New Therapies for Hepatitis C

New Therapies for Hepatitis C

July 08, 2011
By Steven L. Flamm, MD

Chronic hepatitis C virus infection (HCV) is a worldwide problem, afflicting approximately 170 million people. In the U.S., it is estimated that approximately 4 million people are afflicted. A significant number of patients develop cirrhosis and life-threatening complications of portal hypertension, including esophagogastric variceal bleeding, ascites and/or hepatic encephalopathy. In the setting of cirrhosis, hepatocellular carcinoma develops at an annual rate of 1 to 4 percent. Chronic HCV is currently the leading indication for liver transplantation in the U.S.

The standard treatment regimen for many years has included pegylated interferon alfa (PEG) and ribavirin (riba). Sustained virologic response (SVR) rates of approximately 40 percent are expected in patients with the commonest genotype in the U.S. (GT 1). The regimen is complicated by many troublesome side effects, including flu-like symptoms, neuropsychiatric side effects and cytopenias. The low SVR and the adverse tolerability profile have provided the impetus for clinical research to improve outcomes.

There have been many areas of active investigation in recent years. The most advanced has been in the development of the protease inhibitors (PI) for HCV. The new triple-therapy regimens offer substantial increases in SVR. In both treatment-naïve and treatment-experienced patients, the regimens were highly effective compared with re-treatment with PEG and riba. Although additional toxicity was present, the regimens were, in general, relatively well tolerated. The medications also seem to add substantial benefit in African-American and cirrhotic patients. Hence, the FDA approved telaprevir and boceprevir for treatment-naïve and treatment-experienced (relapse, partial responders and null responders) patients with HCV GT 1 in May 2011.

The PIs for HCV offer a major advance in the treatment of HCV GT 1, and many patients will achieve SVR who previously would not. However, there are many implications for clinical practice, as there are major differences in how patients with HCV have previously been treated. First, the PIs are only approved for patients with GT 1. Second, therapy is now individualized (response-guided therapy). If patients are “fast responders,” they may be eligible to receive shorter courses of therapy than the typical 48 weeks. “Slow responders” require a 48-week course. Very sensitive HCV RNA testing is now necessary to ensure that fast responders are truly negative so that appropriate decisions can be made to truncate therapy. Third, the PIs must not be discontinued and restarted, must not be used without both PEG and riba, must be taken with food and strictly every 8 hours, and should not be dose reduced because of toxicity for fear of the development of resistance. Fourth, stopping (futility) rules must be strictly adhered to. If patients continue therapy after meeting the criteria for futility, they almost certainly will not attain SVR, will incur unnecessary side effects and cost, and may develop worse resistance, which could theoretically impact response to anti-viral therapy in the future. Finally, there are numerous drug-drug interactions with very commonly used medications that must be dealt with prior to commencing therapy with the PIs. In some cases, the PI levels may be impaired, leading to increased risk of failure and resistance. In other cases, levels of the other medications may be dramatically increased and cause toxicity.

The approval of the PIs represent the dawn of a new age for the treatment of HCV. The outcomes for patients with HCV GT 1 will improve dramatically. However, clinical practice will also change. Health-care providers for patients with HCV will require a substantial amount of education prior to commencing anti-viral therapy to optimize chances of attaining SVR and minimize chances of failure and the development of resistance and toxicity.

http://www.gastro.org/journals-publications/news/new-therapies-for-hepatitis-c