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FEBRUARY 2008
Main Article:
An Approach To Hepatitis B Virus In The Correctional Setting
Jennifer Cocohoba, Pharm. D. Assistant Clinical Professor University of California San Francisco School of Pharmacy Joseph Bick, MD Chief Deputy, Clinical Services California Medical Facility, California Department of Corrections Introduction Approximately 1.25 million persons in the United States are chronically infected with hepatitis B virus (HBV).1,2 An estimated 2% of inmates in the U.S. have chronic HBV infection, five times the prevalence found in non-incarcerated populations.3 Almost one third of new HBV cases in the U.S. each year occur among inmates or those who have been incarcerated.4 Although most HBV-infected inmates acquired the infection prior to incarceration, transmission of HBV has been well documented within jails and prisons.5 This article will review basic concepts of HBV transmission, prevention, diagnosis, and treatment including special considerations for the management of hepatitis B in correctional settings. Transmission HBV is transmitted percutaneously and by mucosal contact with the blood and body fluids of chronically infected persons. In the United States, most new cases of HBV are due to sexual activity or injection drug use among unvaccinated adults. Less commonly, HBV is transmitted through occupational and health care associated mucosal or percutaneous exposure to blood. Outbreaks of HBV have been linked to contaminated equipment used for injections and acupuncture.6, 7 Other recognized risks for HBV infection include sharing a toothbrush, razor, or other device that has come into contact with blood from a person who is chronically infected with HBV. Although skin or mucosal contact with saliva from an HBV infected person has not been linked to transmission of the virus, transmission has occurred through a human bite.8 Natural history of HBV infection Acute HBV infection is usually asymptomatic. Those who do become clinically ill may experience an insidious onset of nausea, emesis, abdominal discomfort, and anorexia. Arthralgias, rash, and icterus may develop. Primary infection is generally self limited, does not lead to chronic viremia, and results in long term immunity to re-infection. The likelihood that chronic HBV will develop depends upon the age at acquisition and the immune status of the person who becomes infected. Approximately 5% of HIV negative adolescents and adults who become infected with HBV will develop chronic infection, and 15-25% of those who are chronically infected will develop cirrhosis, liver cancer, or liver failure due to HBV.9,10 HIV/HBV co-infection is associated with decreased clearance of hepatitis B surface antigen and e antigen and increased HBV viremia.11 Co-infection with HIV and HBV is also associated with increased mortality as compared to HIV monoinfection.12 Untreated infants who acquire HBV perinatally have a 90% risk of chronic infection.13 Prevention Routine immunization of infants, children, and adolescents has contributed to a dramatic decline in the incidence of new cases of HBV, and continued effort to achieve universal childhood HBV vaccination is the best strategy for HBV elimination. Currently, most acute cases of HBV develop among unvaccinated adults. Although most adults will accept HBV vaccination if it is offered to them, many at-risk adults who are at highest risk for acute HBV infection do not have ready access to free or low cost vaccination services.14 Correctional facilities can be ideal settings in which to reach adults who are at-risk for HBV infection. The Advisory Committee on Immunization Practices (ACIP) recommends that HBV vaccination be provided to all non-immune inmates of correctional facilities. Routine vaccination can be facilitated through the use of standing orders for screening and immunization.15 HBV vaccination consists of 3 intramuscular doses in the deltoid muscle administered by one of the following schedules: 0, 1, and 6 months; 0, 1, and 4 months; 0, 2, and 4 months, or 0, 1, 2, and 12 months. A combined hepatitis A virus (HAV) and HBV vaccine (Twinrix) is also available for adults who are non-immune to both viruses. Twinrix can be administered at either 0, 1, and 6 months; or an accelerated schedule of 0, 7, and 21-30 days, followed by a dose at 12 months. The latter schedule is particularly