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Management of chronic hepatitis C: A consensus
Comment From the Editors Management of Chronic Hepatitis C: A Consensus fter almost a decade of using interferon for chronic hepatitis C, many physicians are growing frustrated. As rewarding as it is to treat a patient who has a sustained response, 10 patients have to be treated to yield five with any response and one or two with a sustained response. Many patients who embrace therapy enthusiastically today will be disappointed several months hence. Although initial attempts to achieve a consensus about interferon therapy for hepatitis C virus (HCV) infection met with limited success, a fruitful National Institutes of Health Consensus Development Conference was convened on March 24–26, 1997 to address the management of hepatitis C.* Conference participants discussed the diagnosis, natural history, epidemiology, and prevention of hepatitis C,but I will focus on therapy. Candidates for Therapy. Based on data presented at the conference, a multidisciplinary panel recommended interferon alpha therapy for patients with elevated alanine aminotransferase (ALT) levels, detectable HCV RNA, and histological evidence of septal fibrosis and/or moderate-to-severe chronic hepatitis (i.e., histological predictors of progression). Because data on other subgroups are inadequate to support a role for therapy, the panel did not recommend therapy for patients with histologically milder disease, compensated cirrhosis,and age <18 or >60;these subgroups were consigned to individualized management, based on a discussion of the potential risks and benefits, preferably in clinical trials. For patients with decompensated cirrhosis, liver transplantation, not therapy with interferon, was recommended. Because patients with persistently normal ALT levels do not respond to interferon and may experience biochemical worsening during therapy, the panel did not endorse treatment of such patients outside of clinical trials.The panel also recommended therapy of acute hepatitis C, after which interferon has been shown to increase the likelihood of
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HCV clearance. Pretreatment patient characteristics are inadequate predictors of responsiveness, and the panel emphasized that therapy with interferon should not be limited by such variables as HCV RNA level and genotype. Relative contraindications include a history of major depression, cytopenias, active alcohol or drug use, hyperthyroidism, renal transplantation, and autoimmune disease. Optimal dose/duration. Based on the superiority of 12-month over 6month regimens, the panel advocated initial therapy with 3 million units three times a week for 12 months. Nonresponse. Nonresponders to interferon, the panel concluded, can be identified early by assessing ALT and HCV RNA after 3 months of therapy; once nonresponsiveness is established, therapy should be stopped. Nonresponders should not be retreated with interferon alone but should be considered for combination therapy or other investigative protocols. Relapse. Patients who relapse after a 6-month course of interferon should be retreated with a 12-month course or considered for combination therapy with ribavirin, preferably in a clinical trial. The Consensus Conference statement is a finely honed, masterful synthesis of available data and a testament to the deliberate work of the conference organizers and panel.The data on which this consensus is based,however, go only so far, and debate over some of the details of the panel’s conclusions is inevitable. For example, doubling the duration of treatment from 6 to 12 months doubles the frequency of a sustained biochemical/virological response from approximately 10% to 20%; however, for 50% of those who have a sustained response,6 months of therapy suffices. An argument can be made for the initiation of a 6-month course in all patients and reserving a 12-month course for the retreatment of relapsers. The panel’s conclusion about compensated cirrhosis merits a careful look. Data presented at the conference indicated that interferon therapy does not improve survival or delay the devel-
opment of hepatocellular carcinoma in compensated cirrhotic patients. Still, the panel did not go so far as to exclude absolutely patients with compensated cirrhosis as candidates for therapy. Cirrhosis has not been shown to be sufficiently predictive of nonresponse to justify withholding of therapy from all cirrhotic patients. Prospective studies in this group are warranted. In considering responses to interferon, the panel concentrated on sustained responses, a lofty goal. Is there no benefit for those with anything less? Relapsers after a transient response to therapy might benefit from long-term therapy to maintain suppression of HCV-induced liver injury. Currently, no data are available to assess the potential benefit of such suppressive therapy, and, because recommendations had to be evidence-based,protracted,suppressive therapy was not recommended. On the other hand, the panel did conclude that patients with essential mixed cryoglobulinemia and hepatitis