Nguyen, Thi Huyen Tram; Anglaret, Xavier; Madelain, Vincent; Taburet, Anne-Marie; Baize, Sylvain; Pastorino, Boris; Rodallec, Anne; Piorkowski, Géraldine; Conde, Mamoudou N.; Bore, Joseph Akoi; Carbonnelle, Caroline; Jacquot, Frédéric; Raoul, Hervé; Malvy, Denis; Mentré, France
Background In 2014–2015, we assessed favipiravir tolerance and efficacy in patients with Ebola virus (EBOV) disease (EVD) in Guinea (JIKI trial). Because the drug had never been used before for this indication and that high concentrations of the drugs were needed to achieve antiviral efficacy against EBOV, a pharmacokinetic model had been used to propose relevant dosing regimen. Here we report the favipiravir plasma concentrations that were achieved in participants in the JIKI trial and put them in perspective with the model-based targeted concentrations. Methods and findings Pre-dose drug concentrations were collected at Day-2 and Day-4 of treatment in 66 patients of the JIKI trial and compared to those predicted by the model taking into account patient’s individual characteristics. At Day-2, the observed concentrations were slightly lower than the model predictions adjusted for patient’s characteristics (median value of 46.1 versus 54.3 μg/mL for observed and predicted concentrations, respectively, p = 0.012). However, the concentrations dropped at Day-4, which was not anticipated by the model (median values of 25.9 and 64.4 μg/mL for observed and predicted concentrations, respectively, p<10−6). There was no significant relationship between favipiravir concentrations and EBOV viral kinetics or mortality. Conclusions Favipiravir plasma concentrations in the JIKI trial failed to achieve the target exposure defined before the trial. Furthermore, the drug concentration experienced an unanticipated drop between Day-2 and Day-4. The origin of this drop could be due to severe sepsis conditions and/or to intrinsic properties of favipiravir metabolism. Dose-ranging studies should be performed in healthy volunteers to assess the concentrations and the tolerance that could be achieved with high doses. Trial registration ClinicalTrials.gov NCT02329054 PMID:28231247
Sissoko, Daouda; Laouenan, Cedric; Folkesson, Elin; M’Lebing, Abdoul-Bing; Beavogui, Abdoul-Habib; Baize, Sylvain; Camara, Alseny-Modet; Maes, Piet; Shepherd, Susan; Danel, Christine; Carazo, Sara; Conde, Mamoudou N.; Gala, Jean-Luc; Colin, Géraldine; Savini, Hélène; Bore, Joseph Akoi; Le Marcis, Frederic; Koundouno, Fara Raymond; Petitjean, Frédéric; Lamah, Marie-Claire; Diederich, Sandra; Tounkara, Alexis; Poelart, Geertrui; Berbain, Emmanuel; Dindart, Jean-Michel; Duraffour, Sophie; Lefevre, Annabelle; Leno, Tamba; Peyrouset, Olivier; Irenge, Léonid; Bangoura, N’Famara; Palich, Romain; Hinzmann, Julia; Kraus, Annette; Barry, Thierno Sadou; Berette, Sakoba; Bongono, André; Camara, Mohamed Seto; Chanfreau Munoz, Valérie; Doumbouya, Lanciné; Souley Harouna; Kighoma, Patient Mumbere; Koundouno, Fara Roger; Réné Lolamou; Loua, Cécé Moriba; Massala, Vincent; Moumouni, Kinda; Provost, Célia; Samake, Nenefing; Sekou, Conde; Soumah, Abdoulaye; Arnould, Isabelle; Komano, Michel Saa; Gustin, Lina; Berutto, Carlotta; Camara, Diarra; Camara, Fodé Saydou; Colpaert, Joliene; Delamou, Léontine; Jansson, Lena; Kourouma, Etienne; Loua, Maurice; Malme, Kristian; Manfrin, Emma; Maomou, André; Milinouno, Adele; Ombelet, Sien; Sidiboun, Aboubacar Youla; Verreckt, Isabelle; Yombouno, Pauline; Bocquin, Anne; Carbonnelle, Caroline; Carmoi, Thierry; Frange, Pierre; Mely, Stéphane; Nguyen, Vinh-Kim; Pannetier, Delphine; Taburet, Anne-Marie; Treluyer, Jean-Marc; Kolie, Jacques; Moh, Raoul; Gonzalez, Minerva Cervantes; Kuisma, Eeva; Liedigk, Britta; Ngabo, Didier; Rudolf, Martin; Thom, Ruth; Kerber, Romy; Gabriel, Martin; Di Caro, Antonino; Wölfel, Roman; Badir, Jamal; Bentahir, Mostafa; Deccache, Yann; Dumont, Catherine; Durant, Jean-François; El Bakkouri, Karim; Gasasira Uwamahoro, Marie; Smits, Benjamin; Toufik, Nora; Van Cauwenberghe, Stéphane; Ezzedine, Khaled; Dortenzio, Eric; Pizarro, Louis; Etienne, Aurélie; Guedj, Jérémie; Fizet, Alexandra; Barte de Sainte Fare, Eric; Murgue, Bernadette; Tran-Minh, Tuan; Rapp, Christophe; Piguet, Pascal; Poncin, Marc; Draguez, Bertrand; Allaford Duverger, Thierry; Barbe, Solenne; Baret, Guillaume; Defourny, Isabelle; Carroll, Miles; Raoul, Hervé; Augier, Augustin; Eholie, Serge P.; Yazdanpanah, Yazdan; Levy-Marchal, Claire; Antierrens, Annick; Van Herp, Michel; Günther, Stephan; de Lamballerie, Xavier; Keïta, Sakoba; Mentre, France
Background Ebola virus disease (EVD) is a highly lethal condition for which no specific treatment has proven efficacy. In September 2014, while the Ebola outbreak was at its peak, the World Health Organization released a short list of drugs suitable for EVD research. Favipiravir, an antiviral developed for the treatment of severe influenza, was one of these. In late 2014, the conditions for starting a randomized Ebola trial were not fulfilled for two reasons. One was the perception that, given the high number of patients presenting simultaneously and the very high mortality rate of the disease, it was ethically unacceptable to allocate patients from within the same family or village to receive or not receive an experimental drug, using a randomization process impossible to understand by very sick patients. The other was that, in the context of rumors and distrust of Ebola treatment centers, using a randomized design at