Lamivudine

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 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]

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.[2][3] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[4] It is available as a generic medication.[1] The wholesale cost in the developing world as of 2014 is about US$0.06 per day.[5] As of 2015 the cost for a typical month of medication in the United States is more than $200.[6]

Lamivudine
Lamivudine structure
Clinical data
Trade namesEpivir, others[1]
Synonyms(−)-L-2′,3′-dideoxy-3′-thiacytidine
AHFS/Drugs.comMonograph
MedlinePlusa696011
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability86%
Protein bindingLess than 36%
Elimination half-life5 to 7 hours
ExcretionKidney (circa 70%)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
NIAID ChemDB
PDB ligand
Chemical and physical data
FormulaC8H11N3O3S
Molar mass229.26 g/mol g·mol−1
3D model (JSmol)
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Medical uses

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. Despite this, lamivudine is still used widely as it is well tolerated.[7]

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.[8] 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-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.[9] 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.[10]

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 hepatic 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.

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.[11]

It has a half-life 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 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. 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.[12] 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.[13][14]

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. It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[15] As of 2015 the cost for a typical month of medication in the United States is more than $200.[6]

Formulations

References

  1. ^ a b c d e f g h i j k l m "Lamivudine". The American Society of Health-System Pharmacists. Archived from the original on 2 June 2016. Retrieved 31 July 2016.
  2. ^ Therapy of Viral Infections Volume 15 of Topics in Medicinal Chemistry. Springer. 2015. p. 6. ISBN 9783662467596. Archived from the original on 2016-08-15.
  3. ^ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 506. ISBN 9783527607495.
  4. ^ "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
  5. ^ "Lamivudine". International Drug Price Indicator Guide. Retrieved 23 July 2016.
  6. ^ a b Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 65. ISBN 9781284057560.
  7. ^ 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. PMID 25937866.
  8. ^ Fox Z, Dragsted UB, Gerstoft J, 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): 761–70. PMID 17310820.
  9. ^ "Archived copy". Archived from the original on 2010-07-01. Retrieved 2010-07-23.CS1 maint: Archived copy as title (link) Stanford University Drug Resistance Database.
  10. ^ Koziel MJ, Peters MG (2007). "Viral hepatitis in HIV infection". N Engl J Med. 356 (14): 1445–54. doi:10.1056/NEJMra065142. PMC 4144044. PMID 17409326.
  11. ^ "Epivir package insert" (PDF). GlaxoSmithKline. Archived from the original (PDF) on September 28, 2011. Retrieved January 20, 2011.
  12. ^ "US Patent Office" (PDF). Archived (PDF) from the original on 2016-06-16.
  13. ^ Sodestrom, Jon (2003). "National Institutes of Health: Moving Research from the Bench to the Bedside". Archived from the original on 2016-03-04.
  14. ^ Gilden, Dave (2000). "The Wide-Ranging Effects of Nucleoside Analogs:A Look at Mitochondrial Toxicity". Archived from the original on 2016-09-16.
  15. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Archived (PDF) from the original on 23 April 2014. Retrieved 22 April 2014.

External links

  • Epivir (manufacturer's website)
ATC code J05

ATC code J05 Antivirals for systemic use is a therapeutic subgroup of the Anatomical Therapeutic Chemical Classification System, a system of alphanumeric codes developed by the WHO for the classification of drugs and other medical products. Subgroup J05 is part of the anatomical group J Antiinfectives for systemic use.

Codes for veterinary use (ATCvet codes) can be created by placing the letter Q in front of the human ATC code: for example, QJ05. National issues of the ATC classification may include additional codes not present in this list, which follows the WHO version.

Abacavir

Abacavir (ABC) is a medication used to prevent and 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.Abacavir is generally well tolerated. Common side effects include vomiting, trouble sleeping, fever, and feeling tired. More severe side effects include hypersensitivity, liver damage, and lactic acidosis. Genetic testing can indicate whether a person is at higher risk of developing hypersensitivity. Symptoms of hypersensitivity include rash, vomiting, and shortness of breath. Abacavir is in the NRTI class of medications, which work by blocking reverse transcriptase, an enzyme needed for HIV virus replication. Within the NRTI class, abacavir is a carbocyclic nucleoside.Abacavir was patented in 1988 and approved for use in the United States in 1998. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. It is available as a generic medication. The wholesale cost in the developing world as of 2014 is between US$0.36 and US$0.83 per day. As of 2016 the wholesale cost for a typical month of medication in the United States is US$70.50. Commonly, abacavir is sold together with other HIV medications, such as abacavir/lamivudine/zidovudine, abacavir/dolutegravir/lamivudine, and abacavir/lamivudine.

Abacavir/dolutegravir/lamivudine

Abacavir/dolutegravir/lamivudine (brand name Triumeq) is a fixed-dose combination drug for the treatment of HIV/AIDS. It is a combination of three drugs with different and complementary mechanisms of action: 600 mg abacavir (reverse transcriptase inhibitor), 50 mg dolutegravir (integrase inhibitor) and 300 mg lamivudine (nucleoside analog reverse transcriptase inhibitor).

