Telaprevir for HIV/Hepatitis C Virus–Coinfected Patients Failing

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 patients. 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 excluded. 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%), hematological (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 patients 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. <50 copies/mL, and no peg-IFN and/or RBV treatment within The 3 drugs were given at standard dose. The telaprevir dose the past 6 months. Inclusion criteria also accounted for the was 750 mg every 8 hours when administered with an atazana- following laboratory parameters: hemoglobin concentration vir/ritonavir- or raltegravir-based cART and was increased to ≥12.0 g/dL for women and ≥13.0 g/dL for men, neutrophil 1125 mg every 8 hours for efavirenz-based cART. The peg- count ≥1.5 × 109/L, and platelet count ≥90 × 109/L. Exclusion IFN dose was 180 µg per week administered subcutaneously

HIV/AIDS • CID 2014:59 (15 December) • 1769 and RBV was given at 1000 mg/day and 1200 mg/day for pa- of target detected. Detectable HCV RNA measures below the tients weighing ≤75 kg and >75 kg, respectively. Erythropoietin LLOQ were considered as positive results with values equal to (EPO), granulocyte colony-stimulating factor (G-CSF), and LLOQ. All HCV genotypes and subtypes were conﬁrmed at thrombopoietin receptor (TPO-R) agonists were allowed. Per Henri Mondor Virology Laboratory using a reference method protocol, EPO had to be started if hemoglobin concentration [27].Resistance monitoring was performed in all patients present- dropped to <11.0 g/dL. Blood transfusions were permitted ing a viral breakthrough or relapse following treatment. The IL28B and RBV dose reduction was allowed only if EPO was not genotype (single-nucleotide polymorphism rs12979860) was de- able to maintain hemoglobin concentration >10.0 g/dL. Stan- termined by means of an original real-time PCR method [28]. dard futility rules were applied: Telaprevir was interrupted if the HCV RNA load was >1000 IU/mL at week 8 or 12; peg- Statistical Analyses IFN and RBV were interrupted if the HCV RNA load was The primary efﬁcacy endpoint was the SVR rate 24 weeks after

>100 IU/mL at week 16, if HCV RNA decline was <2 log10 at the end of treatment (SVR24), measured at week 72 or week 96 week 16, or if HCV RNA was still detectable at week 28 or at according to the duration of treatment (48 or 72 weeks). A mod- Downloaded from https://academic.oup.com/cid/article/59/12/1768/2895305 by guest on 01 October 2021 any time in case of virological breakthrough. ified intent-to-treat analysis (mITT) was performed, including HCV RNA was quantified on site by one of the following every patient who initiated treatment. Missing data for the prima- real-time polymerase chain reaction (PCR) assays: Cobas ry endpoint were considered to be treatment failure. fi AmpliPrep Cobas TaqMan HCV version 2 (Roche Molecular Secondary ef cacy endpoints included RVR8 and SVR at fi Systems, Pleasanton, California) with a lower limit of quanti - week 12 (SVR12). Safety endpoints included treatment-emer- cation (LLOQ) equal to the lower limit of detection (LLOD) of gent adverse events (AEs), laboratory abnormalities [29], and 15 IU/mL or RealTime HCV (m2000, Abbott Diagnostic, Chi- deaths. Particular attention was paid to monitor skin disorders, cago, Illinois) with an LLOQ equal to the LLOD of 12 IU/mL. anemia, and psychiatric disorders. Data are presented as num- For each patient, HCV RNA measurements were carried out by ber and percentage or median and interquartile range (IQR) as thesamelaboratoryandbythesameassaythroughoutthe appropriate. Associations of baseline characteristics with SVR24 study. HCV RNA was considered undetectable in the absence were assessed using 2-sided χ2 or Fisher exact tests with a

Figure 1. Trial proﬁle. All patients received telaprevir, pegylated interferon alfa-2a, and ribavirin in addition to their antiretroviral. Abbreviations: mITT, modiﬁed intent-to-treat; RVR8, rapid virological response at week 8.

