Preventing and treating hepatitis B infection
http://www.100md.com
《英国医生杂志》
1 Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226 014, India
Correspondence to: R Aggarwal rakesh@sgpgi.ac.in
Introduction
Who needs treatment?
Patients with acute hepatitis B do not need treatment; those with fulminant hepatic failure should be considered for liver transplantation.
Patients with chronic hepatitis B virus infection should undergo a detailed evaluation to assess baseline liver function and the need for further treatment and follow up (box 3). Chronic hepatitis B virus infection is a heterogeneous condition and can be divided into many subsets based on clinical status and status of viral replication (table).
Classification of patients with chronic hepatitis B virus infection
Inactive carriers of hepatitis B are healthy; have a low concentration of serum hepatitis B virus DNA (a measure of rate of viral replication; < 105 copies/ml), or none; lack detectable HBeAg; have normal levels of alanine aminotransferase; and show little progression of liver disease. Though the exact relation between hepatitis B virus DNA levels and potential for liver damage is not known, it is generally believed that levels below 105 copies/ml are not associated with progression of liver injury.
Patients with chronic hepatitis B have viral replication, high hepatitis B virus DNA concentrations, and biochemical evidence of hepatitis. Chronic hepatitis B is either HBeAg positive (patients test positive for HBeAg) or HBeAg negative. The HBeAg negative patients lack detectable HBeAg despite a high rate of viral replication and high hepatitis B virus DNA levels; this paradox arises from a mutation (pre-core mutation) which permits viral replication but prevents production of HBeAg. HBeAg negative chronic hepatitis B has a poorer prognosis and treatment response than does HBeAg positive chronic hepatitis B.
Box 3: Initial evaluation of a patient with chronic hepatitis B virus infection
History and physical examination—Specifically look for symptoms and signs of portal hypertension (abdominal wall collaterals, splenomegaly, hypersplenism, ascites) and liver failure (jaundice, haematemesis, ascites, encephalopathy, etc)
Laboratory tests—Liver function tests (aminotransferases, serum albumin, prothrombin time); complete blood counts, renal function tests
Screen for oesophageal varices (upper gastrointestinal endoscopy)
Screen for hepatocellular carcinoma (ultrasonography and -fetoprotein levels)
Tests for viral replication status (HBeAg, anti-HBe, hepatitis B virus DNA)
Screen for coinfection with other parenterally transmitted viruses (anti-hepatitis C virus antibodies, HIV serology)
Liver biopsy (optional)
Liver biopsy is the gold standard for determining disease activity (necro-inflammation) and stage (fibrosis),12 but it is often contraindicated in patients with decompensated liver disease. Even in patients with compensated disease, though biopsy may provide information for therapeutic and prognostic decision making, it is frequently not done.13
The goal of treatment of chronic hepatitis B is to prevent progression to cirrhosis and hepatocellular carcinoma by preventing viral replication and suppressing necro-inflammatory activity. The unpredictable clinical course of hepatitis B virus infection, and poor response to treatment and doubts about its cost effectiveness, render therapeutic decisions difficult. In patients with decompensated cirrhosis, antiviral treatment has not been clearly shown to provide benefit, so liver transplantation is the only option. Histological cirrhosis is a poor prognostic marker among patients with compensated disease.
Patients in inactive carrier stage do not need treatment, since their liver disease progresses very slowly, if at all. The risk of developing hepatocellular carcinoma in these patients, though higher than in people without infection, is much lower than in HBeAg positive patients. Their alanine aminotransferase levels should be determined every 6-12 months,13 and every two years they should be screened for hepatocellular carcinoma with ultrasonography and -fetoprotein levels.14 Though the evidence in favour of this approach is limited,15 raised alanine aminotransferase in such patients may indicate HBeAg negative chronic hepatitis B and should prompt assessment for hepatitis B virus replication (hepatitis B virus DNA testing) and for other unrelated causes of liver injury (other hepatotropic viruses, alcohol, drugs, etc).
Only those patients who have chronic hepatitis B (active hepatitis B virus replication with a high viral load and ongoing necro-inflammation) qualify for treatment. Patients with chronic hepatitis B virus infection (HBsAg positive for > 6 months), alanine aminotransferase persistently exceeding 1.5-fold to twofold higher than normal, hepatitis B virus DNA > 105 copies/ml, and histological activity index > 4 are the most suitable candidates for treatment (box 4); in a large meta-analysis, 32% of such patients showed HBeAg to anti-HBe seroconversion, as compared with 11% of untreated patients.16 However, it is advisable to wait till transaminase has been raised for one to three months, in order to allow time for the spontaneous viral clearance that occurs in a sizeable proportion of such patients.13 14 17 In patients with ongoing viral replication and normal transaminase concentrations, response rate is quite poor; in such patients alanine aminotransferase should be measured every three months, and they should be treated if raised concentrations persist.18
Some categories of patients with chronic hepatitis B (those with hepatitis C virus or HIV coinfection) do not respond as well to treatment.
Treatment end points
Response to treatment is expressed as a combination of the specific aspects of response studied (biochemical or alanine aminotransferase levels, virological or viral DNA levels, or histological activity), and the time of assessment in relation to treatment (box 5).
Alanine aminotransferase concentrations are a surrogate marker of ongoing necro-inflammatory activity and serve as an inexpensive and simple tool for monitoring response to treatment. Seroconversion (loss of HBeAg and appearance of anti-HBe), whether naturally acquired or treatment induced, is an important and a widely used treatment endpoint, since it is associated with a reduced rate of progression to cirrhosis of the liver and reduced likelihood of decompensation.19 20 Although hepatitis B virus is not directly cytopathic, maintaining hepatitis B virus DNA concentration below a specified level is another useful treatment endpoint. Hepatitis B virus DNA level below 105 copies/ml is the most frequently used cut off for virological response; this can be assessed during treatment, at the end of treatment, or after treatment (sustained response). Since the main aim of treating chronic hepatitis B is to prevent progression of fibrosis and development of cirrhosis, liver biopsy may represent an ideal method of assessing response; however, its invasive nature and the risk of complications preclude its routine use. In patients with decompensated disease, Child-Pugh score may be a useful assessment tool.
