Nevirapine
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Nevirapine
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| Systematic (IUPAC) name | |
| 1-cyclopropyl-5,11-dihydro-4-methyl -6H-dipyrido [3,2-b:2',3'-e][1,4] diazepin-6-one |
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| Identifiers | |
| CAS number | |
| ATC code | J05 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C15H14N4O |
| Mol. mass | 266.298 g/mol |
| Pharmacokinetic data | |
| Bioavailability | 93% ± 9% |
| Metabolism | Hepatic |
| Half life | 45 hours |
| Excretion | Renal: <6% (Parent drug) Biliary <5% (Parent drug) |
| Therapeutic considerations | |
| Pregnancy cat. |
C: (USA) |
| Legal status | |
| Routes | Oral |
Nevirapine, also marketed under the trade name Viramune® (Boehringer Ingelheim), is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used to treat HIV-1 infection and AIDS.
As with other antiretroviral drugs, HIV rapidly develops resistance if nevirapine is used alone, so recommended therapy consists of combinations of three or more antiretrovirals.
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[edit] History
Nevirapine was discovered at the Rega Institute for Medical Research in Belgium. Nevirapine was the first NNRTI approved by the Food and Drug Administration (FDA) of the United States. It was approved Jun 21, 1996 for adults and Sep 11, 1998 for children. It was also approved in Europe in 1997.
It was twice rejected by Canada, in 1996 and again in 1998, due to its high toxicity and lack of evidence of its effectiveness,[1] though it was later approved in that country.
[edit] Mode of action
Nevirapine falls in the non-nucleoside reverse transcriptase inhibitor (NNRTI) class of antiretrovirals. Both nucleoside and non-nucleoside RTIs inhibit the same target, the reverse transcriptase enzyme, an essential viral enzyme which transcribes viral RNA into DNA. Unlike nucleoside RTIs, which bind at the enzyme's active site, NNRTIs bind within a pocket termed the NNRTI pocket.
Nevirapine is not effective against HIV-2, as the pocket of the HIV-2 reverse transcriptase has a different structure, which confers intrinsic resistance to the NNRTI class.[2]
As all NNRTIs bind within the same pocket, viral strains which are resistant to nevirapine are usually also resistant to the other NNRTIs, efavirenz and delavirdine. The most common mutations observed after nevirapine treatment are Y181C and K103N, which are also observed with other NNRTIs.[3][4]
[edit] Clinical efficacy
Nevirapine in triple combination therapy has been shown to suppress viral load effectively when used as initial antiretroviral therapy (ie, in antiretroviral-naive patients).[5] Some clinical trials have demonstrated comparable HIV suppression with nevirapine-based regimens to that achieved with protease inhibitors (PIs)[6][7] or efavirenz.[8] Although concerns have been raised about nevirapine-based regimens in those starting therapy with high viral load or low CD4 count, some analyses suggest that nevirapine may be effective in these patients.[8]
Nevirapine may also form a useful component of salvage regimens after virological failure, usually in combination with one or more PIs as well as nRTIs, especially in those who have not previously taken an NNRTI.
[edit] Adverse effects
The most common adverse effect of nevirapine is the development of mild or moderate rash (13%).[3][9] Severe or life-threatening skin reactions have been observed in 1.5% of patients, including Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity.[3]
Nevirapine may cause severe or life-threatening liver toxicity, usually emerging in the first six weeks of treatment.[3][10] In 2000, the U.S. Food and Drug Administration issued a black box label on nevirapine, warning that it could cause severe liver damage, including liver failure.[11] Unacceptably high risk of serious liver symptoms in certain patient groups (women with CD4 count >250 and men >400)[8] has led the U.S. DHSS to recommend the restriction of nevirapine use to those at lower risk, unless the benefit to the patient clearly outweighs the risk;[10] although in the 2NN study which found these CD4 limits, the effect was seen only in patients recruited from Thailand.
[edit] Drug interactions
Significant lowering of nevirapine levels occurs with the anti-tuberculosis drug, rifampicin, and the drugs should not be administered together.[3]
Nevirapine is an inducer of cytochrome P450 isoenzymes CYP3A4 and CYP2B6. It reduces the levels of several co-administered drugs including the antiretrovirals efavirenz, indinavir, lopinavir, nelfinavir and saquinavir, as well as clarithromycin, ketoconazole, oral contraceptives and methadone.[3]
[edit] Preventing mother-to-child transmission
A single dose of nevirapine given to both mother and child reduced the rate of HIV transmission by almost 50% compared with the normal zidovudine (AZT) prophylaxis regimen, in a clinical trial in Uganda.[12] A subsequent study in Thailand showed that prophylaxis with single-dose nevirapine in addition to zidovudine is more effective than zidovudine alone.[13] These and other trials have led to the adoption of nevirapine prophylaxis in some developing countries as a cost-effective way of reducing mother-to-child transmission. The U.S. Public Health Service Task Force, however, advocates caution in the use of nevirapine in pregnancy due to toxicity issues, which may be exacerbated during pregnancy.[14]
Another concern with this approach is that NNRTI resistance mutations are commonly observed in both mothers and infants after single-dose nevirapine,[15] and may compromise the response to future NNRTI-containing regimens.[16] A short course of maternal zidovudine/lamivudine is recommended by the U.S. Public Health Service Task Force to reduce this risk.[14]
Further concerns are raised in the following section.
