Non-profit Org. U.S. Postage PAID Falls Church, VA Permit #118 Center for Liver Diseases Inova Fairfax Hospital 3289 Woodburn Road, Suite 375 Annandale,VA 22003-6800 LIVER UPDATE VOL. 6, NO. 1 / WINTER 2005 A PUBLICATION OF THE CENTER FOR LIVER DISEASES AND THE INOVA TRANSPLANT CENTER Inova Health System is a not-for-profit health care Inside this Issue system based in Northern Virginia that consists of hospitals and other health services including I Update on Chronic Hepatitis B emergency and urgent care centers, home care, Faculty Presentations at International Meetings nursing homes, mental health and blood donor I services, and wellness classes. Governed by a I Publications voluntary board of community members, Inova’s I Current Clinical Trials mission is to provide quality care and improve the health of the diverse communities we serve. www.inova.org Save the Date Liver Update is published by the Center for Liver Diseases I Liver Diseases, Liver Cancer and Liver Transplantation 3289 Woodburn Road, Suite 375 Saturday, Sept. 24, 2005 Annandale,VA 22003-6800 7:30 a.m. - 12:30 p.m. Medical Editor Director, Center for Liver Diseases Inova Fairfax Hospital Physicians Conference Center Zobair M.Younossi,MD, MPH This lecture series will serve to update physicians and others 703-208-6650 in the health care field on new information related to chronic Managing Editor liver diseases and liver transplantation. Denise Tatu 703-321-2912 LIVER UPDATE VOL. 6, NO.1 / WINTER 2005 A PUBLICATION OF THE CENTER FOR LIVER DISEASES AND THE INOVA TRANSPLANT CENTER Update on Chronic Hepatitis B Janus P. Ong, MD, MPH called “precore mutant” type of HBV. TREATMENT OF HEPATITIS B Zobair M.Younossi MD, MPH These patients may have spontaneous Center for Liver Diseases flares and remission with significant The treatment of Chronic Hepatitis B Inova Fairfax Hospital histologic disease. Both HBeAg-positive has for its goal, the prevention of and HBeAg-negative chronic HBV progression of liver disease by sustained Chronic hepatitis B virus (HBV) persons are candidates for antiviral suppression of viral replication. infection is a leading cause of cirrhosis therapy. Evidence from many studies has shown and hepatocellular carcinoma (HCC) that patients who have active replication in the world. Endemic areas include Viral nucleic acid testing in blood has and who have evidence of liver disease Asia,Africa, the Middle East and become increasingly important for the on biopsy are more likely to develop Alaska. It is estimated that 350 million management of chronic hepatitis B, in progressive liver disease. Therefore, individuals worldwide and 1.25 particular in the follow-up of patients treatment is generally recommended for million in the United States are on antiviral therapy and in the the patient with (1) persistently chronically infected with HBV. surveillance for the development of abnormal serum aminotranferases who viral mutants on therapy.There are has (2) active viral replication based on Those who test positive for HBsAg several commercially available assays for the presence of HBV-DNA and (3) if for at least six months are considered HBV-DNA that have varying limits of available, evidence of chronic hepatitis chronically infected with HBV.To sensitivity ranging from 10 2 for the on liver biopsy. assist in the management of chronic polymerase chain reaction (PCR) based HBV,diagnostic criteria have been assays to 105 copies/ml and different At the present time, treatment of proposed. (See Table) HBsAg carriers ranges of linearity. inactive carriers is not recommended with normal liver enzymes and low and that of patients with normal serum level of virus generally have mild Recently, there has been an increase in aminotransferases is controversial. disease and do not require treatment. interest in HBV genotypes and their They may still be at some risk for association with liver disease severity Currently, there are three approved development of HCC and screening and treatment response. HBV has been medications for the treatment of for HCC should be considered, classified into eight genotypes chronic hepatitis B – interferon-alfa, especially in those who have a family (genotypes A to H). The genotypes lamivudine, and more recently, adefovir history of HCC. have a variable worldwide distribution. dipivoxil. Interferon-alfa has been In the United States, all the genotypes approved for treatment of chronic Those persons with elevated liver are represented, with genotypes A and hepatitis B with the usual regimen enzymes and high levels of viral C being the most common. consisting of five million units every day replication usually have chronic Preliminary information suggest that or 10 million units three times a week, hepatitis and are at risk