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  IAS 2013: 7th IAS Conference on HIV
Pathogenesis Treatment and Prevention
June 30 - July 3 2013
Kuala Lumpur, Malaysia
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Telaprevir Regimen for HIV/HCV Patients With PegIFN/RBV Failure and Cirrhosis
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7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur
Mark Mascolini
After 24 weeks of telaprevir plus pegylated interferon and ribavirin (PR), HCV RNA fell below 12 IU/mL in 11 of 20 HIV-positive people HCV genotype 1, prior PR failure, and sometimes cirrhosis [1,2]. Undetectable HCV RNA at week 24 predicted early virologic response.
Combining an HCV protease inhibitor--telaprevir or boceprevir--with PR has increased sustained virologic response rates 30% in previously untreated people. But the impact of these new agents on HCV genotype 1 patients with advanced liver disease, HIV infection, and/or previous PR failure remains uncertain. To address these questions, researchers at two Paris hospitals analyzed the impact of telaprevir/PR in HIV-positive people usually also taking regimens based on efavirenz, raltegravir, or atazanavir.
Eighteen of 20 study participants were men, and median age stood at 52 years (interquartile range [IQR] 49 to 54). Median estimated HIV duration was 22.8 years (IQR 17.8 to 25.4), median nadir and current CD4 count 146 and 449, and median viral load 20 copies. Only 2 people were not taking antiretrovirals. Median estimated HCV duration stood at 15.4 years (IQR 11.2 to 18.3), 17 people had HCV 1a and 2 had HCV 1b. Ten people had no response to previous PR, 7 had a partial response, and 3 had a response and relapse. Fifteen people had METAVIR F4, indicating cirrhosis. None of these variables differed significantly between people who did or did not have an undetectable HCV load at week 24.
By intention-to-treat analysis, proportions of people with undetectable HCV RNA were 35.3% at week 2, 55% at week 4, 65% at week 12, and 55% at week 24. Half of study participants had extended rapid virologic response (undetectable HCV RNA at weeks 4 and 12). An undetectable HCV load at week 12 (HCV RNA below 12 IU/mL) was the only significant predictor of week-24 response (P < 0.001). All 9 people with virologic failure had HCV genotype 1a, and telaprevir-associated resistance mutations arose in all of them. The double mutations V36M/R155K emerged in 6 people before week 24.
Despite rapid virologic response, 1 person stopped HCV therapy at week 8 because of psychiatric adverse events. Grade 3/4 adverse events were evenly distributed between the 11 week-24 responders and the 9 nonresponders: anemia (1 and 0), thrombocytopenia (2 and 2), leukopenia (3 and 1), neutropenia (0 and 1), and rash (0 and 0). Substantial drops in platelet count and hemoglobin required use of growth factor in 11 people.
HIV RNA could be detected at a level above 20 copies in 3 of 18 antiretroviral-treated people when telaprevir therapy began (31 to 42 copies), in none at week 12, and in 1 at week 24 (50 copies). Median CD4 count fell in antiretroviral-treated people from 410 at week 0 to 259 at week 24.
The researchers noted that the 55% week-24 virologic response rate in their patients is lower than a 71% response rate reported in HIV/HCV-coinfected people with no PR history before starting telaprevir [3]. But the response rate in this study is similar to that seen in HCV-1-monoinfected people with bridging fibrosis or cirrhosis [4,5].
The Paris team stressed that the types of patients in this analysis are usually excluded from clinical trials. Because "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," they proposed, "telaprevir may represent an appropriate therapeutic strategy."
1. Lacombe K, Valin N, Stitou H, et al. Efficacy and tolerance of telaprevir in HIV-HCV genotype 1 co-infected patients failing previous anti-HCV therapy: 24-week results. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur. Abstract WEPE485.
2. Lacombe K, Valin N, Stitou H, et al. Efficacy and tolerance of telaprevir in HIV-hepatitis C virus genotype 1-coinfected patients failing previous antihepatitis C virus therapy: 24-week results. AIDS. 2013;27:1356-1359.
3. Sherman K, Rockstroh J, Dieterich D, et al. Telaprevir combination with peginterferon alfa-2a/ribavirin in HCV/HIV coinfected patients: 24-week treatment interim analysis. 62nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD). November 4-8, 2011. San Francisco. Abstract LB-8.
4. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417-2428.
5. Colombo M, Fernandez I, Abdurakhmanov D, et al. Treatment of hepatitis C genotype 1 patients with severe fibrosis or compensated cirrhosis: the International Telaprevir Early Access Program. 63rd Annual Meeting of the Association for the Study of Liver Diseases. November 9-13, 2012. Boston. Abstract LB15.
AIDS May 2013
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, Joele; Thibault, Vincentf; Boyd, Andersc; Poirier, Jean-Marieg; Meynard, Jean-Lucb; Valantin, Marc-Antoined,h; Bottero, Juliea,b,c; Girard, Pierre-Mariea,b,c aUniversite Pierre et Marie CuriebService de Maladies Infectieuses et Tropicales, Hopitaux Universitaires de l'Est Parisien, Hopital Saint-AntoinecInserm UMR-S707dService de Maladies Infectieuses et Tropicales, Groupe Hospitalier Pitie-SalpetriereeService de Bacteriologie-Virologie, Hopitaux Universitaires de l'Est Parisien, Hopital Saint-AntoinefService de Bacteriologie-Virologie, Groupe Hospitalier Pitie-SalpetrieregService de Pharmacologie, Hopitaux Universitaires de l'Est Parisien, Hopital Saint-AntoinehInserm UMR-S943, Paris, France.
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 (Hopital Saint-Antoine, Hopital Pitie-Salpetriere). 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 (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 (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).
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.