Lamivudine

Lamivudine (2',3'-dideoxy-3'-thiacytidine, commonly called 3TC) is a potent nucleoside analog reverse transcriptase inhibitor (nRTI).

It is marketed by GlaxoSmithKline with the brand names Zeffix, Epivir, and Epivir-HBV.

Lamivudine has been used for treatment of chronic hepatitis B at a lower dose than for treatment of HIV. It improves the seroconversion of e-antigen positive hepatitis B and also improves histology staging of the liver. Long term use of lamivudine unfortunately leads to emergence of a resistant hepatitis B virus (YMDD) mutant. Despite this, lamivudine is still used widely as it is well tolerated.

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History

Lamivudine was invented by Bernard Belleau and Nghe Nguyen-Ga at the Montreal-based IAF BioChem International, Inc. laboratories in 1989. Initially designed as an antiviral agent, the drug's effectiveness for treating HIV in combination with AZT was discovered by Yung-Chi (Tommy) Cheng at Yale University. The drug was later licensed to the British pharmaceutical company Glaxo for a 14 percent royalty.

Lamivudine was approved by the Food and Drug Administration (FDA) on November 17 1995 for use with zidovudine (AZT) and again in 2002 as a once-a-day dosed medication. The fifth antiretroviral drug on the market, it was the last NRTI for three years while the approval process switched to protease inhibitors. According to the manufacturer's 2004 annual report, its patent will expire in the United States in 2010 and in Europe in 2011.

Mechanism of action

Lamivudine is an analogue of cytidine. It can inhibit both types (1 and 2) of HIV reverse transcriptase and also the reverse transcriptase of hepatitis B. It needs to be phosphorylated to its triphosphate form before it is active. 3TC-triphosphate also inhibits cellular DNA polymerase.

Lamivudine is administered orally, and it is rapidly absorbed with a bio-availability of over 80%. Some research suggests that lamivudine can cross the blood-brain barrier. Lamivudine is often given in combination with zidovudine, with which it is highly synergistic. Lamivudine treatment has been shown to restore zidovudine sensitivity of previously resistant HIV. Several mutagenicity tests show that lamivudine should not show mutagenic activity in therapeutic doses.

== Physical Interaction with Tenofovir DF == Lamivudine shows brownish coloration with tenofovir disoproxil fumarate, reason behind this is still unknown.

Resistance

See also: resistance mutation

In HIV, high level resistance is associated with the M184V/I mutation in the reverse transcriptase gene. GlaxoSmithKline sought to perpetuate the fiction that the M184V mutation reduces "viral fitness", because of the finding that continued lamivudine treatment causes the HIV viral load to rebound but at a much lower level, and that withdrawal of lamivudine results in a higher viral load rebound with rapid loss of the M184V mutation; GSK therefore argued that there is theoretical benefit in continuing lamivudine treatment even in the presence of high level resistance, because the resistant virus is "less fit". The COLATE study has shown definitively that there is no benefit to continuing lamivudine treatment in patients with lamivudine resistance.^[1] A better explanation of the data is that lamivudine continues to have a partial anti-viral effect even in the presence of the M184V mutation.

In hepatitis B, lamivudine resistance was first described in the YMDD locus of the HBV reverse transcriptase gene. The HBV reverse transcriptase gene is 344 amino acids long and occupies codons 349 to 692 on the viral genome. The most commonly encountered resistance mutations are M204V/I/S. Other resistance mutations are L80V/I, V173L and L180M.^[2]

Dosing

For adults with HIV (or children over 12), the dose is 300mg once daily, or 150mg twice a day. Lamivudine is never used on its own in the treatment of HIV.

For the treatment of adults with hepatitis B, the dose is 100mg once daily. If co-infected with HIV, then the dose is as for HIV.

For a child 3 months to 12 years old, about 1.4-2 mg per lb. of body weight twice a day, no more than 150 mg per dose.

Overdosage

Little is known about the effects of overdosage with lamivudine. Call local poison control center.

Presentation

• Epivir 150 mg or 300 mg tablets (GlaxoSmithKline; US and UK) for the treatment of HIV;
• Epivir-HBV 100 mg tablets (GlaxoSmithKline; US only) for the treatment of hepatitis B;
• Zeffix 100 mg tablets (GlaxoSmithKline; UK only) for the treatment of hepatitis B.

Lamivudine is also available in fixed combinations with other HIV drugs:

• Combivir (with zidovudine);
• Kivexa (with abacavir);
• Trizivir (with zidovudine and abacavir).

References