Analysis of sequences of hepatitis C virus NS5A genotype 1 in HIV-coinfected patients with a null response to nitazoxanide or peg-interferon plus ribavirin

Abstract

Even though new drugs have been approved for HCV treatment, the risk for drug-drug interactions and the concern over overlapping toxicities has hindered the development of studies in HIV/HCV coinfected individuals. Traditional treatment with pegylated interferon plus ribavirin (peg-IFN+RBV) is highly expensive and has low rates of sustained virological response in co-infected patients especially if infected with HCV genotype 1. Nitazoxanide (NTZ) is a drug that is being evaluated for the treatment of chronic HCV infection both in HCV monoinfected and HIV/HCV coinfected patients. To understand NTZ resistance mechanism could allow minimizing the development of resistance and expanding the treatment options mainly in special populations such as HIV/HCV coinfected patients. Similarly to IFN, NTZ increases the activity of the cellular protein kinase activated by double-stranded RNA (PKR), a key kinase in the innate antiviral response. In order to elucidate whether sequence heterogeneity in the PKR-binding domain of the HCV genotype 1 NS5A protein could influence the antiviral activity of either NTZ monotherapy or, peg-IFN+RBV, baseline and end-of-therapy plasma samples from two groups of eleven non-responder HIV/HCV coinfected patients that received NTZ or peg-IFN+RBV were studied. Most of the HCV NS5A sequences examined at end-of-therapy did not change from baseline, even after 30 days course of antiviral therapy. An extensive comparison with database HCV-NS5A genotype 1 and 4 sequences with reported IFN therapy outcome was performed in order to infer their phylogenetic relationships. The HCV genotype 1 NS5A nucleotide sequences from therapy non-responder patients were intermingled amongst those the database, irrespective of their IFN-therapy outcome. When comparing the NS5A-PKRBD amino acid identity, it was only significantly different against those sequences ascribed to genotype 4 but not to those of genotype 1 (p<0.0001 and p>0.05, respectively). In conclusion, despite both IFN and NTZ sharing the protein kinase activated by double-stranded RNA as the cellular target, the HCV genotype 1 strategy to counteract the IFN action mediated by NS5A ISDR/PKRBD does not explain drug resistance in HIV/HCV coinfected patients. Other plausible viral factors involved are discussed as well.