乙型肝炎现有药物的作用

Nancy Leung*. Consultant Physician, Alice Ho Miu Ling Nethersole Hospital, Adjunct Associate Professor, the Chinese University of Hong Kong, Hong Kong SAR, China

The main role of antiviral drug therapy for chronic hepatitis B (CHB) infection is to suppress the hepatitis B virus (HBV) from active replication, thereby preventing hepatitis and the complications. Doctors and patients alike wished for achieving HBV eradication early. This will lower the risk of liver complications and restore health and quality of life of the CHB patients. From the healthcare provider point of view, the transmission of HBV infection can be minimized and the health cost substantially reduced. Eradication of HBV rarely occurs spontaneously; around 0.5 to 2% among CHB individuals lost HBsAg annually. Newer antiviral drugs have higher efficacy and safety. HBsAg loss over and above the estimated spontaneous incidence has been reported after and during therapy. The role of current available antiviral drugs in the full spectrum of CHB disease can be summarized as follows.

There are two main categories of antiviral therapy for HBV infection:

(1) interferon-based injections, and (2) oral nucleos(t)ide analogues. Any HBV disease types with viraemia will benefit from antiviral therapy that is efficacious, safe and affordable. Most international and national HBV treatment guidelines focused on individuals with HBV DNA level over 5 log10 copies/ml (i.e. around 4 log10 IU/L); especially if HBeAg negative; associated with raised serum ALT; and have evidence of significant liver fibrosis. Antiviral therapy is particularly important among males, over middle age, has family history of cirrhosis and hepatocellular carcinoma (HCC). The aim is to halt the existing liver damage, hopefully reverse fibrosis, even cirrhosis, and eliminate the conditions that favour HCC development. Clinical experience and data do support such strategy.

Interferon-based anti-viral drugs have dual actions of viral suppression and immune modulation; thereby have a higher chance of eradicating HBV and the infected hepatocytes. Pegylated interferon alfa-2a therapy for one year resulted in incremental HBsAg loss up to 9% and 11% by year 3 and year 4 respectively after completion of therapy. Higher baseline ALT level, female patients, HBV genotype A have been reported to favour response. The viral kinetics during therapy, the profile of decline in serum HBV DNA, quantitative HBeAg and HBsAg levels, are useful in identifying the patients likely to achieve sustained virologic response, which is relatively low at 30-40%. The defined duration of therapy make pegylated interferon therapy a choice for treating younger patients planning family in the future. These patients need careful counselling and should be warned about immediate and longer term known side-effects. They should be followed and monitored regularly at 4 to 8 weekly intervals. Long term followup data showed a significant reduction in serious complications of CHB including reduced incident of hepatocellular carcinoma among those responded to standard interferon therapy. Similar, if not better, results are anticipated after therapy with peylated interferon.

Oral nuceos(t)ide analogues (NAs) act directly and purely by suppressing the HBV DNA polymerase, though there may be some secondary stimulus effect on the host immune system when viral load is suppressed rapidly. NAs have the distinct advantage of low primary non-responder rate. Lamivudine and adefovir have been available for many years. Clinical experience over the years showed high rate of emergence of resistant mutants and moderate antiviral effect. Patients on these NAs require more frequent monitor and add-on therapy should resistance developed. Telbivudine, by comparison, is more potent and has lower resistant profile. The choice is easier when entecavir and tenofovir become available in the market. The consistent and rapid viral suppression, coupled with a much, much lower incident of drug resistant make long term therapy possible. Side-effects are few. The efficacy is not age, gender, ALT, and HBV genotype dependent and can be used in patients with cirrhosis and decompensated disease.

Pivotal clinical trials usually recruit patients of certain age group and specific disease characteristics. The role and safety of the newer NAs in the children and young adults with CHB, patients in immune tolerant phase, and in pregnant women, are still not clear. The role of NA as a prophylactic therapy to prevent relapse or exacerbation of CHB during chemotherapy or steroid treatment has been demonstrated. Another milestone role of NA is the suppression of HBV in liver and other organ/tissue transplantations. The success of transplantation for CHB patients cannot be realized without potent suppression of HBV to stamp out HBV recurrence in the immune compromised state.

Current available therapy has created a significant impact in HBV infection and has improved the prognosis of CHB patients. Much more advances are needed to control this disease, to inhibitmore profoundly, to eradicate more rapidly. We are at a turning point and should witness a downward trend in mortality and morbidity of cirrhosis and HCC, the real goal of HBV therapy.