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doi: 10.1097/QAD.0b013e32836138d0
Research letters

Efficacy and tolerance of telaprevir in HIV-hepatitis C virus genotype 1-coinfected patients failing previous antihepatitis C virus therapy: 24-week results

Lacombe, Karinea,b,c; Valin, Nadiab; Stitou, Hindd; Gozlan, Joële; Thibault, Vincentf; Boyd, Andersc; Poirier, Jean-Marieg; Meynard, Jean-Lucb; Valantin, Marc-Antoined,h; Bottero, Juliea,b,c; Girard, Pierre-Mariea,b,c

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aUniversité Pierre et Marie Curie

bService de Maladies Infectieuses et Tropicales, Hôpitaux Universitaires de l’Est Parisien, Hôpital Saint-Antoine

cInserm UMR-S707

dService de Maladies Infectieuses et Tropicales, Groupe Hospitalier Pitié-Salpêtrière

eService de Bactériologie-Virologie, Hôpitaux Universitaires de l’Est Parisien, Hôpital Saint-Antoine

fService de Bactériologie-Virologie, Groupe Hospitalier Pitié-Salpêtrière

gService de Pharmacologie, Hôpitaux Universitaires de l’Est Parisien, Hôpital Saint-Antoine

hInserm UMR-S943, Paris, France.

Correspondence to Dr Karine Lacombe, MD, PhD, Service de Maladies Infectieuses et Tropicales, Hôpital Saint-Antoine, 184 rue du Fbg Saint-Antoine, 75012 Paris, France. Tel: +33 1 49283137; fax: +33 1 49282149; e-mail:

Received 23 January, 2013

Revised 13 March, 2013

Accepted 13 March, 2013

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The efficacy and tolerance of telaprevir (TVR) was examined in 20 mostly cirrhotic HIV-hepatitis C genotype 1 (HCV-G1)-infected patients failing previous treatment with pegylated-interferon and ribavirin (PR). HCV-RNA less than 12 IU/ml was observed in 35.3% of patients at W2, 55.0% at W4, 65.0% at W12 and 55.0% at W24. All patients with virological failure (n = 9) exhibited V36M/R155K mutations. Early virological response was a determinant of HCV-RNA less than 12 IU/ml at W24 (P < 0.001). No grade 3–4 dermatological side-effects were reported. TVR-PR tritherapy appeared to be rather effective and well tolerated among difficult-to-treat HIV-HCV-G1 patients.

Direct antiviral agents (DAAs) targeting hepatitis C virus (HCV) protease activity have triggered a major shift in treating HCV genotype 1 (G1) infection. In HCV-HIV coinfected patients, boceprevir (BOC) or telaprevir (TVR) with pegylated-interferon (pegylated-interferon and ribavirin) has led to a 30% increase in sustained virological response rates in treatment-naive patients [1,2]. However, these results may not apply to more difficult-to-treat populations, such as cirrhotic, HIV-infected patients failing previous treatment with pegylated-interferon and ribavirin [3]. The primary objective of the study herein was to evaluate the efficacy and tolerance during 24 weeks of TVR-based tritherapy in HIV-HCV G1-coinfected patients previously treated with pegylated-interferon and ribavirin.

From December 2011 to May 2012, HIV-HCV G1-infected patients receiving TVR [1125 mg three times daily (t.i.d.) with efavirenz (EFV); 750 mg t.i.d. with raltegravir (RAL), atazanavir (ATZ), or without antiretroviral (ARV) therapy], PegIFNα2 (180 μg/week), and ribavirin (1000 mg/day < 75 kg, 1200 mg/day ≥75 kg) were recruited from two outpatient clinics in Paris, France (Hôpital Saint-Antoine, Hôpital Pitié-Salpêtrière). All patients had provided signed informed consent, in accordance with the Helsinki Declaration. At inclusion, response to previous pegylated-interferon and ribavirin treatment was defined according to European AIDS Clinical Society guidelines [4]. HCV-RNA was measured using the Abbott RealTime HCV assay (detection limit: <12 IU/ml) and Il28B polymorphism using the LightMix Il28B kit. In patients failing TVR-based therapy [5], amino acid substitutions in HCV protease were examined by direct sequencing following PCR-amplification of the NS3 encoding region, between nucleotides 3309 and 4054 [6]. A sequence editing program was used (Seqscape; Applied Biosciences, Les Ulis, France) and substitutions associated with TVR resistance further confirmed with the ‘Geno2pheno (hcv)’ tool ( In ARV-treated patients, EFV/ATZ/RAL trough concentrations were measured after a 12-h fast by high-performance liquid chromatography at TVR initiation (Cmin0), and then twice after TVR initiation (week 4 = Cmin1, week 12 = Cmin2). Variation in concentrations before and after TVR initiation was defined as [(Cmin1+Cmin2)/2]/Cmin0. Adverse events were graded according to AIDS Clinical Trial Group classification [7]. Platelet, leukocyte or erythropoietin growth factors, and blood transfusions were permitted.

