HIV/AIDS MAJOR ARTICLE Telaprevir for HIV/Hepatitis C Virus–Coinfected Patients Failing Treatment With Pegylated Interferon/Ribavirin (ANRS HC26 TelapreVIH): An Open-Label, Single-Arm, Phase 2 Trial Downloaded from https://academic.oup.com/cid/article/59/12/1768/2895305 by guest on 01 October 2021 Laurent Cotte,1 Joséphine Braun,2 Caroline Lascoux-Combe,3 Corine Vincent,2 Marc-Antoine Valantin,4 Philippe Sogni,5 Karine Lacombe,6 Didier Neau,7 Hugues Aumaitre,8 Dominique Batisse,9 Pierre de Truchis,10 Anne Gervais,11 Christian Michelet,12 Philippe Morlat,13 Daniel Vittecoq,14 Isabelle Rosa,15 Inga Bertucci,16 Stéphane Chevaliez,17 Jean-Pierre Aboulker,2 and Jean-Michel Molina3; for the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) HC26 Study Groupa 1Hospices Civils de Lyon, Croix-Rousse Hospital, and INSERM U1052, 2INSERM SC10-US019, Villejuif, 3Assistance Publique–Hôpitaux de Paris (AP-HP), Saint-Louis Hospital, University of Paris VII Denis Diderot, and Sorbonne Paris-Cité, INSERM U941, 4AP-HP, Pitié-Salpêtrière Hospital, and UMR-S 943, INSERM, 5AP-HP, Cochin Hospital and Paris Descartes University, INSERM U-1016, 6AP-HP, Saint-Antoine Hospital, Sorbonne Universités, UPMC University Paris 06, UMR-S1136, 7Pellegrin University Hospital, Bordeaux, 8Saint-Jean Hospital, Perpignan, 9AP-HP, Georges Pompidou European Hospital, Paris, 10AP-HP, Raymond Poincaré Hospital, Garches, 11AP-HP, Bichat-Claude Bernard Hospital, Paris, 12Pontchaillou University Hospital, Rennes, 13Saint-André University Hospital, Bordeaux, 14AP-HP, Bicètre Hospital, Le Kremlin-Bicètre, 15Créteil Hospital, 16French National Agency for Research on AIDS and Viral Hepatitis, Paris, and 17AP-HP, Henri Mondor Hospital, Créteil, France (See the Editorial Commentary by Rockstroh on pages 1777–8.) Background. Retreatment with pegylated interferon (peg-IFN) and ribavirin (RBV) results in poor sustained virological response (SVR) rates in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)–coinfected pa- tients. There are limited data regarding the use of telaprevir plus peg-IFN/RBV in this population. Methods. HIV type 1–infected patients who previously failed ≥12 weeks of peg-IFN/RBV for HCV genotype 1 coinfection were enrolled in a single-arm, phase 2 trial. Patients with cirrhosis and previous null response were exclud- ed. Authorized antiretrovirals were tenofovir, emtricitabine, efavirenz, atazanavir, and raltegravir. All patients received peg-IFN alfa-2a (180 µg/week) plus RBV (1000–1200 mg/day) for 4 weeks, followed by telaprevir (750 mg or 1125 mg every 8 hours with efavirenz) plus peg-IFN/RBV for 12 weeks and peg-IFN/RBV for 32–56 weeks according to viro- logical response at week 8. The primary endpoint was the SVR rate at 24 weeks after the end of treatment (SVR24). fi – Results Sixty-nine patients started treatment; SVR24 was achieved in 55 (80% [95% con dence interval, 68% fl fi IL28B 88%). SVR24 was not in uenced by baseline brosis stage, genotype, antiretroviral regimen, HCV subtype, CD4 cell count, previous response to HCV treatment, HCV RNA level, or HCV RNA decline at week 4. HCV treatment was discontinued for adverse events (AEs) in 20% of patients, including cutaneous (4%), psychiatric (4%), hematolog- ical (6%), and other AEs (6%). Peg-IFN or RBV dose reduction was required in 23% and 43% of patients, respectively. Seventy percent of patients required erythropoietin, blood transfusions, or RBV dose reduction for anemia. Two pa- tients died during the study. No HIV breakthrough was observed. Conclusions. Despite a high discontinuation rate related to toxicity, a substantial proportion of treatment-experi- enced HIV-coinfected patients achieved SVR24 with a telaprevir-based regimen. Clinical Trials Registration. NCT01332955. Keywords. HIV/HCV coinfection; HCV retreatment; telaprevir; direct acting agent. Correspondence: Laurent Cotte, MD, Department of Infectious Diseases and Received 8 May 2014; accepted 22 July 2014; electronically published 18 August Tropical Medicine, Croix-Rousse Hospital, 69317 Lyon Cedex 04, France (laurent. 2014. [email protected]). Presented in part: 20th Conference on Retroviruses and Opportunistic Infections, Clinical Infectious Diseases® 2014;59(12):1768–76 Atlanta, Georgia, 2013; 64th Liver Meeting, Washington, D.C., 2013; and 21st © The Author 2014. Published by Oxford University Press on behalf of the Infectious Conference on Retroviruses and Opportunistic Infections, Boston, Massachusetts, Diseases Society of America. All rights reserved. For Permissions, please e-mail: 2014. [email protected]. aThe ANRS HC26 study group members are listed in the Appendix. DOI: 10.1093/cid/ciu659 1768 • CID 2014:59 (15 December) • HIV/AIDS Worldwide, 20%–30% of patients with human immunodefi- criteria were hepatitis B virus coinfection; HIV type 2 infection; ciency virus (HIV) are coinfected with hepatitis C virus active opportunistic infection; active malignancy; organ trans- (HCV) [1, 2]. The advent of