Hepatitis B: Latest Treatment Guidelines

14  In fact, many hepatologists consider cirrhosis to be a contraindication for interferon therapy. In patients who have a history of depression with suicidal ideation, initiate antidepressant therapy before starting interferon; monitor such patients closely throughout treatment. Lamivudine. This well-tolerated nucleoside analog is a potent suppressor of HBV replication. Early studies involved an oral dosage of 100 mg/d for an empiric duration of 52 weeks; the results led to the recommendation that the duration of therapy be 1 year. However, the exact duration of therapy is still undefined; recommendations for patients who are HBeAg-positive range from 1 to 5 years, while for those who are HBeAg-negative, a duration of longer than 1 year is generally recommended. The likelihood of a favorable response to lamivudine therapy is similar in all patient populations. In patients who were HBeAgpositive, 1 year of treatment with lamivudine was associated with HBeAg seroconversion in 16% to 17% of patients, normalization of ALT levels in 41% to 72%, and histologic improvement in 52% to 56%.

15,16  HBeAg seroconversion rates increase with each subsequent year of treatment (to 47% in patients who received continuous treatment for 4 years).17  HBeAg seroconversion is more common in patients with higher baseline ALT levels. Studies in patients with HBeAg-negative chronic hepatitis show response rates of 60% to 70% at 1 year18,19 ; however, relapse is experienced by 90% when treatment is withdrawn. The durability of HBeAg seroconversion or reduced viremia is variable in patients treated with lamivudine; HBeAg seroconversion is seen in 50% to 80% of patients who are HBeAg-positive, and reduction of viremia in less than 10% of those who are HBeAg-negative.11,20  Thus, in patients who are HBeAg-positive, maintenance dosing for 3 to 6 months is often recommended after HBeAg seroconversion. In patients who are HBeAg-negative, long-term therapy is often required because of the poor durability of their response. A significant problem with lamivudine monotherapy is the development of resistant strains of HBV—the YMDD (tyrosine, methionine, aspartate, and aspartate) mutation in the HBV polymerase. The development of resistance to lamivudine is characterized by the appearance of significant HBV viremia and elevation in the serum ALT level. In addition, recent studies have found that patients with resistance to lamivudine do not maintain the initial histologic benefit achieved with therapy.21 The likelihood of a resistant strain developing is between 14% and 32% after 1 year of therapy, and 38%, 49%, 66%, and 69% after 2, 3, 4, and 5 years, respectively.22  Risk factors for resistance to lamivudine include high pretreatment levels of HBV DNA, high pretreatment ALT levels, high histologic activity index, high body mass index, and a slow virologic response.23 Adefovir dipivoxil. This nucleotide analog of adenosine monophosphate can inhibit HBV DNA polymerase and cause chain termination. It is well tolerated—aside from reversible nephrotoxicity, which is more common in patients with decompensated cirrhosis. In patients with chronic hepatitis who were HBeAg-positive, adefovir, 10 mg/d for 48 weeks, resulted in HBeAg seroconversion in 12% of those treated.24  In patients with chronic hepatitis who were HBeAgnegative, the same regimen resulted in undetectable levels of HBV DNA by polymerase chain reaction assay in 51% and in normalization of ALT levels in 72%; when the duration of treatment was 96 weeks, results were similar.12,25 Adefovir has been effective in the treatment of chronic HBV infections in which strains resistant to lamivudine have developed. If there is evidence of breakthrough infection in a patient being treated with lamivudine, adefovir, 10 mg/d PO, can be added to the regimen before discontinuation of lamivudine is considered.26 Other antiviral therapies. Recently, tenofovir disoproxil fumarate, another acyclic nucleotide analog that currently is approved only for the treatment of HIV infection, was compared with adefovir in patients with resistance to lamivudine.27  After 48 weeks of therapy, HBV DNA levels were suppressed to less than 105 copies/mL in 100% of the patients treated with tenofovir but in only 44% of those treated with adefovir. Phase 3 trials are currently ongoing for other antiviral agents, including entecavir, emtricitabine, and telbivudine. The preliminary results are encouraging. Combination therapy is likely to be more successful than monotherapy. However, combination therapy is still in the trial phase. In addition, this approach will be considered only in special situations and in patients under the care of a hepatologist. Dr Shapira is a gastroenterology fellow at the University of British Columbia in Vancouver. Dr Yoshida is associate professor of medicine in the division of gastroenterology at the University of British Columbia. REFERENCES: 1. Centers for Disease Control and Prevention. Hepatitis B fact sheet. Available at: http://www.cdc.gov/hepatitis. Accessed February 24, 2005. 