Box 4: Treating chronic hepatitis B virus infection
Inactive HBsAg carriers
? Alanine aminotransferase every 6-12 months Screening for hepatocellular carcinoma
Chronic hepatitis B (active viral replication)
Normal alanine aminotransferase: Treatment not recommended Alanine aminotransferase every 3-6 months Screening for hepatocellular carcinoma
Raised alanine aminotransferase: Treatment indicated (interferon or lamivudine)
Cirrhosis
Compensated: Treatment indicated (interferon or lamivudine) Poor response to treatment
Decompensated: Lamivudine, liver transplantation
Difficult to treat patients
Hepatitis C virus or hepatitis D virus coinfection
Renal failure
Immunocompromised (human immunodeficiency virus infection, chemotherapy)
Decompensated cirrhosis
Box 5: End points of treatment for chronic hepatitis B virus infection
Treatment responses
Biochemical response—Return of alanine aminotransferase to within normal range
Virological response—Decline in hepatitis B virus DNA to < 10 copies/ml
Serological response—HBeAg loss and appearance of anti-HBe
Histological response—Decrease in necro-inflammatory score by 2 points
Time frame for assessment of response
On-treatment response—Response assessed while receiving treatment
End of treatment response—Response assessed at the end of treatment duration
Sustained response—Response after a period off drugs (6 months or 12 months)
Treatment options
Three drugs—interferon alfa, lamivudine, and adefovir—are approved in several countries for use in chronic hepatitis B. Of these, interferon has both antiviral and immunomodulatory activity; lamivudine and adefovir are primarily antiviral. Use of drugs with only immunomodulatory activity (thymosin -1) is not well established. Emtricitabine, entecavir, telbuvidine, and clevudine are currently under investigation.
General advice
Avoiding alcohol, safe sexual practices, immunisation of household contacts, vaccination against hepatitis A (in low prevalence areas), and weight reduction should be advised. People who might spread hepatitis at work should either undergo treatment or change their profession. Immunosuppressive drugs should be used with caution in order to avoid activating hepatitis B virus infection.
Interferon
Interferon alfa, a host cytokine produced in response to any viral invasion, has immunomodulatory, antiviral, and anti-fibrotic properties. It was first used in the 1980s and was the first drug to be found useful in the treatment of chronic hepatitis B. The dose is 5 million units a day or 10 MU thrice weekly (30-35 MU/week), given subcutaneously, usually for 16 weeks.
Interferon can have several adverse effects. An influenza-like illness (fever, chills, headache, malaise, myalgias) occurs in 25-30% of patients but rarely needs discontinuation of treatment. More serious adverse events (myelosuppression (leucocytes < 1000/μl and platelets < 60 000/μl), emotional lability and depression, development of autoantibodies, and thyroid dysfunction) may lead to discontinuation of interferon; thus, pretreatment screening for psychiatric illness, low leucocyte and platelets counts, autoantibodies, and thyroid function is mandatory. Administration of corticosteroids before interferon treatment is not useful.
Interferon has been used in both types of chronic hepatitis B. In HBeAg positive patients, about a third show virological and histological response.16 The factors that determine response to interferon are listed in box 6. Interferon induced seroconversion in HBeAg positive patients lasts for at least eight years,19 20 but interferon induced responses are less durable in HBeAg negative chronic hepatitis B.21 Though prolonging treatment for one to two years may improve the sustained response rates, the benefit in these patients remains less than that in HBeAg positive chronic hepatitis B.
Use of interferon in decompensated cirrhosis is associated with an increased risk of infections and exacerbation of liver injury. Response rate is also poor in patients with compensated cirrhosis, and there is a risk of precipitating liver decompensation.
Pegylated interferon, a longer acting interferon preparation, may be better than conventional interferon.22 Data on its use in chronic hepatitis B are limited, precluding a recommendation for routine use.
Lamivudine
Lamivudine, a synthetic nucleoside (cytosine) analogue available since 1998, undergoes intracellular phosphorylation to its active metabolite lamivudine triphosphate and inhibits viral reverse transcriptase, causing premature chain termination during viral DNA synthesis.
In initial studies in patients with HBeAg positive chronic hepatitis B, treatment with lamivudine for 52 weeks fared better than placebo in inducing biochemical response, HBeAg to anti-HBe seroconversion, and histological response, and induced a reduction in hepatitis B virus DNA levels throughout the treatment period.23 24 However, the response rate depends on duration of treatment: prolonged treatment is associated with higher seroconversion rates (21% at one year, 29% at two years, 40% at three years).25 However, with increasing duration of treatment, an increasing proportion of patients develop a mutation in the tyrosine-methionine-aspartate-aspartate (YMDD) motif in the catalytic domain of viral DNA polymerase, which confers lamivudine resistance (14% at one year to 69% at five years), which affects the disease course adversely. Higher pretreatment alanine aminotransferase levels predict a higher response rate; hepatitis B virus DNA levels do not influence response to lamivudine.
Box 6: Predictors of non-response to interferon in chronic hepatitis B
Viral factors:
High serum hepatitis B virus DNA levels
Mutant virus (for example, pre-core mutant with negative HBeAg)
Co-infection with hepatitis C virus or hepatitis delta virus
Host factors:
Normal transaminase activity
Infection acquired in early childhood
Male sex
Asian ethnic origin
Immunosuppression (including drugs, HIV infection)
Decompensated liver disease
Additional educational resources
Information for patients
Hepatitis B Foundation (www.hepb.org)—Provides information for patients and families, and for healthcare professionals (in English and several other languages)
British Columbia Centre for Disease Control. Hepatitis (www.bccdc.org/topic.php?item=59)—Educational material on hepatitis B for patients
National Center for Infectious Diseases, Centers for Disease Control and Prevention. Viral hepatitis B (www.cdc.gov/ncidod/diseases/hepatitis/b/index.htm)—Educational material for patients and healthcare professionals on prevention guidelines for hepatitis B
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Hepatitis publications (http://digestive.niddk.nih.gov/ddiseases/pubs/hepatitis/index.htm)—Information for patients on treatment and prevention of various forms of hepatitis. (Some documents are also available in Spanish)
About.com. Hepatitis (www.hepatitis.about.com/cs/hepatitisb)—Comprehensive information about hepatitis B treatment, with web links
Singapore Ministry of Health. Clinical Practice Guidelines. Chronic hepatitis B infection. April 2003. (www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=3749)—Evidence based information about hepatitis B treatment and prevention
Everson GT, Weinberg H. Living with hepatitis B: a survivor's guide. Long Island City, NY: Hatherleigh Press. 2002.—Explains hepatitis B virus, disease associated with this infection, and its prevention and treatment
Green WF, Conjeevaram H. The first year—hepatitis B: an essential guide for the newly diagnosed. Emeryville, CA: Marlowe, 2002—Provides current and empathetic information for those wishing to take an active role in their hepatitis B treatment
Major reviews and guidelines on treatment of hepatitis B
Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000—summary of a workshop. Gastroenterology 2001;120: 1828-53.
