New therapies provide optimism in chronic HCV

Chronic hepatitis C virus infection is currently responsible for more US deaths than HIV; is complicated to treat; is not vaccine preventable; and is a major driver of liver transplants, cirrhosis, chronic and end-stage liver disease, and liver cancer.

Although infection rates peaked more than a decade ago, rates of complications related to hepatitis C virus (HCV), such as cirrhosis, are projected to continue rising until 2020 or later.

Amid this bad news, however, is emerging a remarkably promising treatment picture, said the liver diseases branch at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md.

At the grand rounds, told clinicians that with the current Food and Drug Administration approved regimens, “efficacy of therapy is improving and cure is now possible.” The addition of direct-acting antiviral agents to regimens previously containing only peginterferon and ribavirin has been “a game-changer,” with some patients achieving sustained virologic response (SVR) in as few as 12 weeks.

SVR is normally defined as testing negative for HCV-RNA 24 weeks after the end of treatment.

With chronic HCV infection, SVR is shorthand for cure, with nearly 100% of SVR patients having undetectable HCV-RNA over long-term follow-up. More importantly, “SVR is associated with improved outcomes,” said, citing a large NIH multicenter study in which subjects achieving SVR had vastly lower rates of liver disease, liver-related death, and liver transplantation. Liver cancer, while also reduced, was somewhat more persistent in the SVR population.

Triple therapies using peginterferon, ribavirin, and a direct-acting antiviral agent such as boceprevir or telaprevir, have increased the SVR rate to more than 75% among treatment-naive people with HCV genotype 1, the hardest of the six major genotypes to treat and the one responsible for the lion’s share of infections in the United States. With the earlier dual-therapy regimens, less than half of patients saw SVR.

He described the current optimal therapy for HCV 1 infection as peginterferon alfa-2a 180 mcg weekly or peginterferon alfa-2b 1.5 mcg/kg weekly, plus oral ribarvirin 800-1,400mg in two divided doses daily, combined with either boceprevir 800 mg three times daily or telaprevir 750 mg every 8 hours.

Simple as they may sound, “these regimens are actually quite complex,” with pill burdens as high as 18 a day. Nor are the agents interchangeable; the bocepvir and telaprivir regimens are administered very differently and must be adjusted within specific time frames according to patient response.

Moreover, “the side effects are substantial.” Anemia (including severe anemia), neutropenia, and dysgeusia are all significantly higher with the boceprevir triple regimen than with the dual regimens, and telaprivir is associated with severe body rashes that resolve only when treatment is stopped.

Both regimens come with specific stopping rules for non-response, futility, and resistance prevention. These must be followed to the letter, it was said. Neither telaprevir not boceprevir should ever be used as monotherapy, as resistance can develop in as little as four days. Clinicians should carefully consider the potential for drug interactions, particularly among transplant recipients or HIV-coinfected patients.

The decision whether to treat or observe can be difficult, and clinicians must consider the likelihood of disease progression, response, contra-indications, disease stage, comorbidities, and side effects when working with a patient to choose the right course. Given the toxicity of some regimens, it might do to wait with some patients until safer therapies become available.