Nevirapine 129618-40-2

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 [&r=1&f=G&l=50&s1=5366972. PN. &OS=PN/5366972&RS=PN/5366972 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. 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. Resistance to nevirapine develops rapidly if viral replication is not completely suppressed. 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). or efavirenz. 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. Severe or life-threatening skin reactions have been observed in 1. 5% of patients, including Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity. 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. Unacceptably high risk of serious liver symptoms in certain patient groups (women with CD4 count >250 and men >400) 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; A subsequent study in Thailand showed that prophylaxis with single-dose nevirapine in addition to zidovudine is more effective than zidovudine alone. and as of 2006 the FDA has not approved of such nevirapine prophylaxis. Another clinical trial, Using Nevirapine to Prevent Mother-to-Child HIV Transmission During Breastfeeding is scheduled for completion in March 2011. A major concern with this approach is that NNRTI resistance mutations are commonly observed in both mothers and infants after single-dose nevirapine, and may compromise the response to future NNRTI-containing regimens. A short course of maternal zidovudine/lamivudine is recommended by the U. S. Public Health Service Task Force to reduce this risk. 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 well outside the realm of reasonable scientific thought by the vast majority of the scientific community.