Lok AS, McMahon BJ, Practice Guidelines Committee, American Association for the Study of Liver Diseases. Chronic hepatitis B. Hepatology 2001;34: 1225-41.
EASL Jury. EASL international consensus conference on hepatitis B, 13-14 September 2002, Geneva, Switzerland. Consensus statement (short version). J Hepatol 2003;38: 533-40.
Liaw YF, Leung N, Guan R, Lau GK, Merican I, Asian-Pacific Consensus Working Parties on Hepatitis B. Asian-Pacific consensus statement on the management of chronic hepatitis B: an update. J Gastroenterol Hepatol 2003;18: 239-45.
Keeffe EB, Dieterich DT, Han SH, Jacobson IM, Martin P, Schiff ER, et al. A treatment algorithm for the management of chronic hepatitis B virus in the United States. Clin Gastroenterol Hepatol 2004;2: 87-106.
Lamivudine treatment in HBeAg negative chronic hepatitis B is associated with less durable responses and a higher rate of emergence of YMDD mutants (60% at four years).26
Lamivudine treatment in patients with decompensated cirrhosis related to hepatitis B and active viral replication is associated with higher Child-Pugh score and better transplant-free and overall survival than in historical controls.11
The benefit takes months to appear and increases with time; however, beyond a certain time point, the administration of this drug may be counterproductive because the risk of appearance of mutant strains increases with longer treatment. Lamivudine has an excellent safety profile, even in patients with decompensated liver disease.
In treatment-naive patients with chronic hepatitis B, interferon and lamivudine give similar response rates. Each drug has certain relative advantages and disadvantages (see bmj.com). Given the poor response rate with both drugs, patient's choice and cost may be important considerations. Failure to respond to interferon does not adversely influence response rates with lamivudine, but in patients with decompensated disease, lamivudine is the only viable treatment option.
Adefovir
Adefovir dipivoxil, a nucleotide analogue of deoxyadenosine monophosphate, inhibits viral reverse transcriptase activity in both wild-type and YMDD mutant hepatitis B virus.27 Thus, it is the drug of choice for patients treated with lamivudine who have developed YMDD mutation. It has also been used in patients with HBeAg positive chronic hepatitis B 28 and HBeAg negative chronic hepatitis B,29 with efficacy rates at one year similar to those with lamivudine, albeit with no drug resistant mutations. Adefovir may thus be a useful alternative to lamivudine in all types of patients, though further data are needed. Adefovir resistant mutants of hepatitis B virus have recently been described; their clinical importance needs further study.
Combination treatment
Available data show no benefit of the lamivudine-interferon combination over individual drugs.13 14 Combinations of nucleoside analogues have not been adequately studied.
Liver transplantation in hepatitis B virus related liver disease
Hepatitis B virus related liver disease was once considered a relative contraindication for liver transplantation, but this is no longer the case, particularly in Asian countries. Preventing the graft becoming infected with hepatitis B virus has already been discussed. Treatment with lamivudine before the transplantation reduces the risk of recurrence through reducing the viral DNA load; adefovir may prove to be better because it is not associated with development of YMDD mutants. Antiviral drugs fare better than interferon in treating hepatitis B after liver transplantation.
Patients in special categories
HIV-hepatitis B virus coinfection—Patients with chronic hepatitis B and HIV infection have higher levels of hepatitis B virus DNA, worse outcome, and poor response to treatment. The need for highly active antiretroviral treatment (HAART) and anti-hepatitis B virus treatment should be assessed independently, using standard guidelines. The choice of drugs for hepatitis B virus infection depends on the need for concomitant antiretroviral treatment, level of immune suppression, and details of past drug treatment.30 31 Tenofovir disoproxil has activity against both hepatitis B virus and HIV (wild-type as well as YMDD mutants) and may be particularly useful in such patients.
Summary points
Hepatitis B is major global health problem; chronic infection causes major complications like cirrhosis and hepatocellular carcinoma
Vaccination is the most effective method of preventing hepatitis B virus infection
Acute hepatitis B does not need treatment
The clinical course of hepatitis B is complex and not all patients progress to cirrhosis
Among patients with chronic hepatitis B, only a subset (identified by presence of hepatitis B virus DNA) need treatment
Drug treatment has limited efficacy, may have adverse effects, and is costly, so the need for treatment should be assessed cautiously
Recommended drugs include -interferon, lamivudine, and adefovir
The response of chronic hepatitis B to interferon treatment is reduced in patients with HIV coinfection; this drug should be used only in patients with a CD4 cell count > 500/ml. Lamivudine monotherapy is associated with an inordinately high frequency of development of resistant mutants of both HIV and hepatitis B virus, and should not be used. If the patient needs HAART, lamivudine (150 mg twice daily) along with adefovir or tenofovir should be used in combination with a potent antiretroviral regimen. Even in patients in whom HAART is not indicated, lamivudine monotherapy should be avoided since drug resistant HIV mutants often develop and may prejudice future treatment.
Hepatitis C virus-hepatitis B virus coinfection—Outcomes for hepatitis B virus-hepatitis C virus coinfection are poorer than those of infection with hepatitis B virus alone, despite a lower hepatitis B virus replication rate in such patients. Patients with hepatitis B virus DNA level exceeding 103 copies/ml and undetectable hepatitis C virus RNA should be treated as for hepatitis B virus infection alone. Those with lower hepatitis B virus DNA levels and detectable hepatitis C virus RNA should initially receive interferon and ribavirin, and hepatitis B virus DNA should be measured at three months; if the levels have increased, lamivudine or adefovir may be added.
Patients receiving chemotherapy and immunosuppressants—To prevent reactivation of the hepatitis B virus, patients with evidence of hepatitis B virus infection who are to receive chemotherapy should receive lamivudine until three to six months after they finish. The use of interferon in this setting remains unclear and that of adefovir has not been studied.
