Improving Response to HCV Treatment
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In the United States, the Hepatitis C virus (HCV) is one of the leading causes of chronic liver disease. Accounting for about 15 percent of acute viral hepatitis, 60 to 70 percent of chronic hepatitis and up to 50 percent of cirrhosis, end-stage liver disease and liver cancer, HCV is a major threat to the health of our population. While it has undergone many improvements over the past decade, the current standard of therapy for HCV has a far way to go before this virus can be considered curable. Understanding why those with chronic HCV may not respond to treatment outlines the potential for successful re-treatment.
Sustained Virologic Response
The most common way to measure HCV treatment success is via the virologic response. To measure virologic response, doctors use a blood test to measure how much virus is in the blood. While Hepatitis C RNA may be undetectable immediately following treatment, this test must be repeated six months later to see if any of the virus remained and reproduced. Also referred to as viral load, the best outcome is a sustained virologic response (SVR). When the virus remains undetectable in the blood six months (or more) following HCV therapy, SVR is considered attained. So far, studies following those with HCV for two to three years after SVR have demonstrated a low relapse rate.
While the virologic response is primarily dependent on the action of the pegylated interferon, the prevention of relapse is mostly reflective of the action of ribavirin and the maintenance of its dosing. However, relapse prevention is also affected by the following variables:
- How quickly undetectable HCV RNA is attained after the start of treatment.
- How long the patient remains on treatment after achieving undetectable HCV RNA.
Broken down by the most common HCV genotypes, the following are estimates of how frequently SVR is attained with pegylated interferon and ribavirin therapy:
- Approximately 40 to 45 percent of those with chronic HCV genotype 1, the most common strain in the United States, achieve SVR.
- Approximately 75 to 80 percent of those with chronic HCV genotypes 2 and 3 achieve SVR.
Non-Responders
While those attaining SVR may be permanently free of HCV, the remaining people on pegylated interferon and ribavirin are non-responders. However, there is plenty of evidence that previous non-responders can be re-treated successfully, eventually achieving SVR. Identifying which HCV non-responders are appropriate candidates for re-treatment requires a complete understanding of the various virologic response patterns and the pitfalls associated with achieving and maintaining virologic response.
There are many reasons that a person may not achieve SVR. The individuals without any response to interferon-based therapies are poor candidates for re-treatment. These people have no significant decline in HCV RNA during treatment and are essentially immune to the effects of interferon. Aside from those without any virological response, the four most common reasons assumed responsible for continued HCV infection after treatment are missing doses, premature discontinuation of ribavirin, insufficient ribavirin dosage and infrequent viral load testing.
- Missing a Dose – Recent studies highlight missing a dose of peg-interferon alfa and/or ribavirin as a leading contender for not achieving SVR. Missed doses can be a result of physicians instructing their patients to temporarily stop treatment because of significant treatment-related side effects, patients missing a dose by accident or intentional skipped doses in an attempt to self-treat side effects.
- Premature Discontinuation of Ribavirin – Stopping ribavirin too soon increases the person’s chance of viral load rebound. In those who demonstrate a slow virologic response, several studies have demonstrated that relapse can be significantly reduced in those with HCV genotype 1 patients by prolonging the duration of treatment from 48 to 72 weeks.
- Insufficient Ribavirin Dosing – Another frequently encountered reason for HCV relapse is initiating ribavirin treatment with an insufficient dosage. Three randomized trials have demonstrated that patients who initiate treatment with a higher dose of ribavirin have a lower relapse rate.
- Infrequent Viral Load Testing – In addition, experts believe that SVR is attained by those who quickly recognize when viral load is undetectable and their current treatment regimen is adjusted swiftly. For this reason, viral load must be assessed periodically during treatment to identify this point as soon as possible.
By recognizing the patterns associated with a poor response to interferon-based therapy, physicians can better approximate why therapy failed and who might be a good candidate for re-treatment. If a non-responder attempts pegylated interferon and ribavirin treatment again, all efforts must be made to maintain adequate, sufficient dosing for the required time interval and frequently evaluate viral load. As long as there was some type of viral response to initial treatment, virologists estimate that a sizable percentage of previous non-responders are good candidates for HCV re-treatment.
References:
http://clinicaloptions.com, Understanding HCV Nonresponse and Identifying Candidates for Retreatment, Mitchell L. Shiffman, MD, Clinical Care Options LLC, 2008.
http://digestive.niddk.nih.gov, Chronic Hepatitis C: Current Disease Management, National Institute of Diabetes and Digestive and Kidney Diseases, 2008.
