The end of the beginning for hepatitis C treatment

T hese are extraordinary times in the history of hepatitis C virus (HCV) drug development. We waited 13 years between the approval of ribavirin (RBV) in 1998 and the approval of telaprevir and boceprevir in 2011. The trajectory of drug discovery and clinical trials has gone from exponential to warp speed since the European Association for the Study of the Liver (EASL) meeting in April 2011, and two articles are perfect examples of what has changed the world of hepatitis C: interferon (IFN)-free combination therapy and, in one of the trials, eradication of the virus. The first demonstration in humans of IFN-free combination therapy with direct-acting antivirals (DAAs) was the INFORM-1 trial, the results of which were first presented at the EASL 2009 meeting and published in 2010. It showed that a nucleoside analogue polymerase inhibitor (now known as mericitabine) and a protease inhibitor (now known as danoprevir [presently boosted with ritonavir]) together without polyethylene glycol (PEG) or RBV could reduce HCV viral load by 5 1 log10 IU/mL in 14 days with no sign of resistant virus. This was the proof of principle that two DAAs by themselves could render HCV undetectable in most patients, without the use of PEG or RBV. This combination hit a snag with some danoprevir toxicity issues, and development has slowed. Those issues were successfully resolved with ritonavir boosting; the follow-up study to INFORM is now proceeding apace, and data will be forthcoming from that trial in 2012 or 2013. The Zeuzem et al. study published in this issue of HEPATOLGY compared an all-oral combination of tegobuvir (a nonnucleoside polymerase inhibitor given twice daily) plus GS 9256 (an NS3 serine protease inhibitor) with and without RBV in two arms for 28 days, at which point they received PEG and RBV standard of care. The third arm used quadruple therapy with both DAAs plus PEG and RBV for 28 days and then PEG and RBV alone. All patients with viral rebound of >0.5 log10 from nadir or nonresponse defined as <2.0 log10 decline at day 5 received PEG and RBV immediately. Median maximal reductions in HCV RNA were 4.1 log10 IU/mL, 5.,1 log10 IU/ mL, and 5.7 log10 IU/mL for the tegobuvir plus GS 9256, tegobuvir plus GS 9256 plus RBV, and tegobuvir, GS9256, PEG, and RBV arms, respectively. The results were quite instructive. Rapid virological response (RVR) for the two DAAs alone was 7%, for the two DAAs plus RBV 38%, and for the quadruple therapy arm 100%. The importance of RBV in preventing resistance is very clear with this combination and re-emphasizes the continuing value of using RBV in all oral regimens of DAAs. It also demonstrates the real, but weak antiviral activity of RBV. Why was this result so different from that of INFORM, in which virus was undetectable in virtually all patients at 14 days of dual therapy? The answer lies in the barrier to resistance. The nucleoside/nucleotide analogues in general have a very high barrier to resistance, and the INFORM study used the nucleoside mericitabine. The barrier to resistance for protease inhibitors is relatively low, and lower still for genotype 1a as opposed to genotype 1b, because the 1a virus only requires one mutation to generate resistance to protease inhibitors, whereas the 1b virus requires two. Most nonnucleoside polymerase inhibitors have a relatively low barrier to resistance. When you combine two DAAs with relatively low barriers to resistance, it is easy for the virus to produce the double mutants that are resistant to both drugs. RBV slows this down somewhat, but does not add enough antiviral activity to prevent resistance more than 60% of the time with tegobuvir and GS 9256. There is one other factor involved in preventing resistance and that is the activity of the DAA. These extremely potent agents, which rapidly drop the viral load down to undetectable, also prevent resistance. A good example of this is the combination study of BI 201335 and BI 207127. This study compared two Abbreviations: DAA, direct-acting antiviral; EASL, European Association for the Study of the Liver; EBV; Epstein-Barr virus; HCV, hepatitis C virus; IFN, interferon; PEG, polyethylene glycol; RBV, ribavirin; RVR, rapid virological response; SVR, sustained virological response. Address reprint requests to: Douglas Dieterich, M.D., Liver Disease, Gastroenterology, and Infectious Diseases, Mount Sinai School of Medicine, PO Box 1118, One Gustav L. Levy Place, New York, NY 10029. E-mail: douglas. dieterich@mountsinai.org. CopyrightVC 2011 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.25528 Potential conflict of interest: Dr. Dieterich consults for and advises Gilead, Vertex, and Merck.