Children—Because of immune tolerance, children with hepatitis B virus infection manifest liver disease only infrequently. If treatment is indicated, interferon or lamivudine may be used, as in adults. Adefovir has not been used in children.
Pregnant women—Potential benefits of use of lamivudine and adefovir during pregnancy must be weighed against risks. Lamivudine in the third trimester may prevent transmission of hepatitis B virus to the fetus.
Summary
Hepatitis B virus infection is a global public health problem. Hepatitis B vaccines are highly effective, long acting, and safe, making prevention and even eventual eradication possible. However, treatment options for patients who are already infected are limited. The currently available drugs are effective only in selected subsets of patients and have low efficacy rates, and their long term impact on occurrence of complications remains unknown.
A comparison of lamivudine and interferon for initial treatment is on bmj.com
Editorial by Beeching
Contributors: RA helped with literature review, revised drafts, and approved the final manuscript; PR did the literature search, prepared the first draft, revised drafts, and approved the final manuscript. RA is guarantor.
Funding: None.
Competing interests: RA has conducted a postmarketing surveillance study of a combined hepatitis A and B vaccine for GlaxoSmithKline and has participated in a drug trial for interferon in hepatitis B and C for Shantha Biotechnics, Hyderabad, India. PR has no competing interests.
References
Maddrey WC. Hepatitis B: an important public health issue. J Med Virol 2000;61: 362-6.
Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337: 1733-45.
MacMahon BJ, Alward WL, Hall DB, Heyward WL, Bender TR, Francis DP, et al. Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of carrier state. J Infect Dis 1985;151: 599-603.
Tassopoulos NC, Papaevangelou GJ, Sjogren MH, Roumeliotou-Karayannis A, Gerin JL, Purcell RH. Natural history of acute hepatitis B surface antigen-positive hepatitis in Greek adults. Gastroenterology 1987;92: 1844-50.
Liaw YF, Tai DI, Chu CM, Chen TJ. The development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Hepatology 1988;8: 493-6.
Ganem D, Prince AM. Hepatitis B virus infection—natural history and clinical consequences. N Engl J Med 2004;350: 1118-29.
Szmuness W, Stevens CE, Harley EJ, Zang EA, Oleszko WR, William DC, et al. Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States. N Engl J Med 1980;303: 833-41.
European Consensus Group on Hepatitis B Immunity. Are booster immunizations needed for lifelong hepatitis B immunity? Lancet 2000;355: 561-5.
Chen HL, Chang MH, Ni YH, Hsu HY, Lee PI, Lee CY, et al. Seroepidemiology of hepatitis B virus infection in children: ten years of mass vaccination in Taiwan. JAMA 1996;276: 906-8.
Aggarwal R, Ghoshal UC, Naik SR. Assessment of cost effectiveness of universal hepatitis B immunization in a low-income country with intermediate endemicity using a Markov model. J Hepatol 2003;38: 215-22.
Perrillo RP, Wright T, Rakela J, Levy G, Schiff E, Gish R, et al. A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology 2001;33: 424-32.
Ishak K, Baptista A, Bianchi L, Callela F, DeGroote J, Gudata F, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995;22: 696-9.
Lok AS, McMahon BJ, Practice Guidelines Committee, American Association for the Study of Liver Diseases. Chronic hepatitis B. Hepatology 2001;34: 1225-41.
EASL Jury. EASL International Consensus Conference on Hepatitis B. 13-14 September, 2002: Geneva, Switzerland. Consensus statement (short version). J Hepatol 2003;38; 533-40.
Wun YT, Dickinson JA. Alpha-fetoprotein and/or liver ultrasonography for liver cancer screening in patients with chronic hepatitis B. Cochrane Database Syst Rev 2003;(2):CD002799. www.cochrane.org/cochrane/revabstr/AB002799.htm (accessed 19 Apr 2004).
Wong DK, Cheung AM, O'Rourke K, Naylor CD, Detsky AS, Heathcote J. Effect of alpha-interferon treatment in patients with hepatitis B e antigen positive chronic hepatitis B. A meta-analysis. Ann Intern Med 1993;119: 312-23.
Liaw YF, Leung N, Guan R, Lau GK, Merican I. Asian-Pacific consensus Working Parties on Hepatitis B. Asia-Pacific consensus statement on the management of chronic hepatitis B: an update. J Gastroenterol Hepatol 2003;18: 239-45.
Perrillo RP, Lai CL, Liaw YF, Dienstag JL, Schiff ER, Schalm SW, et al. Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B. Hepatology 2002;36: 186-94.
Lau DT, Everhart J, Kleiner DE, Park Y, Vergalla J, Schmid P, et al. Long-term follow up of patients with chronic hepatitis B treated with interferon alfa. Gastroenterology 1997;113: 1660-7.
Niederau C, Heintges T, Lange S, Goldmann G, Niederau CM, Mohr L, et al. Long term follow up of HBeAg positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med 1996;334: 1422-7.
Manesis EK, Hadjiyannis SJ. Interferon alfa treatment and retreatment of hepatitis B e antigen-negative chronic hepatitis B. Gastroenterology 2001;121: 101-9.
Cooksley WG, Piratvisuth T, Lee SD, Mahachai V, Chao YC, Tanwandee T, 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.
Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HP, Goodman Z, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341: 1256-63.
Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, et al. A one year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med 1998;339: 61-8.
Leung LW, Lai CL, Chang TT, Guan R, Lee CM, Ng KY, et al. Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy. Hepatology 2001;33: 1527-32.
Hadjiyannis SJ, Papatheodoridis GV, Dimou E, Laras A, Papaioannou C. Efficacy of long term lamivudine monotherapy in patients with hepatitis B e-antigen negative chronic hepatitis B. Hepatology 2000;32: 847-51.
Peters MG, Hann Hw H, Martin P, Heathcote EJ, Buggisch P, Rubin R, et al. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine resistant chronic hepatitis B. Gastroenterology 2004;126: 91-101.
Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. Adefovir Dipivoxil 437 Study Group. N Engl J Med 2003;348: 808-16.
Hadjiyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. Adefovir Dipivoxil 438 Study Group. N Engl J Med 2003;348: 800-7.
Thio CL. Hepatitis B in the human immunodeficiency virus-infected patient: epidemiology, natural history and treatment. Semin Liver Dis 2003;23: 125-36.
