JRSM >
Volume 97, Number 7 >
Pp. 318-321
Digestive Disease Research Centre, Queen Mary's School of Medicine and Dentistry, Barts and The London NHS Trust, London, UK
Correspondence to: Professor Graham R Foster, DDRC, Royal London Hospital,
Turner Street, London E1 2AD, UK
E-mail:
g.r.foster{at}qmul.ac.uk
 | INTRODUCTION |
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| PREVALENCE |
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| NATURAL HISTORY |
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Adults who are infected with HBV usually develop an acute hepatitis that resolves spontaneously. However, 3-5% go on to develop chronic hepatitis B which then follows a similar pattern to perinatally acquired chronic HBV infection.5
| PREVENTION |
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Diagnosis
The diagnosis of chronic HBV infection is made from its biochemical,
virological and histological features together with exclusion of other causes
such as HCV.6
Routine liver function tests and serological assays for the detection of HBV
antigens (HBsAg and HBeAg) and antibodies (anti-HBs, anti-HBc and anti-HBe)
should be performed to assess the phase of chronic hepatitis B. HBV DNA can be
monitored in serum by means of DNA hybridization with signal amplification, to
assess disease activity and candidacy for antiviral therapy and to determine
response to treatment. Liver biopsy is essential to confirm the diagnosis, to
identify any intercurrent disease affecting the liver, to stage the fibrosis
and to grade the necroinflammation.
Box 1 HBV markers and their properties. ALT=alanine amino transferase
| HBsAg: surface protein contained within the lipoprotein coat HBsAb: antibody to HBsAg, indicator of recovery/immunity to HBV infection HBeAg: viral product secreted in blood, marker of infectivity, active replication (though absent in precore mutants) HBeAb: antibody to HBeAg, denoting decreased infectivity HBcAg: core antigen (viral capsid), intracellular and not detected in serum HBcAb IgM: antibody denoting recent HBV infection or exacerbation HBcAb IgG: contamination marker, positive after HBV contact HBV DNA: quantitative indicator of virus in blood
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| TREATMENT |
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(10 MU thrice weekly) and oral lamivudine (100 mg once a
day) are licensed for this use in many countries and oral adefovir (10 mg once
a day) has recently been approved. Response to therapy is defined as
undetectable HBV DNA (< 105 copies/mL) in serum, sustained loss
of HBeAg with or without detection of anti-HBe (HBeAg seroconversion), and
improvement in liver disease, normalization of aminotransferases and decrease
in necroinflammation or fibrosis progression
halted.5
Pretreatment factors predictive of response are similar for all three
treatments and include high serum aminotransferases, low serum HBV DNA and
pronounced necroinflammation on
biopsy.6 The advantages of interferon include finite duration of treatment, lack of resistant mutants and durable response; disadvantages are high cost, the need for subcutaneous administration and the side-effects.7,8 Lamivudine is more economical and better tolerated but resistance may develop.9 With adefovir, an expensive drug, resistance is uncommon.10
Treatment is not recommended for patients with mild chronic hepatitis B because of the low efficacy of existing therapies, but these patients should be monitored.6,7,11 Who, then, should receive antiviral therapy? The American Association for the Study of Liver Disease7 recommends that patients who are HBeAg-positive with moderate or severe chronic hepatitis and raised aminotransferases (more than twice the upper limit of normal) should be offered either: (i) a 4-6 month course of interferon (10 MU thrice weekly); or (ii) a 1-year course of lamivudine (100 mg once a day if no HIV infection); or (iii) a 1-year course of adefovir (10 mg once a day). Since the viral response to lamivudine or adefovir is not affected by previous failure with interferon, the European Association for Study of the Liver favours using interferon first.12 Interferon causes loss of HBeAg in 15-25% of patients which is sustained in 80% 1 year after treatment.8,13 Lamivudine gives 10-15% sustained seroconversion of HBeAg at 1 year and a virological response in nearly all, but unfortunately 60% of responders have relapsed 1 year after treatment.9,11 Drug resistance to lamivudine develops in 20% during the first year and increases to 60% at year 4.9,11 Adefovir yields a similar seroconversion rate to lamivudine but durability of response has not been yet established.10 Treatment with lamivudine and adefovir should be continued for 4-6 months after seroconversion has been achieved.12 If no seroconversion is seen after 1 year of oral medication the decision whether to continue treatment will be influenced by the costs (higher for adefovir) and the risk that drug resistance (higher for lamivudine) will develop.
Patients with HBeAg-negative disease who have high aminotransferases, moderate to severe hepatitis and HBV DNA > 105 copies/mL should be treated with interferon (for 1 year) with lamivudine or with adefovir.6,7 As with HBeAg-positive disease, the oral agents can be continued beyond 1 year in viral non-responders, subject to considerations of virus resistance and drug toxicity.12 If lamivudine resistant mutants emerge and HBV DNA and aminotransferases are low, one can continue lamivudine or stop it and monitor levels. An alternative is to switch to adefovir.12
Patients with compensated cirrhosis and raised HBV DNA levels can be treated with lamivudine or adefovir but interferon can cause flares and should be avoided.6,7 Patients with low or undetectable HBV DNA should simply be observed.7 For decompensated cirrhosis with high viral loads lamivudine or adefovir should be continued until liver transplantation.7,12 Withdrawal of lamivudine demands adefovir back-up since it can lead to hepatic decompensation.14 If viral load is low or undetectable, patients should be referred directly for liver transplantation.12 Table 1 summarizes the US recommendations.
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The ideal approach to antiviral therapy in chronic hepatitis B remains uncertain. In most patients monotherapy is insufficient to eradicate infection. Peginterferon alpha-2a is currently under evaluation and data from the phase II trials suggest a greater than twofold higher combined response rate (HBeAg loss, HBV DNA suppression and normalization of alanine aminotransferase) than with conventional interferon after 24 weeks.15 However, the key issue for the future will be the efficacy of combined and/or sequential treatment with oral agents and interferon. Note Professor Foster acts as a consultant to companies that market drugs for treatment of hepatitis B.
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