Lamivudine
Encyclopedia
Lamivudine 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.
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.
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 carcinogen
icity or mutagen
icity in in vivo studies in mice and rats at doses from 10 to 58 times those used in humans.
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.
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.
Lamivudine is also available in fixed combinations with other HIV drugs:
Reverse transcriptase inhibitor
Reverse-transcriptase inhibitors are a class of antiretroviral drug used to treat HIV infection, tumors, and cancer. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase enzyme that retroviruses need to reproduce.-Mechanism:...
(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
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
. It improves the seroconversion
Seroconversion
Seroconversion is the development of detectable specific antibodies to microorganisms in the blood serum as a result of infection or immunization. Serology is used to determine antibody positivity...
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 BelleauBernard Belleau
Bernard Belleau, OC, FRSC was a Canadian molecular pharmacologist best known for his role in the discovery of Lamivudine, a drug used in the treatment of HIV and Hepatitis B infection....
while at work at McGill University
McGill University
Mohammed Fathy is a public research university located in Montreal, Quebec, Canada. The university bears the name of James McGill, a prominent Montreal merchant from Glasgow, Scotland, whose bequest formed the beginning of the 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
Dennis C. Liotta
Dennis Liotta is a Chemistry professor at Emory University in Atlanta, Georgia, United States.Liotta's fields of research are organic synthesis and medicinal chemistry. Along with Dr. Raymond F. Schinazi and Dr...
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
Yale University
Yale University is a private, Ivy League university located in New Haven, Connecticut, United States. Founded in 1701 in the Colony of Connecticut, the university is the third-oldest institution of higher education in the United States...
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
ViiV Healthcare
ViiV Healthcare is a pharmaceutical company specializing in the development of therapies for HIV that was created as a joint venture by Pfizer and GlaxoSmithKline in November 2009 with both companies transferring their HIV assets to the new company. 85% of the company is owned by GlaxoSmithKline...
joint venture in 2009.
Lamivudine was approved by the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) on November 17, 1995 for use with zidovudine
Zidovudine
Zidovudine or azidothymidine is a nucleoside analog reverse-transcriptase inhibitor , a type of antiretroviral drug used for the treatment of HIV/AIDS. It is an analog of thymidine....
(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
Protease inhibitor (pharmacology)
Protease inhibitors are a class of drugs used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of proteases, e.g.HIV-1 protease, enzymes used by the viruses to cleave nascent proteins for final assembly of new...
. 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 analogueAnalog (chemistry)
In chemistry, a structural analog , also known as chemical analog or simply analog, is a compound having a structure similar to that of another one, but differing from it in respect of a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced...
of cytidine
Cytidine
Cytidine is a nucleoside molecule that is formed when cytosine is attached to a ribose ring via a β-N1-glycosidic bond...
. It can inhibit both types (1 and 2) of HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
reverse transcriptase
Reverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
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
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
. Lamivudine is often given in combination with zidovudine
Zidovudine
Zidovudine or azidothymidine is a nucleoside analog reverse-transcriptase inhibitor , a type of antiretroviral drug used for the treatment of HIV/AIDS. It is an analog of thymidine....
, with which it is highly synergistic. Lamivudine treatment has been shown to restore zidovudine sensitivity of previously resistant HIV. Lamivudine showed no evidence of carcinogen
Carcinogen
A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...
icity or mutagen
Mutagen
In genetics, a mutagen is a physical or chemical agent that changes the genetic material, usually DNA, of an organism and thus increases the frequency of mutations above the natural background level. As many mutations cause cancer, mutagens are therefore also likely to be carcinogens...
icity in in vivo studies in mice and rats at doses from 10 to 58 times those used in humans.
Resistance
- See also: resistance mutationResistance mutationThe term resistance mutation is most commonly used to describe point mutations in virus genes that allow the virus to become resistant to treatment with a particular antiviral drug. The term is now being seen with more frequency in bacteriology and parasitology...
In HIV, high level resistance is associated with the M184V/I mutation in the reverse transcriptase
Reverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
gene as first reported by Raymond Schinazi's group at Emory University. GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
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.
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:
- CombivirCombivirLamivudine/zidovudine is a pharmaceutical treatment for HIV infection. It is a fixed dose combination of two antiretroviral drugs, lamivudine and zidovudine...
(with zidovudineZidovudineZidovudine or azidothymidine is a nucleoside analog reverse-transcriptase inhibitor , a type of antiretroviral drug used for the treatment of HIV/AIDS. It is an analog of thymidine....
); - Epzicom/KivexaEpzicomAbacavir/lamivudine is a combination drug for the treatment of HIV infection. It is marketed as Kivexa in most countries except for the United States, where it is branded as Epzicom...
(with abacavirAbacavirAbacavir is a nucleoside analog reverse transcriptase inhibitor used to treat HIV and AIDS. It is available under the trade name Ziagen and in the combination formulations Trizivir and Kivexa/Epzicom...
); - TrizivirTrizivirAbacavir/lamivudine/zidovudine is a pharmaceutical treatment for HIV infection. It is a fixed dose combination of three reverse transcriptase inhibitors patented by GlaxoSmithKline and now marketed by its joint venture with Pfizer, ViiV Healthcare:*abacavir *lamivudine *zidovudine It is indicated...
(with zidovudineZidovudineZidovudine or azidothymidine is a nucleoside analog reverse-transcriptase inhibitor , a type of antiretroviral drug used for the treatment of HIV/AIDS. It is an analog of thymidine....
and abacavirAbacavirAbacavir is a nucleoside analog reverse transcriptase inhibitor used to treat HIV and AIDS. It is available under the trade name Ziagen and in the combination formulations Trizivir and Kivexa/Epzicom...
)
External links
- Epivir (manufacturer's website)
- Epivir-HBV (manufacturer's website)