Adefovir is well tolerated at doses used to treat HBV infection. A reversible increase in serum creatinine has been reported in 3–9% of patients after 4–5 years of treatment. Other potential adverse effects are headache, diarrhea, asthenia, and abdominal pain. As with other NRTI agents, lactic acidosis and hepatic steatosis are a risk owing to mitochondrial dysfunction. Pivalic acid, a by-product of adefovir metabolism, can esterify free carnitine and result in decreased carnitine levels. However, it is not necessary to administer carnitine supplementation with the low doses used to treat patients with HBV (10 mg/d). Adefovir is embryo-toxic in rats at high doses and is genotoxic in preclinical studies.
Entecavir is an orally administered cyclopentyl guanosine nucleoside analog that competitively inhibits all three functions of HBV DNA polymerase, including base priming, reverse transcription of the negative strand, and synthesis of the positive strand of HBV DNA. Oral bioavailability approaches 100% but is decreased by food; therefore, entecavir should be taken on an empty stomach. The intracellular half-life of the active phosphorylated compound is 15 hours and plasma half-life is prolonged at 128–149 hours, allowing once-daily dosing. It is excreted by the kidney, undergoing both glomerular filtration and net tubular secretion, and dosage should be adjusted in the setting of renal insufficiency.
Suppression of HBV DNA levels was greater with entecavir than with lamivudine or adefovir in comparative trials. Entecavir appears to have a higher barrier to the emergence of resistance than lamivudine. Although selection of resistant isolates with the S202G mutation has been documented during therapy, clinical resistance is rare (<1% at 5 years). However, resistance is more frequent in lamivudine-refractory patients (~ 50% at 5 years). Entecavir has weak anti-HIV activity and can induce development of the M184V variant in HBV/HIV co-infected patients, resulting in resistance to emtricitabine and lamivudine.
Entecavir is well tolerated. Potential adverse events are headache, fatigue, dizziness, nausea, and upper abdominal pain. Co-administration of entecavir with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either entecavir or the co-administered drug. Severe lactic acidosis was reported in a case series of entecavir; thus caution is advised for administration in the setting of severe hepatic decompensation. Lung adenomas and carcinomas in mice, hepatic adenomas and carcinomas in rats and mice, vascular tumors in mice, and brain gliomas and skin fibromas in rats have been observed at varying exposures, although clinical relevance is unknown.
The pharmacokinetics of lamivudine are described earlier in this chapter (see Nucleoside and Nucleotide Reverse Transcriptase Inhibitors). The more prolonged intracellular half-life in HBV-infected cell lines (17–19 hours) than in HIV-infected cell lines (10.5–15.5 hours) allows for lower doses and less frequent administration. Lamivudine can be safely administered to patients with decompensated liver disease. Prolonged treatment has been shown to decrease clinical progression of HBV, as well as development of hepatocellular cancer by approximately 50%. Also, lamivudine has been effective in preventing vertical transmission of HBV from mother to newborn when given in the last 4 weeks of gestation.