Benhamou Y. Antiretroviral therapy and HIV/hepatitis B virus coinfection. Clin Infect Dis 2004;38(suppl 2): S98-103.(Rakesh Aggarwal, addition)
Correspondence to: R Aggarwal rakesh@sgpgi.ac.in
Introduction
Who needs treatment?
Patients with acute hepatitis B do not need treatment; those with fulminant hepatic failure should be considered for liver transplantation.
Patients with chronic hepatitis B virus infection should undergo a detailed evaluation to assess baseline liver function and the need for further treatment and follow up (box 3). Chronic hepatitis B virus infection is a heterogeneous condition and can be divided into many subsets based on clinical status and status of viral replication (table).
Classification of patients with chronic hepatitis B virus infection
Inactive carriers of hepatitis B are healthy; have a low concentration of serum hepatitis B virus DNA (a measure of rate of viral replication; < 105 copies/ml), or none; lack detectable HBeAg; have normal levels of alanine aminotransferase; and show little progression of liver disease. Though the exact relation between hepatitis B virus DNA levels and potential for liver damage is not known, it is generally believed that levels below 105 copies/ml are not associated with progression of liver injury.
Patients with chronic hepatitis B have viral replication, high hepatitis B virus DNA concentrations, and biochemical evidence of hepatitis. Chronic hepatitis B is either HBeAg positive (patients test positive for HBeAg) or HBeAg negative. The HBeAg negative patients lack detectable HBeAg despite a high rate of viral replication and high hepatitis B virus DNA levels; this paradox arises from a mutation (pre-core mutation) which permits viral replication but prevents production of HBeAg. HBeAg negative chronic hepatitis B has a poorer prognosis and treatment response than does HBeAg positive chronic hepatitis B.
Box 3: Initial evaluation of a patient with chronic hepatitis B virus infection
History and physical examination—Specifically look for symptoms and signs of portal hypertension (abdominal wall collaterals, splenomegaly, hypersplenism, ascites) and liver failure (jaundice, haematemesis, ascites, encephalopathy, etc)
Laboratory tests—Liver function tests (aminotransferases, serum albumin, prothrombin time); complete blood counts, renal function tests
Screen for oesophageal varices (upper gastrointestinal endoscopy)
Screen for hepatocellular carcinoma (ultrasonography and -fetoprotein levels)
Tests for viral replication status (HBeAg, anti-HBe, hepatitis B virus DNA)
Screen for coinfection with other parenterally transmitted viruses (anti-hepatitis C virus antibodies, HIV serology)
Liver biopsy (optional)
Liver biopsy is the gold standard for determining disease activity (necro-inflammation) and stage (fibrosis),12 but it is often contraindicated in patients with decompensated liver disease. Even in patients with compensated disease, though biopsy may provide information for therapeutic and prognostic decision making, it is frequently not done.13
The goal of treatment of chronic hepatitis B is to prevent progression to cirrhosis and hepatocellular carcinoma by preventing viral replication and suppressing necro-inflammatory activity. The unpredictable clinical course of hepatitis B virus infection, and poor response to treatment and doubts about its cost effectiveness, render therapeutic decisions difficult. In patients with decompensated cirrhosis, antiviral treatment has not been clearly shown to provide benefit, so liver transplantation is the only option. Histological cirrhosis is a poor prognostic marker among patients with compensated disease.
Patients in inactive carrier stage do not need treatment, since their liver disease progresses very slowly, if at all. The risk of developing hepatocellular carcinoma in these patients, though higher than in people without infection, is much lower than in HBeAg positive patients. Their alanine aminotransferase levels should be determined every 6-12 months,13 and every two years they should be screened for hepatocellular carcinoma with ultrasonography and -fetoprotein levels.14 Though the evidence in favour of this approach is limited,15 raised alanine aminotransferase in such patients may indicate HBeAg negative chronic hepatitis B and should prompt assessment for hepatitis B virus replication (hepatitis B virus DNA testing) and for other unrelated causes of liver injury (other hepatotropic viruses, alcohol, drugs, etc).
Only those patients who have chronic hepatitis B (active hepatitis B virus replication with a high viral load and ongoing necro-inflammation) qualify for treatment. Patients with chronic hepatitis B virus infection (HBsAg positive for > 6 months), alanine aminotransferase persistently exceeding 1.5-fold to twofold higher than normal, hepatitis B virus DNA > 105 copies/ml, and histological activity index > 4 are the most suitable candidates for treatment (box 4); in a large meta-analysis, 32% of such patients showed HBeAg to anti-HBe seroconversion, as compared with 11% of untreated patients.16 However, it is advisable to wait till transaminase has been raised for one to three months, in order to allow time for the spontaneous viral clearance that occurs in a sizeable proportion of such patients.13 14 17 In patients with ongoing viral replication and normal transaminase concentrations, response rate is quite poor; in such patients alanine aminotransferase should be measured every three months, and they should be treated if raised concentrations persist.18
Some categories of patients with chronic hepatitis B (those with hepatitis C virus or HIV coinfection) do not respond as well to treatment.
Treatment end points
Response to treatment is expressed as a combination of the specific aspects of response studied (biochemical or alanine aminotransferase levels, virological or viral DNA levels, or histological activity), and the time of assessment in relation to treatment (box 5).
Alanine aminotransferase concentrations are a surrogate marker of ongoing necro-inflammatory activity and serve as an inexpensive and simple tool for monitoring response to treatment. Seroconversion (loss of HBeAg and appearance of anti-HBe), whether naturally acquired or treatment induced, is an important and a widely used treatment endpoint, since it is associated with a reduced rate of progression to cirrhosis of the liver and reduced likelihood of decompensation.19 20 Although hepatitis B virus is not directly cytopathic, maintaining hepatitis B virus DNA concentration below a specified level is another useful treatment endpoint. Hepatitis B virus DNA level below 105 copies/ml is the most frequently used cut off for virological response; this can be assessed during treatment, at the end of treatment, or after treatment (sustained response). Since the main aim of treating chronic hepatitis B is to prevent progression of fibrosis and development of cirrhosis, liver biopsy may represent an ideal method of assessing response; however, its invasive nature and the risk of complications preclude its routine use. In patients with decompensated disease, Child-Pugh score may be a useful assessment tool.