1770 • CID 2014:59 (15 December) • HIV/AIDS significant level of P < .05. Statistical analyses were performed Table 1. Baseline Demographics and Disease Characteristics using SAS version 9.3. (N = 69) An independent data and safety monitoring board regularly evaluated safety and side effects of the study regimen. This study Characteristic No. (%) is registered with ClinicalTrials.gov (identifier NCT01332955). Age, y, median [IQR] 50 [47–52] Male sex 55 (80) RESULTS Non–black race 59 (85) IVDU 39 (56) BMI ≥25 kg/m2 26 (38) Eighty patients were assessed for eligibility, among whom 70 HIV infection CDC stage C 13 (19) were enrolled. One patient never started treatment, resulting CD4 cells/µL, median [IQR] 630 [459–736] in 69 patients who initiated treatment and were included in HIV RNA <50 copies/mL 68 (99) the mITT (Figure 1). Eighteen patients (26%) discontinued Antiretroviral treatment treatment, either before (n = 7) or after (n = 11) week 8. Reasons TDF-FTC-ATV/r 34 (49) Downloaded from https://academic.oup.com/cid/article/59/12/1768/2895305 by guest on 01 October 2021 for discontinuation included adverse events in 14 patients TDF-FTC-EFV 13 (19) (20%), virological breakthrough in 3 patients (4%), and lack TDF-FTC-RAL 12 (17) of efficacy in 1 patient (1%). Sixty-two patients reached week Other combinations 10 (14)

8, of whom 59 had a complete RVR8 and were assigned a 48- HCV subgenotype week duration of treatment, whereas 3 patients had a partial 1a 48 (70) 1b 21 (30) RVR8 and were assigned a 72-week duration of treatment. – One patient died after the end of treatment, leading to 50 pa- Log HCV RNA, IU/mL, median [IQR] 6.2 [5.8 6.7] IL28B genotype (n = 68) tients (72%) who terminated the study. CC 21 (31) Demographics and baseline characteristics of the patients are CT 34 (50) presented in Table 1. Most patients were male (80%), were of a TT 13 (19) race other than black (85%), and were infected with HCV geno- Fibrosis score (METAVIR) type 1a (70%). All patients had a controlled HIV infection. An- F1 12 (17) tiretroviral treatment was tenofovir/emtricitabine/atazanavir/ F2 30 (43) ritonavir in most cases (49%). Twenty-seven patients (39%) F3 11 (16) had a severe fibrosis or cirrhosis. Only 1 patient had a serum F4 16 (23) albumin level <3.5 g/dL at baseline and 4 had a platelet count Response to previous HCV treatment <100 × 109/L. However, none had both conditions. Twenty- Relapse 27 (39) one patients (30%) were previous null responders. Breakthrough 6 (9) At the end of the lead-in phase, 1 patient had an undetectable Partial responder 15 (22) Null responder 21 (30) HCV RNA, whereas 50 patients (72%) had an HCV RNA decrease >1 log. At week 8, by the end of the first 4 weeks of triple Data are No. (%) unless otherwise specified. therapy, 74% of the patients had an undetectable HCV RNA Abbreviations: ATV/r, ritonavir-boosted atazanavir; BMI, body mass index; CDC, Centers for Disease Control and Prevention; EFV, efavirenz; FTC, emtricitabine; load. The proportion of patients with undetectable HCV RNA HCV, hepatitis C virus; HIV, human immunodeficiency virus; IQR, interquartile reached 88% at the end of the triple-therapy phase. One patient range; IVDU, intravenous drug user; RAL, raltegravir; TDF, tenofovir. had a primary nonresponse and stopped treatment at week 8, 3 patients presented a virological breakthrough at weeks 28, 36, and 40 and stopped treatment, and another patient presented SVR24 rate of 80%. Figure 2 depicts the virological response dur- a virological breakthrough at week 44 but pursued the treatment ing treatment and follow-up. Table 3 reports SVR24 according until week 48. Resistance data for these patients are presented in to baseline characteristics and virological response at the end Table 2. Fourteen patients (20%) stopped treatment for AEs: 6 of the lead-in phase. None of the characteristics examined before week 8 (none of whom reached SVR) and 8 after week 8, were associated with virological outcome, including fibrosis including 1 patient who died at week 40, 1 patient who prema- stage, HCV subgenotype, IL28B polymorphism, and type of an- turely stopped the treatment at week 48 despite a partial RVR8 tiretroviral treatment. Among 16 cirrhotic patients, 3 had a and subsequently relapsed, and 6 others who reached SVR de- <1.0 log HCV RNA decline during the 4-week lead-in phase. spite a shortened treatment. Two patients died during the study: Two of them achieved SVR24 and 1 stopped therapy at week 7 1 at week 40 from an intracerebral hemorrhage following auto- because of a psychiatric decompensation. immune thrombocytopenia, and 1 at week 55 from an upper The most common AEs observed during treatment were ane- gastrointestinal hemorrhage, leading to an overall SVR12 and mia, asthenia, dry skin, and pruritus (Table 4). Most AEs were

