Lamivudine, commonly called 3TC, is an

antiretroviral medication Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do n ...

used to prevent and treat

HIV/AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...

. It is also used to treat chronic

hepatitis B Hepatitis B is an infectious disease caused by the '' Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection. Many people have no symptoms during an initial infection. ...

when other options are not possible. It is effective against both HIV-1 and HIV-2. It is typically used in combination with other antiretrovirals such as

zidovudine Zidovudine (ZDV), also known as azidothymidine (AZT), is an antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals. It may be used to prevent mother-to-child ...

and

abacavir Abacavir, sold under the brand name Ziagen among others, is a medication used to treat HIV/AIDS. Similar to other nucleoside analog reverse-transcriptase inhibitors (NRTIs), abacavir is used together with other HIV medications, and is not rec ...

. Lamivudine may be included as part of post-exposure prevention in those who have been potentially exposed to HIV. Lamivudine is taken by mouth as a liquid or tablet. Common side effects include nausea, diarrhea, headaches, feeling tired, and cough. Serious side effects include liver disease,

lactic acidosis Lactic acidosis is a medical condition characterized by a build-up of lactate (especially -lactate) in the body, with formation of an excessively low pH in the bloodstream. It is a form of metabolic acidosis, in which excessive acid accumulates d ...

, and worsening hepatitis B among those already infected. It is safe for people over three months of age and can be used during

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

. The medication can be taken with or without food. Lamivudine is a

nucleoside reverse transcriptase inhibitor Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replicatio ...

and works by blocking the

HIV reverse transcriptase A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...

and hepatitis B virus polymerase. Lamivudine was patented in 1995 and approved for use in the United States in 1995. It is on the World Health Organization's List of Essential Medicines. It is available as a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ...

Medical uses

Lamivudine (Epivir) is indicated in combination with other antiretroviral agents for the treatment of HIV‑1 infection. Lamivudine (Epivir HBV) is indicated for the treatment of chronic hepatitis B virus infection associated with evidence of hepatitis B viral replication and active liver inflammation. Lamivudine has been used for treatment of chronic

at a lower dose than for treatment of

. It improves the

seroconversion In immunology, seroconversion is the development of specific antibodies in the blood serum as a result of infection or immunization, including vaccination. During infection or immunization, antigens enter the blood, and the immune system begins t ...

of e-antigen positive hepatitis B and also improves histology staging of the liver. Long-term use of lamivudine leads to emergence of a resistant hepatitis B virus (YMDD) mutant. Despite this, lamivudine is still used widely as it is well tolerated.

Resistance

In HIV, high level resistance is associated with the M184V/I mutation in the

reverse transcriptase A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genom ...

gene as reported by Raymond Schinazi's group at

Emory University Emory University is a private research university in Atlanta, Georgia. Founded in 1836 as "Emory College" by the Methodist Episcopal Church and named in honor of Methodist bishop John Emory, Emory is the second-oldest private institution of ...

GlaxoSmithKline GSK plc, formerly GlaxoSmithKline plc, is a British multinational pharmaceutical and biotechnology company with global headquarters in London, England. Established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham. GSK is the tent ...

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 (

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the G ...

methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ...

aspartate Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...

-aspartate) 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.

Side effects

# Minor side effects may include

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...

fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...

headaches Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a resu ...

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...

cough A cough is a sudden expulsion of air through the large breathing passages that can help clear them of fluids, irritants, foreign particles and microbes. As a protective reflex, coughing can be repetitive with the cough reflex following three ph ...

and

nasal congestion Nasal congestion is the blockage of nasal breathing usually due to membranes lining the nose becoming swollen from inflamed blood vessels. Background In about 85% of cases, nasal congestion leads to mouth breathing rather than nasal breathin ...

. # Do not prescribe lamivudine/zidovudine, abacavir/lamivudine, or abacavir/lamivudine/zidovudine to patients taking

emtricitabine Emtricitabine (commonly called FTC, systematic name 2',3'-dideoxy-5-fluoro-3'-thiacytidine), with trade name Emtriva (formerly Coviracil), is a nucleoside reverse-transcriptase inhibitor (NRTI) for the prevention and treatment of HIV infection i ...

. # Long-term use of lamivudine can trigger a resistant hepatitis B virus (YMDD) mutant. # HIV or HBV-infected women on lamivudine are warned to discontinue

breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that bre ...

as this puts the baby at risk for HIV transmission and medication side effects. # Patients who are infected with HIV and HCV and are on both

interferon Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten th ...

and lamivudine can experience liver damage. # The drug can trigger an inflammatory response to opportunistic infections (e.g.,

Mycobacterium avium complex ''Mycobacterium avium ''complex is a group of mycobacteria comprising ''Mycobacterium intracellulare'' and ''Mycobacterium avium'' that are commonly grouped because they infect humans together; this group, in turn, is part of the group of nontub ...