Box 4: Treating chronic hepatitis B virus infection
Inactive HBsAg carriers
? Alanine aminotransferase every 6-12 months Screening for hepatocellular carcinoma
Chronic hepatitis B (active viral replication)
Normal alanine aminotransferase: Treatment not recommended Alanine aminotransferase every 3-6 months Screening for hepatocellular carcinoma
Raised alanine aminotransferase: Treatment indicated (interferon or lamivudine)
Cirrhosis
Compensated: Treatment indicated (interferon or lamivudine) Poor response to treatment
Decompensated: Lamivudine, liver transplantation
Difficult to treat patients
Hepatitis C virus or hepatitis D virus coinfection
Renal failure
Immunocompromised (human immunodeficiency virus infection, chemotherapy)
Decompensated cirrhosis
Box 5: End points of treatment for chronic hepatitis B virus infection
Treatment responses
Biochemical response—Return of alanine aminotransferase to within normal range
Virological response—Decline in hepatitis B virus DNA to < 10 copies/ml
Serological response—HBeAg loss and appearance of anti-HBe
Histological response—Decrease in necro-inflammatory score by 2 points
Time frame for assessment of response
On-treatment response—Response assessed while receiving treatment
End of treatment response—Response assessed at the end of treatment duration
Sustained response—Response after a period off drugs (6 months or 12 months)
Treatment options
Three drugs—interferon alfa, lamivudine, and adefovir—are approved in several countries for use in chronic hepatitis B. Of these, interferon has both antiviral and immunomodulatory activity; lamivudine and adefovir are primarily antiviral. Use of drugs with only immunomodulatory activity (thymosin -1) is not well established. Emtricitabine, entecavir, telbuvidine, and clevudine are currently under investigation.
General advice
Avoiding alcohol, safe sexual practices, immunisation of household contacts, vaccination against hepatitis A (in low prevalence areas), and weight reduction should be advised. People who might spread hepatitis at work should either undergo treatment or change their profession. Immunosuppressive drugs should be used with caution in order to avoid activating hepatitis B virus infection.
Interferon
Interferon alfa, a host cytokine produced in response to any viral invasion, has immunomodulatory, antiviral, and anti-fibrotic properties. It was first used in the 1980s and was the first drug to be found useful in the treatment of chronic hepatitis B. The dose is 5 million units a day or 10 MU thrice weekly (30-35 MU/week), given subcutaneously, usually for 16 weeks.
Interferon can have several adverse effects. An influenza-like illness (fever, chills, headache, malaise, myalgias) occurs in 25-30% of patients but rarely needs discontinuation of treatment. More serious adverse events (myelosuppression (leucocytes < 1000/μl and platelets < 60 000/μl), emotional lability and depression, development of autoantibodies, and thyroid dysfunction) may lead to discontinuation of interferon; thus, pretreatment screening for psychiatric illness, low leucocyte and platelets counts, autoantibodies, and thyroid function is mandatory. Administration of corticosteroids before interferon treatment is not useful.
Interferon has been used in both types of chronic hepatitis B. In HBeAg positive patients, about a third show virological and histological response.16 The factors that determine response to interferon are listed in box 6. Interferon induced seroconversion in HBeAg positive patients lasts for at least eight years,19 20 but interferon induced responses are less durable in HBeAg negative chronic hepatitis B.21 Though prolonging treatment for one to two years may improve the sustained response rates, the benefit in these patients remains less than that in HBeAg positive chronic hepatitis B.
Use of interferon in decompensated cirrhosis is associated with an increased risk of infections and exacerbation of liver injury. Response rate is also poor in patients with compensated cirrhosis, and there is a risk of precipitating liver decompensation.
Pegylated interferon, a longer acting interferon preparation, may be better than conventional interferon.22 Data on its use in chronic hepatitis B are limited, precluding a recommendation for routine use.
Lamivudine
Lamivudine, a synthetic nucleoside (cytosine) analogue available since 1998, undergoes intracellular phosphorylation to its active metabolite lamivudine triphosphate and inhibits viral reverse transcriptase, causing premature chain termination during viral DNA synthesis.
In initial studies in patients with HBeAg positive chronic hepatitis B, treatment with lamivudine for 52 weeks fared better than placebo in inducing biochemical response, HBeAg to anti-HBe seroconversion, and histological response, and induced a reduction in hepatitis B virus DNA levels throughout the treatment period.23 24 However, the response rate depends on duration of treatment: prolonged treatment is associated with higher seroconversion rates (21% at one year, 29% at two years, 40% at three years).25 However, with increasing duration of treatment, an increasing proportion of patients develop a mutation in the tyrosine-methionine-aspartate-aspartate (YMDD) motif in the catalytic domain of viral DNA polymerase, which confers lamivudine resistance (14% at one year to 69% at five years), which affects the disease course adversely. Higher pretreatment alanine aminotransferase levels predict a higher response rate; hepatitis B virus DNA levels do not influence response to lamivudine.
Box 6: Predictors of non-response to interferon in chronic hepatitis B
Viral factors:
High serum hepatitis B virus DNA levels
Mutant virus (for example, pre-core mutant with negative HBeAg)
Co-infection with hepatitis C virus or hepatitis delta virus
Host factors:
Normal transaminase activity
Infection acquired in early childhood
Male sex
Asian ethnic origin
Immunosuppression (including drugs, HIV infection)
Decompensated liver disease
Additional educational resources
Information for patients
Hepatitis B Foundation (www.hepb.org)—Provides information for patients and families, and for healthcare professionals (in English and several other languages)
British Columbia Centre for Disease Control. Hepatitis (www.bccdc.org/topic.php?item=59)—Educational material on hepatitis B for patients
National Center for Infectious Diseases, Centers for Disease Control and Prevention. Viral hepatitis B (www.cdc.gov/ncidod/diseases/hepatitis/b/index.htm)—Educational material for patients and healthcare professionals on prevention guidelines for hepatitis B
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Hepatitis publications (http://digestive.niddk.nih.gov/ddiseases/pubs/hepatitis/index.htm)—Information for patients on treatment and prevention of various forms of hepatitis. (Some documents are also available in Spanish)
About.com. Hepatitis (www.hepatitis.about.com/cs/hepatitisb)—Comprehensive information about hepatitis B treatment, with web links
Singapore Ministry of Health. Clinical Practice Guidelines. Chronic hepatitis B infection. April 2003. (www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=3749)—Evidence based information about hepatitis B treatment and prevention
Everson GT, Weinberg H. Living with hepatitis B: a survivor's guide. Long Island City, NY: Hatherleigh Press. 2002.—Explains hepatitis B virus, disease associated with this infection, and its prevention and treatment
Green WF, Conjeevaram H. The first year—hepatitis B: an essential guide for the newly diagnosed. Emeryville, CA: Marlowe, 2002—Provides current and empathetic information for those wishing to take an active role in their hepatitis B treatment
Major reviews and guidelines on treatment of hepatitis B
Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000—summary of a workshop. Gastroenterology 2001;120: 1828-53.
