeok; Koh, Kwang Cheol; Paik, Seung Woon
We investigated whether long-term clinical outcomes such as disease progression or inactive hepatitis B virus (HBV) carrier state can be predicted by baseline factors in hepatitis B e antigen (HBeAg)-negative HBV infected patients with an elevated viral load. A retrospective cohort of 527 HBeAg-negative chronic HBV infected patients with an elevated viral load (HBV DNA ≥ 2,000 IU/ml) was assessed for disease progression defined by the development of hepatocellular carcinoma (HCC) or cirrhotic complication, as well as becoming an inactive carrier. During a median 3.6 years of follow-up, disease progression was detected in 46 patients (40 with HCC, 6 with cirrhotic complication), and 31 of 309 non-cirrhotic patients became inactive carriers. Older age, male gender, cirrhosis, high HBV DNA levels at baseline, and short antiviral therapy duration were independent risk factors for HCC. Low HBV DNA and quantitative hepatitis B surface antigen (qHBsAg) levels were independent predictors for becoming inactive carriers in patients without cirrhosis. In non-cirrhotic patients with both low qHBsAg and HBV DNA levels, the 5-year cumulative incidence of an inactive carrier was 39.8%, while that of disease progression was 1.6%. HBeAg negative patients without cirrhosis can be closely monitored for becoming an inactive carrier when both HBV DNA and qHBsAg levels are low, as the risk of disease progression is low while incidence of an inactive carrier is high.
Yang, Fan; Zhu, Huan-Ling; He, Chuan; Li, Jian-Jun; Xiang, Bing; Cui, Xu; Huang, Jie; Ji, Jie; Ma, Hong-Bing; Liu, Ting
Recent data indicates that nucleoside/nucleotide analogue (NUC) is effective in preventing and controlling hepatitis B virus (HBV) reactivation in HBV-carrying cancer patients who undergo chemotherapy, but the ideal antiviral agent and optimal application protocol still needs to be determined. Meanwhile, it is uncertain whether those with past HBV infection require antiviral prophylaxis during chemotherapy. This report retrospectively analyzed non-Hodgkin's lymphoma (NHL) patients seen from January, 2004 to June, 2009 in West China Hospital. We found that the prevalence of chronic HBV infection in our NHL patients was 20.7 % while that of past HBV infection was 21.05 %. Compared with the high rate (25.6 %) of HBV reactivation in patients with chronic HBV infection, none of those with past HBV infection in fact had occult HBV infection thus none experienced reactivation. Of the 82 patients with chronic HBV infection who received chemotherapy, antiviral prophylaxis could significantly reduce the incidence of HBV reactivation (5.0 vs. 45.2 % in the control group) and the incidence of liver function damage (32.5 vs. 73.8 % in the control group). The results of the current study confirmed previous reports that prophylactic NUCs administration can effectively prevent HBV reactivation and significantly reduce the incidence of HBV reactivation especially for patients receiving rituximab-containing regimens. Due to the fact that none of individuals who had past HBV infection developed HBV reactivation reported in our study, antiviral prophylaxis may not be required for patients with past HBV infection. Close observation of alanine aminotransferase and HBV-DNA contributes to early diagnosis and timely treatment of HBV reactivation.
Zhang, X; Jia, J; Dong, J; Yu, F; Ma, N; Li, M; Liu, X; Liu, W; Li, T; Liu, D
Two recent genome-wide studies showed that the single-nucleotide polymorphisms in the HLA-DQ region (rs2856718 and rs9275572) were associated with chronic hepatitis B virus infection and chronic hepatitis C virus-associated hepatocellular carcinoma in Japanese patients. We tested the effects of the two single-nucleotide polymorphisms for all major HBV outcomes and lamivudine treatment in Han Chinese. A total of 1649 samples were enrolled, and peripheral blood samples were collected in this study. The single-nucleotide polymorphisms in the HLA-DQ region were genotyped using matrix-assisted laser desorption/ionization time of flight mass spectrometry. Our study demonstrated the clear relevance of HLA-DQ rs2856718 and rs9275572 with HBV susceptibility, natural clearance and HBV-associated HCC. HLA-DQ rs2856718G and rs9275572A were strongly associated with decreased risk of chronic HBV infection (odds ratio = 0.641; P = 2.64 × 10(-4) ; odds ratio = 0.627, P = 7.22 × 10(-5) ) and HBV natural clearance (odds ratio = 0.610; P = 4.80 × 10(-4) ; odds ratio = 0.714, P = 0.013). Moreover, rs9275572A was also associated with development of cirrhosis and hepatocellular carcinoma (odds ratio = 0.632, P = 0.008). In addition, we showed for the first time to our knowledge that rs9275572 was a predictor for lamivudine therapy (viral response: odds ratio = 2.599, P = 4.43 × 10(-4) ; biochemical response: odds ratio = 2.279, P = 4.23 × 10(-4) ). Our study suggested that HLA-DQ loci were associated with both HBV clearance and HBV-related diseases and outcomes of lamivudine treatment in Han Chinese.
Lu, Hai-Ying; Zeng, Zheng; Xu, Xiao-Yuan; Zhang, Nai-Lin; Yu, Min; Gong, Wei-Bo
AIM: To investigate the clinical significance and presence of mutations in the surface (S) and overlapping polymerase gene of hepatitis B patients with coexisting HBsAg and anti-HBs. METHODS: Twenty-three patients with chronic hepatitis B were studied. Of the 23 patients, 11 were both positive for hepatitis B virus (HBV) surface antigen (HBsAg) and antibody to HBV surface antigen (anti-HBs), 12 were negative for anti-HBs while positive for HBsAg. DNA was extracted from 200 μL serum of the patients. Nucleotide of the surface and overlapping polymerase gene from HBV-infected patients was amplified by PCR, and the PCR products were sequenced. RESULTS: Forty-one mutations were found within the surface gene protein of HBV in 15 patients (10 with coexisting HBsAg and anti-HBs). Six (14.6%) out of 41 mutations were located at “α” determinant region in 5 patients (4 positive for HBsAg and anti-HBs). Eleven mutations (26.8%) occurred in the downstream or upstream of “α” determinant region. Lamivudine (LMV)-selected mutations were found in three patients who developed anti-HBs, which occurred in amino acid positions (196, 198, 199) of the surface protein and in YMDD motif (M204I/V) of the polymerase protein simultaneously. Presence of these mutations did not relate to changes in ALT and HBV DNA levels. CONCLUSION: Besides mutations in the “α” deter-minant region, mutations at downstream or upstream of the “α” determinant region may contribute to the development of anti-HBs. These mutations do not block the replicating competency of HBV in the presence of high titer of anti-HBs. PMID:16830379
Phillips, Sandra; Mistry, Sameer; Riva, Antonio; Cooksley, Helen; Hadzhiolova-Lebeau, Tanya; Plavova, Slava; Katzarov, Krum; Simonova, Marieta; Zeuzem, Stephan; Woffendin, Clive; Chen, Pei-Jer; Peng, Cheng-Yuan; Chang, Ting-Tsung; Lueth, Stefan; De Knegt, Robert; Choi, Moon-Seok; Wedemeyer, Heiner; Dao, Michael; Kim, Chang-Wook; Chu, Heng-Chen; Wind-Rotolo, Megan; Williams, Roger; Cooney, Elizabeth; Chokshi, Shilpa
IFN-lambda (IFNλ) is a member of the type III IFN family and is reported to possess anti-pathogen, anti-cancer, and immunomodulatory properties; however, there are limited data regarding its impact on host immune responses in vivo. We performed longitudinal and comprehensive immunosurveillance to assess the ability of pegylated (peg)-IFNλ to augment antiviral host immunity as part of a clinical trial assessing the efficacy of peg-IFNλ in chronic hepatitis B (CHB) patients. These patients were pretreated with directly acting antiviral therapy (entecavir) for 12 weeks with subsequent addition of peg-IFNλ for up to 32 weeks. In a subgroup of patients, the addition of peg-IFNλ provoked high serum levels of antiviral cytokine IL-18. We also observed the enhancement of natural killer cell polyfunctionality and the recovery of a pan-genotypic HBV-specific CD4(+) T cells producing IFN-γ with maintenance of HBV-specific CD8(+) T cell antiviral and cytotoxic activities. It was only in these patients that we observed strong virological control with reductions in both viral replication and HBV antigen levels. Here, we show for the first time that in vivo peg-IFNλ displays significant immunostimulatory properties with improvements in the main effectors mediating anti-HBV immunity. Interestingly, the maintenance in HBV-specific CD8(+) T cells in the presence of peg-IFNλ is in contrast to previous studies showing that peg-IFNα treatment for CHB results in a detrimental effect on the functionality of this important antiviral T cell compartment. ClinicalTrials.gov NCT01204762.