The drug was developed by ViiV Healthcare and approved by the Food and Drug Administration for use in the United States in August 2014.Abacavir is a nucleotide reverse transcriptase inhibitor. Specifically, abacavir is a guanosine analogue that interferes with HIV viral RNA-dependent DNA polymerase, ultimately resulting in inhibition of replication of HIV. Dolutegravir inhibits the HIV replication cycle by binding to the integrase active site and inhibiting the strand transfer step of HIV-1 DNA integration. Lamivudine is a cytosine analogue that inhibits HIV reverse transcription by terminating the viral DNA chain.

Abacavir/lamivudine

Abacavir/lamivudine, sold under the brand name Kivexa among others, is a medication used to treat HIV/AIDS. It is a fixed dose combination of 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.Common side effects include trouble sleeping, headache, depression, feeling tired, nausea, rash, and fever. Serious side effects may include high blood lactate levels, allergic reactions, and enlargement of the liver. It is not recommended in people with a specific gene known as HLA-B*5701. Safety in pregnancy has not been well studied but it appears to be okay. Lamivudine and abacavir are both nucleoside reverse transcriptase inhibitors (NRTI).Abacavir/lamivudine was approved for medical use in the United States in 2004. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. The wholesale cost in the developing world is about US$14.19 to $16.74 per month as of 2014. As of 2015 the cost for a typical month of medication in the United States is more than $200.

Abacavir/lamivudine/zidovudine

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

abacavir (ABC)

lamivudine (3TC)

zidovudine (AZT or ZDV)It is indicated in the treatment of AIDS/HIV. For this purpose, the combination is very useful in pregnant women to decrease the risk of mother-to-child transmission.The combination of drugs helps to reduce HIV's resistance (through mutation) to the drugs individually. Of the three, AZT and ABC have passed out of United States patent protection.

In December 2013, Lupin Limited launched a generic version of Trizivir. As of 2016 the wholesale cost for a typical month of medication in the United States is more than 669.30 USD.

Apricitabine

Apricitabine (INN, codenamed AVX754 and SPD754, sometimes abbreviated to ATC) 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.

Bernard Belleau

Bernard Belleau, (March 15, 1925 – September 4, 1989) 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.

Dolutegravir/lamivudine

Dolutegravir/lamivudine (trade name Dovato) is a combination drug for the treatment of HIV/AIDS. It was approved for use in the United States in April 2019. It contains dolutegravir, an integrase inhibitor, and lamivudine, a reverse-transcriptase inhibitor.

Doravirine

Doravirine (MK-1439) is a non-nucleoside reverse transcriptase inhibitor developed by Merck & Co. for use in the treatment of HIV/AIDS. In August 2018, the FDA approved doravine under the product name Pifeltro, and in a combination tablet, doravirine/lamivudine/tenofovir disoproxil fumarate (Delstrigo).

Doravirine/lamivudine/tenofovir disoproxil

Doravirine/lamivudine/tenofovir disoproxil (brand name Delstrigo) is a fixed-dose combination drug for the treatment of HIV/AIDS. It contains doravirine, lamivudine, and tenofovir disoproxil. In the United States, it was approved by the Food and Drug Administration in August 2018 for the treatment of HIV-1 infection.

Elvucitabine

Elvucitabine is an experimental nucleoside reverse transcriptase inhibitor (NRTI), developed by Achillion Pharmaceuticals, Inc. for the treatment of HIV infection.

Elvucitabine belongs to a class (group) of HIV drugs called nucleoside reverse transcriptase inhibitors (NRTIs). NRTIs block an HIV enzyme called reverse transcriptase. (An enzyme is a protein that starts or increases the speed of a chemical reaction). By blocking reverse transcriptase, NRTIs prevent HIV from multiplying and can reduce the amount of HIV in the body.

Elvucitabine is similar in chemical structure to the FDA-approved NRTIs lamivudine (brand name Epivir) and emtricitabine (brand name Emtriva). However, in vitro studies have suggested that elvucitabine may work on certain HIV strains against which other NRTIs, such as lamivudine and emtricitabine, no longer work. (In vitro studies are studies done in test tubes or other laboratory equipment and not on animals or humans).

Studies have also suggested that elvucitabine may be effective against hepatitis B virus (HBV).Currently, it is in Phase II clinical trials.

Fixed-dose combination (antiretroviral)

Fixed-dose combinations of antiretrovirals are multiple antiretroviral drugs combined into a single pill, which helps reduce pill burden. They may combine different classes of antiretrovirals (e.g., Atripla) or contain only a single class (e.g., Epzicom). Licensed fixed-dose combinations are shown in the table below. Some are complete single-tablet regimens for the management of HIV/AIDS (the drug is one pill taken once daily); the others must be combined with one or more additional pills to complete a regimen.

Lamivudine/nevirapine/stavudine

Lamivudine/nevirapine/stavudine (3TC/NVP/d4T) is a medication used to treat HIV/AIDS. It is a fixed dose combination of lamivudine, nevirapine, and stavudine. It is either used by itself or along with other antiretrovirals. It is taken by mouth twice a day.The medication is generally well tolerated. Side effects are those of the underlying medications. This may include rash, numbness, pancreatitis, and high blood lactate levels. Use is not recommended in those with significant liver problems. It is unclear if use in pregnancy is safe for the baby and recommendations include starting in the second trimester if possible.It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. The wholesale cost in the developing world is about 9.56 USD per month. As of 2015 it is not commercially available in the United States.