Lok AS, McMahon BJ, Practice Guidelines Committee, American Association for the Study of Liver Diseases. Chronic hepatitis B. Hepatology 2001;34: 1225-41.
EASL Jury. EASL international consensus conference on hepatitis B, 13-14 September 2002, Geneva, Switzerland. Consensus statement (short version). J Hepatol 2003;38: 533-40.
Liaw YF, Leung N, Guan R, Lau GK, Merican I, Asian-Pacific Consensus Working Parties on Hepatitis B. Asian-Pacific consensus statement on the management of chronic hepatitis B: an update. J Gastroenterol Hepatol 2003;18: 239-45.
Keeffe EB, Dieterich DT, Han SH, Jacobson IM, Martin P, Schiff ER, et al. A treatment algorithm for the management of chronic hepatitis B virus in the United States. Clin Gastroenterol Hepatol 2004;2: 87-106.
Lamivudine treatment in HBeAg negative chronic hepatitis B is associated with less durable responses and a higher rate of emergence of YMDD mutants (60% at four years).26
Lamivudine treatment in patients with decompensated cirrhosis related to hepatitis B and active viral replication is associated with higher Child-Pugh score and better transplant-free and overall survival than in historical controls.11
The benefit takes months to appear and increases with time; however, beyond a certain time point, the administration of this drug may be counterproductive because the risk of appearance of mutant strains increases with longer treatment. Lamivudine has an excellent safety profile, even in patients with decompensated liver disease.
In treatment-naive patients with chronic hepatitis B, interferon and lamivudine give similar response rates. Each drug has certain relative advantages and disadvantages (see bmj.com). Given the poor response rate with both drugs, patient's choice and cost may be important considerations. Failure to respond to interferon does not adversely influence response rates with lamivudine, but in patients with decompensated disease, lamivudine is the only viable treatment option.
Adefovir
Adefovir dipivoxil, a nucleotide analogue of deoxyadenosine monophosphate, inhibits viral reverse transcriptase activity in both wild-type and YMDD mutant hepatitis B virus.27 Thus, it is the drug of choice for patients treated with lamivudine who have developed YMDD mutation. It has also been used in patients with HBeAg positive chronic hepatitis B 28 and HBeAg negative chronic hepatitis B,29 with efficacy rates at one year similar to those with lamivudine, albeit with no drug resistant mutations. Adefovir may thus be a useful alternative to lamivudine in all types of patients, though further data are needed. Adefovir resistant mutants of hepatitis B virus have recently been described; their clinical importance needs further study.
Combination treatment
Available data show no benefit of the lamivudine-interferon combination over individual drugs.13 14 Combinations of nucleoside analogues have not been adequately studied.
Liver transplantation in hepatitis B virus related liver disease
Hepatitis B virus related liver disease was once considered a relative contraindication for liver transplantation, but this is no longer the case, particularly in Asian countries. Preventing the graft becoming infected with hepatitis B virus has already been discussed. Treatment with lamivudine before the transplantation reduces the risk of recurrence through reducing the viral DNA load; adefovir may prove to be better because it is not associated with development of YMDD mutants. Antiviral drugs fare better than interferon in treating hepatitis B after liver transplantation.
Patients in special categories
HIV-hepatitis B virus coinfection—Patients with chronic hepatitis B and HIV infection have higher levels of hepatitis B virus DNA, worse outcome, and poor response to treatment. The need for highly active antiretroviral treatment (HAART) and anti-hepatitis B virus treatment should be assessed independently, using standard guidelines. The choice of drugs for hepatitis B virus infection depends on the need for concomitant antiretroviral treatment, level of immune suppression, and details of past drug treatment.30 31 Tenofovir disoproxil has activity against both hepatitis B virus and HIV (wild-type as well as YMDD mutants) and may be particularly useful in such patients.
Summary points
Hepatitis B is major global health problem; chronic infection causes major complications like cirrhosis and hepatocellular carcinoma
Vaccination is the most effective method of preventing hepatitis B virus infection
Acute hepatitis B does not need treatment
The clinical course of hepatitis B is complex and not all patients progress to cirrhosis
Among patients with chronic hepatitis B, only a subset (identified by presence of hepatitis B virus DNA) need treatment
Drug treatment has limited efficacy, may have adverse effects, and is costly, so the need for treatment should be assessed cautiously
Recommended drugs include -interferon, lamivudine, and adefovir
The response of chronic hepatitis B to interferon treatment is reduced in patients with HIV coinfection; this drug should be used only in patients with a CD4 cell count > 500/ml. Lamivudine monotherapy is associated with an inordinately high frequency of development of resistant mutants of both HIV and hepatitis B virus, and should not be used. If the patient needs HAART, lamivudine (150 mg twice daily) along with adefovir or tenofovir should be used in combination with a potent antiretroviral regimen. Even in patients in whom HAART is not indicated, lamivudine monotherapy should be avoided since drug resistant HIV mutants often develop and may prejudice future treatment.
Hepatitis C virus-hepatitis B virus coinfection—Outcomes for hepatitis B virus-hepatitis C virus coinfection are poorer than those of infection with hepatitis B virus alone, despite a lower hepatitis B virus replication rate in such patients. Patients with hepatitis B virus DNA level exceeding 103 copies/ml and undetectable hepatitis C virus RNA should be treated as for hepatitis B virus infection alone. Those with lower hepatitis B virus DNA levels and detectable hepatitis C virus RNA should initially receive interferon and ribavirin, and hepatitis B virus DNA should be measured at three months; if the levels have increased, lamivudine or adefovir may be added.
Patients receiving chemotherapy and immunosuppressants—To prevent reactivation of the hepatitis B virus, patients with evidence of hepatitis B virus infection who are to receive chemotherapy should receive lamivudine until three to six months after they finish. The use of interferon in this setting remains unclear and that of adefovir has not been studied.
Children—Because of immune tolerance, children with hepatitis B virus infection manifest liver disease only infrequently. If treatment is indicated, interferon or lamivudine may be used, as in adults. Adefovir has not been used in children.