HIV/AIDS • CID 2014:59 (15 December) • 1771 Table 2. Resistance Proﬁle in Patients With Virological Failure

Patient HCV Genotype Baseline Mutations Time of Failure Time of Analysis Log HCV RNA, IU/mL Emerging Mutations 1 1a V36M, Q80K Week 8 Week 8 6.4 V36M, Q80K, R155K 2 1a Q80K Week 28 Week 36 2.9 Q80K, R155K 3 1b WT Week 36 Week 52 5.0 WT 4 1a WT Week 40 Week 48 6.3 R155K 5 1a WT Week 44 Week 52 5.6 T54S, R155K 6 1a WT Week 52 Week 64 5.2 Amplification failure

Abbreviations: HCV, hepatitis C virus; WT, wild type.

mild or moderate in severity. However, 15 patients (22%) pre- transfusion, and TPO-R agonist. Overall, 70% of the patients Downloaded from https://academic.oup.com/cid/article/59/12/1768/2895305 by guest on 01 October 2021 sented a grade 4 AE, including anemia in 7 (10%), neutropenia presented with grade 3–4 anemia and required EPO, RBC trans- in 3 (4%), and thrombocytopenia in 1 (1%). No grade 4 rash oc- fusion, or RBV dose reduction (Table 5). curred, but 3 patients presented a grade 3 cutaneous AE leading Four patients had an HIV RNA load >50 copies/mL during to triple therapy withdrawal at weeks 8, 9, and 12, respectively. the treatment period and 1 patient during follow-up, which The proportion of AEs was similar between patients with cirrho- were not confirmed on subsequent control and were considered sis (8/16 [50%]) and those without cirrhosis (20/53 [38%]). as “blips.” None of these blips occurred during the telaprevir Telaprevir dose was temporarily reduced in 4 patients (6%) phase. Two of these patients later presented a detectable HIV because of hemorrhoids (n = 1) and the patient’s own decision RNA load during follow-up that was related to poor compli- (n = 3). The peg-IFN alfa-2a dose was reduced in 15 patients ance, and 1 other patient reported a 2-week antiretroviral inter- (22%) and RBV dose in 30 patients (43%). Forty-five patients ruption leading to a viral rebound at week 60. Three patients (65%) received EPO and 16 (23%) required red blood cell presented oral candidiasis during the study. No other opportu- (RBC) transfusion. Four patients (6%) required intermittent nistic infection occurred. The antiretroviral treatment was mod- G-CSF use. The patient with autoimmune thrombocytopenia ified in 11 patients (16%) during the study (in 7 because of AEs received corticosteroid, immunoglobulin transfusion, platelet attributed to 1 of the antiretrovirals).

Figure 2. Virological response during treatment and follow-up (modiﬁed intent-to-treat analysis with missing data counted as failure). Abbreviations: EOT, end of treatment; HCV, hepatitis C virus; SVR, sustained virological response.