Lamivudine/nevirapine/zidovudine

Lamivudine/nevirapine/zidovudine (3TC/NVP/AZT) is a medication used to treat HIV/AIDS. It is a fixed dose combination of 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.The medication is generally well tolerated. Side effects are those of the underlying medications. This includes rash, pancreatitis, low white blood cell levels, and muscle pain. Use is not recommended in those with significant liver problems. Use in pregnancy and breastfeeding appear to be safe. The combination tablet is typically not appropriate for children.It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. The wholesale cost in the developing world is about 8.54 to 18.94 USD a month as of 2014. The combination is not commercially available in the United States as of 2018.

Lamivudine/raltegravir

Lamivudine/raltegravir, sold under the brand name Dutrebis, is a combination medication of lamivudine and raltegravir which is used in the treatment of HIV/AIDS. It is taken by mouth. Side effects may include lactic acidosis, pancreatitis, liver failure, and severe skin rashes. It was approved for medical use in the United States in 2015.

Lamivudine/zidovudine

Lamivudine/zidovudine, sold under the brand name Combivir among others, is a medication used to treat HIV/AIDS. It is a combination of two antiretroviral medications, lamivudine and zidovudine. It is used together with other antiretrovirals. It is taken by mouth twice a day.Common side effects include headache, feeling tired, nausea, diarrhea, and fever. Severe side effects may include bone marrow suppression, muscle damage, worsening of hepatitis B if previously infected, high blood lactate and liver enlargement. It may be part of a recommended treatment during pregnancy. The medications are both of the nucleoside reverse transcriptase inhibitor (NRTI) class. They work by blocking the action of the enzyme, reverse transcriptase, that the virus requires to reproduce.Lamivudine/zidovudine was approved for medical use in the United States in 1997. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. It is available as a generic medication. The wholesale cost in the developing world is about US$6.90 to $29.64 per month. As of 2015 the cost for a typical month of medication in the United States more than $200.

Raltegravir

Raltegravir (RAL), sold under the brand name Isentress, 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.Common side effects include trouble sleeping, feeling tired, nausea, high blood sugar, and headaches. Severe side effects may include allergic reactions including Stevens-Johnson syndrome, muscle breakdown, and liver problems. It is unclear if use during pregnancy or breastfeeding is safe. Raltegravir is an HIV integrase strand transfer inhibitor which blocks the functioning of HIV integrase which is needed for viral replication.Raltegravir was approved for medical use in the United States in 2007. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. The wholesale cost in the developing world is about 50 USD per month. In the United Kingdom it costs the NHS about 472.00 pounds per month. Lamivudine/raltegravir, a combination with lamivudine, is also available.

UB421

UB421 is an experimental HIV antibody, under development by United Biomedical, Inc. (UBI), headquartered in Hauppauge, New York, U.S. for use in the treatment of HIV infection. By blocking the CDR2 domain of the CD4 receptor of the virus, it prevents initial viral attachment to the host T cell and entry into the host immune cell via a competitive inhibition mechanism. The antibody is unlikely to promote resistance to itself via generation of CD4-independent virus, and has performed well in phase 2 open-label trials. Additionally, it offers hope to HIV patients whose infection has become multi-drug resistant. Furthermore, the antibody has shown long term suppression, which requires the patient to be treated less often, which improves treatment adherence. Previous experimental infusions of broadly neutralizing antibodies, or BNabs, have suppressed HIV for about two weeks by targeting proteins on the virus itself, but the rapid mutation rate of HIV induces antibody-resistant strains that render the treatment ineffective. UB421 theoretically avoids this possibility by blocking a stable human protein that HIV uses to infect T cells. Its advantages include its competitive inhibition, a high affinity of UB-421 to CD4 T cells which is 100 times stronger than HIV, its neutralization of multiple sub-types of HIV, its inhibition of both cell-to-cell and cell-free transmission of HIV, and its immune modulation of training the immune system to better attack HIV, all of which provide potential as monotherapy.

ViiV Healthcare

ViiV Healthcare ( VEEV) is a pharmaceutical company specialising in the development of therapies for HIV infection 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. In 2012 Shionogi joined the company. 76.5% of the company is now owned by GlaxoSmithKline, 13.5% by Pfizer and 10% by Shionogi. This ownership structure may change depending upon the achievement of certain milestones.ViiV Healthcare's products have a market share of approximately 19% of the global HIV market, which makes it the second largest healthcare company, following after Gilead Sciences, that is working on the treatment of HIV.ViiV Healthcare's headquarters are in Brentford in the United Kingdom and it has sites in a number of other countries including; the United States, Australia, Belgium, Canada, France, Germany, Italy, Japan, Mexico, the Netherlands, Portugal, Puerto Rico, Russia, Spain and Switzerland.

Antiviral drugs: antiretroviral drugs used against HIV (primarily J05)
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