Stanojević, Boban; Osiowy, Carla; Schaefer, Stephan; Bojović, Ksenija; Blagojević, Jelena; Nešić, Milica; Yamashita, Shunichi; Stamenković, Gorana
Hepatitis B virus (HBV) is classified into 8 genotypes with distinct geographical distribution. Genotype D (HBV/D) has the widest distribution area and is comprised of 7 subgenotypes. Subgenotypes D1, D2 and D3 appear worldwide, while D4-D7 have a more restricted distribution. Within the Mediterranean area, HBV/D and subgenotype D3 are the most prevalent. The purpose of this study was to characterize the full genome of Serbian HBV/D3 isolates by comparison and phylogenetic analysis with HBV/D3 sequences (66 samples) found in GeneBank/DDBJ databases from different parts of the world. Isolates were obtained from three patients diagnosed with chronic hepatitis B (HBsAg+). All three isolates have two very rare nucleotide substitutions, A929T and T150A, which indicate the same ancestor. Phylogenetic analysis of HBV/D3 genome sequences throughout the world follows an ethno-geographical origin of isolates with rare exceptions, which could be explained by human travelling and migration. The geographically close but ethnically different Serbian and Italian isolates clustered in the same subnode, and on a common branch with strains from Northern Canada. To test the apparently close HBV phylogenetic relationship between completely separated patients from Serbia and Northern Canada we analyzed in depth a 440 bp region of the HBsAg from Canadian (n=73) and Serbian (n=70) isolates. The constructed parsimony tree revealed that strains from Serbia and Northern Canada fell along the same branch which indicates independent evolution within regions of each country. Considering that HBsAg sequence has limited variability for phylogenetic analyses, our hypothesis needs further confirmation with more HBV complete genome sequences.
Dultz, G; Gerber, L; Farnik, H; Berger, A; Vermehren, J; Pleli, T; Zeuzem, S; Piiper, A; Kronenberger, B; Waidmann, O
Soluble CD163 (sCD163), a marker for macrophage activation, was found to be associated with the severity of liver cirrhosis. The aim of the current study was to investigate whether serum sCD163 levels correlate with liver inflammation and fibrosis in patients with chronic hepatitis B virus (HBV) infection. In a retrospective cohort study, serum sCD163 levels were assessed by ELISA together with clinical and laboratory data in 186 patients with chronic HBV infection and 15 healthy controls. The relation between parameters for liver fibrosis and necroinflammation and sCD163 levels was analysed. Additionally, sCD163 was quantified in a subset of follow-up serum samples after initiation of antiviral treatment. sCD163 levels differed among phases of chronic HBV infection (P < 0.0001), and sCD163 concentrations were associated with inflammatory activity and fibrosis in the liver. sCD163 levels ≥ 1961 ng/l had a high specificity in the identification of subjects with substantial fibrosis (F ≥ 2). sCD163 concentrations decreased significantly after initiation of antiviral treatment. The correlation of sCD163 levels with necroinflammation and fibrosis and the sCD163 decline under treatment indicates that macrophage activation plays a role in HBV-related liver pathogenesis. © 2014 John Wiley & Sons Ltd.
Perrillo, Robert; Buti, Maria; Durand, Francois; Charlton, Michael; Gadano, Adrian; Cantisani, Guido; Loong, Che-Chuan; Brown, Kimberly; Hu, Wenhua; Lopez-Talavera, Juan Carlos; Llamoso, Cyril
For patients undergoing liver transplantation (LT) for hepatitis B virus (HBV)-related liver disease, the current standard of care for preventing reinfection of the allograft is nucleoside analogue therapy combined with hepatitis B immune globulin (HBIG). Entecavir has demonstrated high efficacy and a favorable safety profile for chronic hepatitis B (CHB) treatment, but data for patients undergoing HBV-related LT are limited. This study assessed the safety and efficacy of entecavir combined with various HBIG regimens after CHB-related LT. In this phase 3b, single-arm, open-label study, 65 patients undergoing LT for CHB-related liver disease with an HBV DNA load <172 IU/mL at LT received entecavir (1.0 mg daily) for 72 weeks after LT. The primary endpoint was the proportion of evaluable patients (treated for ≥4 weeks) with virological recurrence (HBV DNA level ≥50 IU/mL) through week 72. Concomitant HBIG therapy was received by 64 of the 65 enrolled patients, and 44% of these patients received high-dose HBIG (any HBIG dose in the specified interval ≥10,000 IU). Through week 72, all 61 patients evaluable for the efficacy analysis had undetectable HBV DNA. The Kaplan-Meier estimate of patients without hepatitis B surface antigen (HBsAg) recurrence at week 72 was 0.9655. Two patients experienced a reappearance of HBsAg, but both remained HBV DNA(-) until the last follow-up. The frequency and nature of adverse events were consistent with those expected for this patient population. Serum creatinine increments ≥0.3 mg/dL and ≥0.5 mg/dL occurred in 62% and 39% of the patients, respectively, and all of these patients received calcineurin inhibitor therapy. In conclusion, in this population of patients treated with entecavir after CHB-related LT, entecavir was well tolerated and effective in maintaining viral suppression, even in individuals who experienced a reappearance of HBsAg.
Chen, Fei; Zhang, Jian; Wen, Bo; Luo, Shan; Lin, Yingbiao; Ou, Wensheng; Guo, Fengfan; Tang, Ping; Liu, Wenpei; Qu, Xiaowang
Hepatitis B virus/hepatitis C virus (HBV/HCV) dual infection is common among high-risk individuals. To characterize the virological and immunological features of patients with HBV/HCV dual infection, we enrolled 1,049 individuals who have been identified as injection drug users. Patients were divided into single and dual infection groups according to the serological markers. We found the average HCV RNA level was significantly lower; however, HBV viral load was significantly higher in HBV/HCV dual-infected patients (n = 42) comparing HCV single infection (n = 340) or HBV single infection (n = 136). The level of anti-HBs in patients who experienced spontaneous HBV clearance was higher than that in HCV single-infected patients with HBV spontaneous clearance. The level of anti-HCV E2 in HBV/HCV dual infection was lower than that detected in HCV single infection. Serum levels of IL-6, IL-8, and TNF-α were significantly lower in HBV/HCV dual-infected patients than in patients infected with HBV or HCV alone. Taken together, two viral replications are imbalanced in dual infected patients. The anti-HBs and anti-HCV E2 antibody production were impaired and proinflammatory IL-6, IL-8, and TNF-α also downregulated due to dual infection. These findings will help further understanding the pathogenesis of HBV/HCV dual infection. PMID:28009018
El-Mowafy, Mohammed; Elgaml, Abdelaziz; El-Mesery, Mohamed; Elegezy, Mohamed
Hepatitis B virus (HBV) is one of the major causes of viral hepatitis worldwide. Despite the prevalence of HBV infection in Egypt, few studies have focused on sub-genotyping of the virus. Moreover, no studies are available regarding the mutational analysis of the preS1/preS2 region of the viral genome, or its impact on hepatocellular carcinoma (HCC) development in Egypt. In this study, we have analyzed the sub-genotypes and incidence of mutations in the preS1/preS2 region of HBV present in HBV-infected patients, from Mansoura city (located in the center of Nile Delta region of Egypt), via partial sequencing of this specific region. Moreover, we have investigated the impact of these mutations on HCC development by measuring serum alpha fetoprotein (AFP) level and abdominal ultrasound examination of the HBV-infected patients. According to our results, all samples were genotype D in which sub-genotype D1 was predominant. In addition, the results revealed mutations in the preS1/preS2 region, which could result in either immature preS1 protein or completely inhibit the translation of the preS2 protein. However, there was no incidence of HCC development in patients infected with mutated HBV in the preS1/preS2 region. In summary, for the first time our work has proved the predominance of sub-genotype D1 among HBV-infected Egyptian patients in Mansoura city, Nile Delta region, Egypt, and incidence of mutations in the preS1/preS2 region of HBV genome. This current study opens up research opportunities to discuss the impact of HBV mutations on the development of HCC in Egypt. © 2017 Wiley Periodicals, Inc.
