Lamivudine (3TC) is a cytosine analog with in vitro activity against both HIV-1 and HBV.
Oral bioavailability exceeds 80% and is not food-dependent. The mean cerebrospinal fluid:plasma ratio of lamivudine is 0.1–0.2. Serum half-life is 2.5 hours, whereas the intracellular half-life of the triphosphorylated compound is 11–14 hours. Lamivudine is predominantly eliminated in the urine by active organic cation secretion.
Lamivudine is one of the recommended NRTI agents for use in pregnant women (Table 49–5).
Adverse effects are uncommon but include headache, dizziness, insomnia, fatigue, dry mouth, and gastrointestinal discomfort. Due to its activity against HBV, exacerbation of HBV may occur if therapy is interrupted or discontinued in patients co-infected with HIV and HBV. Since both emtricitabine and lamivudine may select for the M184V/I mutation, these agents should not be used together. Levels of lamivudine may increase when administered with trimethoprim-sulfamethoxazole. Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another; therefore, their concurrent use should be avoided if possible.
The thymidine analog stavudine (d4T) has high oral bioavailability (86%) that is not food-dependent. The serum half-life is 1.1 hours, the intracellular half-life is 3.0–3.5 hours, and mean cerebrospinal fluid concentrations are 55% of those of plasma. Excretion is by active tubular secretion and glomerular filtration.
The major toxicity is a dose-related peripheral sensory neuropathy; incidence may be increased with concomitant neurotoxic drugs such as didanosine, vincristine, isoniazid, or ribavirin, or in patients with advanced immunosuppression. Other potential adverse effects are pancreatitis, arthralgias, and elevation in serum aminotransferases. Caution is advised in patients with liver dysfunction. A rare adverse effect is a rapidly progressive ascending neuromuscular weakness. Lactic acidosis with hepatic steatosis, as well as lipodystrophy, appear to occur more frequently in patients receiving stavudine than in those receiving other NRTI agents. Stavudine should not be administered with didanosine due to increased risk of both lactic acidosis and pancreatitis. This combination has been implicated in several deaths in HIV-infected pregnant women. Since zidovudine may reduce the intracellular phosphorylation of stavudine, these two drugs should not be used together.
Tenofovir is an acyclic nucleoside phosphonate (ie, nucleotide) analog of adenosine with activity against HIV and HBV. Like the nucleoside analogs, tenofovir competitively inhibits HIV reverse transcriptase and causes chain termination after incorporation into DNA. However, only two rather than three intracellular phosphorylations are required for active inhibition of DNA synthesis.
Tenofovir disoproxil fumarate is a water-soluble prodrug of active tenofovir. The oral bioavailability increases from 25% in the fasted state to 39% after a high-fat meal. The prolonged serum (12–17 hours) and intracellular half-lives allow once-daily dosing. Elimination occurs by both glomerular filtration and active tubular secretion, and dosage adjustment in patients with renal insufficiency is recommended.