Genomic Analysis of Hepatitis C Viral Factors Related to IFN Response in HIV-Coinfected Patients

1BOLCIC F, 2BULL L, 2MARTINEZ L, 1SALOMON H, 2ARDUINO R, 2BARNETT B, 1QUARLERI J.

Mexico

Conferencia; XVII International AIDS Conference; 2008

IAS

Background: Interferon-based treatment is the standard therapy for chronic hepatitis C virus (HCV) in HIV+ patients. We explored the role of two HCV genomic regions in the response to IFN among HIV/HCV co-infected patients. Using a retrospective, homogenous cohort, we assessed the frequency of E2 and NS5A mutations among patients with and without sustained virological response (SVR) to IFN-based therapy. Methods: We identified 7 HCV/HIV co-infected patients treated with IFN and ribavirin combination therapy. Among them, 4 achieved SVR (48 weeks therapy), 3 were non-responders (NRs). HCV genomic analysis was assessed at 2 time points in HCV viremic patients: baseline and week 12 post-therapy initiation. HCV genotype (based on 5’NCR+NS5B phylogenetic relatedness) and E2 and NS5A genomic analysis were performed in two compartments: plasma and peripheral blood mononuclear cells. We explored carboxy-terminal mutations of E2, including PKR/eIF2alpha phosphorylation homology domain (PePHD), and protein kinase-binding domain mutations of nonstructural 5A (PKRBD). Results: Patients with SVR were infected with HCV genotype Gt-1 (n=3) and Gt-4 (n=1); patients with NR were infected with Gt-1 (n=4) and Gt-2 (n=1). Genotype distribution was the same in both compartments. HCV from both groups of patients showed E2-PePHD and NS5A-PKRBD mutations at baseline and at week 12 of treatment. The frequency of mutations from baseline to week 12 was similar in the E2-PePHD region among both groups, but it was higher in the NS5A-PKRBD region among NRs. The number of mutations was higher in NRs for both genomic regions. Interestingly, both groups of patients exhibited HCV with conserved E2/NS5A genomic variations in both studied compartments at the two time points examined. At baseline, no statistically significant differences were found among CD4+ and CD8+ T cells counts or HIV and HCV viral loads among studied patients (p>0.05). Conclusions: The frequency of mutations in defined regions of HCV envelope 2 (E2) PePHD and nonstructural 5A (NS5A) protein (PKRBD) appear neither to influence the capacity of IFN-alpha to block HCV replication nor to reliably predict the treatment outcome in HIV/HCV co-infected patients.