By Liz Highleyman

Given the limited efficacy and difficult side effects of interferon-based therapy for chronic hepatitis C virus (HCV) infection, researchers have explored a variety of targeted oral antiviral agents, including HCV protease inhibitors (PIs).

Many HIV-HCV coinfected patients use antiretroviral regimens containing HIV PIs, but there has been limited research looking at the effect of HIV PIs on the HCV protease enzyme. Hypothetically, HIV PIs might exert selective pressure that promotes the emergence of HCV mutations conferring resistance to investigational HCV PIs such as telaprevir (VX-950), boceprevir (SCH 503034), and ITMN-191 (also known as R7227).

In a correspondence in the August 20, 2008 issue of AIDS, French researchers reported findings from a study was to identify the natural polymorphism (variation) of the NS3 protease sequence in different HCV strains, and to compare the diversity of the HCV protease in HCV monoinfected and HIV-HCV coinfected individuals.

"Limited analysis by population sequencing has been reported for the selection of isolates with mutations within the NS3 protease that confer resistance to the HCV protease inhibitors," the authors wrote as background. "Selection of drug-resistant mutants was demonstrated by in vitro and clinical studies with HCV NS3/4A protease inhibitors. It appeared, in in vitro and in vivo studies, that mutations V36M, A71T, T72I, P88L, R155Q A156T, D168V, and V170I/M were selected that confer resistance to each protease inhibitor."

The study included 33 HCV monoinfected patients (16 with genotype 1a; 17 with genotype 1b) and 17 HIV-HCV coinfected patients (12 with genotype 1a; 5 with genotype 1b) receiving HIV PIs. Among the HIV positive patients, 7 used ritonavir-boosted atazanavir (Reyataz), 8 used boosted fosamprenavir (Agenerase), and 2 used boosted saquinavir (Invirase).

The HCV NS3 protease domain (amino acids 54-197) was amplified by reverse transcriptase PCR, and the resulting products were purified and sequenced for genotypic and phenotypic analysis of amino acid changes.

Results

In conclusion, the study authors wrote, "in this cohort of HCV [mono]infected and HIV-HCV coinfected patients, the natural strains of the NS3 protease domain related to resistance to HCV protease inhibitors were well conserved.'

"Anti-HIV protease inhibitor therapy had no influence on the mutation rate in the NS3 protease," they added. "This finding could have implications for future monitoring of HIV-HCV coinfected patients receiving anti-HCV protease inhibitors. Further studies on larger cohorts should confirm this finding."

Laboratoire Alphabio, Infectious Diseases Department, Hôpital Ambroise Paré, Marseille, France; Liver Unit Hôpital Saint-Joseph, France; Département Biostatistiques, CDL Pharma, France; Genoscience Pharma, Marseille, France.

9/26/08

Reference
P Halfon, M Bourliere, H Khiri, and others. Mutation rate in hepatitis C virus NS3 protease is not influenced by HIV-1 protease inhibitor therapy [Correspondence]. AIDS 22(13): 1694-1696. August 20, 2008.