useful in jails and other short-stay situations. (See Table 1 for additional dosing information) The percentage of those who will develop a protective level of HBV antibodies is decreased in hemodialysis patients, HIV infected persons, men, those > 50 years old, and smokers.16 Using a double dose of vaccine has been shown to improve the response rate to immunization in dialysis patients and those who are HIV infected.17 In general, it is not necessary to test for immunity following HBV vaccine. Testing should be considered for those who will be at high risk for ongoing exposure to blood or body fluids. Those who failed to develop a protective level of HBsAb should receive another course of three doses of vaccine. Revaccination leads to protective antibody levels in 50-100% of recipients.18 Persons with chronic HBV should not donate organs, blood, or semen. Post Exposure Prophylaxis (PEP) for HBV Pregnant women should be screened for HBV so that prophylaxis can be given to the newborns of those with chronic HBV infection. Administration of one dose of hepatitis B immune globulin and initiating the three dose HBV vaccination series within 24 hours after birth is 85%-95% effective in preventing both HBV infection and the chronic carrier state.13 HBV PEP should be initiated for any non-immune person who has occupational percutaneous or mucosal exposure to blood from a chronically infected individual.13,19 (See Table 2) Screening and diagnosis The American Association for the Study of Liver Diseases recommends HBV screening for all inmates of correctional facilities.20 If screening is conducted solely to identify those who are unlikely to benefit from immunization, testing for anti-HBc (HBcAb) and anti-HBsAg (HBsAb) will identify those who have previously been infected or immunized. If the goal is to identify both those who are immune and those who have chronic HBV, it may be more useful to obtain both HBsAg and anti-HBsAg (HBsAb). Table 3 describes the interpretation of HBV serologic markers. Vaccinating those who are already immune to HBV because of prior immunization or infection does not cause adverse effects. Whether or not screening should be conducted prior to vaccination depends upon the baseline prevalence of immunity and chronic HBV infection in the population being immunized. In a study conducted in the Texas Department of Corrections, the cost of prevaccination testing was equivalent to that of vaccination without testing when the underlying HBV prevalence reached 25%.21 Diagnosis of chronic HBV infection Chronic HBV infection should be considered in those who have persistent elevations in liver transaminases. The diagnosis can be confirmed by the presence of hepatitis B surface antigen that persists for greater than 6 months. Occasionally, the only HBV serologic marker that is present is anti-HBc. Isolated anti-HBc can be a false positive, can be found in those who have recovered from HBV infection but have waning levels of HBsAb, who are chronically infected and have low levels of HBsAg. The initial evaluation of a patient who has chronic HBV should include a complete history and physical examination. Blood testing should include a complete blood count with platelets, transaminases, albumin, prothrombin time, and serologies for hepatitis A, C, delta, and HIV. Hepatitis B specific laboratory tests include hepatitis B surface antigen, e antigen, anti-HBe, and hepatitis B viral DNA. A serum alpha fetoprotein and ultrasound or CT should be obtained every 6-12 months to screen for hepatocellular carcinoma. Liver biopsy is not routinely necessary in the diagnosis and management of chronic HBV.20 Treatment of HBV Goals of therapy The goals of HBV treatment are to suppress viral replication, seroconvert from HBsAg to HBsAb and HBeAg to HBeAb, and prevent long-term liver damage that can result in cirrhosis, liver failure, and hepatocellular carcinoma. Treatment is generally recommended for chronically infected patients who are HBeAg(+) with ALT levels persistently greater than 2 times upper limit of normal, and for patients who are HBeAg(-) with HBV DNA greater than 20,000 IU/mL and ALT levels persistently greater than 2 times upper limit of normal.20 Treatment should be considered for patients who are HBeAg(+) with ALT levels 1-2 times the upper limit of normal and those who are HBeAg(-) with HBV DNA levels between 2,000 and 20,000 IU/mL