Nevirapine

Nevirapine

Systematic (IUPAC) name
11-cyclopropyl-4-methyl-5,11-dihydro-6H- dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one
Clinical data
Trade names	Viramune
AHFS/Drugs.com	monograph
MedlinePlus	a600035
Pregnancy cat.	B: (USA)
Legal status	?
Routes	Oral
Pharmacokinetic data
Bioavailability	93% ± 9%
Metabolism	Hepatic
Half-life	45 hours
Excretion	Renal: <6% (Parent drug) Biliary <5% (Parent drug)
Identifiers
CAS number	129618-40-2
ATC code	J05AG01
PubChem	CID 4463
DrugBank	APRD00705
ChemSpider	4308 Y
UNII	99DK7FVK1H Y
KEGG	D00435 Y
ChEMBL	CHEMBL57 Y
Chemical data
Formula	C15H14N4O
Mol. mass	266.888 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C15H14N4O/c1-9-6-8-17-14-12(9)18-15(20)11-3-2-7-16-13(11)19(14)10-4-5-10/h2-3,6-8,10H,4-5H2,1H3,(H,18,20) Y Key:NQDJXKOVJZTUJA-UHFFFAOYSA-N Y
Y(what is this?)  (verify)

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.

History

Nevirapine was discovered by Hargrave et al. at Boehringer Ingelheim Pharmaceuticals, Inc., one of the Boehringer Ingelheim group of companies. It is covered by U.S. Patent 5,366,972 and corresponding foreign patents. Nevirapine was the first NNRTI approved by the U.S. Food and Drug Administration (FDA). It was approved June 21, 1996 for adults and September 11, 1998 for children. It was also approved in Europe in 1997.

Mode of action

Nevirapine falls in the non-nucleoside reverse transcriptase inhibitor (NNRTI) class of antiretrovirals.^[1] 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 allosterically at a distinct site away from the active site 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]

Resistance to nevirapine develops rapidly if viral replication is not completely suppressed.^[3] The most common mutations observed after nevirapine treatment are Y181C and K103N, which are also observed with other NNRTIs.^[4][5] 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.

Clinical efficacy

Nevirapine in triple combination therapy has been shown to suppress viral load effectively when used as initial antiretroviral therapy (i.e., in antiretroviral-naive patients).^[3] 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.

Adverse effects

The most common adverse effect of nevirapine is the development of mild or moderate rash (13%).^[4][9] Severe or life-threatening skin reactions have been observed in 1.5% of patients, including Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity.^[4]

Nevirapine may cause severe or life-threatening liver toxicity, usually emerging in the first six weeks of treatment.^[4][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][12] 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. More recent studies on the use of Nevirapine in people with higher CD4 cell counts have come to the following conclusion: Treatment-experienced patients who start NVP-based combination therapy with low pre–ART and high current CD4 cell counts and an undetectable VL have a similar likelihood for discontinuing NVP therapy because of hypersensitivity reactions (HSRs), compared with treatment-naive patients with low CD4 cell counts. This suggests that NVP-based combination therapy may be safely initiated in such patients. However, in similar patients with a detectable VL, it is prudent to continue to adhere to current CD4 cell count thresholds.^[13] The U.S. Public Health Service Task Force advocates caution in the use of nevirapine in pregnancy due to toxicity issues, which may be exacerbated during pregnancy.^[14]

Drug interactions

Significant lowering of nevirapine levels occurs with the anti-tuberculosis drug, rifampicin, and the drugs should not be administered together.^[4]

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, forms of hormonal contraception, and methadone.^[4]

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 a very short course of zidovudine (AZT) prophylaxis, in a clinical trial in Uganda.^[15] A subsequent study in Thailand showed that prophylaxis with single-dose nevirapine in addition to zidovudine is more effective than zidovudine alone.^[16] These and other trials have led the World Health Organization to endorse the use of single-dose nevirapine prophylaxis in many developing world settings as a cost-effective way of reducing mother-to-child transmission. However, in the United States the Ugandan study was deemed flawed ^[17] and as of 2006 the FDA has not approved of such nevirapine prophylaxis.^[18] Another clinical trial, Using Nevirapine to Prevent Mother-to-Child HIV Transmission During Breastfeeding is scheduled for completion in March 2011.^[19]

A major concern with this approach is that NNRTI resistance mutations are commonly observed in both mothers and infants after single-dose nevirapine,^[20] and may compromise the response to future NNRTI-containing regimens.^[21] A short course of maternal zidovudine/lamivudine is recommended by the U.S. Public Health Service Task Force to reduce this risk.^[14]

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.