1772 • CID 2014:59 (15 December) • HIV/AIDS Table 3. Sustained Virological Response Rate at 24 Weeks After Table 3 continued. Treatment According to Baseline Characteristics and Week 4

Virological Response SVR24 (n = 55 No SVR24 (n = 14 P Characteristic [80%]) [20%]) Valuea P SVR24 (n = 55 No SVR24 (n = 14 HCV RNA decrease at week 4 Characteristic [80%]) [20%]) Valuea <1 log 14 (74) 5 (26) .51 Age ≥1 log 41 (82) 9 (18) <50 y 28 (85) 5 (15) .378 Data are presented as No. (%). ≥50 y 27 (75) 9 (25) Abbreviations: ATV/r, ritonavir-boosted atazanavir; CDC, Centers for Disease Sex Control and Prevention; EFV, efavirenz; FTC, emtricitabine; HCV, hepatitis C Male 43 (78) 12 (22) .718 virus; HIV, human immunodeficiency virus; IVDU, intravenous drug user; Female 12 (86) 2 (14) RAL, raltegravir; SVR24, sustained virological response rate at 24 weeks after the end of treatment; TDF, tenofovir. Ethnicity a Fisher exact test. Black 8 (80) 2 (20) .999 Downloaded from https://academic.oup.com/cid/article/59/12/1768/2895305 by guest on 01 October 2021 Other than 47 (80) 12 (20) black IVDU The CD4 count decreased from a median of 630 cells/µL Yes 29 (74) 10 (26) .242 (IQR, 456–736 cells/µL) at baseline to 263 cells/µL (IQR, No 26 (87) 4 (13) 194–403 cells/µL) at week 16 and 282 cells/µL (IQR, 230–415 HIV infection CDC stage cells/µL) at week 48, and returned to baseline level at week 52 A/B 44 (79) 12 (21) .999 (519 cells/µL [IQR, 348–687 cells/µL]). Thirteen patients (19%) C 11 (85) 2 (15) presented a conﬁrmed CD4 count <200 cells/µL during the CD4 cells/µL study and 7 (10%) required the introduction of Pneumocystis <350 6 (60) 4 (40) .109 prophylaxis. ≥350 49 (83) 10 (17) Antiretroviral treatment DISCUSSION TDF-FTC-ATV/r Yes 35 (81) 8 (19) .760 – No 20 (77) 6 (23) In this phase 2 trial, HIV/HCV genotype 1 coinfected patients, TDF-FTC-EFV who had previously failed peg-IFN/RBV, reached SVR24 in 80% Yes 12 (75) 4 (25) .724 of cases, despite a discontinuation rate of 20% due to toxicity. No 43 (81) 10 (19) This elevated SVR rate was similar to that observed in both TDF-FTC-RAL naive monoinfected (80%) [17, 21, 22] and naive HIV/HCV- Yes 10 (71) 4 (29) .460 coinfected patients (74%) [24]. This elevated SVR rate was rath- No 45 (82) 10 (18) er unexpected as the SVR rate in HIV/HCV-coinfected patients HCV genotype treated with peg-IFN/RBV was known to be lower than that in 1a 36 (75) 12 (25) .199 monoinfected subjects [9, 11, 30]. A higher SVR12 rate in HIV/ 1b 19 (90) 2 (10) HCV-coinfected patients (60.6%) treated with triple therapy as Log HCV RNA, IU/mL <6 15 (71) 6 (29) .332 ≥6 40 (83) 8 (17) Table 4. Treatment-Emergent Adverse Events (N = 69) IL28B polymorphism (n = 68) CC 17 (81) 4 (19) .856 Total Adverse Grade 4 Adverse CT 26 (76) 8 (24) Adverse Event Eventsa Events TT 11 (85) 2 (15) Anemia 46 (67%) 7 (10%) Fibrosis score (METAVIR) Asthenia 39 (57%) . . . F1–F2 34 (81) 8 (19) .767 Pruritus 32 (46%) . . . F3–F4 21 (78) 6 (22) Dry skin 24 (35%) . . . Response to previous HCV treatment Decreased appetite 18 (26%) . . . Relapse 20 (74) 7 (26) .097 Thrombocytopenia 17 (25%) 1 (1%) Breakthrough 5 (83) 1 (17) Nausea 16 (23%) . . . Partial 15 (100) 0 (0) responder Data are presented as No. (%). Adverse events that occurred in >20% of patients are listed. Null responder 15 (71) 6 (29) a Adverse events of any grade collected until the end of the study.