Ferrari, T.C.A.; Xavier, M.A.P.; Vidigal, P.V.T.; Amaral, N.S.; Diniz, P.A.; Resende, A.P.; Miranda, D.M.; Faria, A.C.; Lima, A.S.; Faria, L.C.
Estimates of occult hepatitis B virus (HBV) infection prevalence varies among different studies depending on the prevalence of HBV infection in the study population and on the sensitivity of the assay used to detect HBV DNA. We investigated the prevalence of occult HBV infection in cirrhotic patients undergoing liver transplantation in a Brazilian referral center. Frozen liver samples from 68 adults were analyzed using a nested polymerase chain reaction assay for HBV DNA. The specificity of the amplified HBV sequences was confirmed by direct sequencing of the amplicons. The patient population comprised 49 (72.1%) males and 19 (27.9%) females with a median age of 53 years (range=18-67 years). Occult HBV infection was diagnosed in three (4.4%) patients. The etiologies of the underlying chronic liver disease in these cases were alcohol abuse, HBV infection, and cryptogenic cirrhosis. Two of the patients with cryptic HBV infection also presented hepatocellular carcinoma. Markers of previous HBV infection were available in two patients with occult HBV infection and were negative in both. In conclusion, using a sensitive nested polymerase chain reaction assay to detect HBV DNA in frozen liver tissue, we found a low prevalence of occult HBV infection in cirrhotic patients undergoing liver transplant, probably due to the low prevalence of HBV infection in our population. PMID:25296362
Tao, Jingjing; Su, Kunkai; Yu, Chengbo; Liu, Xiaoli; Wu, Wei; Xu, Wei; Jiang, Bingxun; Luo, Rui; Yao, Jian; Zhou, Jiawei; Zhan, Yan; Ye, Chao; Yuan, Wenji; Jiang, Xianzhong; Cui, Wenyan; Li, Ming D; Li, Lianjuan
Recent genome-wide association studies have revealed the HLA region on chromosome 6p21 as a susceptibility locus for hepatitis B virus (HBV) infection, a finding subsequently replicated in independent samples. However, only limited single nucleotide polymorphisms (SNPs) were analyzed in most of these studies, and it remains to be determined which SNPs contribute to the detected association. After genotyping 140 SNPs within this genomic region in a total of 1657 HBV-positive patients and 1456 HBV-negative controls, we conducted a series of genetic epidemiological and bioinformatics analysis, including individual SNP-based association analysis, haplotype-based association analysis, and conditional analysis. We identified 76 SNPs and 5 LD blocks in HLA-DP/DQ clusters that are significantly associated with HBV infection, with the smallest P value being 3.88 × 10(-18) for rs9277535 in HLA-DPB1. With conditional analysis, we further revealed that the genes contributing to the effects of variants in HLA-DP/DQ on infection are independent of each other, and the LD block 5 in the 3'-UTR region of HLA-DPB1 had a predominant effect in the association of HLA-DP with HBV infection. We also found that the SNPs in the 3'-UTR region of HLA-DPB1 were significant between the subgroups of inactive HBV carrier, chronic hepatitis B, or hepatic cirrhosis from the case group and the spontaneous HBV-clearance subgroup from the control group. Finally, we did further association analysis of SNPs in this region with different subgroups from the case group, which revealed no association of these SNPs with the progression of HBV-related diseases. In sum, we showed, for the first time, that the HLA-DP/DQ clusters contribute independently to HBV infection, and the 3'-UTR region of HLA-DPB1 represents an important functional region involved in HBV infection.
Ba Alawi, Fatma; Robertson, Peter W; LePage, Amelia K; Jayamaha, Jude; Baleriola, Cristina; Rawlinson, William D
Accurate diagnosis of hepatitis B virus (HBV) infection is essential for infection control, treatment and screening of potential blood, organ and tissue donors. We assessed the sensitivity of the HBsAg and HBcAb as screening assays alone and in combination for detecting HBV infection in a series of Australian patients. The performance of the Architect (Abbott Diagnostics, Germany) and the Elecsys (Roche Diagnostics, Germany) platforms were assessed for detection of HBcAb. There were 2778 blood samples assessed using the COBAS Ampliprep/TaqMan test for HBV DNA, of which 331 sera had concurrent HBV serology testing. This allowed determination of the correlation between HBV DNA and different serological markers. Of the 331 sera, 260 had sufficient residual volume to be retested for HBcAb using both Elecsys and the Architect assays. Of the 331 patients, one (0.3%) was negative by the Architect Anti-HBc II assay, in the presence of HBV DNA and positive HBsAg, consistent with recent infection. Positive HBcAb in the absence of HBV DNA was found in 67 of 331 (20.2%) patients. Of these, 18 of 67 had isolated HBcAb with negative results on all other tests, with 12 of 18 (3.6%) demonstrating low HBcAb signals on chemiluminscent microparticle assay. No cases of detectable HBV DNA in the presence of negative serology were found. When the HBcAb was used as a marker for past exposure or chronic HBV infection, the Architect Anti-HBc II assay demonstrated sensitivity and specificity of 98% and 79.9%, respectively, compared to 90% and 78.9%, respectively, for the Elecsys Anti-HBc assay. The combination of the Architect Anti-HBc II and HBsAg assays, as per conventional solid organ donor and recipient screening protocols, had 90% specificity and 100% sensitivity for determining HBV infection. This study shows that the use of combined HBsAg and HBcAb is sensitive and reliable for screening and predicting HBV nucleic acid test (NAT) positivity, whereas HBcAb alone missed an acute
Fei, Q J; Yang, X D; Ni, W H; Pan, C S; Huang, X F
Hepatitis B virus (HBV) in semen is important for father-to-child transmission of HBV and has adverse effects on sperm quality. However, risk factors associated with HBV in semen remain unclear. Serum HBV DNA and hepatitis B e antigen (HBeAg) levels may pose a risk on HBV in semen. This study aims to examine whether serum HBV DNA, HBeAg, and hepatitis B surface antigen (HBsAg) level were associated with HBV DNA in semen. 151 male patients chronically infected with HBV from infertile couples were included. Serum HBsAg and HBeAg were determined using an electrochemiluminescence immune assay (ECLIA). Serum and seminal plasma HBV DNA were detected by the QIAGEN Real-Time HBV DNA assay. Of 151 patients, 143 (94.7%) were serum HBV DNA-positive and 65 (43.0%) were seminal plasma HBV DNA-positive. Serum HBV DNA and HBeAg level of seminal plasma HBV DNA-positive patients were significantly higher (p < 0.001) as compared with those of seminal plasma HBV DNA-negative patients, HBsAg level of seminal plasma HBV DNA-positive patients was significantly lower (p < 0.001) compared with that of seminal plasma HBV DNA-negative patients. The best serum HBV DNA, HBeAg, and HBsAg value for discriminating between seminal plasma HBV DNA-positive and HBV DNA-negative patients were ≥6.9 log10 IU/mL (sensitivity 100.0%, specificity 90.7%), >14.8 S/CO (sensitivity 96.9%, specificity 81.5%), and <1791.5 S/CO (sensitivity 81.5%, specificity 81.2%), respectively. The combination of serum HBV DNA and HBeAg had high diagnostic sensitivity (100.0%) and specificity (95.4%) for the presence of HBV DNA in semen. As such, these serum markers especially the combination of HBV DNA and HBeAg are useful predictors of the presence of HBV DNA in semen in HBV chronically infected men from infertile couples. © 2015 American Society of Andrology and European Academy of Andrology.
