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
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Even though new drugs have been approved for treatment of hepatitis C virus (HCV) infection, the risk of drug-drug interactions and concern about overlapping toxicities has hindered the development of studies in HIV/HCV-coinfected individuals. Traditional treatment with pegylated interferon plus ribavirin (peg-IFN + RBV) is very expensive and has a low rate of sustained virological response in coinfected patients, especially if they are 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. Understanding the NTZ resistance mechanism could allow the development of resistance to be minimized and would expand 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 HCV NS5A genotype 1 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 had received NTZ or peg-IFN + RBV were studied. Most of the HCV NS5A sequences examined at the end of therapy did not change from the baseline, even after 30 days course of antiviral therapy. An extensive comparison of HCV NS5A genotype 1 and 4 sequences from the database 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 from the database, irrespective of their IFN-therapy outcome. When comparing NS5A-PKRBD amino acid sequences, significant differences were observed in genotype 4, but not in genotype 1 (p < 0.0001 and p > 0.05, respectively). In conclusion, despite IFN and NTZ sharing the protein kinase activated by double-stranded RNA as their 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 viral factors that are possibly involved are discussed as well.
KeywordsSustained Virological Response Nitazoxanide NS5A Sequence Sustained Virological Responder NS5A Amino Acid
This study was supported partially by grants from the University of Buenos Aires (SECYT-UBA 2012-2015), and the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET-PIP112 200801 01773).
The authors have no conflict(s) of interest.
- 31.Hall TA (1999) BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucleic Acids Symposium Series, pp 91–98Google Scholar
- 35.Bolcic F, Laufer N, Torres C, Cassino L, Reynoso R et al (2012) Longitudinal analysis of the 5′UTR, E2-PePHD and NS5A-PKRBD genomic regions of hepatitis C virus genotype 1a in association with the response to peginterferon and ribavirin therapy in HIV-coinfected patients. Antiviral Res 95:72–81PubMedCrossRefGoogle Scholar
- 36.Bolcic F, Sede M, Moretti F, Westergaard G, Vazquez M et al (2012) Analysis of the PKR-eIF2alpha phosphorylation homology domain (PePHD) of hepatitis C virus genotype 1 in HIV-coinfected patients by ultra-deep pyrosequencing and its relationship to responses to pegylated interferon-ribavirin treatment. Arch Virol 157:703–711PubMedCrossRefGoogle Scholar
- 46.Bolcic F, Laufer N, Torres C, Cassino L, Reynoso R et al (2012) Longitudinal analysis of the 5′UTR, E2-PePHD and NS5A-PKRBD genomic regions of hepatitis C virus genotype 1a in association with the response to peginterferon and ribavirin therapy in HIV-coinfected patients. Antiviral Res 95:72–81PubMedCrossRefGoogle Scholar
- 55.Yano Y, Seo Y, Miki A, Saito M, Kato H et al (2012) Mutations in non-structural 5A and rapid viral response to pegylated interferon-alpha-2b plus ribavirin therapy are associated with therapeutic efficacy in patients with genotype 1b chronic hepatitis C. Int J Mol Med 30:1048–1052PubMedGoogle Scholar
- 62.Osinusi AWC, Zhang X, Shivabesan G, Shivakumar B, Silk R, Doonquah L, Henn S, Teferi G, Masur H, Kottilil S, Fishbein D (2012) Augmentation of Interferon signaling pathway by Nitazoxanide: a therapeutic strategy for HIV/HCV Coinfected Relapsers to Peg-interferon and Ribavirin therapy. In: 19th Conference on Retroviruses and Opportunistic Infections (CROI). Seattle, USAGoogle Scholar
- 63.Amorosa VU, T, Johnson V, Kang M, Luetkemeyer A, Bardin M, Haas D, Chung R, Yesmin S, Coughlin K, Martinez A, Adams MB, Alston-Smith B, Tebas P, Peters M (2012) The addition of nitazoxanide to peginterferon alfa-2a and ribavirin does not significantly improve sustained virologic response in HCV treatment-naïve genotype 1 HIV-1/HCV co-infected subjects: results of ACTG 5269. XIX International AIDS Conference. Washington, USAGoogle Scholar