Pregnant women—Potential benefits of use of lamivudine and adefovir during pregnancy must be weighed against risks. Lamivudine in the third trimester may prevent transmission of hepatitis B virus to the fetus.
Summary
Hepatitis B virus infection is a global public health problem. Hepatitis B vaccines are highly effective, long acting, and safe, making prevention and even eventual eradication possible. However, treatment options for patients who are already infected are limited. The currently available drugs are effective only in selected subsets of patients and have low efficacy rates, and their long term impact on occurrence of complications remains unknown.
A comparison of lamivudine and interferon for initial treatment is on bmj.com
Editorial by Beeching
Contributors: RA helped with literature review, revised drafts, and approved the final manuscript; PR did the literature search, prepared the first draft, revised drafts, and approved the final manuscript. RA is guarantor.
Funding: None.
Competing interests: RA has conducted a postmarketing surveillance study of a combined hepatitis A and B vaccine for GlaxoSmithKline and has participated in a drug trial for interferon in hepatitis B and C for Shantha Biotechnics, Hyderabad, India. PR has no competing interests.
References
Maddrey WC. Hepatitis B: an important public health issue. J Med Virol 2000;61: 362-6.
Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337: 1733-45.
MacMahon BJ, Alward WL, Hall DB, Heyward WL, Bender TR, Francis DP, et al. Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of carrier state. J Infect Dis 1985;151: 599-603.
Tassopoulos NC, Papaevangelou GJ, Sjogren MH, Roumeliotou-Karayannis A, Gerin JL, Purcell RH. Natural history of acute hepatitis B surface antigen-positive hepatitis in Greek adults. Gastroenterology 1987;92: 1844-50.
Liaw YF, Tai DI, Chu CM, Chen TJ. The development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Hepatology 1988;8: 493-6.
Ganem D, Prince AM. Hepatitis B virus infection—natural history and clinical consequences. N Engl J Med 2004;350: 1118-29.
Szmuness W, Stevens CE, Harley EJ, Zang EA, Oleszko WR, William DC, et al. Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States. N Engl J Med 1980;303: 833-41.
European Consensus Group on Hepatitis B Immunity. Are booster immunizations needed for lifelong hepatitis B immunity? Lancet 2000;355: 561-5.
Chen HL, Chang MH, Ni YH, Hsu HY, Lee PI, Lee CY, et al. Seroepidemiology of hepatitis B virus infection in children: ten years of mass vaccination in Taiwan. JAMA 1996;276: 906-8.
Aggarwal R, Ghoshal UC, Naik SR. Assessment of cost effectiveness of universal hepatitis B immunization in a low-income country with intermediate endemicity using a Markov model. J Hepatol 2003;38: 215-22.
Perrillo RP, Wright T, Rakela J, Levy G, Schiff E, Gish R, et al. A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology 2001;33: 424-32.
Ishak K, Baptista A, Bianchi L, Callela F, DeGroote J, Gudata F, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995;22: 696-9.
Lok AS, McMahon BJ, Practice Guidelines Committee, American Association for the Study of Liver Diseases. Chronic hepatitis B. Hepatology 2001;34: 1225-41.
EASL Jury. EASL International Consensus Conference on Hepatitis B. 13-14 September, 2002: Geneva, Switzerland. Consensus statement (short version). J Hepatol 2003;38; 533-40.
Wun YT, Dickinson JA. Alpha-fetoprotein and/or liver ultrasonography for liver cancer screening in patients with chronic hepatitis B. Cochrane Database Syst Rev 2003;(2):CD002799. www.cochrane.org/cochrane/revabstr/AB002799.htm (accessed 19 Apr 2004).
Wong DK, Cheung AM, O'Rourke K, Naylor CD, Detsky AS, Heathcote J. Effect of alpha-interferon treatment in patients with hepatitis B e antigen positive chronic hepatitis B. A meta-analysis. Ann Intern Med 1993;119: 312-23.
Liaw YF, Leung N, Guan R, Lau GK, Merican I. Asian-Pacific consensus Working Parties on Hepatitis B. Asia-Pacific consensus statement on the management of chronic hepatitis B: an update. J Gastroenterol Hepatol 2003;18: 239-45.
Perrillo RP, Lai CL, Liaw YF, Dienstag JL, Schiff ER, Schalm SW, et al. Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B. Hepatology 2002;36: 186-94.
Lau DT, Everhart J, Kleiner DE, Park Y, Vergalla J, Schmid P, et al. Long-term follow up of patients with chronic hepatitis B treated with interferon alfa. Gastroenterology 1997;113: 1660-7.
Niederau C, Heintges T, Lange S, Goldmann G, Niederau CM, Mohr L, et al. Long term follow up of HBeAg positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med 1996;334: 1422-7.
Manesis EK, Hadjiyannis SJ. Interferon alfa treatment and retreatment of hepatitis B e antigen-negative chronic hepatitis B. Gastroenterology 2001;121: 101-9.
Cooksley WG, Piratvisuth T, Lee SD, Mahachai V, Chao YC, Tanwandee T, 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.
Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HP, Goodman Z, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341: 1256-63.
Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, et al. A one year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med 1998;339: 61-8.
Leung LW, Lai CL, Chang TT, Guan R, Lee CM, Ng KY, et al. Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy. Hepatology 2001;33: 1527-32.
Hadjiyannis SJ, Papatheodoridis GV, Dimou E, Laras A, Papaioannou C. Efficacy of long term lamivudine monotherapy in patients with hepatitis B e-antigen negative chronic hepatitis B. Hepatology 2000;32: 847-51.
Peters MG, Hann Hw H, Martin P, Heathcote EJ, Buggisch P, Rubin R, et al. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine resistant chronic hepatitis B. Gastroenterology 2004;126: 91-101.
Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. Adefovir Dipivoxil 437 Study Group. N Engl J Med 2003;348: 808-16.
Hadjiyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. Adefovir Dipivoxil 438 Study Group. N Engl J Med 2003;348: 800-7.
Thio CL. Hepatitis B in the human immunodeficiency virus-infected patient: epidemiology, natural history and treatment. Semin Liver Dis 2003;23: 125-36.
Benhamou Y. Antiretroviral therapy and HIV/hepatitis B virus coinfection. Clin Infect Dis 2004;38(suppl 2): S98-103.(Rakesh Aggarwal, addition)