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Greetings from Digestive Disease Week 2003: Report 1 - TREATMENT OF HEPATITIS
C NON-RESPONDERS
Reported by Jules Levin
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It's about 95 degrees and HUMID in Orlando, Florida where this year's DDW conference is being held. This conference is for stomach, digestive, and related diseases. Amid the reports on irritable bowel syndrome and pancreatitis are oral and poster reports on hepatitis C and B, which I'll be reporting to you. The conference starts Monday morning and some of the studies being presented here address retreatment of non-responders with peginterferon and ribavirin, treatment of HCV/HIV coinfection with peginterferon plus ribavirin, an interaction study between methadone and Pegasys, Procrit for anemia resulting from ribavirin/interferon therapy, diabetes and hepatitis C, the effect of moderate alcohol use on fibrosis, tenofovir therapy for hepatitis B, racial differences in response the HCV therapy, and 48-week results of adefovir therapy for hepatitis B. NATAP will be reporting proceedings and study results from the conference.
Here is a report on retreatment for non-responders from a pre-conference meeting this weekend.
TREATMENT OF HEPATITIS C NON-RESPONDERS
Adrian Bisceglie, Division of Gastroenterogy and Hepatology, St Louis University School of Medicine, St Louis, MO.
There have been considerable advances in the management of patients with chronic hepatitis C. The recent NIH Consensus Panel noted that the optimal results were obtained with the combination of pegylated interferon and ribavirin. Even with this combination, 40% to 50% of patients do not achieve a sustained virologic response (undetectable HCV RNA 6 months after completion of a 6 to 12 month course of therapy). Factors affecting the rate of response include HCV genotype and viral load. The degree of hepatic fibrosis also appears to play a role. Interestingly, SVR rates are low among African-Americans, suggesting that as-yet-unidentified host factors may play a role in response to therapy.
Large numbers of patients have previously been treated with standard interferon with or without ribavirin. For those previously treated with interferon alone, SVR rates of up to 30% can be achieved when these patients are re-treated with interferon and ribavirin. There is little information available on the role of re-treatment with pegylated interferon for those patients who have not responded to an adequate course of standard interferon with ribavirin. At this conference Ira Jacobson will report final 48-week results from his study of retreatment of non-responders with PegIntron plus ribavirin. Jacobson reported data from this study at AASLD November 2002, and reported 9% of genotype combination therapy non-responders receiving PegIntron 1.5 mcg/week plus 800 mg ribavirin/day had an SVR.
One of the largest studies to address this is the HALT-C study, an NIH-funded multicenter clinical trial aimed at patients with advanced hepatic fibrosis who are non-responders to interferon therapy. Although the main objective of this study is to determine whether long-term treatment with Pegasys can reduce the rate of disease progression (development of cirrhosis, liver failure, and hepatocellular carcinoma), patients must first undergo a 6 month lead-in period of treatment in which they are treated with Pegasys and ribavirin. Those patients who become HCV RNA undetectable in serum at 6 months then have their treatment extended for a full 12 months to determine if they can achieve SVR while those who remain HCV RNA positive are randomized into the long-term phase of the study. Preliminary results from the lead-in phase of the study have been presented.
Here is a link to a detailed report of the preliminary HALT-C study results reported at AASLD 2002: http://www.natap.org/2002/AASLD/day8.htm
Of 293 patients enrolled, 18% went on to have an SVR (editorial note: genotype 2/3 had SVR rate of 52%). Those who previously only received interferon had a much higher rate of SVR (26%) than those previously treated with interferon and ribavirin (11%). Recent data from a small study of consensus alpha interferon with ribavirin has suggested some benefit in non-responders, but these findings need to be confirmed in a larger number of patients.
It appears therefore, that a disappointingly low proportion of patients who do not respond to standard interferon and ribavirin will clear their HCV infection when treated with pegylated interferon plus ribavirin (editorial note: except if they are genotype 2; it's always possible the patient was not adherent with previous therapy and might respond better now to peg/ribavirin wirh full adherence). It has become apparent that the outcome of therapy can be predicted with some accuracy as early as 12 weeks into treatment. Thus, if patients remain HCV RNA positive at 12 weeks, they have only a very small chance (2% to 3%) of going on to achieve SVR. This information is valuable to physicians and patients making decisions about how long to continue therapy. It has been suggested that prolonged therapy with interferon (so-called maintenance therapy) may decrease the risk of liver disease progression. This suggestion is currently under study in several large clinical trials, icluding HALT-C. Factors to consider in deciding whether to re-treat previous non-responders include the severity of liver disease (based on liver biopsy), viral load, HCV genotype and hoe well the patient tolerated interferon when previously treated.
An alternative for some patients is to consider enrolling in a clinical trial of new therapy for hepatitis C. This includes trials of anti-fibrotic agents (interferon gamma), alternatives to ribavirin to be used in combination with pegylated interferon (thymalfasin, viramidine) and novel agents targeted directly against the hepatitis C virus and its replicative machinery, ie. Antiviral hepatitis C drugs such as protease inhibitors and polymerase inhibitors, which are in development. It is these novel agents that hold out the most hope for non-responders to interferon, but they may be some time in becoming widely available.
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