[edit] Controversy in Africa
U.S. President George W. Bush's $500 million plan to help combat the African AIDS epidemic includes nevirapine, among other medications and programs. Nevirapine has also been tested in trials in Africa, some of which have been highly controversial.
Jonathan M Fishbein, MD (former director of the Office for Policy in Clinical Research Operations at the NIH Division of AIDS [DAIDS]) has alleged that the Ugandan mother-to-child transmission trial (HIVNET 012) -- which was pivotal to establishing single-dose nevirapine prophylaxis in Africa and other countries -- was not conducted in accordance with good clinical practice.[1][17][18] Fishbein claims that DAIDS are "Implementing a double standard regarding the quality of clinical trial practices – one standard for Africa and a higher standard for the U.S."[17]
Recently, South African President Thabo Mbeki accused the United States of using Africans as "guinea pigs".[19] Questions regarding the efficacy of the antiretroviral nevirapine when compared with its side effects were the main stated reason for President Mbeki's concern. Until recently, however, Mbeki endorsed claims by some scientists that HIV is not the cause of AIDS--findings which are considered unfounded by the mainstream scientific community.[20]
[edit] References
- ^ a b Out of Control – Celia Farber's article in Harper's Magazine on nevirapine drug trials in Uganda
- ^ Ren J, Bird LE, Chamberlain PP, et al. (2002) Structure of HIV-2 reverse transcriptase at 2.35-A resolution and the mechanism of resistance to non-nucleoside inhibitors. Proc Natl Acad Sci USA 99: 14410–15
- ^ a b c d e f Viramune® (nevirapine) tablets; Viramune® (nevirapine) oral suspension prescribing information
- ^ Conway B, Wainberg MA, Hall D, et al. (2001) Development of drug resistance in patients receiving combinations of zidovudine, didanosine and nevirapine. AIDS 15:1269-74
- ^ Montaner JS, Reiss P, Cooper D, et al. (1998) A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS Trial. Italy, The Netherlands, Canada and Australia Study. JAMA 279: 930-7
- ^ van Leeuwen R, Katlama C, Murphy RL, et al. (2003). "A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients". AIDS 17: 987–99.
- ^ Podzamczer D, Ferrer E, Consiglio E, et al.. "A randomized clinical trial comparing nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients (the Combine Study)". Antiviral Ther 7: 81–90.
- ^ a b c van Leth F, Andrews S, Grinsztejn B, et al. (2005). "The effect of baseline CD4 cell count and HIV-1 viral load on the efficacy and safety of nevirapine or efavirenz-based first-line HAART". AIDS 19: 463–71.
- ^ Facts sheet from the AIDS Treatment Data Network. Retrieved on 2006-01-16.
- ^ a b DHHS panel. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (May 4, 2006). (Available for download from AIDSInfo)
- ^ Viramune (nevirapine) letter (November 2000)
- ^ Guay LA, Musoke P, Fleming T, et al. (1999) Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 354: 795-802
- ^ Lallemant M, Gonzague Jourdain G, Sophie Le Coeur S, et al. (2004) Single-Dose Perinatal Nevirapine plus Standard Zidovudine to Prevent Mother-to-Child Transmission of HIV-1 in Thailand. N Engl J Med 351: 217-28
- ^ a b Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States. Public Health Service Task Force. (November 17, 2005) (Available for download from [http://www.aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=9&ClassID=2 AIDSInfo)
- ^ Johnson JA, Li JF, Morris L, et al. (2005) Emergence of drug-resistant HIV-1 after intrapartum administration of single-dose nevirapine is substantially underestimated. J Infect Dis 192: 16-23
- ^ Jourdain G, Ngo-Giang-Huong N, Le Coeur S, et al. (2004) Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med 351: 229-40
- ^ a b Allegations Of Waste, Fraud and Abuse at Jonathan Fishbein's website
- ^ Associated Press (2006-01-04). Whistleblower says government bungled AIDS study. USA Today. Retrieved on 2006-01-16.
- ^ Nevirapine Controversy. Retrieved on 2006-01-16.
- ^ AEGiS-M&G: Mbeki's Aids Letter Defies Belief. Retrieved on 2006-04-12.
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| Anti-herpesvirus | Aciclovir, Cidofovir, Docosanol, Famciclovir, Fomivirsen, Foscarnet, Ganciclovir, Idoxuridine, Penciclovir, Trifluridine, Tromantadine, Valaciclovir, Valganciclovir, Vidarabine |
| Anti-influenza agents | Amantadine, Arbidol, Oseltamivir, Peramivir, Rimantadine, Zanamivir |
| Antiretrovirals: NRTIs | Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine, Zalcitabine, Zidovudine |
| Antiretrovirals: NtRTIs | Tenofovir |
| Antiretrovirals: NNRTIs | Efavirenz, Delavirdine, Nevirapine, Loviride |
| Antiretrovirals: PIs | Amprenavir, Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lopinavir, Nelfinavir, Ritonavir, Saquinavir, Tipranavir |
| Antiretrovirals: Fusion inhibitors | Enfuvirtide |
| Other antiviral agents | Adefovir, Fomivirsen, Imiquimod, Inosine, Interferon, Podophyllotoxin, Ribavirin, Viramidine |
