Barrier to resistance: lessons from 2 direct-acting hepatitis C virus inhibitors, MK-5172 and Sofosbuvir.

Hepatitis C virus (HCV) is a positivestrand RNA virus that infects >170 million people worldwide, including approximately 3.2 million people in the United States. Chronic HCV infection can result in chronic inflammation, liver damage, and death, with 350 000 deaths per year globally. The most exciting advance in antiviral therapy in the last decade has been the development of direct-acting antivirals (DAAs) against HCV [1, 2]. The studies by Howe et al and Svaroskaia et al, in this issue of Clinical Infectious Diseases, describe sequence and phenotypic analysis of baseline samples and samples from patients with virologic failure to MK-5172, a third-generation HCV protease inhibitor (PI), and sofosbuvir, an HCV polymerase nucleotide active site inhibitor, respectively, and are important contributions to our understanding of how sofosbuvir and MK-5172 can be used in future therapy. We have entered an interferon-free treatment era in which the majority of HCV patients in the United States and European Union can obtain a sustained virologic response (SVR) or cure with 12 weeks of off-label treatment with 2 approved oral drugs—sofosbuvir, an HCV NS5B polymerase nucleotide (active site) inhibitor, and simeprevir, an HCV NS3 PI. As shown in Table 1, the advanced HCV combinations can be divided into those that are based on an HCV polymerase nucleotide inhibitor (sofosbuvir) vs those that are based on an HCV PI (simeprevir, asunaprevir, MK5172). When an NS5A inhibitor alone, or in combination with an NS5B polymerase non nucleoside (allosteric site) inhibitor is added to sofosbuvir or PIs, the majority of patients can be cured with 6–12 weeks of dosing. Properties that affect the ability of an inhibitor to be successfully combined into an HCV combination include (1) potency and pan-genotypic activity, (2) pharmacokinetic properties compatible with co-dosing, (3) safety and tolerability, (4) prevalence of baseline resistance, and (5) the barrier to treatment-emergent resistance. Sofosbuvir is the only approved nucleotide polymerase inhibitor; its high barrier to resistance as well as its efficacy, excellent safety and pharmacokinetic profile, and minimal drug–drug interactions has made sofosbuvir the most desirable drug to include in a combination. MK5172 is an investigational once-daily pan-genotypic PI that is active against the major known resistant variants to other PIs in vitro [13]. The resistance profile of sofosbuvir and MK-5172 is important to evaluate the role that they might play in combination regimens, the potential to shorten treatment duration by rapidly shutting down the replication of wild-type and resistant variants, and the potential to re-treat patients who have failed an initial round of therapy. Because of the high genetic variability of HCV due to a replication rate of approximately 10 virions/day and an error-prone mode of viral replication, resistance-associated variants with amino acid changes that confer decreased susceptibility to antiviral drugs are continuously being made. The barrier to the development of resistance is determined by multiple factors including, first, the genetic barrier to resistance, which is affected by the number of nucleotide changes required to create a single amino acid substitution that confers resistance. This is exemplified by the effect of genotype/ subtype on SVR rates with some PIs. Second, similarly, the barrier to resistance is increased by the number of linked amino acid changes that are required to confer resistance. This is exemplified by single amino acid changes in subtype 1a HCV protease such as R155K and V36M, which confer a low-level decrease in susceptibility in in vitro assays to the first-generation PI Received 22 August 2014; accepted 24 August 2014; electronically published 28 September 2014. Correspondence: Ann D Kwong, PhD, InnovaTID Pharmaceuticals Inc, 125 Cambridge Park Drive, Ste 301, Cambridge, MA 02140 ([email protected]). Clinical Infectious Diseases 2014;59(12):1675–7 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/cid/ciu700