The virological endpoints were the proportions of patients with undetectable HCV-RNA at W2, W4, W12, and W24. Analysis on treatment response was intention-to-treat (ITT). Determinants of HCV-RNA less than 12 UI/ml at W24 were compared between treatment response groups, while no P value adjustments for multiple comparisons were made. Statistical analysis was performed using STATA (v11.2; College Station, Texas, USA) and significance was determined as P < 0.05.

Baseline characteristics are presented in Table 1, stratified by W24 response. A previous null response was observed in 50% of patients and 75% were cirrhotic. The proportion of patients with undetectable HCV-RNA was 35.3% at W2, 55.0% at W4, 65.0% at W12, and 55.0% at W24; and 50% had extended rapid virological response (undetectable HCV-RNA at W4 and W12) [4]. Following stopping rules, nine patients ended treatment early: W4 = 3, W12 = 3, W24 = 3. One patient terminated treatment at W8 due to psychiatric adverse events despite rapid virological success. Undetectable HCV-RNA at W12 was the only significant determinant among those with versus without treatment response (P <0.001). All nine patients with virological failure harbored genotype 1a, with TVR-resistant variants appearing at the time of failure. Six double amino acid substitutions at positions V36M+R155K were the only mutations observed prior to W24. HCV population sequencing for those harboring resistant variants at the end of TVR treatment showed different mutation patterns with a potentially lower genetic barrier to TVR resistance (V36L+Q80K+R155K, R155K, or V36M+T54A).

Table 1
Table 1
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HIV-RNA was detectable (>20 copies/ml) for three ARV-treated patients at baseline (range: 31–42 copies/ml), 0 at W12, and one at W24 (50 copies/ml). Median (interquartile range, IQR) CD4+ cell counts dropped in both ARV-treated [W0: 410/μl (275–550), W24: 259/μl (202–375)] and ARV-naive patients (dropping to 289–293/μl at W24). Variation of trough concentrations ranged as follows: EFV = −46.6–17.5, ATZ = −7.2–65.3, and RAL = −93.7–688.0, observing a substantial decrease in one RAL-treated patient suspected of nonadherence (detectable HIV-RNA and Cmin = 31 ng/ml at W24).

The following grade 3–4 adverse events occurred during treatment: thrombopenia (20%), leukopenia (20%), anemia (5%), and neutropenia (5%). Accordingly, a substantial drop in platelet count and hemoglobin was observed, requiring the use of growth factors in 11 patients (erythropoietine: n = 11, eltrombopag: n = 5) and iterative blood transfusions in two patients. No grade 3–4 dermatological side-effects were reported.

In this well defined cohort, 55% responded to TVR-containing tritherapy after 24 weeks. This rate is lower than that found in previous reports in HIV-HCV-coinfected patients, with rates reaching upward of 71% in treatment-naive and less frequently cirrhotic patients [8]. In HCV-G1-monoinfected patients with higher prevalence of bridging fibrosis or cirrhosis, both early and W24 response rates in previous partial or nonresponders were closer to what was observed in our study [9,10]. Smaller studies have reported no difference in early treatment response according to HIV status [11]. Recent drugs, such as sofosbuvir, have also shown similar early-treatment HCV kinetics between treatment-naive HIV-HCV and HCV-infected patients [12]. Patients experiencing virological failure exhibited the V36M+R155K double mutant, common in genotype 1a-infected individuals experiencing ‘on-treatment’ failure [13,14]. As expected, no 1b subtype-infected patient selected this mutation. Although baseline resistance was not assessed, it is rather uncommon and cannot rule out TVR therapeutic success [15,13]. Hematologic tolerance also appeared to be reasonable, as both rates of grade 3–4 hematological adverse events and/or use of growth factors seemed to be lower than those in cirrhotic HCV G1-monoinfected patients [1,10,16]. Importantly, no grade 3 or 4 rash was reported in our study, compared to 7.4% among HCV-monoinfected patients [16] and a 5% discontinuation rate due to rashes [10]. Better TVR tolerance among HIV-HCV-coinfected patients may be due to the lack of immune-mediated skin reactions via HIV-induced immunosuppression [17,18]. Taken together, HIV coinfection is probably not a detrimental factor toward virological response to DAAs.

In conclusion, combined TVR-PR exhibited comparatively good efficacy and tolerability, to monoinfected patients, in a difficult-to-treat population of HIV-infected patients with chronic G1 hepatitis C. Notwithstanding the small number of patients, this population is generally excluded from clinical trials, bringing into light barriers to current anti-HCV therapy. As HIV-infected, cirrhotic patients failing previous HCV therapy have a high risk of developing end-stage liver disease and may not be able to wait for newer drugs to become available, TVR may represent an appropriate therapeutic strategy.

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Conflicts of interest

There are no conflict of interest.

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