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OVERVIEW

Although progression to cirrhosis is more likely in severe than in mild or moderate chronic hepatitis B, all forms of chronic hepatitis B can be progressive, and progression occurs primarily in patients with active HBV replication. Moreover, in populations of patients with chronic hepatitis B who are at risk for HCC (Chap. 78), the risk is highest for those with continued, high-level HBV replication and lower for persons in whom initially high-level HBV DNA falls spontaneously over time. Therefore, management of chronic hepatitis B is directed at suppressing the level of virus replication. Although clinical trials tend to focus on clinical endpoints achieved over 1−2 years (e.g., suppression of HBV DNA to undetectable levels, loss of HBeAg/HBsAg, improvement in histology, normalization of ALT), these short-term gains translate into reductions in the risk of clinical progression, hepatic decompensation, HCC, liver transplantation, and death; regression of cirrhosis and of esophageal varices have been documented to follow long-term pharmacologic suppression of HBV replication. In addition, restoration of impaired HBV-specific T-cell function has been shown following successful suppression of HBV replication with antiviral therapy. To date, seven drugs have been approved for treatment of chronic hepatitis B: injectable interferon (IFN) α and pegylated interferon (long-acting IFN bound to polyethylene glycol, PEG [PEG IFN]) and the oral agents lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate (TDF).

Antiviral therapy for hepatitis B has evolved rapidly since the mid-1990s, as has the sensitivity of tests for HBV DNA. When IFN and lamivudine were evaluated in clinical trials, HBV DNA was measured by insensitive hybridization assays with detection thresholds of 105−106 virions/mL; when adefovir, entecavir, telbivudine, tenofovir, and PEG IFN were studied in clinical trials, HBV DNA was measured by sensitive amplification assays (polymerase chain reaction [PCR]) with detection thresholds of 101−103 viral copies/mL or IU/mL. Recognition of these distinctions is helpful when comparing results of clinical trials that established the efficacy of these therapies (reviewed below in chronological order of publication of these efficacy trials).

INTERFERON

IFN-α was the first approved therapy (1992) for chronic hepatitis B. Although it is no longer used to treat hepatitis B, standard IFN is important historically, having provided important lessons about antiviral therapy in general. For immunocompetent adults with HBeAg-reactive chronic hepatitis B (who tend to have high-level HBV DNA [>105−106 virions/mL] and histologic evidence of chronic hepatitis on liver biopsy), a 16-week course of IFN given subcutaneously at a daily dose of 5 million units, or three times a week at a dose of 10 million units, resulted in a loss of HBeAg and hybridization-detectable HBV DNA (i.e., a reduction to levels below 105−106 virions/mL) in ~30% of patients, with a concomitant improvement in liver histology. Seroconversion from HBeAg to anti-HBe occurred in ~20%, and, in early trials, ~8% lost HBsAg. Successful IFN ...

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