Nevirapine

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 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, though it was later approved in that country. The drug is currently recalled by Roche because of the presence of ethyl methanesulfonate as a byproduct from the manufacturing process.

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.

Resistance to nevirapine develops rapidly if viral replication is not completely suppressed. The most common mutations observed after nevirapine treatment are Y181C and K103N, which are also observed with other NNRTIs. 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). Some clinical trials have demonstrated comparable HIV suppression with nevirapine-based regimens to that achieved with protease inhibitors (PIs) 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.

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%). Severe or life-threatening skin reactions have been observed in 1.5% of patients, including Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity.

Nevirapine may cause severe or life-threatening liver toxicity, usually emerging in the first six weeks of treatment. 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 &gt;250 and men &gt;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; although in the 2NN study which found these CD4 limits, the effect was seen only in patients recruited from Thailand. 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.

Drug interactions
Significant lowering of nevirapine levels occurs with the anti-tuberculosis drug, rifampicin, and the drugs should not be administered together.

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.

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. A subsequent study in Thailand showed that prophylaxis with single-dose nevirapine in addition to zidovudine is more effective than zidovudine alone. 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.

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.

Further concerns are raised in the following section.

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. Fishbein claims that DAIDS has "Implement[ed] a double standard regarding the quality of clinical trial practices – one standard for Africa and a higher standard for the U.S." An independent review of that study by the Institute of Medicine determined "...the Ugandan drug trial's findings that the AIDS medication nevirapine is effective and safe in preventing HIV transmission from mother to unborn child during birth were well-supported." Fishbein has called the value of that review into question, however, alleging that the authors of the review refused to consider certain testimony and evidence that would have vitiated the drug trial, and also that six of the nine authors were, at the time of the review, receiving grants from DAIDS, the very body whose conduct they were reviewing. Fishbein has argued that this conflict of interest must also undermine confidence in the review. Recently, South African President Thabo Mbeki accused the United States of using Africans as "guinea pigs". 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.