and ALT 1-2 times upper limit of normal.20 Available treatments (See HBV 101) Interferons Interferon alfa was the first FDA approved agent for the treatment of hepatitis B. In clinical trials, therapy with interferon resulted in 32-79% of participants clearing HBV-DNA, but only 10-15% demonstrated seroreversion of the HBsAg.22-26 Predictors of a favorable response to interferon therapy include lower baseline levels of HBV DNA and high aminotransferase levels. Due to the inconvenience of multiple weekly subcutaneous injections, treatment with interferon has largely been replaced by once weekly pegylated interferon and oral nucleoside/nucleotide analogs. Seroconversion of HBeAg and HBsAg is more frequent with peg-interferon compared to lamivudine over shorter study periods. However, treatment with lamivudine is not usually given short term.27,28 Nucleoside and Nucleotide analogs Nucleoside and nucleotide analogs interfere with the ability of the HBV polymerase to synthesize viral DNA. With all agents in this class, there is a risk of acute HBV exacerbation upon abrupt cessation of therapy. In clinical trials, most cases were marked by asymptomatic increases in liver transaminases and increases in HBV viremia, although a few cases were fatal. Care must be taken to taper, substitute, or monitor closely when these HBV therapies are discontinued. Lamivudine (Epivir HB) Lamivudine was the first oral medication approved by the FDA for the treatment of HBV, and is generally well-tolerated A study of 651 Chinese patients randomly assigned to receive lamivudine or placebo was terminated after a median of 32.4 months due to a difference in hepatic disease progression and death between the treatment and placebo arms (7.8% versus 17.7%, HR for progression =0.45, p =0.001).29 In an Italian study, 93.9% of HBeAg(-) patients achieved a HBV virological response after approximately 22 months treatment. At the 4-year follow up, the proportion with a virologic response had decreased to 39%. In the multivariable analyses, viral breakthrough increased the risk for hepatocellular carcinoma and end stage liver disease. (p< 0.001).30 In another double-blind placebo controlled clinical trial of 139 HBeAg(-) patients, a median 3.21 log copies/mL reduction in HBV DNA was achieved in the lamivudine arm compared to only 0.47 log copies/mL (p < 0.001) for placebo. After 244 months, more lamivudine patients (56% vs. 11%, p < 0.001) had achieved a complete response to therapy.31 In a smaller study of 34 HBeAg(+) patients treated with lamivudine for one year, 70.6% at one year, 64.7% at 2 years, and 55.8% at 3 years had undetectable HBV DNA and normalization of transaminase levels.32 Another small study of 20 Japanese patients treated with lamivudine for more than one year, and followed for a median of 8.5 years, found a 30% increase in HBeAg clearance and a 55% increase in the proportion of patients with undetectable HBV DNA at the end of the study.33 The efficacy of lamivudine does not appear to be affected by renal transplant or hemodialysis.34 Resistance to lamivudine is conferred by a mutation in the YMDD region of the HBV polymerase. This mutation is common and occurs in 24%, 56%, and 75% of patients after one, two, and three years respectively. A small study in 30 patients suggests that early detection of the YMDD mutation may be useful for predicting virologic breakthrough at 24 months (p=0.003).35 Clinical benefits to lamivudine therapy may be decreased in patients who develop the YMDD mutation. In a study of 74 patients who continued on lamivudine therapy for 3 years, 15% versus 64% demonstrated histologic improvement at 3 years, 54% versus 32% remained unchanged, and 31% versus 5% worsened histologically for those with the YMDD versus wild-type variant.36 Adefovir (Hepsera) Adefovir was initially evaluated for its anti-HIV activity before dose-limiting renal toxicity halted further study. It was later discovered that adefovir completely inhibits HBV viral replication at lower, less nephrotoxic doses. One large clinical trial of adefovir in 185 HBeAg(-) patients randomly assigned participants to receive treatment or placebo for 48 weeks.37 At 48 weeks, participants were again randomly assigned to receive adefovir versus placebo for an additional 48 weeks of therapy. Median HBV DNA reduction among those receiving adefovir was 3.63 log copies/mL, and 79% of participants had an undetectable HBV DNA at 144 weeks. Potential adefovir resistance mutations were identified in 5.9% of patients after 144 weeks of therapy. 