||Vol.6 No.2 (April 2001)
The Hong Kong Association for the Study of Liver
Diseases Position Statement - Therapy for Chronic Hepatitis B
Dr. Nancy Leung
Department of Medicine and Therapeutics, Prince of Wales Hospital,
The Chinese University of Hong Kong
Natural History of Chronic Hepatitis B Infection
Most Asians are infected at birth or early childhood. 3 stages are identified
in the natural history. It is important to realize that patients proceed through
them at different speed. Immune tolerance stage is followed by immune clearance
state. Final quiescent stage may be reached with no hepatic injury if there
is early HBeAg seroconversion with negative HBV-DNA and resolved inflammatory
activity. On the other hand, prolonged immune clearance with fluctuating viral
level and ALT elevation may lead to cirrhosis and increase risk for hepatocellular
carcinoma. HBeAg negative viraemic patients with precore/core promotor mutant
virus is recently recognized as another subgroup of chronic hepatitis.
Therapeutic Options for Chronic Hepatitis B Infection
Therapeutic agents act by direct antiviral action and/or immune modulation.
Many potential agents are found in recent years and being assessed in clinical
trials. At present, only interferon and lamivudine are registered in Hong Kong.
- Meta-analysis of interferon treatment for >= 3 months in HBeAg positive
viraemic patients showed 33% HBeAg seroconversion compared with control 12%.
Asian patients showed similar trend.
- Interferon is suitable for non-cirrhotic patients with mild to moderate
disease activity (ALT2-5 x ULN).
- Close monitor is required for adverse effects ("flu" symptoms,
bone marrow suppression, depression, weight loss, thyroid dysfuntion) and
possible ALT flare during and after therapy; dose reduction may be necessary.
- Daily dosing of 100 mg reduced serum HBV-DNA to <1.5 pg/ml (solution
hybribridisation assay) within 4 weeks. 4 major phase III international clinical
trials showed 16-18% HBeAg seroconversion in one year among HBeAg positive
compensated patients. This was associated with significant improvement in
histological activity index.
- HBeAg seroconversion rate at 1 year increased with higher baseline ALT:
<2 x ULN 5%; 2-5 x ULN 26%; >5 x ULN 64%. Patients with normal ALT will
not benefit from treatment.
- 58 of 358 patients in the Asian multi-centre study were treated for 4 years.
Incremental HBeAg seroconversion rate of 22, 29, 40, 47% were observed over
4 years. Among patients with ALT >2 x ULN, it increased to 38, 42, 65 and
73%. However drug resistant YMDD variants emerged in this group at the rate
of 15, 38, 55 and 67% respectively.
- YMDD variant virus behaved in an unpredictable manner. Lamivudine was continued
in all clinical trials. ALT flare, decompensation and fatality have been reported.
No data is available if lamivudine is stopped.
- Limited data suggested similar clinical efficacy of lamivudine in HBeAg
negative viraemic patients.
- Patients with hepatitis B cirrhosis with disease activity may benefit from
- The role of lamivudine in preventing reinfection of the liver graft after
transplantation is established.
- Little data is available for treating patients with HBV-related nephropathy
and in immunocompromised host.
- Lamivudine has few reported adverse effects.
- Duration of lamivudine treatment is still not well defined. Treatment can
be stopped 2 months after HBeAg seroconversion. Long-term therapy with lamivudine
is associated with high emergence rate of drug resistance. The risk and benefit
of continuing treatment must be carefully considered and discussed with the
Interferon and Lamivudine Combination
Clinical trials showed improved efficacy predominantly in those with ALT 2-5
x ULN. This needs to be confirmed with more large scale studies.
Though interferon and lamivudine monotherpay yielded significant response,
this is still far from ideal. The strategy for therapy should be a combination
of two and more effective agents that can rapidly and strongly suppress viral
replication and eliminate infected hepatocytes that harbour HBV cccDNA. The
potential candidate include nucleoside analogues (emtricitabine, adefovir dipivoxil,
entecavir, FMAU), thymosin and therapeutic vaccines.