New agents for hepatitis C and the challenges in treating co‐infected patients

Abstract

More recently, the improved understanding of the hepatitis C viral life cycle has led to the identification of numerous potential targets for novel, direct‐acting antiviral compounds. Two NS3/4A protease inhibitors, telaprevir and boceprevir, were the first oral HCV protease inhibitors which were approved in Europe and the United States in 2011 in combination with pegylated interferon (IFN)‐α and ribavirin for the treatment of chronic hepatitis C related to HCV genotype 1, in both treatment‐naïve and treatment‐experienced patients. Sustained virological response rates in the range of 66–75% and 59–66% have been achieved in these two patient populations, respectively, with treatment durations of 24 to 48 weeks. Despite these significant advances the high rate of adverse events and the high costs of these regimens have limited the uptake of these new regimens. In particular, the quest for removal of interferon from HCV therapy remains one of the great unmet medical needs in HCV therapy development. With an increasing number of other DAAs in clinical development including second‐wave, first‐generation, and second‐generation NS3/4A protease inhibitors, nucleoside/nucleotide analogue inhibitors and non‐nucleoside inhibitors of HCV‐RNA‐dependent RNA polymerase, inhibitors of nonstructural protein 5A (NS5A) and host‐targeted compounds such as cyclophilin inhibitors and silibinin, the hope for better tolerated HCV therapies and potentially interferon‐free HCV combination therapies has grown considerably. The proof of concept that IFN‐free regimens may lead to HCV eradication has recently been brought in GT2/3 patients treated with PSI‐7977 and ribavirin for 12 weeks as well as in GT1b patients treated with BMS‐790052 + BMS‐650032 for 24 weeks. Although some patients with GT1a infection were also cured under this regimen, the majority of patients relapsed after treatment discontinuation, suggesting that at least for the 1a HCV genotype more effective interferon‐free regimens still need to be developed. Interestingly, also GT1 non‐responders treated with GS‐7977+ribavirin showed a high relapse rate, again underlining that more challenging patient populations will still exist which either need broader oral combinations or longer treatment durations. Overall, the dramatic increase in efficacy has also been seen in DAA‐based HCV therapy in HIV/HCV‐coinfected patients. However, complex drug‐drug interactions and tolerability issues remain a concern for all HCV patients, but particularly for HIV patients receiving antiretroviral therapy with a high potential for drug interactions.