C could benefit from long-term therapy, despite the fact that data supporting this conclusion are lacking. The value of suppressive therapy remains an important void in our understanding of interferon therapy for hepatitis C. The consensus statement focused primarily on a first-generation drug that has been pushed to its limit. Now, attention can shift to more promising advances. Data presented at the conference suggest that ribavirin combined with interferon may more than double the rate of sustained responsiveness. If the development of protease inhibitors and other specific HCV inhibitors proceeds apace, interferon could be supplanted entirely within a few years. Beyond the millenium, the landscape of antiviral therapy for hepatitis C should be very different indeed. JULES L. DIENSTAG, M.D. Associate Editor, GASTROENTEROLOGY
*Complete proceedings of the conference are scheduled to be published this fall, but a summary statement is available now on the internet [www.nih.gov, Consensus Development Conference statement no.105]. GASTROENTEROLOGY 1997;113:375
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HCV clearance. Pretreatment patient characteristics are inadequate predictors of responsiveness, and the panel emphasized that therapy with interferon should not be limited by such variables as HCV RNA level and genotype. Relative contraindications include a history of major depression, cytopenias, active alcohol or drug use, hyperthyroidism, renal transplantation, and autoimmune disease. Optimal dose/duration. Based on the superiority of 12-month over 6month regimens, the panel advocated initial therapy with 3 million units three times a week for 12 months. Nonresponse. Nonresponders to interferon, the panel concluded, can be identified early by assessing ALT and HCV RNA after 3 months of therapy; once nonresponsiveness is established, therapy should be stopped. Nonresponders should not be retreated with interferon alone but should be considered for combination therapy or other investigative protocols. Relapse. Patients who relapse after a 6-month course of interferon should be retreated with a 12-month course or considered for combination therapy with ribavirin, preferably in a clinical trial. The Consensus Conference statement is a finely honed, masterful synthesis of available data and a testament to the deliberate work of the conference organizers and panel.The data on which this consensus is based,however, go only so far, and debate over some of the details of the panel’s conclusions is inevitable. For example, doubling the duration of treatment from 6 to 12 months doubles the frequency of a sustained biochemical/virological response from approximately 10% to 20%; however, for 50% of those who have a sustained response,6 months of therapy suffices. An argument can be made for the initiation of a 6-month course in all patients and reserving a 12-month course for the retreatment of relapsers. The panel’s conclusion about compensated cirrhosis merits a careful look. Data presented at the conference indicated that interferon therapy does not improve survival or delay the devel-
opment of hepatocellular carcinoma in compensated cirrhotic patients. Still, the panel did not go so far as to exclude absolutely patients with compensated cirrhosis as candidates for therapy. Cirrhosis has not been shown to be sufficiently predictive of nonresponse to justify withholding of therapy from all cirrhotic patients. Prospective studies in this group are warranted. In considering responses to interferon, the panel concentrated on sustained responses, a lofty goal. Is there no benefit for those with anything less? Relapsers after a transient response to therapy might benefit from long-term therapy to maintain suppression of HCV-induced liver injury. Currently, no data are available to assess the potential benefit of such suppressive therapy, and, because recommendations had to be evidence-based,protracted,suppressive therapy was not recommended. On the other hand, the panel did conclude that patients with essential mixed cryoglobulinemia and hepatitis C could benefit from long-term therapy, despite the fact that data supporting this conclusion are lacking. The value of suppressive therapy remains an important void in our understanding of interferon therapy for hepatitis C. The consensus statement focused primarily on a first-generation drug that has been pushed to its limit. Now, attention can shift to more promising advances. Data presented at the conference suggest that ribavirin combined with interferon may more than double the rate of sustained responsiveness. If the development of protease inhibitors and other specific HCV inhibitors proceeds apace, interferon could be supplanted entirely within a few years. Beyond the millenium, the landscape of antiviral therapy for hepatitis C should be very different indeed. JULES L. DIENSTAG, M.D. Associate Editor, GASTROENTEROLOGY
*Complete proceedings of the conference are scheduled to be published this fall, but a summary statement is available now on the internet [www.nih.gov, Consensus Development Conference statement no.105]. GASTROENTEROLOGY 1997;113:375