Clinical trial NCT01482767
Conditions: HIV Infections Hepatitis C
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2012-04-01; Completion date: 2015-04-01
Enrollment: 262 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Hepatitis C virus (HCV) infection is a leading cause of death and illness in people with HIV-1. At the time the study was designed, the standard treatment for people with HIV-1 and HCV coinfection included two drugs: pegylated-interferon alfa 2b (PEG-IFN) and ribavirin (RBV). The purpose of this study was to evaluate the effectiveness of giving boceprevir (BOC) together with standard treatment in treating HCV infection in people with HIV-1 and HCV coinfection.

Detailed description:
For HIV-1-infected individuals, HCV infection is a leading cause of morbidity and mortality, and the prevalence of HCV infection is higher among those infected with HIV-1. At the time the study was designed, the standard-of-care (SOC) therapy for HCV infection was treatment with both PEG-IFN and RBV. This therapy is 40%-45% effective in patients with HCV infection but is significantly less effective in patients with both HCV and HIV-1 (Shire et al. J Viral Hepat., 2007). The purpose of this study was to evaluate the effectiveness of adding BOC (Kwo et al. Lancet, 2010), an HCV protease inhibitor, to SOC therapy in treating HCV infection (genotype 1) in HCV/HIV-1-coinfected adults.

Participants were enrolled into one of two groups based on previous HCV treatment experience.

1. Group A: HCV treatment-naive participants who had never received treatment with PEG-IFN or experimental agents used to treat HCV, with or without RBV (N=170, refer to the note below).
2. Group B: HCV treatment-experienced participants who had received any treatment with standard interferon or with PEG-IFN with or without RBV, provided the last dose of treatment was 90 days or more before study entry (N=140, refer to the note below).

Note: The team correspondence with the FDA led to an amendment to close enrollment in December 2013, prior to the target sample sizes of 170 in Group A and 140 in Group B, as the study power could be lowered while still meeting the key study objectives.

All participants had to be on stable antiretroviral therapy (ART) for at least 8 weeks prior to study entry using a dual nucleos(t)ide reverse transcriptase inhibitor (NRTI) backbone plus one of the following: efavirenz (EFV), raltegravir (RAL), lopinavir (LPV)/ritonavir (RTV) 400/100 mg twice daily, atazanavir (ATV)/RTV, darunavir (DRV)/RTV 600/100 mg twice daily OR must not have received any ART for at least 4 weeks immediately prior to entry. Participation in this study lasted approximately 72 weeks.

HCV treatment-naive participants (Group A) were treated with PEG-IFN and RBV for 4 weeks (lead-in). Then BOC was added to the treatment regimen (triple therapy). Cirrhotic participants received 44 weeks of triple therapy. Among non-cirrhotics, the Week 8 HCV RNA was used to determine total duration of therapy. Those who had undetectable HCV RNA at Week 8 completed therapy at Week 28. Those with detectable HCV RNA at Week 8 received 32 weeks of triple therapy followed by 12 additional weeks of double-drug therapy with PEG-IFN/RBV. HCV treatment-experienced participants (Group B) also had a lead-in followed by 32 weeks of triple therapy and 12 weeks of PEG-IFN/RBV double therapy if non-cirrhotic, or by 44 weeks of triple therapy if cirrhotic.

Treatment was to be discontinued due to HCV virologic failure if:

1. HCV RNA ≥100 IU/mL at Week 12,
2. detectable HCV RNA at Week 24, or
3. confirmed HCV RNA \>1000 IU/mL any time after Week 12.

Undetectable HCV RNA was defined as below the lower limit of quantification (LLOQ) and target not detected (TND) by Roche COBAS® TaqMan® HCV Test v2.0.

Study visits were scheduled at screening and at Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24 and 28 for both study groups. Group A participants who completed treatment at Week 28 had further study visits at Weeks 40, 52, 60, and 72. Participants who were prescribed 48-weeks of therapy (Group A and Group B) had further study visits at Weeks 32, 36, 40, 44, 48, 60, and 72. At each visit, a physical examination and blood collection were conducted. Participants also completed an HCV treatment adherence questionnaire. Select visits included urine collection and pregnancy testing (for women of reproductive potential). Plasma, serum, and peripheral blood mononuclear cells (PBMCs) were be stored for use in future studies. After experiencing HCV virologic failure as defined above or premature treatment discontinuation due to safety or other reasons, participants were followed on a separate schedule of events with visits every 12 weeks from Week 24 to 72. The evaluations at these follow-up visits were limited to safety evaluations and stored plasma/serum sample collection.

The A5294 study consisted of single-arm evaluations to assess the efficacy of BOC added to PEG-IFN/RBV in the two study populations:

1. HCV treatment-naive participants (Group A)
2. HCV treatment-experienced participants (Group B).

The two study populations were addressed together in this single trial - rather than in two separate trials - mainly for administrative efficiency. The analyses were conducted separately for each Study Group. The study was not designed for comparison. The pooled summaries for Baseline Characteristics provided in the Results Section in this record were prepared solely for the ClinicalTrials.gov results submission.

Arms: arm 1: Participants were prescribed a lead-in with PEG-IFN and RBV for 4 weeks. After the lead-in, BOC was added. Cirrhotic participants received 44 weeks of triple therapy (BOC+PEG-IFN+RBV). Among non-cirrhotics, the Week 8 HCV RNA was used to determine total duration of therapy. Those who had undetectable HCV RNA at Week 8 completed therapy at Week 28. Those with detectable HCV RNA at Week 8 received 32 weeks of triple therapy followed by 12 additional weeks of PEG-IFN+RBV. arm 2: Participants were prescribed a lead-in with PEG-IFN and RBV for 4 weeks. After the lead-in, BOC was added. Cirrhotic participants received 44 weeks of triple therapy (BOC+PEG-IFN+RBV), and non-cirrhotics received 32 weeks of triple therapy followed by 12 additional weeks of PEG-IFN+RBV.
Interventions: intervention 1: Pegylated-Interferon Alfa 2b (PEG-IFN) intervention 2: Ribavirin (RBV) intervention 3: Boceprevir (BOC)
Intervention descriptions: intervention 1: 1.5 mcg/kg subcutaneously (SC) once a week (based on participant's weight at entry) for up to 48 weeks depending on cirrhosis status and, in Group A, Week 8 HCV viral response. intervention 2: 800-1400 mg orally per day with food (based on participant's weight at entry) for up to 48 weeks depending on cirrhosis status and, in Group A, Week 8 HCV viral response. intervention 3: 800 mg orally every 8 hours with food from Week 5 to up to Week 48 depending on cirrhosis status and, in Group A, Week 8 HCV viral response

Protocol documents: