A potent inhibitor of HIV and hepatitis B virus---Lamivudine

Lamivudine is the negative enantiomer of 2u-deoxy-3u-thiacytidine, the racemic mixture of the two enantiomers previously known as both BCH 189 and GR103365X. It is a member of the nucleoside analog reverse transcriptase inhibitor class of antiretroviral drugs. This dideoxynucleoside analog of cytidine is a potent inhibitor of HIV-1 and HIV-2, as well as of hepatitis B virus. Lamivudine, manufactured by GlaxoSmithKline and FDA approved in 1995, is registered for the treatment of HIV-1 infection and hepatitis B virus infection in a number of countries.

 Its trade name is Epivirs, but it also comes in a number of fixed formulations, including with zidovudine (Combivirs), with zidovudine and abacavir (Trizivirs), and with abacavir as a single tablet (Kivexas, Epzicoms). A tenofovir-lamivudine combination tablet, manufactured by Hetero Drugs Limited in India, has recently been approved by the FDA for use outside the United States (US FDA, 2009).  The chemical name of lamivudine is (2R-cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5- yl)-(1H)-pyrimidin-2-1. The compound has the molecular formula C8H11N8O3S. The chemical structure of lamivudine differs from that of zidovudine in that a sulfur atom replaces the 3u carbon atom of the ribose. In addition, lamivudine has a beta-L-sugar configuration and carries a cytosine base moiety. The concentration of the drug can be reported in mM or mg/ml (1 mM is approximately equivalent to 0.2 mg/ml).

MECHANISM OF DRUG ACTION

Lamivudine triphosphate inhibits HIV-1 replication via competitive inhibition of HIV-1 reverse transcriptase. Chain termination occurs when lamivudine triphosphate is incorporated into the growing DNA chain in place of deoxycytidine triphosphate. Like didanosine, lamivudine produces higher ratios of dideoxycytidine triphosphate than deoxycytidine triphosphate in resting cells than in activated cells, and is thus more potent against HIV-1 in resting cells. 

Lamivudine inhibits hepatitis B virus replication by acting as a chain terminator of DNA polymerase [a reverse transcriptase of hepatitis B virus] activity. The deoxycytidine deaminaseresistant (–) enantiomer of 2u3u-dideoxy-3u-thiacytidine (lamivudine) is the active stereoisomer that inhibits the replication of hepatitis B virus. Lamivudine inhibits the reverse transcription of pregenomic RNA to form the hepatitis B virus minus-strand DNA. In addition, lamivudine suppresses the replication of duck hepatitis B virus in primary hepatocyte cultures and leads to a reduction of hepatitis B virus DNA in the serum of hepatitis B virus infected chimpanzees and ducks.

Drug interactions

Coadministration with zidovudine, didanosine, stavudine, abacavir, tenofovir, or nevirapine is not associated with a change in the pharmacokinetics of lamivudine, and no toxicities are likely as a result of lamivudine coadministration with these drugs. Lamivudine would not be expected to interact with the protease inhibitors as these interactions are usually mediated by cytochrome P450 (CYP) 3A4 enzyme inhibition or induction. Coadministration of trimethoprim sulphamethoxazole with lamivudine has been repoted to cause an increase in the lamivudine AUC by 43% and reduced renal clearance of the drug by 31%.

TOXICITY

The (-) enantiomer of racemic 2u-deoxy-3u-thiacytidine is considerably less toxic than the (+) enantiomer, although they are equipotent against HIV-1 and HIV-2 (Coates et al., 1992a). Lamivudine is associated with relatively few adverse reactions. In an open-label phase I trial of lamivudine in 20 asymptomatic HIV-1- infected people, the main adverse event was mild headache (van Leeuwen et al., 1992). In two phase I/II trials of lamivudine (0.5–20 mg/ kg daily) in patients with AIDS or advanced HIV-1 infection, as well as those at earlier stages of disease, the only reported symptoms were mild headache, insomnia, nausea, diarrhea, and abdominal pain, and a trend towards a lower neutrophil count in patients receiving the higher doses. When used in combination with zidovudine in patients with predominantly asymptomatic HIV-1 infection, adverse events were similar to those encountered with zidovudine monotherapy and of similar incidence. When lamivudine was used in adult patients with chronic hepatitis B virus infection, in doses of up to 300 mg/day, the drug was well tolerated, with only minor adverse reactions reported that were not dose-related. Alterations in laboratory tests were rarely associated with symptoms, and usually resolved with continuation of therapy. These included elevations in serum lipase (in 12%) and amylase (in 6%) and transient elevations in creatinine kinase (in 12%). There were no reported cases of acidosis, anion gap, myopathy, hepatic decompensation, or renal impairment.

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