HIV/AIDS • CID 2014:59 (15 December) • 1773 Table 5. Hematological Toxicity and Treatment Management In the absence of a controlled group, we cannot conclude on During the Study (N = 69) the true beneﬁt of the lead-in phase in our population. In the absence of reference data, the duration of treatment Event/Intervention No. (%) was extended to 72 weeks in patients presenting a partial

Grade 4 AE 14 (20) RVR8. This situation occurred in only 3 patients, of whom Hematological 11 (16) one relapsed after ending treatment at week 48, leading us to Psychiatric 1 (1.4) conclude that there was little benefit, if any, in such an extended Cutaneous 0 (0) treatment. Infectious 2 (3) In the present study, factors usually associated with virolog- Death 2 (3) ical response such as IL28B polymorphism, HCV subtype, Grade 4 anemia (<6.5 g/dL) 4 (6) fibrosis stage, baseline treatment status, and virological response EPO use 45 (65) RBC transfusion 16 (23) during the lead-in phase had no clear-cut impact on treatment 9 response. The limited impact of IL28B polymorphism was al- Grade 4 neutropenia (<0.50 × 10 /L) 3 (4) Downloaded from https://academic.oup.com/cid/article/59/12/1768/2895305 by guest on 01 October 2021 G-CSF use 4 (6) ready described in telaprevir-treated monoinfected patients Grade 4 thrombocytopenia (<20 × 109/L) 1 (1.4) with prior treatment failure [32] and seems to be confirmed in TPO-R agonist use 1 (1.4) coinfected patients. As already reported [19, 22], patients with Platelet transfusion 1 (1.4) HCV subtype 1b tended to achieve slightly higher SVR rates Telaprevir dose reduction 4 (6) than those with HCV subtype 1a, as well as previous partial re- Peg-IFN dose reduction 15 (22) sponders compared with other patients, although the differences RBV dose reduction 30 (43) did not reach statistical significance, probably because of a limited Treatment Interruption Failure AE number of patients. A possible explanation for the lack of associ- – Week 0 week 16 1 (1.4) 7 (10) ation between fibrosis stage and treatment response in our study After week 16 3 (4) 7 (10) is that cirrhotic patients with previous null response were exclud- Abbreviations: AE, adverse event; EPO, erythropoietin; G-CSF, granulocyte ed from the analysis, whereas previous null response was present colony-stimulating factor; IFN, interferon; RBC, red blood cell; RBV, ribavirin; TPO-R, thrombopoietin receptor. in about 30% of patients without cirrhosis. Tolerance was rather poor, with 20% of patients discontinu- ing treatment because of AEs. However, no unexpected toxicity or drug interactions occurred, and the observed safety was con- compared with HCV-monoinfected (42.2%) patients was previ- sistent with that previously observed in monoinfected patients ously observed in a retrospective study [31]. However, SVR rate treated with telaprevir-based regimen [33]. The most frequent in HCV-monoinfected patients was unusually low in this study, AEs were consistent with common AEs observed during peg- and closer to SVR rates observed among patients treated with IFN/RBV combination therapy. A significant hematological peg-IFN/RBV than to those expected with triple therapy. toxicity resulting in treatment withdrawal was observed in Several hypotheses may explain our elevated SVR rate. HIV- 16% of patients despite a proactive management of anemia. infected patients are accustomed to taking antiretroviral treat- Moreover, 70% of patients required EPO, blood transfusion, ment and could be more observant than unselected monoin- or RBV dose reduction for severe anemia. Two patients died fected patients. It is also possible that previously treated during the study, the first at week 40 from an intracerebral hem- patients were highly motivated for undergoing a new treatment, orrhage secondary to autoimmune thrombocytopenia while re- hereby showing optimal treatment adherence. The inclusion of ceiving peg-IFN/RBV. Autoimmune thrombocytopenia [34, 35] patients who have failed a previous treatment may have also se- is a known but unusual complication of IFN therapy, leading to lected patients with a good tolerance to peg-IFN/RBV. Even prolonged and difficult-to-treat peripheral thrombocytopenia, though patients with cirrhosis or a previous null response different from the central thrombocytopenia observed with in- were allowed to enter the study, patients with both conditions terferon, mostly in cirrhotic patients [36]. Because the onset of were excluded, and we cannot draw conclusions on the response thrombocytopenia in this patient occurred several months fol- rate in this population. The proactive management of anemia lowing the interruption of telaprevir, we believe that this AE was could also have contributed to the high SVR rate in our probably secondary to IFN and was not related to telaprevir. study, by maintaining high concentrations of RBV. The other patient died at week 55, several months after inter- Unlike with boceprevir, a lead-in phase is unusual with telap- ruption of peg-IFN/RBV, from a sudden upper gastrointestinal revir, although a nonsignificantly higher SVR rate was observed hemorrhage, presumed to be a complication of portal hyperten- with a lead-in phase (88%), compared with the standard regi- sion in a cirrhotic patient. Unlike in the Compassionate Use men (83%), in the retreatment of monoinfected patients [19]. of Protease Inhibitors in Viral C Cirrhosis study [37], the rate

