Lamivudine

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Lamivudine
Lamivudine structure.svg
Clinical data
Trade names Epivir, Epivir-HBV, Zeffix, others [1]
Other names(−)-L-2′,3′-dideoxy-3′-thiacytidine
AHFS/Drugs.com Monograph
MedlinePlus a696011
License data
Pregnancy
category
  • AU:B3
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 86%
Protein binding Less than 36%
Elimination half-life 5 to 7 hours
Excretion Kidney (circa 70%)
Identifiers
  • 2',3'-dideoxy-3'-thiacytidine 4-Amino-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2-dihydropyrimidin-2-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
NIAID ChemDB
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.132.250 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C8H11N3O3S
Molar mass 229.25 g·mol−1
3D model (JSmol)
  • O=C1/N=C(/N)\C=C/N1[C@@H]2O[C@@H](SC2)CO
  • InChI=1S/C8H11N3O3S/c9-5-1-2-11(8(13)10-5)6-4-15-7(3-12)14-6/h1-2,6-7,12H,3-4H2,(H2,9,10,13)/t6-,7+/m1/s1 Yes check.svgY
  • Key:JTEGQNOMFQHVDC-RQJHMYQMSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Lamivudine, commonly called 3TC, is an antiretroviral medication used to prevent and treat HIV/AIDS. [1] It is also used to treat chronic hepatitis B when other options are not possible. [1] It is effective against both HIV-1 and HIV-2. [1] It is typically used in combination with other antiretrovirals such as zidovudine, dolutegravir, and abacavir. [1] Lamivudine may be included as part of post-exposure prevention in those who have been potentially exposed to HIV. [1] Lamivudine is taken by mouth as a liquid or tablet. [1]

Contents

Common side effects include nausea, diarrhea, headaches, feeling tired, and cough. [1] Serious side effects include liver disease, lactic acidosis, and worsening hepatitis B among those already infected. [1] It is safe for people over three months of age and can be used during pregnancy. [1] The medication can be taken with or without food. [1] Lamivudine is a nucleoside reverse transcriptase inhibitor and works by blocking the HIV reverse transcriptase and hepatitis B virus polymerase. [1]

Lamivudine was patented in 1995 and approved for use in the United States in 1995. [8] [9] It is on the World Health Organization's List of Essential Medicines. [10] It is available as a generic medication. [1]

Medical uses

Lamivudine (Epivir) is indicated in combination with other antiretroviral agents for the treatment of HIV‑1 infection. [4] [6] 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. [5] [7]

Lamivudine has been used for treatment of chronic hepatitis B at a lower dose than for treatment of HIV/AIDS. It improves the seroconversion 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. [11] Despite this, lamivudine is still used widely as it is well tolerated. [12]

Resistance

In HIV, high level resistance is associated with the M184V/I mutation in the reverse transcriptase gene as 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. [13] 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.[ original research? ]

In hepatitis B, lamivudine resistance was first described in the YMDD (tyrosine-methionine-aspartate-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. [14] 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. [15]

Side effects

  1. Minor side effects may include nausea, fatigue, headaches, diarrhea, cough and nasal congestion.
  2. Do not prescribe lamivudine/zidovudine, abacavir/lamivudine, or abacavir/lamivudine/zidovudine to patients taking emtricitabine.
  3. Long-term use of lamivudine can trigger a resistant hepatitis B virus (YMDD) mutant.
  4. HIV or HBV-infected women on lamivudine are warned to discontinue breastfeeding as this puts the baby at risk for HIV transmission and medication side effects.
  5. Patients who are infected with HIV and HCV and are on both interferon and lamivudine can experience liver damage.
  6. The drug can trigger an inflammatory response to opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii).
  7. Autoimmune disorders have been reported and symptoms can occur many months after initiation of the antiretroviral therapy.
  8. Use with caution for patients with impaired renal function and do not prescribe this treatment to patients with impaired liver function.

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 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.[ medical citation needed ]

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. 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. [4]

It has a half-life of 5–7 hours in adults and 2 hours in children.[ medical citation needed ]

History

Racemic BCH-189 (the minus form is known as lamivudine) was invented by Bernard Belleau while at work at McGill University 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 for study of its toxicity. [16] 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. [17] 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. [18] [19]

Lamivudine was approved by the US Food and Drug Administration (FDA) in November 1995, for use with zidovudine (AZT) and again in 2002. It is on the World Health Organization's List of Essential Medicines. [10]

Formulations

Related Research Articles

The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple drugs that act on different viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patient's total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death. HAART also prevents the transmission of HIV between serodiscordant same-sex and opposite-sex partners so long as the HIV-positive partner maintains an undetectable viral load.