125 subjects enrolled in a continuation arm of this study to 240 weeks demonstrated a durable response. In 67% of participants HBV DNA remained < 1000 copies/mL, ALT levels remained normalized in 69%, and 73% had decreased fibrosis.38 A randomized clinical trial of adefovir versus placebo in 515 HBeAg(+) patients found 53% versus 25% histologic improvement (p < 0.001), 21% versus 0% undetectable HBV-DNA (p<0.001), and 48% versus 16% ALT normalization (p<0.001) at 48 weeks.39 In addition, HBeAg seroconversion was achieved in 12% versus 6% of patients (p=0.049). A randomized double-blind placebo-controlled clinical trial of adefovir in 480 Chinese subjects found a median reduction of 4.5 log copies/mL, 28% of subjects undetectable HBV DNA, and 79% of subjects with normalization of ALT at 52 weeks.40 Adefovir is active versus lamivudine-resistant HBV and may be useful for salvage therapy. A number of studies have looked at the combination of lamivudine and adefovir for the treatment of lamivudine resistant HBV, however the clinical and serologic benefits of combination therapy are not yet well-established.41-47 There is insufficient data to recommend combination therapy in treatment naive individuals. Adefovir is effective in patients with renal insufficiency, those undergoing hemodialysis, and those who have had a kidney transplant.48, 49 Entecavir (Baraclude) Entecavir is a potent guanosine nucleoside analogue for the treatment of HBV. In a phase 3 double blind randomized study of entecavir versus lamivudine in 648 HBeAg(-) patients, a higher proportion of entecavir treated subjects demonstrated histologic improvement (70% versus 61%, p=0.001), undetectable HBV DNA (90% vs 72%, p < 0.001) and normalization of ALT levels (78% vs. 71%, p=0.045) at 48 weeks.50 A phase 3 trial of entecavir versus lamivudine in 715 HBeAg(+) patients also found a higher proportion of histologic improvement (72% vs 62%, p =0.009), undetectable HBV DNA (67% vs. 36%, p < 0.001) and normalization of ALT (68% vs. 60%, p =0.02) for entecavir treated subjects.51 These outcomes appear to be similar after 2 years of therapy: in a study of 709 HBeAg(+) patients 80% vs 39% (p< 0.0001) achieved undetectable HBV DNA and 87% vs 79% ( p = 0.0056) demonstrated normalization of ALT levels at 96 weeks, though there was no difference in HBeAg seroconversion (31% vs. 25%).52 The incidence of resistance to entecavir is thought to be low and develops via a two-step process which requires lamivudine resistance mutations to develop in combination with further mutations. Therefore, although entecavir appears to be effective in the treatment of lamivudine-resistant HBV, it is not recommended to use them in combination.53-55 In comparison to adefovir, entecavir has been shown to be superior for virological endpoints in both HBeAg(-) and HBeAg(+) populations and for ALT normalization and seroconversion in HBeAg(+) individuals. Entecavir was also superior to adefovir for histological endpoints in HBeAg(+) persons, and comparable in HbeAg(-) persons.56 Telbivudine (Tyzeka) Telbivudine is the newest nucleoside analogue approved for the treatment of hepatitis B. In a 1370 person, randomized, non-inferiority trial of telbivudine 600mg versus lamivudine 100mg, telbivudine was non-inferior to lamivudine for HBeAg(-) patients in achieving normalization of ALT or a histologic response after 52 weeks of therapy.57 For HBeAg(+) patients, a higher proportion achieved a histologic response in the telbivudine arm (64.7% vs 56.3%, p =0.01) compared to lamivudine arm. Telbivudine has also been compared to adefovir in a 52-week open label study of 135 HBeAg(+) patients.58 Subjects received telbivudine for 52 weeks, adefovir for 52 weeks, or adefovir for 24 weeks, followed by telbivudine for 28 weeks. At week 24, patients in the telbivudine arm had a higher odds of having undetectable HBV DNA compared to the other arms pooled together (OR 4.46 1.86-10.72, p=0.001). There do not appear to be significant drug-drug interactions between telbivudine and adefovir or lamivudine.59 Single dose studies have suggested that telbivudine can be used across varying degrees of hepatic impairment and that its pharmacokinetics are unaltered if co-administered with food.60,61 