combination antiretroviral therapy plant; Child-Pugh score B or C; severe psychiatric, cardiac, or (cART) has dramatically decreased HIV-related mortality, but pulmonary disease; severe hemoglobinopathy; uncontrolled seri- liver-related mortality is still increasing [3, 4]. ous comorbidity; or history of decompensated cirrhosis. The standard treatment in HCV-monoinfected patients used Authorized antiretrovirals were defined according to known to be a combination of pegylated interferon (peg-IFN) plus interactions with telaprevir [25, 26] and associated a tenofovir/ ribavirin (RBV) for 48 weeks in patients infected with HCV emtricitabine backbone with either efavirenz, raltegravir, or genotype 1 or 4, allowing a sustained virological response (SVR) ritonavir-boosted atazanavir, or any combination of these in about 50% of cases [5–7]. In HIV/HCV-coinfected patients, drugs. response rates were much lower [8–11], and retreatment of Previous HCV virological failure was defined by the persis- genotype 1 patients who had previously failed a course of tence of a detectable HCV RNA level following treatment, with peg-IFN/RBV led to an SVR rate of about 10% [12–15]. the same genotype. The virological response to treatment was Downloaded from https://academic.oup.com/cid/article/59/12/1768/2895305 by guest on 01 October 2021 Triple therapy based on peg-IFN/RBV and NS3/4A protease classified as relapse (ie, patient with undetectable HCV RNA at inhibitors (boceprevir or telaprevir) became the new standard of the end of treatment and detectable HCV RNA thereafter), care in 2011 [16–19]. For telaprevir-based triple therapy [20], breakthrough (ie, patient with undetectable HCV RNA at least SVR is achieved in about 75% of treatment-naive patients once under treatment, becoming detectable thereafter), and non- monoinfected with HCV [17, 21] and 71% of previous relapsers responder including partial responder (ie, >2 log10 HCV RNA or partial nonresponders [22]. In addition to common side decline at week 12 and still detectable HCV RNA at week 24) fl effects associated with peg-IFN/RBV such as asthenia, in uen- and null responder (ie, <2 log10 HCV RNA decline at week 12). za-like illness, depression, anemia, and pruritus [5–7], an in- Fibrosis stage had to be documented by a liver biopsy within creased rate of anemia and rashes has been described with the past 3 years. Patients with a previous liver biopsy exhibiting telaprevir-based treatment [23]. cirrhosis lesions (ie, METAVIR score F4) were included without In HIV/HCV genotype 1–coinfected patients who were a new biopsy. Null responders without cirrhosis were limited to HCV treatment naive, an SVR of 74% has been reported with a maximum of 30% of all included patients. Patients with both telaprevir-based treatment [24]. No prospective trial has cur- cirrhosis and previous null response were not included. rently studied the effect of telaprevir-based regimens in HIV/ The study protocol, its amendments, and informed consent HCV-coinfected patients who had failed a previous treatment. documents were approved by the French Regulatory Authority The objective of the present study was to estimate the efficacy and and by the local ethics committee. The study was performed in safety of a 12-week treatment with telaprevir combined with accordance with the International Conference on Harmonisa- peg-IFN/RBV for a total of 48 or 72 weeks in HIV/HCV geno- tion Good Clinical Practice guidelines and the Declaration of type 1–coinfected patients who had failed a previous treatment. Helsinki. All patients provided written informed consent. METHODS Procedures All patients received the same treatment regimen. Treatment Study Design and Participants started with a 4-week lead-in phase with peg-IFN alfa-2a and The French National Agency for Research on AIDS and viral RBV, followed by 12 weeks of triple therapy with telaprevir/ hepatitis (ANRS) HC26 TelapreVIH study was a single-arm, peg-IFN/RBV, and by a double-therapy phase with peg-IFN/ open-label, phase 2 clinical trial. Patients were recruited from RBV. The total duration of treatment was determined by the 23 tertiary care centers from May to December 2011. Eligible pa- rapid virological response (RVR) 4 weeks after the introduction tients were aged ≥18 years, infected with HIV-1 and HCV geno- of telaprevir—that is, at week 8 (RVR8). A complete RVR8 was fi type 1, and had previously failed a treatment of at least 12 weeks de ned as HCV RNA load <15 IU/mL and a partial RVR8 as with peg-IFN alfa-2a ≥135 µg/week or peg-IFN alfa-2b ≥1.0 µg/ HCV RNA load between 15 and 1000 IU/mL at week 8. For pa- ≥ kg/week and RBV 600 mg/day. Other inclusion criteria includ- tients with a complete RVR8, the total duration of treatment was ≥ ≤ ed body weight 40 kg and 125 kg, stable cART for >3 months, 48 weeks and for patients with a partial RVR8,thepeg-IFN/ CD4 count >200 cells/µL and CD4 percentage >15%, HIV RNA RBV phase was extended, for a total duration of 72 weeks.