Mutant Ninja viruses

A s the epidemic of morbidity and mortality from end-stage liver disease resulting from hepatitis C threatens to engulf us, new treatment regimes have emerged that seem likely to turn back the tide and allow us to consider a total victory over this virus. Some, including myself, believe that global eradication of hepatitis C may now be possible. This issue of HEPATOLOGY contains an article from Hongmei Mo’s team, which suggests that declarations of victory may be premature and the virus may still have a few tricks up its sleeve. The new all-oral treatments for chronic hepatitis C infection focus on combination regimes with multiple drugs that attack different viral proteins that are critical for viral replication. Two, subtly different, approaches are leading the way—one involves augmented triple therapy with a protease inhibitor (ABT450), a nonstructural (NS)5A inhibitor (ombitasvir), and a non-nucleotide inhibitor (dasabuvir) and the other is based around the nucleotide inhibitor, sofosbuvir (SOF), either with or without a second directacting antiviral agent. The hepatitis C virus (HCV) is a highly divergent virus that can be classified into seven genotypes, which differ from one another in their genomic sequence and their geographical distribution: Genotype 1 is common in the United States, Japan, and Europe, whereas genotype 4 is found in Egypt and genotype 3 dominates in the Indian subcontinent. The all-oral treatment regimes require different drug combinations for the different viral genotypes, for example, the current triple-therapy regime based around ABT-450 is only active against genotype 1, with small-scale studies suggesting activity against genotype 4, and SOF-based regimes require different adjuncts for the different genotypes. For genotype 2 infection, 12 weeks of SOF plus ribavirin (RBV) is required, but for genotype 1–infected patients, this is insufficient and an additional drug (either an NS5A inhibitor [such as ledipasvir] or a protease inhibitor [simeprevir] is required. For genotype 3–infected patients, a further 12 weeks of SOF plus RBV is needed, although adding SOF to pegylated interferon (Peg-IFN) and RBV for 12 weeks may suffice. Genotyping the virus to decide the optimal treatment regime is a well-established technique involving an assessment of a conserved region of the virus that is known to differ among genotypes. The viral sequence can be determined by direct sequencing or monitoring hybridization of viral polymerase chain reaction products to genotype-specific control DNA sequences. Both approaches are believed to generate identical results, and commercial hybridization assays based on the 5’ region of the virus and sequencing assays commonly based on the 3’ (NS5B) regions of the virus are often employed. The article by Hedskog et al. suggests that the approach used may be very important in determining which drugs to use. Hepatitis C is a flavivirus that replicates through RNA intermediates. It is well established that, for some flaviviridae, infection of a cell with two different viral strains may occur and allow “crossover” of the replicating viral strands with the generation of a hybrid, recombinant virus that contains features of both viruses. These hybrid virions have been described in HCV, but they are believed to be rare and of doubtful clinical significance. Hedskog et al.’s article confirms that these hybrid viruses are indeed rare, but they may be of clinical importance. The article examines samples collected as part of the extensive SOF clinical development program. All samples were assigned a genotype using a commercial hybridization assay (InnoLipa), which looks at conserved sequences in the 5’ region of the virus. Over 2,000 samples were reexamined and regenotyped using a technique in which the 3’ region of the virus was sequenced. In 0.5% of the cases, the two assays gave divergent results, with genotyping of the 5’ end indicating infection with genotype 2 HCV and sequencing of the 3’ (opposite end) indicating genotype 1. Figure 1 illustrates how the different assays lead to different results. Abbreviations: HCV, hepatitis C virus; NS, nonstructural; Peg-IFN, pegylated interferon; RBV, ribavirin; SOF, sofosbuvir. Received September 22, 2014; accepted September 26, 2014. Address reprint requests to: Graham R. Foster, Ph.D., FRCP, Queen Mary’s University of London, The Blizard Institute, 4 Newark Street, London E1 2AT, UK. E-mail: g.r. foster@qmul.ac. uk; fax: 144 (0) 207 882 2187. Copyright VC 2014 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27540 Potential conflict of interest: Prof. Foster consults, advises, and is on the speakers’ bureau of Boehringer Ingelheim, Bristol-Myers Squibb, Roche, Gilead, Merck, Novartis, and Janssen.