As of 2017 eight drugs were approved for treatment of chronic HBV infection in the United States: five oral nucleoside/nucleotide analogs (lamivudine, adefovir dipivoxil, tenofovir disoproxil, tenofovir alafenamide, entecavir, telbivudine) and two injectable interferon drugs (interferon alfa-2b, pegylated interferon alfa-2a) (Table 49–6). The use of standard interferon has been supplanted by long-acting pegylated interferon, allowing once-weekly rather than daily or thrice-weekly dosing. The advantages of interferon are its finite duration of treatment, the absence of selection of resistant variants, and a more durable response. However, adverse effects from interferon are more frequent, and may be severe. Furthermore, interferon cannot be used in patients with decompensated disease. In general, nucleoside/nucleotide analog therapies have better tolerability and produce a higher response rate than the interferons, and are now considered the first line of therapy.
Combination therapies may reduce the development of resistance. The optimal duration of therapy remains unknown.
Several anti-HBV agents have anti-HIV activity as well, including tenofovir disoproxil, tenofovir alafenamide, lamivudine, and adefovir dipivoxil. Emtricitabine, an NRTI used in HIV infection, has resulted in excellent biochemical, virologic, and histologic improvement in patients with chronic HBV infection, although it is not approved for this indication. Although agents with dual HBV and HIV activity are particularly useful as part of a first-line regimen in co-infected patients, it is important to note that acute exacerbation of hepatitis may occur upon discontinuation or interruption of these agents; this may be severe or even fatal.
Although initially and abortively developed for treatment of HIV infection, adefovir dipivoxil gained approval, at lower and less toxic doses, for treatment of HBV infection. Adefovir dipivoxil is the diester prodrug of adefovir, an acyclic phosphonated adenine nucleotide analog. It is phosphorylated by cellular kinases to the active diphosphate metabolite and then competitively inhibits HBV DNA polymerase and causes chain termination after incorporation into viral DNA. Adefovir is active in vitro against a wide range of DNA and RNA viruses, including HBV, HIV, and herpesviruses.
Oral bioavailability of adefovir dipivoxil is ~ 59% and is unaffected by meals; it is rapidly and completely hydrolyzed to the parent compound by intestinal and blood esterases. Protein binding is low (<5%). The intracellular half-life of the diphosphate is prolonged, ranging from 5 to 18 hours in various cells; this makes once-daily dosing feasible. Adefovir is excreted by both glomerular filtration and active tubular secretion and requires dose adjustment for renal dysfunction; however, it may be administered to patients with decompensated liver disease.
Of the oral agents, adefovir may be slower to suppress HBV DNA levels and the least likely to induce HBeAg seroconversion. Emergence of resistance is up to 29% after 5 years of use. However, there is no cross-resistance between adefovir and lamivudine or entecavir.