Takagi, Hitoshi; Hoshino, Takashi; Naganuma, Atsushi; Koitabashi, Eri; Uehara, Sanae; Sakamoto, Naomi; Kudo, Tomohiro; Ryusaki, Keiichirou; Kakizaki, Satoru; Okamoto, Hiroaki
Sixty year-old male positive for both HCV-RNA and HBsAg was treated by triple therapy of peginterferon alpha2b, ribavirin and telaprevir. Eight weeks after the beginning of the therapy, the patient developed drug induced hypersensitivity syndrome (DIHS) with general erythema multiforme and 64 times anti-HHV6 antibody elevation. Sixty milligram of prednisolone was administered with gradual dose reduction and the skin lesion was improved. HBV-DNA and transaminase elevated one week after the steroid induction and entecavir improved them. DIHS itself and the aggravation of hepatitis B by corticosteroid should be kept in mind in cases with dual infection of HBV and HCV treated by antivirals including telaprevir.
Zhou, Tai-Cheng; Li, Xiao; Li, Long; Li, Xiao-Fei; Zhang, Liang; Wei, Jia
Although the evolutionary changes of viral quasispecies are correlated to the pathological status of a disease, little is known in the coexistence of hepatitis B surface antigen (HBsAg) and antibodies to these antigens (anti-HBs). To examine evolutionary changes in hepatitis B virus (HBV) and their relationship to the coexistence of HBsAg and anti-HBs antibodies, HBV genomes in patients with a coexistence of HBsAg and anti-HBs antibodies (experimental group) and HBsAg positive without anti-HBs (control group) were assessed. Our results showed that quasispecies diversity was significantly higher in the experimental group for large HBsAg (LHBsAg), middle HBsAg (MHBsAg), and HBsAg genes. LHBsAg harbored dN/dS values eight times higher in the experimental group; however, the mean dN/dS ratios in genes HbxAg, Pol and PreC/C of the experimental patients had an opposite trend. Phylogenetic trees in the experimental group were more complex than the control group. More positive selection sites, mutations and deletions were observed in the experimental group in specific regions. Furthermore, several amino acid variants in epitopes were potentially associated with the immune evasion. In conclusion, cumulative evolutionary changes in HBV genome that facilitate immune evasion provide insights into the genetic mechanism of a coexistence of HBsAg and anti-HBs antibodies.
Martinot-Peignoux, Michelle; Marcellin, Patrick
Molecular biology techniques are routinely used to diagnose and monitor treatment in patients with chronic hepatitis B (CHB). These tools can detect and quantify viral genomes and analyse their sequences to determine genotype. The increasing use of these tools to monitor patients has greatly improved the management of CHB infection by maximizing the potential for individualized treatment. HBV genotyping has become increasingly important and provides additional information to predict a response to therapy. More sensitive methods to determine HBV DNA levels are now available and the units of measurements have been standardized. HBsAg levels in serum have been shown to reflect active intrahepatic covalently closed circular DNA (cccDNA) and to have additional value in treatment decisions, especially as an on-treatment marker.
Zhu, L G; Tian, H; Jiang, J; Song, C; Zou, Y; Xu, J F; Liu, H J; Peng, H; Hu, Z B; Zhu, F C; Shen, H B; Zhai, X J
Objective: To understand characteristics and influencing factors of reversion of HBeAg in chronic hepatitis B patients with HBeAg sero-conversion, and provide epidemiological evidence for the regular management of chronic hepatitis B patients. Methods: From 2012 to 2014, a cohort study was conducted among the chronic hepatitis B patients with sero-conversion of HBeAg in Jiangsu province. Association between participants' demographics, ALT, HBV DNA and incidence of HBeAg reversion was analyzed by Cox regression model. HBV DNA changing trend between patients with HBeAg reversion and patients with persistent HBeAg sero-conversion was compared by repeated measure data variance analysis. Results: In 2012, there were 5 068 HBeAg seroconverted chronic hepatitis B patients aged (51.9 ± 12.8) years enrolled. By 2014, HBeAg had reversed in 121 cases with the rate of 1.3/100 person-years. The probability of HBeAg reversion decreased with the age of the patients. By Cox regression analysis, HBV DNA level was an important influencing factor for the progress of HBeAg reversion. The patients with HBV DNA≥200 000 IU/ml had a higher HBeAg reversion rate DNA (3.8/100 person-years) than those with HBV DNA <2 000 IU/ml (1.1 person-years) (HR=3.44, 95% CI: 1.91-6.20, P=0.000). Compared with the persistent HBeAg sero-conversion group, HBV DNA and ALT showed a more dramatic increase in the HBeAg reversion group (P=0.000). Conclusions: There was a certain HBeAg reversion rate in chronic hepatitis B patients with HBeAg sero-conversion. Younger chronic CHB patients with HBeAg sero-conversion and those with higher HBV DNA lever had higher HBeAg reversion rate. Following up and management of chronic CHB patients with HBeAg sero-conversion is important and helpful for the control of hepatitis B.
Kaymakoglu, Sabahattin; Oguz, Dilek; Gur, Gurden; Gurel, Selim; Tankurt, Ethem; Ersöz, Galip; Ozenirler, Seren; Kalayci, Cem; Poturoglu, Sule; Cakaloglu, Yılmaz; Okten, Atilla
Forty-eight hepatitis B virus (HBV) E antigen-negative chronic hepatitis B patients received pegylated interferon alfa-2b either alone or with lamivudine for 48 weeks and were followed for an additional 24 weeks. At the end of follow-up, virological response rates (HBV DNA levels of <400 copies/ml) were similar in the monotherapy (24%) and combination therapy (26%) groups. PMID:17517832
There were no differences in serum HBV DNA level between HBeAg-positive and HBeAg-negative chronic hepatitis B with same liver histological necroinflammation grade but differences among grades 1, 2, 3 and 4 apportioned by the same hepatic parenchyma cell volume.
Ke, W-M; Xie, S-B; Li, X-J; Zhang, S-Q; Lai, J; Ye, Y-N; Gao, Z-L; Chen, P-J
Hepatitis B virus (HBV) DNA levels and liver histological necroinflammation grades are correlated with the antiviral efficacy. It is necessary to clarify the relationship between HBV replication levels apportioned by the same hepatic parenchyma cell volume and severity of liver histological necroinflammation grades in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative chronic hepatitis B. The serum HBV DNA levels apportioned by the same hepatic parenchyma cell volume were compared between HBeAg-positive and HBeAg-negative chronic hepatitis B as well as among liver histological necroinflammation grades 1, 2, 3 and 4, respectively. There were no differences in the serum HBV DNA levels between HBeAg-positive and HBeAg-negative chronic hepatitis B as well as among liver histological necroinflammation grades 1, 2, 3 and 4. However, there were differences in the serum HBV DNA levels apportioned by the same hepatic parenchyma cell volume among liver histological necroinflammation grades 1, 2, 3 and 4 in both HBeAg-positive and HBeAg-negative chronic hepatitis B, respectively. There were no differences in HBV DNA levels with the same liver histological necroinflammation grade activated by HBV wild-type and variant strains. After the differences in hepatic parenchyma cell volume for HBV replication of the same liver histological necroinflammation grade accompanied by different hepatic fibrosis stages were adjusted, the serum HBV DNA level apportioned by the same hepatic parenchyma cell volume was correlated with the severity of liver histological necroinflammation grade. © 2011 Blackwell Publishing Ltd.
