Guideline on prevention and treatment of chronic hepatitis B in China (2005)

Chronic hepatitis B is one of the most common epidemic diseases in China and has become a major health issue. To help standardize the prevention, diagnosis, and treatment of chronic hepatitis B, the Guideline on prevention and treatment of chronic hepatitis B (abbr. Guideline) was created by a group of appropriate experts belonging to the Society of Hepatology and the Society of Infectious Disease, the Chinese Medical Association according to the principles of evidence-based medicine using the latest clinical research data. The evidence used to formulate the recommendation has been classified into 3 classes and 5 grades, which are indicated by Roman numerals in brackets.1 It should be noted that the Guideline is not mandatory, only aims to offer advice to clinicians in order to make an appropriate decision in the prevention, diagnosis, and treatment of chronic hepatitis B, and it could not be including all issues in the diagnosis and treatment of chronic hepatitis B. Therefore, facing an individual patient, the clinicians should rely on their own knowledge and experience to determine the optimal treatment regimen based on fully understanding the best clinical evidence and current available medical resources of this disease, as well as the patient's medical condition and his willingness. ETIOLOGY Hepatitis B virus (HBV) belongs to the family of hepadnaviruises. Its genome consists of approximately 3200 base pairs with relaxed circular and partially double-stranded DNA. After entering the human body, HBVs attach to the receptors on hepatocyte membranes. Before penetrating into the cytoplasm, the virus envelope is removed. In the hepatocyte cytoplasm, HBVs remove the capsid and release the circular and partially double-stranded DNA into the hepatocyte nucleus. With the help of the host cells' enzymes, the positive-sense strand is elongated with negative-sense DNA as the template. After the fissure in the positive-sense strand is patched, the viral genome is converted into covalently closed circular DNA (cccDNA). The cccDNA is the template for transcribing into various mRNAs using host cells' RNA polymerase. The 3.5 kb mRNA, which includes all of the genetic information, is called the pregenomic RNA. After exporting from the nucleus into the cytoplasm, the pregenomic RNA is used as the template to synthesize the negative-sense DNA by viral reverse-transcriptase. Then, the negative-strand DNA acts as the template for the synthesis of positive-strand DNA. The new HBV particle is released after the filial partially double-stranded DNA is synthesized and packaged. The filial circular, partially double-stranded DNA may also enter into the hepatocellular nucleus and form cccDNA. Due to cccDNA's long half-life, it is difficult to totally eliminate it from the body.1,2 There are 4 partially overlapped open reading frames: the pre S/S region, the pre C/C region, the P region, and the X region. The pre S/S region encodes the large (pre S1, pre S2, and S), middle (pre S2 and S), and small (S) surface antigens. The Pre C/C region encodes HBeAg and HBcAg. The P region encodes polymerase, while the X region encodes X protein. Mutations in the pre C region and the basic core promoter (BCP) region may result in an HBeAg-negative mutant. The most frequent mutation in the pre C region is the G1896A point mutation, which results in terminal codons (TAG) and does not express HBeAg. The most frequent mutation of the BCP region is the A1762T/G1764A combined point mutation, which reduces the synthesis of HBeAg by selectively suppressing the transcription of pre C mRNA.3 The mutation on the P gene is mainly in the POL/RT gene (349-692 aa, rt1-rt344). The most frequently occurring mutation during lamivudine treatment is YMDD variation, which results in YMDD changing to YIDD (rtM204I) or to YVDD (rtM204V). This YMDD variation can be complicated by an rt180M mutation, and becomes the predominant resistant variant due to the drug selection pressure.4 Mutation of the S gene may result in occult HBV infection, with negative HBsAg and low levels of replication (usual serum HBV DNA levels <104 copies/ml).5 Based on the definition of divergence of the whole HBV genome sequence ≥8% or variance of the S gene sequence ≥4%, HBV is classified into 8 genotypes from A to H. The genotype is further divided into subgenotypes. Genotype A has a higher response rate to interferon than genotype D; genotype B has a higher response rate to interferon than genotype C.6 However, the effects of genotype on treatment response to nucleot(s)ide analogs are still unknown. Mutations are often observed in HBV. There is often a group of variants with the predominant mutants (quasispecies) in the host. The clinical significance of this finding is still under investigation. HBV is comparatively stable in the environment. It can be deactivated by heating at 65°C for 10 hours, by boiling for 10 minutes, or by autoclave. HBV is easily deactivated by chlorine, ethylene oxide, glutaraldehyde, peracetic acid, and iodophors. EPIDEMIOLOGY Although there is a worldwide distribution of HBV infection, the infection rates are quite different in various areas. It was reported by WHO that over 350 million people have chronic HBV infection and 2 billion people have been infected by HBV. Approximately 1 million HBV patients die annually, such as hepatic decompensation, cirrhosis and hepatocellular carcinoma (HCC).1 In China, the HBV prevalence is high. The HBsAg carrier rate among the general population is 9.09%; the rate among the vaccinated population is 4.51%, and 9.51% among the unvaccinated.7 The prevalent serotypes of HBV in China are adrq+ and adw2+; while seldom found, ayw3 is found mainly in Xinjiang, Tibet and Inner Mongolia autonomous regions. 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