Telbivudine also selects for mutations in the YMDD region of HBV polymerase though at a slower rate than lamivudine (4.4% after 1 year, 21.6% after 2 years). Adefovir may also be useful for patients who have developed resistance to telbivudine. Combination Interferon/nucleoside therapy In a randomized, controlled, open-label trial of 100 HBeAg-positive patients, sustained seroconversion and HBV DNA < 500,000 copies was achieved in a higher proportion of patients treated with peg-interferon plus lamivudine (36%) versus lamivudine alone (14%).27 In a study of 814 HBeAg-positive patients more subjects assigned to peg-interferon plus lamivuine or peg-interferon alone achieved HBeAg seroconversion (32% vs. 27% vs. 19 %; p = 0.02 and p < 0.001 respectively) compared to treatment with lamivudine alone after 24 weeks. Sixteen patients in the peg-interferon groups had HBSAg seroconversion compared to zero in the lamivudine only group.62 A study in HBeAg-negative patients treated for 48 weeks found HBV DNA suppression was achieved in a higher proportion of patients on pegylated interferon monotherapy (19%) or combination lamivudine therapy (20%) as compared to lamivudine alone (7%) at 24 weeks post treatment.28 Normalization of ALT was also higher in the peg-interferon groups (59% and 60%) versus lamivudine alone (44%). Selection of therapy Selection of therapy should be based on a variety of factors including efficacy, toxicity, availability, duration, route of administration, patient preference, provider preference, co-presence of HIV infection, and potential for resistance. For HBeAg(-) patients that require more than one year of therapy, lamivudine and telbivudine may be less optimal choices due to the potential for resistance after long treatment. For patients who are unable to be monitored closely, interferon therapy may not be optimal due to the many side effects and numerous laboratory studies required. For HIV positive patients, antiretroviral therapies may already provide suppression of HBV and additional therapy may not be required. Treatment of HBV/HIV co-infection Special considerations should be made to optimize therapy for patients who are co-infected with HIV and HBV. For co-infected patients who meet clinical indications for treatment of both HIV and HBV, the antiretroviral regimen should include agents that are active against both viruses. Tenofovir and either lamivudine or emtricitabine in combination with a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor is a good initial choice. For co-infected patients who do not meet clinical indications for treatment of HIV but require therapy for hepatitis B, interferon or adefovir can be utilized. Less is known about telbivudine, but it is thought to have no anti-HIV activity and could potentially be used. Lamivudine, emtricitabine, tenofovir and entecavir should not be given as monotherapy to an HIV/HBVinfected patient because HIV resistance mutations may develop. Acute hepatitis flare-ups can occur when HBV replication increases, such as when the antiretroviral regimen is changed and drugs active against HBV are discontinued. Therefore, the selection of HIV salvage regimens must take into account the HBV status of the patient. Flares can also occur when HBV develops resistance, or when antiretroviral therapy leads to an immune reconstitution inflammatory response (IRIS). Monitoring and follow-up Treatment success can be determined by monitoring for seroconversion of HBeAg in HBeAg(+) patients, appearance of anti-HBeAg, normalization of aminotransferases, viral suppression of HBV DNA, and histologic improvement. For patients treated with interferon, 16-24 weeks is ideal for HBeAg(+) patients while 12 months of therapy might be required for HBeAg(-) patients. Liver function tests can be monitored every 3 months during treatment and HBV DNA should be monitored every 3-6 months. One year after treatment, and every 3-6 months thereafter, patients should be tested for the eAg and anti-HBe. If seroconversion occurs, treatment should continue for at least 6 months after appearance of anti-HBeAg, then stopped. Sustained virologic suppression can be achieved in a significant number of HBeAg(+) patients who seroconvert. If seroconversion does not occur, treatment may be continued. If virologic breakthrough is present, the treating clinician may consider switching to another active agent. For