1774 • CID 2014:59 (15 December) • HIV/AIDS of AEs was similar between cirrhotic and noncirrhotic pat- Gilead; personal fees from Janssen, MSD, Gilead, and BMS; and nonfinan- ients, which could be explained by the exclusion of patients cial support from BMS and Abbott. All other authors report no potential conflicts. with history of cirrhotic decompensation and Child-Pugh All authors have submitted the ICMJE Form for Disclosure of Potential score B or C. Conflicts of Interest. Conflicts that the editors consider relevant to the con- The strength of this study is that a large set of cART regimens tent of the manuscript have been disclosed. were allowed as interaction data between telaprevir and most References of the currently used antiretrovirals were available. Even for antiretrovirals with known interactions, dosage adaptation had 1. Pol S, Soriano V. 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The authors gratefully thank the patients and their patients failing a previous standard interferon-based regimen. J Antimi- families; Dr Isabelle Fournier from INSERM SC10; and Ms Ventzislava crob Chemother 2008; 62:793–6. Petrov-Sanchez from ANRS. 13. Labarga P, Vispo E, Barreiro P, et al. Rate and predictors of success in Financial support. This work was supported by ANRS. Janssen-Cilag the retreatment of chronic hepatitis C virus in HIV/hepatitis C virus co- provided telaprevir. infected patients with prior nonresponse or relapse. J Acquir Immune Potential conflicts of interest. L. C. has received research grants from Defic Syndr 2010; 53:364–8. MSD and ViiV; personal fees from Mylan; and nonfinancial support from 14. Myers RP, Benhamou Y, Bochet M, Thibault V, Mehri D, Poynard T. MSD, ViiV, Janssen, Gilead, and BMS. M.-A. V. has received personal fees Pegylated interferon alpha 2b and ribavirin in HIV/hepatitis C virus- from Janssen, Gilead, ViiV, and BMS, and nonfinancial support from Jans- co-infected non-responders and relapsers to IFN-based therapy. AIDS sen and MSD. P. S. has received personal fees from Janssen, MSD, Gilead, 2004; 18:75–9. BMS, and Mayoly-Spindler, and nonfinancial support from Janssen, MSD, 15. Rodriguez-Torres M, Rodriguez-Orengo JF, Rios-Bedoya CF, et al. Effi- Gilead, Roche, and Mayoly-Spindler. K. L. has received research grants from cacy and safety of peg-IFN alfa-2a with ribavirin for the treatment of Janssen and personal fees from Janssen, Gilead, BMS, MSD, AbbVie, and HCV/HIV coinfected patients who failed previous IFN based therapy. ViiV. H. A. has received personal fees from Gilead and Janssen, and nonfi- J Clin Virol 2007; 38:32–8. nancial support from Gilead, Janssen, Merck, Roche, Sanofi-Pasteur, and 16. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated ViiV. P. d. T. has received research grants from BMS; nonfinancial support chronic HCV genotype-1 infection. N Engl J Med 2011; 364:1207–17. from Gilead, MSD, ViiV, Janssen, and BMS; and other support from 17. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previ- AbbVie. P. M. has received personal fees from ViiV, BMS, Gilead, Abbott, ously untreated chronic hepatitis C virus infection. N Engl J Med 2011; MSD, and Janssen. J.-M. M. has received grants from ANRS, MSD, and 364:2405–16.

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