taken with or without food. Mechanism of action The combination of lamivudine and zidovudine is composed of two nucleotide reverse transcriptase inhibitors (NRTIs). Lamivudine and zidovudine both competitively inhibit and reduce the activity of reverse transcriptase (RT) causing HIV infected cells to decrease the number of viruses in the body. Lamivudine and zidovudine act as nucleoside analogs, which are substrates for the human nucleoside kinases. The initial phosphorylation step is crucial for the drug's activity, then converted into the active 5’-triphosphate form by host kinases. The drug is then incorporated to the end of the growing chain of the viral DNA causing the chain to be terminated, where nucleotides can no longer be added to the growing viral DNA. Lamividuine and zidovudine combination therapy is believed to work synergistically together to prevent mutations in the HIV virus, which can contribute to drug resistance. Pharmacokinetics Lamivudine is well absorbed in the body and distributes widely into the extravascular space. Oral bioavailability is >80% and overall metabolism is insignificant where approximately 95% of the drug is found unchanged in the urine. The only known metabolite found in humans is trans-sulfoxide. The half-life of lamivudine is 10 to 15 hours and binds poorly to plasma proteins. Zidovudine is also well absorbed in the body and penetrates into the cerebrospinal fluid. Oral bioavailability is 75% and primarily metabolized by the liver by glucuronidation. The primary metabolite is GZDV, an inactive metabolite produced after first pass metabolism. The half-life of zidovudine is 0.5 to 3 hours and binds poorly to plasma proteins. Lamivudine and zidovudine are not extensively metabolized by CYP450 liver enzymes. History Lamivudine/zidovudine (brand name Combivir) was introduced to the market with FDA approval in 1997. Its impact in history is significant as it was the first combination therapy with a fixed dose for HIV-positive people, and soon solidified its title as a gold standard as it was the most prescribed NRTI in initial HIV treatment for newly diagnosed patients. The arrival of Combivir was seen as a new revolution in HIV therapy, with its improved toxicity profile and tolerability, especially compared to the undesirable side effects of lone AZT therapy or the unfavorable facial and lipoatrophy seen in Stavudine monotherapy at that time. Society and culture Lamivudine/zidovudine is on the World Health Organization's List of Essential Medicines. Drug formulations Drug formulations: tablets by mouth Combivir: lamivudine 150 mg and zidovudine 300 mg