HBeAg(-) patients optimal treatment duration is less clear but is usually one year or longer. Doses and common adverse effects for all anti-hepatitis B agents are presented in HBV 101. Conclusions Jails and prisons provide unique opportunities and challenges for the prevention, diagnosis, and treatment of chronic viral hepatitis. Improving hepatitis B management programs within correctional institutions has the potential to benefit the individual, the correctional population, and the larger public health. The optimal treatment of chronic HBV continues to evolve, especially in the HIV co-infected person. References: 1. U.S. Disease Burden Data, 1980-2006: Disease Burden from Hepatitis A, B, and C In the United States. Centers For Disease Control. December 8, 2006. Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/resource/PDFs/disease_burden.pdf. 2. McQuillan GM, Coleman PJ, Kruszon-Moran D, Moyer LA, Lambert SB, Margolis HS. Prevalence of hepatitis B virus infection in the United States: the National Health and Nutrition Examination Surveys, 1976 through 1994. Am J Public Health. 1999;89(1):14-18. 3. The health status of soon-to-be-released inmates: a report to Congress. National Commission on Correctional Health Care. Available at: http://www.ncchc.org/pubs/pubs_stbr.html. Accessed Jan 20, 2007. 4. Conklin TJ, Lincoln T, Flanigan TP. Public health model to connect correctional health care with communities. Am J Public Health. 1998;88:1249-50. 5. Centers for Disease Control and Prevention. Transmission of Hepatitis B Virus in Correctional Facilities - Georgia, January 1999-June 2002. MMWR. 2004;53(30):678-81. 6. Kent G.P., Brondum J. et al. A large outbreak of acupuncture-associated hepatitis B. Am. J. Epidemiol. 1988;127:591-98.7. Centers for Disease Control and Prevention Transmission of Hepatitis B and C Viruses in Outpatient Settings - New York, Oklahoma, and Nebraska, 2000-2002. MMWR. 2003;52(38):901-06. 8. Transmission of Hepatitis B by Human Bite- confirmation by detection of virus in saliva and full genome sequencing. Hui, A. Y., Hung, L. C. T., Tse, P. C. H., et al. Journal of Clinical Virology. 2005;33(3):254-56. 9. Bosch FX, Ribes J, Cleries R, Diaz M. Epidemiology of hepatocellular carcinoma. Clin Liver Dis. May 2005;9(2):191-211. 10. Beasley RP. Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer. May 15 1988;61(10):1942-56. 11. Bodsworth NJ, Cooper DA, Donovan B. The influence of human immunodeficiency virus type 1 infection on the development of the hepatitis B virus carrier state. J Infect Dis 1991; 163: 1138-40. 12. Thio CL, Seaberg EC, Skolasky R et al. HIV-1, hepatitis B virus, and risk of liver related mortality in the Multicenter Cohort Study (MACS). Lancet 2002; 360: 1921-6. 13. Centers for Disease Control and Prevention. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination-recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR. 1991;40(RR-13):1-25. 14. Centers for Disease Control and Prevention. Hepatitis B Vaccination Among High-Risk Adolescents and Adults -- San Diego, California, 1998—2001 MMWR. 2002;51(28):618-21. 15. Centers for Disease Control and Prevention. A Comprehensive Immunization Strategy to Eliminate Transmission of Hepatitis B Virus Infection in the United States. Recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II: Immunization of Adults. MMWR. 2006;55(RR16):1-25. 16. Alimonos K, Nafziger A, Murray J et al. Prediction of Response to Hepatitis B Vaccine in Health Care Workers: Whose Titers of Antibody to Hepatitis B Surface Antigen Should Be Determined After a Three-Dose Series, and What Are the Implications in Terms of Cost-Effectiveness? Clin Inf Dis 1998; 26:566–71 17. Vries-Sluijs T, Hansen B, van Doornum G, et al. A Prospective Open Study of the Efficacy of High-Dose Recombinant Hepatitis B Rechallenge Vaccination in HIV-Infected Patients. J Inf Dis 2008; 197: 292-95. 18. Averhoff F, Mahoney F, Coleman P, Schatz G, Hurwitz E, Margolis H. Immunogenicity of hepatitis B vaccines: implications for persons at occupational risk of hepatitis B virus infection. Am J Prev Med. 1998;15:1-8. 19. Centers for Disease Control and Prevention. Updated U.S. Public Health Service guidelines for the management of occupational exposures to HBV, HCV, and HIV and recommendations for postexposure prophylaxis. MMWR. 2001;50(RR-11):1-42. 20. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. Feb 2007;45(2):507-39. 