Banerjee, Priyanka; Mondal, Rajiv Kumar; Nandi, Madhuparna; Ghosh, Sumantra; Khatun, Mousumi; Chakraborty, Nabendu; Bhattacharya, Swatilekha; RoyChoudhury, Arindam; Banerjee, Soma; Santra, Amal; Sil, Samir; Chowdhury, Abhijit; Bhaumik, Pradip; Datta, Simanti
Background/Aims HBV has been classified into ten genotypes (A–J) and multiple subgenotypes, some of which strongly influence disease outcome and their distribution also correlate with human migration. HBV infection is highly prevalent in India and its diverse population provides an excellent opportunity to study the distinctiveness of HBV, its evolution and disease biology in variegated ethnic groups. The North-East India, having international frontiers on three sides, is one of the most ethnically and linguistically diverse region of the country. Given the paucity of information on molecular epidemiology of HBV in this region, the study aimed to carry out an in-depth genetic characterization of HBV prevailing in North-East state of Tripura. Methods From sera of chronically HBV infected patients biochemical/serological tests, HBV DNA quantification, PCR-amplification, sequencing of PreS/S or full-length HBV genomes were done. HBV genotype/subgenotype determination and sequence variability were assessed by MEGA5-software. The evolutionary divergence times of different HBV subgenotypes were estimated by DNAMLK/PHYLIP program while jpHMM method was used to detect any recombination event in HBV genomes. Results HBV genotypes D (89.5%), C (6.6%) and A (3.9%) were detected among chronic carriers. While all HBV/A and HBV/C isolates belonged to subgenotype-A1 and C1 respectively, five subgenotypes of HBV/D (D1–D5) were identified including the first detection of rare D4. These non-recombinant Indian D4 (IndD4) formed a distinct phylogenetic clade, had 2.7% nucleotide divergence and recent evolutionary radiation than other global D4. Ten unique amino acids and 9 novel nucleotide substitutions were identified as IndD4 signatures. All IndD4 carried T120 and R129 in ORF-S that may cause immune/vaccine/diagnostic escape and N128 in ORF-P, implicated as compensatory Lamivudine resistance mutation. Conclusions IndD4 has potential to undermine vaccination programs or anti
Shirvani-Dastgerdi, Elham; Winer, Benjamin Y; Celià-Terrassa, Toni; Kang, Yibin; Tabernero, David; Yagmur, Eray; Rodríguez-Frías, Francisco; Gregori, Josep; Luedde, Tom; Trautwein, Christian; Ploss, Alexander; Tacke, Frank
Patients chronically infected with the hepatitis B virus (HBV) and receiving long-term treatment with nucleoside or nucleotide analogues are at risk of selecting HBV strains with complex mutational patterns. We herein report two cases of HBV-infected patients with insufficient viral suppression, despite dual antiviral therapy with entecavir (ETV) and tenofovir (TDF). One patient died from aggressive hepatocellular carcinoma (HCC). Serum samples from the two patients at different time points were analyzed using ultra-deep pyrosequencing analysis. HBV mutations were identified and transiently transfected into hepatoma cells in vitro using replication-competent HBV vectors, and functionally analyzed. We assessed replication efficacy, resistance to antivirals and potential impact on HBV secretion (viral particles, exosomes). Sequencing analyses revealed the selection of the rtS78T HBV polymerase mutation in both cases that simultaneously creates a premature stop codon at sC69 and thereby deletes almost the entire small HBV surface protein. One of the patients had an additional 261bp deletion in the preS1/S2 region. Functional analyses of the mutations in vitro revealed that the rtS78T/sC69∗ mutation, but not the preS1/S2 deletion, significantly enhanced viral replication and conferred reduced susceptibility to ETV and TDF. The sC69∗ mutation caused truncation of HBs protein, leading to impaired detection by commercial HBsAg assay, without causing intracellular HBsAg retention or affecting HBV secretion. The rtS78T/sC69∗ HBV mutation, associated with enhanced replication and insufficient response to antiviral treatment, may favor long-term persistence of these isolates. In addition to the increased production of HBV transcripts and the sustained secretion of viral particles in the absence of antigenic domains of S protein, this HBV mutation may predispose patients to carcinogenic effects. Long-term treatment with antiviral drugs carries the risk of selecting
... Loss Surgery? A Week of Healthy Breakfasts Shyness Hepatitis B (HBV) KidsHealth > For Teens > Hepatitis B (HBV) A A A What's in this article? ... poisons). There are several different types of hepatitis . Hepatitis B is a type that can move from one ...
La Torre, Giuseppe; Mannocci, Alice; Saulle, Rosella; Colamesta, Vittoria; Meggiolaro, Angela; Mipatrini, Daniele; Sinopoli, Alessandra
To conduct a systematic review of the economic evaluations (EE) of HBV vaccination, taking also into account the studies published in the new millennium. An extensive scientific literature review was conducted using two electronic medical journal databases: Scopus and PubMed engines for published studies on EE of HBV vaccination. 22 articles were reviewed, 9, 5 and 8 cost-effectiveness, cost-benefit and cost-utility analysis, respectively. Studies were mainly concerning EE of universal vaccination (UV), mostly with regards to low or low-medium income countries. For high income countries, EE were focused on the possible implementation of HBV vaccination in particular settings, such as diabetic, renal and other chronic conditions care, as well as infectious diseasesUV has usually a very good cost-effectiveness ratio (80%), ranging from cost-saving (China) or few Euro per LY/QALY gained (in Thailand, and Vietnam) to 630.00$/QALY in USA (Asian and Pacific Islands) Moreover, EE of HBV vaccination are favorable in the infectious diseases field as well as for chronic conditions. In relation to diabetes the studies gave controversial results. This systematic review highlighted the importance of introducing HBV vaccination not only for infant UV program but also for other settings in which patients are people affected by communicable and non-communicable diseases.