for progressive genotype B is associated with less severe given subcutaneously for 16 weeks liver disease. HBeAg-positive chronic liver disease than genotype C, and in HBeAg-positive patients and 12 hepatitis B patients have detectable genotype A and B may be associated months for HBeAg-negative patients. HBeAg and believed to have the so- with better response rates to interferon Interferon-alfa has both antiviral and called “wild-type” of HBV.Patients alfa therapy compared to genotypes C immunomodulatory activity and has with chronic hepatitis B and viremia, and D. These findings need L but without HBeAg, have the so- confirmation in larger studies. see HEPATITIS B, page 2 L HEPATITIS B, from page 1 than the response rates seen in patients infected hepatocytes, patients with who are HBeAg positive. advanced liver disease and cirrhosis can been found in a meta-analysis of 15 decompensate with this form of randomized, controlled trials in Recently, peginterferon-alfa 2a alone treatment. Therefore, patients with HBeAg-positive chronic hepatitis B to given over a year was shown to lead to decompensated liver disease or those at result in HBeAg loss in about one third higher rates of sustained viral risk for decompensation should not be of the patients. Long-term follow-up of suppression in HBeAg-negative patients treated with interferon-alfa. patients who achieved HBeAg when compared to lamivudine alone. seroconversion showed improvement in The addition of lamivudine to Lamivudine is a nucleoside analogue survival compared to patients who did peginterferon-alfa 2a did not improve that inhibits HBV replication. Several not achieve seroconversion. HBeAg response rates. More importantly, large randomized clinical trials have seroconversion with interferon-alfa may HBsAg seroconversion was observed shown that HBeAg seroconversion be accompanied by a transient rise in only in those who received occurred in up to 18 percent of patients serum aminotransferases right before peginterferon-alfa 2a and not in those at the end of one year of treatment. losing HBeAg. who received lamivudine alone. Durability of response among those who Preliminary data in HBeAg-positive achieved HBeAg seroconversion can be Factors that have been shown to predict patients showed higher rates of HBeAg seen in close to 80 percent of patients in a favorable response to interferon-alfa seroconversion in those who received some studies. Discontinuation of include low HBV-DNA levels, high peginterferon-alfa alone or in lamivudine treatment in patients who do serum aminotransferases, and evidence combination with lamivudine not achieve HBeAg seroconversion of active liver disease on liver biopsy. In compared to lamivudine alone. generally results in relapse with patients with HBeAg-negative chronic Additionally, as in the HBeAg-negative reappearance of HBV-DNA in serum. hepatitis B, the efficacy of interferon- patients, HBsAg seroconversion was alfa is determined more by having a observed only in those who received In patients with HBeAg-negative sustained loss of HBV-DNA peginterferon-alfa 2a and not in those chronic hepatitis B, lamivudine has also accompanied by persistently normal who received lamivudine alone. been shown to be highly effective in serum aminotransferases. Response rates suppressing viral replication which is of up to 40 to 60 percent have been The main drawback of interferon-alfa accompanied by improvements in liver shown, but relapse after discontinuation therapy is the adverse side effects that histology. However, relapse is very high of therapy is high, resulting in a may become intolerable in some after discontinuation of treatment. sustained response rate of only about patients. Because interferon-alfa can Extended use of lamivudine has been 15 to 25 percent. That is slightly lower cause immunologic clearance of HBV- employed to address the issue of relapse after discontinuation of therapy.This strategy has been associated with the emergence of resistant strains of hepatitis Diagnostic criteria for chronic HBV* B virus and recurrence of liver disease at rates of up to 14 percent at one year, 38 Inactive HBsAg carrier percent at two years, and 66 percent at I HBeAg negative, anti-HBe positive three years. In a recently published study, I serum HBV-DNA < 105 copies/ml the use of lamivudine was shown to I persistently normal ALT/AST levels delay disease progression in patients with I liver biopsy showing no significant hepatitis (not routinely recommended) advanced liver disease, underscoring the importance of identifying those patients HBeAg-positive chronic hepatitis B with advanced liver disease for I HBeAg positive, anti-HBe negative consideration for antiviral therapy. I serum HBV-DNA > 105 copies/ml I persistent or intermittent