21. Centers for Disease Control and Prevention. Hepatitis B Vaccination of Inmates in Correctional Facilities-Texas, 2000-2002. MMWR. 2004;53(30):681-83. 22. Gonzalez-Mateos F, Garcia-Monzon C, Garcia-Buey L, Garcia-Sanchez A, Pajares JM, Moreno-Otero R. Long-term effect of interferon alpha alone or after prednisone withdrawal in chronic hepatitis B. Interim report and review of the literature. Hepatogastroenterology. Nov-Dec 1995;42(6):893-99. 23. Di Bisceglie AM, Fong TL, Fried MW, et al. A randomized, controlled trial of recombinant alpha-interferon therapy for chronic hepatitis B. Am J Gastroenterol. Nov 1993;88(11):1887-92. 24. Hoofnagle JH, Peters M, Mullen KD, et al. Randomized, controlled trial of recombinant human alpha-interferon in patients with chronic hepatitis B. Gastroenterology. Nov 1988;95(5):1318-25. 25. Korenman J, Baker B, Waggoner J, Everhart JE, Di Bisceglie AM, Hoofnagle JH. Long-term remission of chronic hepatitis B after alpha-interferon therapy. Ann Intern Med. Apr 15 1991;114(8):629-34. 26. Niederau C, Heintges T, Lange S, et al. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med. May 30 1996;334(22):1422-27. 27. Chan HL, Leung NW, Hui AY, et al. A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone. Ann Intern Med. Feb 15 2005;142(4):240-50. 28. 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. Sep 16 2004;351(12):1206-17. 29. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. Oct 7 2004;351(15):1521-31. 30. Di Marco V, Marzano A, Lampertico P, et al. Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine. Hepatology. Oct 2004;40(4):883-91. 31. Chan HL, Wang H, Niu J, Chim AM, Sung JJ. Two-year lamivudine treatment for hepatitis B e antigen-negative chronic hepatitis B: a double-blind, placebo-controlled trial. Antivir Ther. 2007;12(3):345-53. 32. Scotto G, Palumbo E, Fazio V, et al. Prolonged lamivudine treatment in patients with chronic active anti-HBe-positive hepatitis. Am J Ther. May-Jun 2006;13(3):218-22. 33. Akuta N, Suzuki F, Suzuki Y, et al. Favorable efficacy of long-term lamivudine therapy in patients with chronic hepatitis B: an 8-year follow-up study. J Med Virol. Apr 2005;75(4):491-98. 34. Lapinski TW, Flisiak R, Jaroszewicz J, Michalewicz M, Kowalczuk O. Efficiency and safety of lamivudine therapy in patients with chronic HBV infection, dialysis or after kidney transplantation. World J Gastroenterol. Jan 21 2005;11(3):400-02. 35. Paik YH, Han KH, Hong SP, et al. The clinical impact of early detection of the YMDD mutant on the outcomes of long-term lamivudine therapy in patients with chronic hepatitis B. Antivir Ther. 2006;11(4):447-55. 36. Rizzetto M, Tassopoulos NC, Goldin RD, et al. Extended lamivudine treatment in patients with HBeAg-negative chronic hepatitis B. J Hepatol. Feb 2005;42(2):173-79. 37. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med. Jun 30 2005;352(26):2673-81. 38. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology. Dec 2006;131(6):1743-51. 39. Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. Feb 27 2003;348(9):808-16. 40. Zeng M, Mao Y, Yao G, et al. A double-blind randomized trial of adefovir dipivoxil in Chinese subjects with HBeAg-positive chronic hepatitis B. Hepatology. Jul 2006;44(1):108-16. 41. Lampertico P, Vigano M, Manenti E, Iavarone M, Sablon E, Colombo M. Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients. Gastroenterology. Nov 2007;133(5):1445-51. 42. Perrillo R, Hann HW, Mutimer D, et al. Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus. Gastroenterology. 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Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology. Jan 2004;126(1):91-101. 48. Izzedine H, Hulot JS, Launay-Vacher V, et al. Renal safety of adefovir dipivoxil in patients with chronic hepatitis B: two double-blind, randomized, placebo-controlled studies. Kidney Int. Sep 2004;66(3):1153-58. 49. Fontaine H, Vallet-Pichard A, Chaix ML, et al. Efficacy and safety of adefovir dipivoxil in kidney recipients, hemodialysis patients, and patients with renal insufficiency. Transplantation. Oct 27 2005;80(8):1086-92. 50. Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. Mar 9 2006;354(10):1011-20. 51. Chang TT, Gish RG, de Man R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. Mar 9 2006;354(10):1001-1010. 52. Gish RG, Lok AS, Chang TT, et al. 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