Viral hepatitis is believed to have existed in antiquity, with references traced back to the fifth century bc. A new era in viral hepatitis was ushered in by the landmark discovery of Australia antigen, subsequently renamed hepatitis B surface antigen (HbsAg) by Blumberg and coworkers in 1965.1 What followed was a rapid growth in information about the hepatitis B virus (HBV), development of sero-logic and molecular tests for HBV, understanding of the natural history and pathogenesis of infection, development and approval of antiviral therapies, and most importantly, the development of effective vaccines for prevention of HBV infection.

Although non-A, non-B hepatitis was thought to have a viral etiology since 1974, the virus eluded investigators for more than a decade. It was discovered in 1989 by a brute force application of molecular cloning techniques through the joint efforts of the Centers for Disease Control and Prevention (CDC) and the Chiron Corporation, and was named the hepatitis C virus (HCV).2 This discovery led rapidly to the development of serologic screening assays for HCV infection prior to blood donation, which dramatically reduced the incidence of posttransfusion chronic hepatitis. Sequencing of the HCV genome also provided impetus for the development of molecular assays for detection, quantitation, and characterization of HCV. Although there has been explosive growth in information about this medically important virus since its discovery, much remains to be learned about its pathogenesis, treatment, and prevention.

The key characteristics of HBV and HCV are summarized in Table 37-1. Both viruses represent major global public health problems, with an estimated 350 million and 170 million persons chronically infected with HBV and HCV, respectively. Although clinical characteristics and risk factors for infection may give some indication of the specific etiology of viral hepatitis, the diagnosis is laboratory based. Laboratory diagnosis is based on serologic and molecular tests because cell culture techniques for isola tion of HBV and HCV are not effective. This chapter reviews the molecular tests that are available to detect, quantitate, and characterize HBV and HCV and how these tests can be used for effective diagnosis and clinical management of patients.


The HBV genome is a 3.2 kilobase (kb), relaxed circular, partially double-stranded DNA molecule. It has four partially overlapping open reading frames encoding the viral envelope (pre-S and S), nucleocapsid (precore and core), polymerase, and X proteins. Although HBV is a DNA virus, it replicates by a reverse transcriptase that lacks proofreading activity and, as a result, is prone to errors. The overlapping open reading frames of the genome limit the types of mutations that can be tolerated. However, variations in HBV sequences have been detected in almost all regions of the genome. Consequently, HBV exists as quasi-species, and different patients may be infected with different strains and genotypes.

There are seven phylogenetic genotypes (A through G), most of which have distinct geographic distribution. Genotypes are defined by intergroup divergence of greater than 8% in the complete genome nucleotide sequence. Genotypes A and D are common in the United States and Europe; genotypes B and C are most frequent in China and Southeast Asia. There is insufficient data to determine whether differences in clinical outcome or response to treatment correlate with virus genotype.

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