AC M.

tuberculosis Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, ...

cytomegalovirus ''Cytomegalovirus'' (''CMV'') (from ''cyto-'' 'cell' via Greek - 'container' + 'big, megalo-' + -''virus'' via Latin 'poison') is a genus of viruses in the order '' Herpesvirales'', in the family '' Herpesviridae'', in the subfamily '' Betah ...

Pneumocystis The Pneumocystidomycetes are a class of ascomycete fungi. It includes the single order Pneumocystidales, which contains the single monotypic family Pneumocystidaceae, which in turn contains the genus Genus ( plural genera ) is a taxonomic ...

jirovecii ormerly_P._carinii). #_Autoimmune_disorders_have_been_reported_and_symptoms.html" ;"title="Autoimmune.html" ;"title="ormerly P. carinii). # Autoimmune">ormerly P. carinii). # Autoimmune disorders have been reported and symptoms">Autoimmune.html" ;"title="ormerly P. carinii). # Autoimmune">ormerly P. carinii). # Autoimmune disorders have been reported and symptoms can occur many months after initiation of the antiretroviral therapy. # Use with caution for patients with impaired renal function and do not prescribe this treatment to patients with impaired hepatic function.

Mechanism of action

Lamivudine is an analogue of

cytidine Cytidine (symbol C or Cyd) is a nucleoside molecule that is formed when cytosine is attached to a ribose ring (also known as a ribofuranose) via a β-N1- glycosidic bond. Cytidine is a component of RNA. It is a white water-soluble solid. which ...

. It can inhibit both types (1 and 2) of HIV

and also the reverse transcriptase of hepatitis B virus. 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 by mouth, and it is rapidly absorbed with a bio-availability of over 80%. Some research suggests that lamivudine can cross the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable border of endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of the central nervous system where ne ...

. Lamivudine is often given in combination with

, 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 A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive sub ...

icity or

mutagen In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer i ...

icity in ''in vivo'' studies in mice and rats at doses from 10 to 58 times those used in humans. It has a

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ...

of 5–7 hours in adults and 2 hours in HIV-infected children.

History

Racemic BCH-189 (the minus form is known as lamivudine) was invented by Bernard Belleau while at work at

McGill University McGill University (french: link=no, Université McGill) is an English-language public research university located in Montreal, Quebec, Canada. Founded in 1821 by royal charter granted by King George IV,Frost, Stanley Brice. ''McGill Univer ...

and Paul Nguyen-Ba at the Montreal-based IAF BioChem International, Inc. laboratories in 1988 and the minus enantiomer isolated in 1989. Samples were first sent to Yung-Chi Cheng of

Yale University Yale University is a private research university in New Haven, Connecticut. Established in 1701 as the Collegiate School, it is the third-oldest institution of higher education in the United States and among the most prestigious in the w ...

for study of its toxicity. When used in combination with AZT, he discovered that lamivudine's negative form reduced side effects and increased the drug's efficiency at inhibiting reverse transcriptase. The combination of lamivudine and AZT increased the efficiency at inhibiting an enzyme HIV uses to reproduce its genetic material. As a result, lamivudine was identified as a less toxic agent to mitochondria DNA than other retroviral drugs. Lamivudine was approved by the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(FDA) on November 17, 1995, for use with

(AZT) and again in 2002 as a once-a-day dosed medication. It is on the World Health Organization's List of Essential Medicines.

Formulations

* Epivir tablets (GlaxoSmithKline; US and UK) for the treatment of HIV * Epivir-HBV tablets (GlaxoSmithKline; US only) for the treatment of hepatitis B * Zeffix tablets (GlaxoSmithKline; UK only) for the treatment of hepatitis B * 3TC tablets (GlaxoSmithKline; South Africa) for the treatment of HIV * Lamivudine is available in fixed-dose combinations with other HIV drugs such as: ** Lamivudine/zidovudine (with

) ** Abacavir/lamivudine (with

) ** Abacavir/lamivudine/zidovudine (with zidovudine and abacavir) **

Dolutegravir/lamivudine Dolutegravir/lamivudine, sold under the brand name Dovato, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. It contains dolutegravir, as the salt, an integrase strand transfer inhibitor (INSTI), and lamivudine ...

(with dolutegravir)

References

External links

* {{Portal bar , Medicine , Viruses Hepatotoxins Nucleoside analog reverse transcriptase inhibitors World Health Organization essential medicines Nucleosides Pyrimidones Wikipedia medicine articles ready to translate Hydroxymethyl compounds Oxathiolanes GSK plc brands