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 . 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 . 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 , amino acid substitutions in HCV protease were examined by direct sequencing following PCR-amplification of the NS3 encoding region, between nucleotides 3309 and 4054 . 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 (http://www.geno2pheno.org). In ARV-treated patients, EFV/ATZ/RAL trough concentrations were measured after a 12-h fast by high-performance liquid chromatography at TVR initiation (C min0), and then twice after TVR initiation (week 4 = C min1, week 12 = C min2). Variation in concentrations before and after TVR initiation was defined as [(C min1+C min2)/2]/C min0. Adverse events were graded according to AIDS Clinical Trial Group classification . 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) . 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).
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 C min = 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 . 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 . Recent drugs, such as sofosbuvir, have also shown similar early-treatment HCV kinetics between treatment-naive HIV-HCV and HCV-infected patients . 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  and a 5% discontinuation rate due to rashes . 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.
Conflicts of interest
There are no conflict of interest.
1. Sulkowski M, Sherman K, Soriano V, Rockstroh J, Dieterich D, Girard P, et al.Telaprevir in combination with peginterferon alfa-2a/ribavirin in HCV/HIV co-infected patients: SVR24 final study results. The 63rd Annual Meeting of the Association for the Study of Liver Diseases
; 9–13 November 2012Boston, MA, USA.
2. Boceprevir + pegylated interferon + ribavirin for the treatment of HCV/HIV-co-infected patients: end of treatment (week-48) interim results.
Conference on Retroviruses and Opportunistic Infections Abst. #47; 5–8 March 2012; Seattle, USA.
3. Lacombe K, Rockstroh J. HIV and viral hepatitis coinfections: advances and challenges
2012; 61 (Suppl 1):i47–i58.
4. EACS. European AIDS Clinical Society, GuidelinesVersion 6; October 2011.
5. Thomas DL, Bartlett JG, Peters MG, Sherman KE, Sulkowski MS, Pham PA. Provisional guidance on the use of hepatitis C virus protease inhibitors for treatment of hepatitis C in HIV-infected persons
. Clin Infect Dis
6. Colson P, Brouk N, Lembo F, Castellani P, Tamalet C, Gerolami R. Natural presence of substitution R155K within hepatitis C virus NS3 protease from a treatment-naive chronically infected patient
8. Sherman K, J Rockstroh, Dieterich D, V Soriano, P Girard, McCallister S, et al. Telaprevir combination with peginterferon alfa-2a/ribavirin in HCV/HIV coinfected patients: 24-week treatment interim analysis
[abstract LB-8]. 62nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD).
San Francisco, USA; 4–8 November 2011.
9. Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, et al. Telaprevir for retreatment of HCV infection
. N Engl J Med
10. Treatment of hepatitis C genotype 1 patients with severe fibrosis or compensated cirrhosis: the International Telaprevir Early Access Program. Abstract #LB15.
The 63rd Annual Meeting of the Association for the Study of Liver Diseases; 9–13 November, Boston, MA, USA; 2012.
11. Does HIV infection reduce initial safety and efficacy of boceprevir (BOC) or telaprevir (TPV)-based initial therapy in cirrhotic patients in the ‘real life’? Abstract S07.
The 63rd Annual Meeting of the Association for the Study of Liver Diseases; 9–13 November, Boston, MA, USA; 2012.
12. HIV/HCV coinfected and HCV monoinfected patients have similar early HCV viral kinetics with the potent HCV nucleotide polymerase inhibitor sofosbuvir (SOF). Abstract H1921a.
52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012); 9–12 September, San Francisco, USA; 2012.
13. De Meyer S, Dierynck I, Ghys A, Beumont M, Daems B, Van Baelen B, et al. Characterization of telaprevir treatment outcomes and resistance in patients with prior treatment failure: results from the REALIZE trial
14. Kieffer TL, De Meyer S, Bartels DJ, Sullivan JC, Zhang EZ, Tigges A, et al. Hepatitis C viral evolution in genotype 1 treatment-naive and treatment-experienced patients receiving telaprevir-based therapy in clinical trials
. PLoS One
15. Bartels DJ, Zhou Y, Zhang EZ, Marcial M, Byrn RA, Pfeiffer T, et al. Natural prevalence of hepatitis C virus variants with decreased sensitivity to NS3.4A protease inhibitors in treatment-naive subjects
. J Infect Dis
16. Safety and efficacy of telaprevir or boceprevir in combination with peginterferon alfa/ribavirin, in 455 cirrhotic non responders. Week 16 analysis of the French Early Access Program (ANRS CO20-CUPIC) in real-life setting.
The 63rd Annual Meeting of the Association for the study of Liver Diseases; 9–13 November, Boston, MA, USA; 2012.
17. Picard O, Cacoub P. Dermatological adverse effects during genotype-1 hepatitis C treatment with the protease inhibitors telaprevir and boceprevir. Patient management
. Clin Res Hepatol Gastroenterol
18. Cacoub P, Bourliere M, Lubbe J, Dupin N, Buggisch P, Dusheiko G, et al. Dermatological side effects of hepatitis C and its treatment: patient management in the era of direct-acting antivirals
. J Hepatol