Wang, Hong; Xue, Li; Yan, Rong; Zhou, Yin; Wang, Ming-Shan; Cheng, Mei-Juan; Hai-Jun Huang
Liver disease can develop in chronic hepatitis B (CHB) patients with normal or mildly elevated alanine aminotransferase (ALT) who seldom undergo liver biopsy. We aimed to determine histologic characteristics of a large cohort of Chinese CHB patients undergoing liver biopsy and to evaluate the utility of ALT and HBV DNA values at the time of biopsy in predicting liver disease in this population. This prospective study enrolled 230 treatment-naïve patients with persistently normal or mildly elevated ALT. All patients had a liver biopsy. ALT, aspartate aminotransferase (AST), and HBV DNA levels were some of the other parameters measured. Using Scheuer's classification, significant histology was defined as stage ≧2 fibrosis and/or stage 1 fibrosis plus≧ grade 2 inflammation. Liver disease was observed in 34.4% and 61.8% of patients with normal ALT and mildly elevated ALT, respectively. Patients with mildly elevated ALT levels had significantly more events, including liver disease, elevated AST, and moderate to severe inflammation and liver fibrosis, than patients with normal ALT (all P≤0.005). A total of 107 patients (46.5%) had liver disease and 123 (53.5%) did not. PLT and ALT were significantly associated with liver disease (both P<0.001). Patients with elevated ALT, lower platelet count and HBV DNA < 7 log10copies/mL may have histologically significant changes associated with liver disease. Multivariate analysis showed that PLT and HBV DNA levels were significantly associated with liver disease in patients with normal ALT while gender and HBV DNA levels were significantly associated with liver disease in patients with mildly elevated ALT. Assessing liver damage via biopsy in patients with normal or mildly elevated ALT may help to identify those who would benefit from antiviral therapy. PMID:24260428
Li, Xingku; Liu, Wei; Wang, Hongyan; Jin, Xi; Fang, Shaohong; Shi, Yuguang; Liu, Zhen; Zhang, Shuyun; Yang, Shufen
Hepatitis B virus (HBV) infection has a wide variety of clinical outcomes, it could be spontaneouly recovered and also could develop fulminant liver failure or cirrhosis with hepatocellular carcinoma. Human leukocyte antigen (HLA) polymorphism and HBV (sub)genotypes have been speculated to associate with the outcome of HBV infection because the data obtained from various populations who bear different HLA alleles have shown a HLA polymorphism associated outcome of HBV infection. However, as the most important viral and host genetic factors, the impact of HBV (sub)genotypes in combination with HLA polymorphism on the clinical outcomes of HBV infections remains unclear. To demonstrate the association of HLA allele polymorphism in combination with HBV subgenotypes with the outcome of HBV infection in Northeastern Han Chinese population, a total of 230 HBV-infected individuals (Infection group) were compared to 210 random selected controls (Control group) who are negative for HBV infection for their HLA alleles frequency as well as the associations with the virus infection, clearance and persistence in combination with HBV subgenotypes. Of the 230 HBV-infected subjects, 54 were acute self-limited hepatitis (ASH) with HBV subgenotype C2 (ASH-C2), 144 were chronic hepatitis (CH) with HBV subgenotype C2 and B2 (CH-C2 and CH-B2), and 32 were spontaneously recovered (SR) without subgenotype results. When two groups are compared, the results suggest that B*48, B*51 and DRB1*12 carrier may have a high risk for HBV infection, but B*51 is likely association with spontaneous recovery and DRB1*07, 12 may be implied in viral persistence. HLA-B*15, DRB1*11 and 14 associated with viral clearance in the cases of HBV-C2 infection; HLA-B*54 carriers in chronic group are more sensitive to with the infection of HBV subgenotype B2; HLA-B*07 and DRB1*13 may protect subjects from HBV infection. The data presented a link between HLA polymorphism and HBV pathogenesis and suggested potential
Yang, Fu-Qiang; Rao, Gui-Rong; Wang, Gui-Qiang; Li, Yue-Qi; Xie, Yao; Zhang, Zhan-Qing; Deng, Cun-Liang; Mao, Qing; Li, Jun; Zhao, Wei; Wang, Mao-Rong; Han, Tao; Chen, Shi-Jun; Pan, Chen; Tan, De-Ming; Shang, Jia; Zhang, Ming-Xiang; Zhang, Yue-Xin; Yang, Ji-Ming; Chen, Guang-Ming
AIM To assess the efficacy and safety of in vivo electroporation (EP)-mediated dual-plasmid hepatitis B virus (HBV) DNA vaccine vs placebo for sequential combination therapy with lamivudine (LAM) in patients with chronic hepatitis B. METHODS Two hundred and twenty-five patients were randomized to receive either LAM + vaccine (vaccine group, n = 109) or LAM + placebo (control group, n = 116). LAM treatment lasted 72 wk. Patients received the DNA vaccine or placebo by intramuscular injection mediated by EP at weeks 12 (start of treatment with vaccine or placebo, SOT), 16, 24, and 36 (end of treatment with vaccine or placebo, EOT). RESULTS In the modified intent-to-treat population, more patients had a decrease in HBV DNA > 2 log10 IU/mL in the vaccine group at week 12 after EOT compared with the control group. A trend toward a difference in the number of patients with undetectable HBV DNA at week 28 after EOT was obtained. Adverse events were similar. In the dynamic per-protocol set, which excluded adefovir (ADV) add-on cases at each time point instantly after ADV administration due to LAM antiviral failure, more patients had a decrease in HBV DNA > 2 log10 IU/mL in the vaccine group at week 12 and 28 after EOT compared with the control group. More patients with undetectable HBV DNA at week 28 after EOT in the vaccine group were also observed. Among patients with a viral load < 1000 copies/mL at week 12, more patients achieved HBeAg seroconversion in the vaccine group than among controls at week 36 after EOT, as well as less virological breakthrough and YMDD mutations. CONCLUSION The primary endpoint was not achieved using the HBV DNA vaccine. The HBV DNA vaccine could only be beneficial in subjects that have achieved initial virological response under LAM chemotherapy. PMID:28127204
Toscanini, Federica; De Leo, Pasqualina; Calcagno, Giuseppe; Malfatti, Federica; Grasso, Alessandro; Anselmo, Marco
Hepatitis B virus (HBV) reactivation is an increasingly recognized cause of morbidity and mortality in patients undergoing chemotherapy. In haematology, the risk of reactivation of B hepatitis among HBsAg-positive patients has been documented; therefore, use of lamivudine prophylaxis is recommended before starting chemotherapy. Differently, for HBsAg-negative patients with markers of previous HBV infection (i.e., presence of isolated anti-HBc positivity) (anticore patients) management strategies are not univocal. We describe a rare case of HBV reactivation in an anticore patient after fludarabine therapy for chronic lymphocytic leukaemia. The patient fully recovered after a 6-month course of lamivudine with persistent HBV-DNA clearance and loss of HBsAg. The most important feature of this case is that fludarabine alone infrequently determines HBV reactivation, especially in anticore patients. Therefore, we suggest that patients candidates to receive fludarabine therapy should be considered for lamivudine prophylaxis, not only if HBsAg-positive, but even if anticore-positive only.
Han, Junyan; Wang, Lijia; Li, Mengge; Jiang, Yuyong; Wang, Xianbo; Yang, Zhiyun
Background The neutrophil–lymphocyte ratio (NLR) is a new prognostic predictor for patients with liver cancer. The association of NLR and T lymphocytes with the pathogenesis and progression of liver cancer is poorly understood. Methods Seventy-three patients with hepatitis B virus (HBV)-associated primary liver cancer (HBV-PLC), 50 patients with HBV-associated liver cirrhosis (HBV-LC) and 37 patients with chronic HBV infection (CHB) were prospectively enrolled from July 1, 2013 to February 28, 2014 in Beijing Ditan Hospital, Capital Medical University (Beijing, China). The NLR, proportions and concentrations of neutrophils and lymphocytes, concentration of subpopulations of lymphocytes, and the expression of CD31 (index for recent thymic output) and HLA-DR (index for activation of T lymphocytes) of T cells in the peripheral blood samples of the patients were assessed and statistically compared between different groups. Results The NLR was significantly increased from patients with CHB, those with HBV-LC to those with HBV-PLC (P<0.05), along with significant increase of neutrophils and decrease of lymphocytes in the same way (P<0.05). The concentrations of T lymphocytes, natural killer cells, B cells, CD4+ T cells and CD8+ T cells were decreased from patients with CHB, those with HBV-LC to those with HBV-PLC, and were significantly reduced in patients with HBV-PLC compared with those in patients with CHB (P<0.05). The CD31 and HLA-DR expression of naive CD4+ and CD8+ T cells was significantly decreased and increased, respectively in patients with HBV-PLC compared with that in patients with CHB. Conclusions Elevated NLR, resulted from the increase of neutrophils and decrease of lymphocytes, is positively associated with the pathogenesis and progression of HBV-PLC. The reduced thymic output and hyperactivation of T lymphocytes may contribute to the decrease of T lymphocytes, which could be also related to the pathogenesis of HBV-PLC. PMID:28231294
Detection of Hepatitis B Virus (HBV) Genotype E Carried—Even in the Presence of High Titers of Anti-HBs Antibodies—by an Argentinean Patient of African Descent Who Had Received Vaccination against HBV
Mathet, Verónica L.; Cuestas, María L.; Ruiz, Vanesa; Minassian, María L.; Rivero, Cintia; Trinks, Julieta; Daleoso, Graciela; León, Liliana M.; Sala, Andrea; Libellara, Beatriz; Corach, Daniel; Oubiña, José R.
Genotype E hepatitis B virus (HBV) was detected in two Argentine sisters exhibiting an African mitochondrial lineage. One of them (who had been vaccinated against HBV) exhibited anti-HBs cocirculating antibodies without HBsAg escape mutants, while her unvaccinated sister showed a D144A HBsAg escape mutant without anti-HBs antibodies. Both sisters carried an unusual L209V substitution within HBsAg. PMID:16954295
Detection of hepatitis B virus (HBV) genotype E carried--even in the presence of high titers of anti-HBs antibodies--by an Argentinean patient of African descent who had received vaccination against HBV.
Mathet, Verónica L; Cuestas, María L; Ruiz, Vanesa; Minassian, María L; Rivero, Cintia; Trinks, Julieta; Daleoso, Graciela; León, Liliana M; Sala, Andrea; Libellara, Beatriz; Corach, Daniel; Oubiña, José R
Genotype E hepatitis B virus (HBV) was detected in two Argentine sisters exhibiting an African mitochondrial lineage. One of them (who had been vaccinated against HBV) exhibited anti-HBs cocirculating antibodies without HBsAg escape mutants, while her unvaccinated sister showed a D144A HBsAg escape mutant without anti-HBs antibodies. Both sisters carried an unusual L209V substitution within HBsAg.
Wang, Hong-wei; Gao, Hai-li; Wei, Xiao-xia; Wang, Xin-hong
Hepatitis B virus (HBV) replicates noncytopathically in hepatocytes, but HBV or proteins encoded by HBV genome could induce cytokines, chemokines expression by hepatocytes.IL-12 is a typical proinflammatory cytokine that plays a critical role in host defense against pathogens, including the HBV. However, the role of IL-12 in chronic hepatitis B (CHB) remains unclear. The aims of this study were to detect the expression of IL-12 in CHB patients and explore the molecular mechanism of HBV-induced IL-12 expression. The results showed that serum levels and hepatic expression of IL-12 were significantly upregulated in CHB patients. HBx protein increased IL-12 expression in a dose-dependent manner. Furthermore, inhibition of PI3K/Akt significantly decreased the HBx-induced IL-12 expression and Akt activation. Taken together, these results indicate that the molecular mechanism of HBV-induced IL-12 expression involves activation of the PI3K/Akt pathway by HBx, leading to transactivation of the IL-12 p35 and p40 promoters.
Yeh, Ming-Lun; Huang, Ching-I; Hsieh, Ming-Yen; Huang, Chung-Feng; Hsieh, Meng-Hsuan; Huang, Jee-Fu; Dai, Chia-Yen; Lin, Zu-Yau; Chen, Shinn-Chern; Yu, Ming-Lung; Chuang, Wan-Long
The subsequent maintenance therapy in chronic hepatitis B (CHB) patients after long-term viral replication suppression is still uncertain. We aim to evaluate the efficacy of lamivudine (LAM) maintenance therapy in CHB patients achieving undetectable hepatitis B virus (HBV) DNA after 3 years of entecavir (ETV) therapy. Consecutive CHB patients who received at least 3 years of ETV and achieved HBV DNA negativity were allocated either LAM switch therapy or stopped ETV therapy in a prospective, open-label study. Another group of sex- and age-matched patients with continuous ETV therapy for at least 4 years served as historical control group. The primary outcome measurement of the study was relapse of HBV DNA (defined as serum HBV DNA level ≥ 2000 IU/mL). A total of 74 patients, including 42 of LAM switch and 32 of the nonswitch group, were enrolled. There were no significant differences in demographics, except a higher proportion of patients with positive hepatitis B envelope antigen in the nonswitch group at the initiation of ETV therapy. The LAM switch group had significantly lower 1-year relapse rate of HBV within 1 year compared to the nonswitch group (14.3% vs. 75%, p<0.001). However, none of the 48 historical control patients developed relapse of HBV, which was significantly lower than the rate in LAM switch group (p < 0.001). LAM switch was the only factor associated with HBV DNA relapse. In conclusion, continuous long-term potent nucleot(s)ide analogue therapy is mandatory for prevention of viral relapse in CHB patients.
Liu, Chao; Huang, Xuan; Werner, Melanie; Broering, Ruth; Ge, Jun; Li, Yongyin; Liao, Baolin; Sun, Jian; Peng, Jie; Lu, Mengji; Hou, Jinlin; Zhang, Xiaoyong
C–X–C-chemokine ligand 13 (CXCL13), the ligand for C–X–C chemokine receptor type 5 (CXCR5), is a major regulator of B-cell trafficking and plays an integral role in age-dependent clearance of hepatitis B virus (HBV) in the mouse model. However, the expression and function of CXCL13 in patients with chronic hepatitis B (CHB) remain unknown. By use of liver cell subpopulations isolated from CHB patients, we found that CXCL13 mRNA was abundantly expressed in Kupffer cells (KCs), but not in primary hepatocytes, liver sinusoidal endothelial cells, and hepatic stellate cells. Interestingly, KC isolated from HBV-positive liver had much higher level of CXCL13 expression than non-HBV-infected controls. And its expression was induced by toll-like receptor 3 ligand poly I:C stimulation. Moreover, intense expression of CXCL13 protein and accumulation of CD4+ T and B cells were evident in follicular-like structures in the liver tissue of CHB patients, which indicated its chemotactic effect on CXCR5+ CD4+ cells and B cells. Consistently, the levels of serum CXCL13 were significantly higher in the CHB patients than in healthy controls. Furthermore, CXCL13 concentration was increased in the complete response (CR) group during weeks 0–12 and did not change significantly during the course of telbivudine treatment, compared with the patients who didn’t achieve CR. In conclusion, the HBV-related increase of CXCL13 production in KC and serum CXCL13 level during telbivudine treatment might be associated with immune control of chronic HBV infection. PMID:28386259
McMahon, Brian J
All providers, regardless of specialty, should perform screening for HBV on high-risk persons, especially those born in endemic countries. The primary care physician can perform the initial evaluation and follow-up of patients with chronic HBV by following the algorithm in this article and consulting with specialists when appropriate. Chronically infected patients should be followed on a regular basis, preferably every 6 months, with liver function tests, and when appropriate, HBV DNA levels. Those who meet the criteria for high risk for HCC should undergo liver ultrasound every 6 months. Powerful antiviral medications are available that can suppress but not cure HBV and result in resolution of liver inflammation and fibrosis, even cirrhosis, as well as decrease the risk of developing HCC. They should be used in those patients who meet the criteria outlined in the practice guidelines of the major liver societies. Copyright © 2014 Elsevier Inc. All rights reserved.
Ding, Y; Duan, S; Ye, R; Yang, Y; Yao, S; Wang, J; Cao, D; Liu, X; Lu, L; Jia, M; Wu, Z; He, N
We examined the effect of combination antiretroviral therapy (cART) on liver fibrosis among HIV-infected patients with or without hepatitis B (HBV) or C virus (HCV) co-infection. This was a retrospective cohort study of HIV-infected patients receiving cART during 2004-2016. Liver fibrosis was assessed using Fibrosis-4 (FIB-4) score with three classifications: Class 1, <1.45; Class 2, 1.45-3.25; Class 3, >3.25. Of 3900 participants, 68.6% were HIV mono-infected, 5.3% were HIV/HBV co-infected, 23.8% were HIV/HCV co-infected and 2.3% were HIV/HBV/HCV co-infected. Participants received follow-up treatment (median was 3.3 years). Improvement to a lower class was observed in Class 2 (52.6%) and Class 3 (74.2%), respectively. Progression to a higher class was observed in 12.8% and 5.0% in Class 1 and Class 2, respectively, and with a median time of 5.7 months. For improvement to lower classes, older age, male, Dai ethnicity, injection drug use, HCV co-infection and tenofovir for treatment were negative predictors, but in Class 3 of FIB-4 and time-updated increases in CD4 count from baseline were positive predictors. For progression to higher classes, older age, male, Jingpo ethnicity and HCV co-infection were positive predictors, while baseline CD4 count and in Class 2 of FIB-4 were negative predictors. Improvement to lower class linked with decreased mortality risk among patients in Class 3. Early cART initiation for HIV-infected patients with and without hepatitis co-infections may mitigate or slow down some of liver fibrosis, but special attention should be given to those who are older, male, co-infected with HCV.
