The Fast-Paced Evolution of Hepatitis C Treatment and Cures

Nothing else in the history of biomedical sciences has evolved faster than the treatment of hepatitis C virus (HCV) infection. Only recently did the first direct antiviral agents (boceprevir [Victrelis] and telaprevir [Incivek]) receive FDA (U.S. Food and Drug Administration) approval and they are already retired. Now we are learning about fully oral regimens without interferon and ribavirin, and the potential of curing the vast majority of treated patients.

As evidence of the rate of change, there were presentations of two large phase-3 studies with HCV second-generation protease inhibitors (one with simeprevir [Olysio], the other with faldaprevir), whose results were obsolete even before being presented because of their limited sustained virologic response (SVR) rates; side-effect prone, interferon-containing study design; and longer treatment duration. Indeed, newer all-oral regimens have outstanding overall cure rates.

Sofosbuvir (Sovaldi) is one of the newest approved direct acting antivirals (DAAs). Results of the HIV/HCV coinfection study PHOTON 1 were presented at CROI 2014:

  • Among those with HCV genotype 1, SVR after 24 weeks of treatment with sofosbuvir and ribavirin at 12 and 24 weeks was 75%.
  • Among those with genotype 2, SVR after 12 weeks of treatment was about 90%, and after 24 weeks of treatment was about 92%.
  • Among those with genotype 3, SVR after 24 weeks of treatment was about 92%.

Taken together, these results and other clinical studies of newer DAAs among HIV/HCV coinfected people show no significant difference in responses. Maybe it's time to conclude that DAAs work as well in HIV-infected as in HIV-uninfected individuals and focus our limited research dollars not on coinfected studies, but on the relevant drug-drug interaction studies with DAAs and important medications (like antiretrovirals).

Sofosbuvir is likely the present and future of HCV treatment. However, 12 or 24 weeks of ribavirin-containing treatment isn't ideal and a 75% SVR leaves something to be desired. How about shorter course treatment? How about higher SVR rates?

SYNERGY was a small study exploring the future possibilities. Three once-daily, all oral DAA combinations with sofosbuvir were studied: dual therapy sofosbuvir with ledipasvir; triple therapy with sofosbuvir + ledipasvir + GS-9669 (a non-nuke NS5B inhibitor); and sofosbuvir + ledipasvir + GS-9451 (a protease/NS3/4 inhibitor).

Overall, after six to 12 weeks of treatment in all three arms, between 95% - 100% of individuals achieved SVR. It would appear that regimens containing a core of sofosbuvir + ledipasvir will be the future of HCV treatments, with an all oral, very short treatment course nearly in reach, and with possibilities of coformulation of all the treatment in single-tablet regimens. Now, if we can only figure out the cost and access issues of these curative treatments.

Which other studies presented at CROI 2014 will have lasting impact? Read more of Dr. Llibre and Dr. Young's top picks.