Sustained long-term antiviral maintenance therapy in HCV/HIV-coinfected patients (SLAM-C)

Abstract

Background: Hepatitis C virus (HCV)/HIV coinfection treatment is suboptimal with low sustained viral response rates to standard therapies. A multicenter randomized clinical trial designed to assess the efficacy/safety of pegylated interferon maintenance therapy was performed by the National Institutes of Health-funded AIDS Clinical Trials Group network.

Methods: HCV treatment-naive and nonresponding interferon-experienced subjects with confirmed HCV and HIV, CD4 >200 cells per cubic millimeter, and at least stage 1 fibrosis were enrolled and treated for 12 weeks with pegylated interferon alfa 2a 180 mcg per week (PEG) + weight-based ribavirin to determine response status. Nonresponder subjects (failure to clear HCV RNA or achieve 2-log drop) underwent liver biopsy and were randomized to receive full dose PEG or observation only for 72 weeks. Paired biopsies were evaluated by a central pathologist.

Results: Three hundred thirty subjects were enrolled; median age was 48 years; 43% white, 37% black, non-Hispanic; 83% male; CD4+ 498 cells per cubic millimeter; 32% were interferon experienced; 74% had entry HIV RNA <50 copies per milliliter. early virologic responder was observed in 55.9% and 42.5% achieved complete Early Viral Response (cEVR). A planned interim analysis of occurred when 84 subjects were randomized. With data on 40 paired biopsies available, a safety monitoring board stopped the trial due to lack of fibrosis progression (median = 0 Metavir units/year) in the observation arm.

Conclusions: Lack of fibrotic progression in the control arm was unexpected and may represent a short-term PEG/ribavirin therapy effect, high levels of HIV viral suppression, and use of antiretroviral regimens that may be less toxic than prior generations of therapy.

Trial registration: ClinicalTrials.gov NCT00078403.

Figure 1

Study Schema * denotes direct entry of nonresponders from comparable non-study treatments, or roll-back of nonresponders from Step 1

Figure 2

Early viral response rates (%) by race. EVR represents either 2 log drop in HCV viral load from baseline at 12 weeks of treatment or viral undetectable at 12 weeks. cEVR refers to subjects who were HCV undetectable (<600 IU/ml HCV RNA). p values by Fisher’s exact test.

Figure 3

Bubble-plot of absolute change in Metavir fibrosis score for subjects in Step 2, randomized to receive either pegylated interferon alfa for 72 weeks or observation as untreated controls. Paired biopsies compared in blinded manner by single pathologist. Composite change in fibrosis score shown. Bubble size is proportionate to number of subjects.

Figure 4

Subject outcomes during course of clinical trial accounting for all randomized subjects. Step 2 entry total does not include direct admission/rollback subjects (n=5) or 1 misclassified subject as described in text.

Figure 5

Toxicity grades during Step 2. Total numbers of patients with all toxicities greater than Grade 1 during course of pegylated interferon maintenance vs. observation control arm.