Yavuz, Fatma; Biyik, Murat; Asil, Mehmet; Dertli, Ramazan; Demir, Ali; Polat, Hakkı; Uysal, Saliha; Ataseven, Hüseyin
Albumin is the most important protein synthesized by the liver. Posttranscriptional changes occur in the molecular structure of albumin due to various factors and isoforms arise. Ischemic modified albumin (IMA) is one such isoform. This study was conducted to evaluate serum IMA concentrations in patients with hepatitis B virus (HBV)-related chronic liver diseases. This study included 74 treatment-naive chronic hepatitis B patients, 25 patients with HBV-related cirrhosis, and 49 healthy controls. Serum IMA concentration was measured spectrophotometrically using the albumin cobalt binding test. The mean IMA concentrations in the chronic hepatitis B group and healthy controls were 0.33 ± 0.11 ABSU and 0.27 ± 0.70 ABSU, respectively, and the difference was statistically significant (P < 0.001). Mean IMA/albumin ratios (IMAR) in the chronic hepatitis B and control groups were 0.08 ± 0.04 and 0.06 ± 0.17, respectively, and the difference was also statistically significant (P < 0.001). Higher serum IMA concentrations and IMAR were detected in patients with advanced fibrosis. Serum IMA concentration and IMAR are increased in patients with HBV-related chronic liver diseases and IMA and IMAR are associated with the degree of liver fibrosis. IMA and IMAR may have potential use as noninvasive markers of fibrosis in chronic hepatitis B patients.
Visvanathan, K; Lang, T; Ryan, K; Wilson, R; Skinner, N A; Thompson, A J V; Ahn, S H; Weilert, F; Abbott, W; Gane, E; Colledge, D; Li, K; Locarnini, S; Mansell, A; Revill, P A
Patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) have suppressed TLR2 expression, function and cytokine production. The aim of this study was to explore the importance of hepatitis B virus (HBV) genotype in innate immune responses and investigate whether Toll-like receptor (TLR) expression/function has potential roles as predictive biomarkers of successful therapy with pegylated interferon (Peg-IFN) therapy of HBeAg seroconversion in HBeAg-positive patients. We showed that as early as 4 weeks after initiation of Peg-IFN, future HBeAg seroconverters had significantly elevated levels of TLR2 expression on monocytes. TLR2-associated IL-6 production at baseline and week 4 of therapy and TLR4 IL-6 production at week 4 were also markedly elevated in HBeAg seroconverters. HBV genotype also influenced treatment response, with genotypes A and B more likely to seroconvert than D. We were able to demonstrate that these differences were due in part to the interaction of the specific HBeAg proteins with TLR pathway adaptor molecules, and these interactions were genotype dependent. HBeAg-mediated modulation of TLR signalling was also observed in Huh7 cells, following stimulation with Pam3Cys. Importantly, the addition of IFN-α to TLR2-stimulated cells cotransfected with an HBeAg expression plasmid reversed HBeAg-mediated suppression of hepatocytes. These findings demonstrate that patients with an activated inflammatory response are much more likely to respond to IFN therapy, with TLR responses showing promise as potential biomarkers of HBeAg seroconversion in this setting. Furthermore, our findings suggest there is differential genotype-specific HBeAg suppression of innate signalling pathways which may account for some of the clinical differences observed across the CHB spectrum. © 2015 John Wiley & Sons Ltd.
Changotra, H; Sehajpal, P K
Hepatitis B virus (HBV) infection is a major public health problem and a leading cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma. Worldwide, there are about 350 million carriers of this pathogen and India bears the second highest carrier pool in the world. Early diagnosis and measurement of viral load in hepatitis B patients is very helpful for the better management of this disease. The existing methods for viral quantification are either cumbersome or expensive. Since viral replication correlate well with HBV DNA levels a new sensitive, reliable and cost effective competitive PCR assay has been developed for quantifying the viral load in the serum of hepatitis B patients. The S gene based cPCR assay was able to detect as low as 100 genome equivalent/ml of HBV DNA from human serum and was applied to determine viral load among inactive and chronic hepatitis B carriers demonstrating the usefulness of the developed test.
Wang, J-Y; Mao, R-C; Zhang, Y-M; Zhang, Y-J; Liu, H-Y; Qin, Y-L; Lu, M-J; Zhang, J-M
Patients with chronic hepatitis B virus (HBV) infection and normal or mildly increased transaminases may have sustained significant liver damage, as verified by liver biopsy. However, no suitable noninvasive method exists for identifying liver necroinflammation in such patients. We aimed to investigate the power of microRNA-124 as a novel biomarker for liver necroinflammation. A total of 131 recruited patients with chronic HBV infection underwent liver biopsy for grading of necroinflammation (G) and staging of fibrosis (S). Thirty healthy individuals were included as controls (HCs). Serum microRNA-124 and microRNA-122 levels were measured using qRT-PCR. Forty-five patients from the study population receiving entecavir therapy were monitored for changes in serum microRNA-124 levels in association with improved liver histology. The capacity of serum microRNA-124 levels in discriminating the grade of liver necroinflammation was compared with alanine aminotransferase (ALT) with liver biopsy validation. Serum microRNA-124 levels were significantly higher in patients with chronic HBV infection than in HCs (P < 0.0001). Patients with considerable liver necroinflammation (G ≥ 2) had significantly higher serum miRNA-124 levels than those without or with mild necroinflammation (P < 0.0001). After 48 weeks of antiviral therapy, serum microRNA-124 levels considerably declined in 45 patients (P < 0.0001), which were associated with histological improvement. In patients with normal ALT and a serum HBV DNA load >10(4) copies/mL, receiver operating characteristic (ROC) curve of serum microRNA-124 levels yielded an area under ROC curve (AUC) of 0.840, with 58.3% sensitivity and 91.7% specificity in discriminating between moderate-to-severe liver necroinflammation (G ≥ 2).
Iser, David M; Lewin, Sharon R
Liver disease is a major cause of mortality in individuals with HIV-HBV coinfection. The pathogenesis of liver disease in this setting is unknown, but is likely to involve drug toxicity, infection of hepatic cells with both HIV and HBV, and an altered immune response to HBV. The availability of therapeutic agents that target both HIV and HBV replication enable dual viral suppression, and assessment of chronic hepatitis B is important prior to commencement of antiretroviral therapy. Greater importance is now placed on HBV DNA levels and staging of liver fibrosis, either by liver biopsy or noninvasive measurement, such as transient elastography, since significant liver fibrosis may exist in the presence of normal liver function tests. Earlier treatment of both HIV and HBV is now generally advocated and treatment is usually lifelong.
Haijun, Deng; Yong, Huang; Ailong, Huang; Quanxin, Long
There are significant differences in clinical characteristics between chronic hepatitis B virus infected (CHB) child and adult patients. Viral quasispecies characteristics are associated with its pathogenic properties. For hepatitis B virus (HBV), its core region is the main immune recognition region for its enriched epitopes. In our study, we discuss the quasispecies characteristics and positive selection within core gene within chronic HBV infected child and adult patients. By analyzing 170 core gene sequences from child CHB patients and 121 core genes sequences from adult CHB patients, quasispecies characteristics were described by sequence complexity, diversity, non-synonymous substitution ratio (dN) and synonymous substitution ratios (dS). In addition, positive selection sites were also determined by bioinformatics tools. Then, all these parameters were compared between child and adult CHB patient groups. Compared with child patients, adult patients with CHB showed distinct quasispecies characteristics within the core region, had a higher sequence complexity and diversity and more positive selection sites, suggesting that the adult CHB patients had a higher immune selection pressure on the HBV core gene. Reduced selection pressure on the HBV core gene in hepatitis B e antigen (HBeAg)-positive CHB patients than HBeAg negative CHB patients were observed in both adult and child patient groups. The majority of the screened positive selection sites lay within human leukocyte antigens (HLA)-restricted epitopes. In conclusion, this study analyzed the quasispecies characteristics discrepancy between child and adult patients with CHB, and revealed the possible reason for the distinct clinical characteristics in the perspective of population genetics.