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, Heptovir, 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.

History
Racemic BCH-189 (the minus form is known as Lamivudine) was invented by DrBernard Belleau while at work at McGill University and Dr Paul Nguyen-Ba at the Montreal-based IAF BioChem International, Inc. laboratories in 1988 and the minus enantiomer isolated in 1989. Subsequently the group at Emory University headed by Dr. Dennis C. Liotta and R.F. Schinazi developed a synthesis for the BCH-189 that gave exclusively the beta-enantiomers. They then went on to resove the two enantiomers and demonstrated that the antiviral activity at non-toxic concentrations resided in the (-)-enantiomer, now called Lamivudine. The Emory patents to lamivudine were later invalidated by the original inventors. The drug's effectiveness for treating HIV in combination with AZT was discovered accidentally when a patient took Zidovudine secretly while in a clinical trial of Lamivudine monotherapy. Dr. Yung-Chi Cheng of Yale University in collaboration with R.F. Schinazi and D.C. Liotta first reported the anti-hepatitis B virus (HBV) activity of Lamivudine in cell culture which eventually led to the first oral antiviral agent for the treatment of HBV. The drug was later licensed to the British pharmaceutical company Glaxo by Biochem Pharma (now Shire Pharmaceuticals) for a 14 percent royalty. GlaxoSmithKline subsequently ceded the product to its ViiV Healthcare joint venture in 2009.

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 is phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and act as a chain terminator of DNA synthesis. The lack of a 3'-OH group in the incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated.

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. Lamivudine showed no evidence of carcinogenicity or mutagenicity in in vivo studies in mice and rats at doses from 10 to 58 times those used in humans.

Resistance

 * See also: resistance mutation

In HIV, high level resistance is associated with the M184V/I mutation in the reverse transcriptase gene as first reported by Raymond Schinazi's group at Emory University. GlaxoSmithKline claimed 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 may be benefit in continuing lamivudine treatment even in the presence of high level resistance, because the resistant virus is "less fit". The COLATE study has suggested that there is no benefit to continuing lamivudine treatment in patients with lamivudine resistance. 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. The change in amino acid sequence from YMDD to YIDD results in a 3.2 fold reduction in the error rate of the reverse transcriptase, which correlates with a significant growth disadvantage of the virus. Other resistance mutations are L80V/I, V173L and L180M.

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
No information is avalible about the effects of overdosage with lamivudine.

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.
 * Lamivir HBV as lamivudine 100 mg for treatment of CHB available from Cipla Ltd, India

Lamivudine is also available in fixed combinations with other HIV drugs:
 * Combivir (with zidovudine);
 * Epzicom/Kivexa (with abacavir);
 * Trizivir (with zidovudine and abacavir)