2. Andre F. Hepatitis B epidemiology in Asia, the Middle East, and Africa. Vaccine. 2000;18:520-522. 3. McMahon BJ. Hepatocellular carcinoma and viral hepatitis. In: Wilson RA, ed. Viral Hepatitis. New York: Marcel Dekker; 1997:315-330. 4. Centers for Disease Control and Prevention. Hepatitis B frequently asked questions. Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/b/faqb.htm. Accessed February 24, 2005. 5. Hepatitis B Foundation. CDC recommendations for pregnant women. Available at: http://www.hepb.org/professionals/pregnancy_cdc_summary.htm. Accessed April 12, 2005. 6. Cooksley W, Piratvisuth T, Lee SD, et al. Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepat. 2003;10:298-305. 7. Wong DK, Cheung AM, O’Rourke K, et al. Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-- analysis. Ann Intern Med. 1993;119:312-323. 8. Manesis EK, Hadziyannis SJ. Interferon alpha treatment and retreatment of hepatitis B e antigennegative chronic hepatitis B. Gastroenterology. 2001; 121:101-109. 9. Lampertico P, Del Ninno E, Vigano M, et al. Long-term suppression of hepatitis B e antigen-negative chronic hepatitis B by 24 month interferon therapy. Hepatology. 2003;37:756-763. 10. Lau DT, Everhart J, Kleiner DE, et al. Longterm follow-up of patients with chronic hepatitis B treated with interferon alpha. Gastroenterology. 1997; 113:1660-1667. 11. Tassopoulos NC, Volpes R, Pastore G, et al. Post lamivudine treatment follow-up of patients with HBeAg-negative chronic hepatitis B [abstract]. J Hepatol. 1999;30:117. 12. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al; for the Adefovir Dipivoxil 438 Study Group. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med. 2003;348:800-807. 13. Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2004;351: 1206-1217. 14. Hoofnagle JH, Di Bisceglie AM, Waggoner JG, Park Y. Interferon alfa for patients with clinically apparent cirrhosis due to hepatitis B. Gastroenterology. 1993;104:1116-1121. 15. Lai CL, Chien RN, Leung NW, et al. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med. 1998;339:61-68. 16. Dienstag JL, Schiff ER, Wright TL, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med. 1999;341:1256-1263. 17. Chang TT, Lai CL, Chien RN, et al. Four years of lamivudine treatment in Chinese patients with chronic hepatitis B. J Gastroenterol Hepatol. 2004;19: 1276-1282. 18. Tassopoulos NC, Volpes R, Pastore G, et al. Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore Mutant Study Group. Hepatology. 1999;29: 889-896. 19. Hadziyannis SJ, Papatheodoridis GV, Dimou E, et al. Efficacy of long-term lamivudine monotherapy in patients with hepatitis B e antigen-negative chronic hepatitis B. Hepatology. 2000;32(4, pt 1):847-851. 20. Dienstag JL, Cianciara J, Karayalcin S, et al. Durability of serologic response after lamivudine treatment of chronic hepatitis B. Hepatology. 2003; 37:748-755. 21. Dienstag JL, Goldin RD, Heathcote EJ, et al. Histologic outcome during long-term lamivudine therapy. Gastroenterology. 2003;124:105-117. 22. Guan R, Lai CL, Liaw YF, et al. Efficacy and safety of 5 years of lamivudine treatment of Chinese patients with chronic hepatitis B. J Gastroenterol Hepatol. 2001;16(suppl 1):A60. 23. Yuen MR, Sablon E, Hui CK, et al. Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy. Hepatology. 2001;34:785-791. 24. Marcellin P, Chang TT, Lim SG, et al, for the Adefovir Dipivoxil 437 Study Group. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003;348:808-816. 25. Hadziyannis S, Tassopoulos N, Heathcote J, et al. Two year results from a double-blind, randomized, placebo-controlled study of adefovir dipivoxil (ADV) for presumed precore mutant chronic hepatits B. J Hepatol. 2003;39(suppl 2):143. 26. Lok AS, McMahon BJ; Practice Guidelines Committee, American Association for the Study of Liver Diseases (AASLD). Chronic hepatitis B: update of recommendations. Hepatology. 2004;39:857-861. 27. van Bommel F, Wunsche T, Mauss S, et al. Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. Hepatology. 2004;40:1421-1425.