Former President of South Africa Thabo Mbeki accused the United States of using Africans as "guinea pigs".^[22] Questions regarding the efficacy of the antiretroviral nevirapine when compared with its side effects were the main stated reason for President Mbeki's concern.

Chemistry

Hargrave, K. D.; Peoudfoot, J. R.; Grozinger, K. G.; Cullen, E.; Kapadia, S. R.; Patel, J. R.; Fuchs, V. U.; Mauldin, S. C.; Vitous, S. J.; Behnke, M. L.; et al.; J. Med. Chem. 1991, 34, 2231.

http://dx.doi.org/10.1021/jm00111a045

References

1. ^ Patel SS, Benfield P (Oct 1996). "New drug profile: nevirapine". Clinical Immunotherapeutics 6 (4): 307–317. 
2. ^ Ren J, Bird LE, Chamberlain PP, Stewart-Jones GB, Stuart DI, Stammers DK (Oct 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 (22): 14410–5. doi:10.1073/pnas.222366699. PMC 137897. PMID 12386343. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=137897. 
3. ^ ^{a b} Montaner JS, Reiss P, Cooper D (Mar 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 (12): 930–7. doi:10.1001/jama.279.12.930. PMID 9544767. http://jama.ama-assn.org/cgi/reprint/279/12/930. 
4. ^ ^{a b c d e f} Viramune (nevirapine) tablets; Viramune (nevirapine) oral suspension prescribing information
5. ^ Conway B, Wainberg MA, Hall D (Jul 2001). "Development of drug resistance in patients receiving combinations of zidovudine, didanosine and nevirapine". AIDS 15 (10): 1269–74. doi:10.1097/00002030-200107060-00008. PMID 11426071. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0269-9370&volume=15&issue=10&spage=1269. 
6. ^ van Leeuwen R, Katlama C, Murphy RL (May 2003). "A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients". AIDS 17 (7): 987–99. doi:10.1097/00002030-200305020-00007. PMID 12700448. 
7. ^ Podzamczer D, Ferrer E, Consiglio E. "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. 
8. ^ ^{a b c} van Leth F, Andrews S, Grinsztejn B (Mar 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 (5): 463–71. doi:10.1097/01.aids.0000162334.12815.5b. PMID 15764851. 
9. ^ "Facts sheet from the AIDS Treatment Data Network". http://www.aegis.com/factshts/network/simple/nevi.html. Retrieved 2006-01-16. 
10. ^ ^{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)
11. ^ Viramune (nevirapine) letter (November 2000)
12. ^ Stern JO, Robinson PA, Love J, Lanes S, Imperiale MS, Mayers DL (2003). "A comprehensive hepatic safety analysis of nevirapine in different populations of HIV-infected patients". J Acquir Immune Defc Syndr 34 (Suppl 1): S21–S33. doi:10.1097/00126334-200309011-00005. 
13. ^ Wit FW, Kesselring AM, Gras L (Mar 2008). "Discontinuation of nevirapine because of hypersensitivity reactions in patients with prior treatment experience, compared with treatment-naive patients: the ATHENA cohort study". Clin Infect Dis. 46 (6): 933–40. doi:10.1086/528861. PMID 18271750. http://www.journals.uchicago.edu/doi/abs/10.1086/528861. 
14. ^ ^{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 AIDSInfo)
15. ^ Guay LA, Musoke P, Fleming T (Sep 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 (9181): 795–802. doi:10.1016/S0140-6736(99)80008-7. PMID 10485720. 
16. ^ 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
17. ^ The HIVNET 012 Study and the Safety and Effectiveness of Nevirapine in Preventing Mother-to-Infant Transmission of HIV, http://www3.niaid.nih.gov/news/newsreleases/2004/hivnet012.htm
18. ^ Celia Farber, "Out of Control: AIDS and the Corruption of Science" http://www.harpers.org/archive/2006/03/0080961
19. ^ http://clinicaltrials.gov/show/NCT00074412
20. ^ Johnson JA, Li JF, Morris L (Jul 2005). "Emergence of drug-resistant HIV-1 after intrapartum administration of single-dose nevirapine is substantially underestimated". J Infect Dis. 192 (1): 16–23. doi:10.1086/430741. PMID 15942889. 
21. ^ Jourdain G, Ngo-Giang-Huong N, Le Coeur S (Jul 2004). "Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy". N Engl J Med. 351 (3): 229–40. doi:10.1056/NEJMoa041305. PMID 15247339. http://content.nejm.org/cgi/content/full/351/3/229. 
22. ^ "Nevirapine Controversy". Archived from the original on 2005-12-01. http://web.archive.org/web/20051201003321/http://gnn.tv/articles/article.php?id=1011. Retrieved 2006-01-16.