Lamivudine inhibits HBV DNA polymerase and HIV reverse transcriptase by competing with deoxycytidine triphosphate for incorporation into the viral DNA, resulting in chain termination. Although lamivudine results in rapid and potent virus suppression, chronic therapy is limited by the emergence of lamivudineresistant HBV isolates (eg, L180M or M204I/V), estimated to occur in 15–30% of patients at 1 year and in up to 65% after 5 years of therapy. Resistance has been associated with flares of hepatitis and progressive liver disease. Cross-resistance between lamivudine and emtricitabine or entecavir may occur; however, adefovir and tenofovir maintain activity against lamivudineresistant strains of HBV.
In the doses used for HBV infection, lamivudine has an excellent safety profile. Headache, nausea, diarrhea, dizziness, myalgia, and malaise are rare. Co-infection with HIV may increase the risk of pancreatitis.
Telbivudine is a thymidine nucleoside analog with activity against HBV DNA polymerase. It is phosphorylated by cellular kinases to the active triphosphate form, which has an intracellular half-life of 14 hours. The phosphorylated compound competitively inhibits HBV DNA polymerase, resulting in incorporation into viral DNA and chain termination. It is not active in vitro against HIV-1.
Oral bioavailability is unaffected by food. Plasma protein binding is low (3%) and distribution wide. The serum half-life is approximately 15 hours and excretion is renal. There are no known metabolites and no known interactions with the CYP450 system or other drugs.
Telbivudine induced greater rates of virologic response than either lamivudine or adefovir in comparative trials. However, emergence of resistance, typically due to the M204I mutation, may occur in up to 22% of patients with durations of therapy exceeding 1 year, and may result in virologic rebound. Telbivudine is not effective in patients with lamivudine-resistant HBV.
Adverse effects are mild; they include fatigue, headache, cough, nausea, and diarrhea. Both uncomplicated myalgia and myopathy with elevated creatinine kinase levels have been reported, as has peripheral neuropathy. As with other nucleoside analogs, lactic acidosis and severe hepatomegaly with steatosis may occur during therapy as well as flares of hepatitis after discontinuation.
Tenofovir, a nucleotide analog of adenosine in use as an antiretroviral agent, has potent activity against HBV. The characteristics of tenofovir disoproxil are described earlier in this chapter. Tenofovir maintains activity against lamivudineand entecavir-resistant hepatitis virus isolates. Although similar in structure to adefovir dipivoxil, comparative trials show a higher rate of virologic response and histologic improvement, and a lower rate of emergence of resistance in patients with chronic HBV infection. Resistance to tenofovir has not been documented in clinical trials, even among patients who have been treated with tenofovir for up to 8 years. However, efficacy is lower in patients who have resistance to adefovir and double mutations (A181T/V and N236T).