the outset might lead even more patients to refuse to seek care. Therefore, we chose to conduct a multicenter non-randomized trial, in which all patients would receive favipiravir along with standardized care. The objectives of the trial were to test the feasibility and acceptability of an emergency trial in the context of a large Ebola outbreak, and to collect data on the safety and effectiveness of favipiravir in reducing mortality and viral load in patients with EVD. The trial was not aimed at directly informing future guidelines on Ebola treatment but at quickly gathering standardized preliminary data to optimize the design of future studies. Methods and Findings Inclusion criteria were positive Ebola virus reverse transcription PCR (RT-PCR) test, age ≥ 1 y, weight ≥ 10 kg, ability to take oral drugs, and informed consent. All participants received oral favipiravir (day 0: 6,000 mg; day 1 to day 9: 2,400 mg/d). Semi-quantitative Ebola virus RT-PCR (results expressed in “cycle threshold” [Ct]) and biochemistry tests were performed at day 0, day 2, day 4, end of symptoms, day 14, and day 30. Frozen samples were shipped to a reference biosafety level 4 laboratory for RNA viral load measurement using a quantitative reference technique (genome copies/milliliter). Outcomes were mortality, viral load evolution, and adverse events. The analysis was stratified by age and Ct value. A “target value” of mortality was defined a priori for each stratum, to guide the interpretation of interim and final analysis. Between 17 December 2014 and 8 April 2015, 126 patients were included, of whom 111 were analyzed (adults and adolescents, ≥13 y, n = 99; young children, ≤6 y, n = 12). Here we present the results obtained in the 99 adults and adolescents. Of these, 55 had a baseline Ct value ≥ 20 (Group A Ct ≥ 20), and 44 had a baseline Ct value < 20 (Group A Ct < 20). Ct values and RNA viral loads were well correlated, with Ct = 20 corresponding to RNA viral load = 7.7 log10 genome copies/ml. Mortality was 20% (95% CI 11.6%–32.4%) in Group A Ct ≥ 20 and 91% (95% CI 78.8%–91.1%) in Group A Ct < 20. Both mortality 95% CIs included the predefined target value (30% and 85%, respectively). Baseline serum creatinine was ≥110 μmol/l in 48% of patients in Group A Ct ≥ 20 (≥300 μmol/l in 14%) and in 90% of patients in Group A Ct < 20 (≥300 μmol/l in 44%). In Group A Ct ≥ 20, 17% of patients with baseline creatinine ≥110 μmol/l died, versus 97% in Group A Ct < 20. In patients who survived, the mean decrease in viral load was 0.33 log10 copies/ml per day of follow-up. RNA viral load values and mortality were not significantly different between adults starting favipiravir within <72 h of symptoms compared to others. Favipiravir was well tolerated. Conclusions In the context of an outbreak at its peak, with crowded care centers, randomizing patients to receive either standard care or standard care plus an experimental drug was not felt to be appropriate. We did a non-randomized trial. This trial reaches nuanced conclusions. On the one hand, we do not conclude on the efficacy of the drug, and our conclusions on tolerance, although encouraging, are not as firm as they could have been if we had used randomization. On the other hand, we learned about how to quickly set up and run an Ebola trial, in close relationship with the community and non-governmental organizations; we integrated research into care so that it improved care; and we generated knowledge on EVD that is useful to further research. Our data illustrate the frequency of renal dysfunction and the powerful prognostic value of low Ct values. They suggest that drug trials in EVD should systematically stratify analyses by baseline Ct value, as a surrogate of viral load. They also suggest that favipiravir monotherapy merits further study in patients with medium to high viremia, but not in those with very high viremia. Trial registration ClinicalTrials.gov NCT02329054 PMID:26930627
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Minor Peters, Melissa
This paper examines the ways in which HIV-related programmes for heterosexual Ugandans and also for men who have sex with men work to deny healthcare services to transgender people in Uganda. Contrary to current conventional wisdom, the study found that the widespread use of the term 'men who have sex with men' produces greater barriers to healthcare for queer Ugandans than identity categories such as 'lesbian' or 'transgender'. Interventions for men who have sex with men assume a male-identified sexual subject with agency over sexual practices, such as frequency of condom use. Based on two years of ethnographic research in Kampala, I suggest that the focus on individual sexual practices harms transgender people in two ways. First, current HIV prevention and treatment programmes fail to account for risk factors that accrue to both male and female transgender Ugandans due to the social enforcement of gender norms. Second, the term men who have sex with men directs attention towards stigmatised sexual practices, producing the neglect and abuse of non-heteronormative individuals. In the context of Ugandan healthcare, terms such as 'transgender' and kuchu instead focus attention on the dignity and humanity of the rights-bearing person. These findings emphasise how health practitioners must pay attention to emic categories in order to address the ways in which vulnerability is distributed along social vectors of difference.