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 replication of HIV and other retroviruses.

<span class="mw-page-title-main">Zalcitabine</span> Chemical compound

Zalcitabine, also called dideoxycytidine, is a nucleoside analog reverse-transcriptase inhibitor (NRTI) sold under the trade name Hivid. Zalcitabine was the third antiretroviral to be approved by the Food and Drug Administration (FDA) for the treatment of HIV/AIDS. It is used as part of a combination regimen.

<span class="mw-page-title-main">Abacavir</span> Chemical compound

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 recommended by itself. It is taken by mouth as a tablet or solution and may be used in children over the age of three months.

<span class="mw-page-title-main">Emtricitabine</span> Antiretroviral drug used to treat HIV infection

Emtricitabine, with trade name Emtriva, is a nucleoside reverse-transcriptase inhibitor (NRTI) for the prevention and treatment of HIV infection in adults and children. In 2019, it was the 494th most commonly prescribed medication in the United States, with more than 3 thousand prescriptions.

<span class="mw-page-title-main">Adefovir</span> Chemical compound

Adefovir is a prescription medicine used to treat (chronic) infections with hepatitis B virus. A prodrug form of adefovir was previously called bis-POM PMEA, with trade names Preveon and Hepsera. It is an orally administered nucleotide analog reverse-transcriptase inhibitor (ntRTI). It can be formulated as the pivoxil prodrug adefovir dipivoxil.

<span class="mw-page-title-main">Nevirapine</span> Chemical compound

Nevirapine (NVP), sold under the brand name Viramune among others, is a medication used to treat and prevent HIV/AIDS, specifically HIV-1. It is generally recommended for use with other antiretroviral medications. It may be used to prevent mother to child spread during birth but is not recommended following other exposures. It is taken by mouth.

<span class="mw-page-title-main">Entecavir</span> Chemical compound

Entecavir (ETV), sold under the brand name Baraclude, is an antiviral medication used in the treatment of hepatitis B virus (HBV) infection. In those with both HIV/AIDS and HBV antiretroviral medication should also be used. Entecavir is taken by mouth as a tablet or solution.

<span class="mw-page-title-main">Nucleoside analogue</span> Biochemical compound

Nucleoside analogues are structural analogues of a nucleoside, which normally contain a nucleobase and a sugar. Nucleotide analogues are analogues of a nucleotide, which normally has one to three phosphates linked to a nucleoside. Both types of compounds can deviate from what they mimick in a number of ways, as changes can be made to any of the constituent parts. They are related to nucleic acid analogues.

<span class="mw-page-title-main">Abacavir/lamivudine/zidovudine</span> Mixture of chemical compounds

Abacavir/lamivudine/zidovudine, sold under the brand name Trizivir, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. It contains three reverse transcriptase inhibitors patented by GlaxoSmithKline and marketed by a joint venture with Pfizer, ViiV Healthcare:

<span class="mw-page-title-main">Lamivudine/zidovudine</span> Combination drug for HIV

Lamivudine/zidovudine, sold under the brand name Combivir among others, is a fixed-dose combination antiretroviral medication used to treat HIV/AIDS. It contains two antiretroviral medications, lamivudine and zidovudine. It is used together with other antiretrovirals. It is taken by mouth twice a day.

<span class="mw-page-title-main">Abacavir/lamivudine</span> Combination drug for HIV

Abacavir/lamivudine, sold under the brand name Kivexa among others, is a fixed-dose combination antiretroviral medication used to treat HIV/AIDS. It contains abacavir and lamivudine. It is generally recommended for use with other antiretrovirals. It is commonly used as part of the preferred treatment in children. It is taken by mouth as a tablet.

<span class="mw-page-title-main">Apricitabine</span> Chemical compound

Apricitabine is an experimental nucleoside reverse transcriptase inhibitor (NRTI) against HIV. It is structurally related to lamivudine and emtricitabine, and, like these, is an analogue of cytidine.

ViiV Healthcare is a British multinational pharmaceutical company specializing in the research and development of medicines to treat and prevent HIV/AIDS, with its global headquarters in London. The company was created as a joint venture by GSK and Pfizer in November 2009, with both companies transferring their HIV assets to the new company. In 2012, Shionogi joined the company. As of December 2023, 76.5% of the company is owned by GSK, 13.5% by Pfizer and 10% by Shionogi. According to The Financial Times, the company’s co-ownership structure may change depending on the achievement of certain milestones.

Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors began in the 1980s when the AIDS epidemic hit Western societies. NRTIs inhibit the reverse transcriptase (RT), an enzyme that controls the replication of the genetic material of the human immunodeficiency virus (HIV). The first NRTI was zidovudine, approved by the U.S. Food and Drug Administration (FDA) in 1987, which was the first step towards treatment of HIV. Six NRTI agents and one NtRTI have followed. The NRTIs and the NtRTI are analogues of endogenous 2´-deoxy-nucleoside and nucleotide. Drug-resistant viruses are an inevitable consequence of prolonged exposure of HIV-1 to anti-HIV drugs.

<span class="mw-page-title-main">Dolutegravir</span> Chemical compound

Dolutegravir (DTG), sold under the brand name Tivicay, is an antiretroviral medication used, together with other medication, to treat HIV/AIDS. It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potential exposure. It is taken by mouth.

<span class="mw-page-title-main">Abacavir/dolutegravir/lamivudine</span> Drug combination for HIV

Abacavir/dolutegravir/lamivudine, sold under the brand name Triumeq among others, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. It is a combination of three medications with different and complementary mechanisms of action: abacavir, dolutegravir and lamivudine.

Lamivudine/nevirapine/zidovudine (3TC/NVP/AZT) is a fixed-dose combination antiretroviral medication used to treat HIV/AIDS. It contains lamivudine, nevirapine, and zidovudine. It is either used by itself or along with other antiretrovirals. It is a recommended treatment in those who are pregnant. It is taken by mouth twice a day.

<span class="mw-page-title-main">Bictegravir/emtricitabine/tenofovir alafenamide</span> Fixed dose combination HIV drug

Bictegravir/emtricitabine/tenofovir alafenamide, sold under the brand name Biktarvy, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. One tablet, taken orally once daily, contains 50 mg bictegravir, 200 mg emtricitabine, and 25 mg tenofovir alafenamide.

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, a nucleoside analogue reverse transcriptase inhibitor (NRTI). It is taken by mouth.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 "Lamivudine". The American Society of Health-System Pharmacists. Archived from the original on 2 June 2016. Retrieved 31 July 2016.
  2. ↑ "3TC (lamivudine, Epivir)". Catie. 2014. Retrieved 22 August 2022.
  3. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  4. 1 2 3 "Epivir- lamivudine tablet, film coated Epivir- lamivudine solution". DailyMed. 1 August 2020. Retrieved 28 November 2020.
  5. 1 2 "Epivir HBV- lamivudine tablet, film coated Epivir HBV- lamivudine solution". DailyMed. 17 August 2020. Retrieved 28 November 2020.
  6. 1 2 "Epivir EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 29 November 2020.
  7. 1 2 "Zeffix EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 28 November 2020.
  8. ↑ Therapy of Viral Infections Volume 15 of Topics in Medicinal Chemistry. Springer. 2015. p. 6. ISBN   9783662467596. Archived from the original on 15 August 2016.
  9. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 506. ISBN   9783527607495.
  10. 1 2 World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  11. ↑ Cane PA, Mutimer D, Ratcliffe D, Cook P, Beards G, Elias E, Pillay D (1999). "Analysis of hepatitis B virus quasispecies changes during emergence and reversion of lamivudine resistance in liver transplantation". Antiviral Therapy. 4 (1): 7–14. doi: 10.1177/135965359900400101 . PMID   10682123. S2CID   35040816.
  12. ↑ Kasırga E (April 2015). "Lamivudine resistance in children with chronic hepatitis B". World Journal of Hepatology. 7 (6): 896–902. doi: 10.4254/wjh.v7.i6.896 . PMC   4411531 . PMID   25937866.
  13. ↑ Fox Z, Dragsted UB, Gerstoft J, Phillips AN, Kjaer J, Mathiesen L, et al. (2006). "A randomized trial to evaluate continuation versus discontinuation of lamivudine in individuals failing a lamivudine-containing regimen: the COLATE trial". Antiviral Therapy. 11 (6): 761–770. doi: 10.1177/135965350601100608 . PMID   17310820. S2CID   25783477.
  14. ↑ "Index". Archived from the original on 1 July 2010. Retrieved 23 July 2010.Stanford University Drug Resistance Database.
  15. ↑ Koziel MJ, Peters MG (April 2007). "Viral hepatitis in HIV infection". The New England Journal of Medicine. 356 (14): 1445–1454. doi:10.1056/NEJMra065142. PMC   4144044 . PMID   17409326.
  16. ↑ "Hunting Down HIV".
  17. ↑ "US Patent Office" (PDF). Archived (PDF) from the original on 16 June 2016.
  18. ↑ Soderstrom J (2003). "National Institutes of Health: Moving Research from the Bench to the Bedside". Archived from the original on 4 March 2016.
  19. ↑ Gilden D (2000). "The Wide-Ranging Effects of Nucleoside Analogs:A Look at Mitochondrial Toxicity". Archived from the original on 16 September 2016.
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