Nevirapine

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Nevirapine (NVP), sold under the brand name Viramune among others, is a medication used to treat and prevent HIV/AIDS, specifically HIV-1.<ref name=AHFS2016/> It is generally recommended for use with other antiretroviral medications.<ref name=AHFS2016/> It may be used to prevent mother to child spread during birth but is not recommended following other exposures.<ref name=AHFS2016/> It is taken by mouth.<ref name=AHFS2016>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Common side effects include rash, headache, nausea, feeling tired, and liver problems.<ref name=AHFS2016/> The liver problems and skin rash may be severe and should be checked for during the first few months of treatment.<ref name=AHFS2016/><ref name=Ric2015>Template:Cite book</ref> It appears to be safe for use during pregnancy.<ref name=AHFS2016/> It is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and works by blocking the function of reverse transcriptase.<ref name=AHFS2016/>

Nevirapine was approved for medical use in the United States in 1996.<ref name=AHFS2016/> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">Template:Cite book</ref> It is available as a generic medication.<ref name=AHFS2016/>

Medical uses

Nevirapine is used in people six years of age and older infected with HIV-1 as part of combination antiretroviral treatment (ART or cART). Monotherapy with nevirapine is not indicated due to rapid emergence of resistance.<ref name="Viramune FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Viramune XR FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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).<ref name="INCAS_1998" /> Some clinical trials have demonstrated comparable HIV suppression with nevirapine-based regimens to that achieved with regimens based on a protease inhibitor (PI)<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> or efavirenz.<ref name="2NN">Template:Cite journal</ref>

This drug is generally only to be considered for use if the CD4 cell count is very low.<ref name="Viramune FDA label" />

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 this group of people.<ref name="2NN" />

Nevirapine may also form a useful component of salvage regimens after virological failure, usually in combination with one or more PIs as well as nucleotide reverse transcriptase inhibitor (NRTIs), especially in those who have not previously taken an NNRTI.

Dosing in children is based on body surface area (BSA),<ref name="Viramune FDA label" /> however, weight-based dosing algorithms have been released. These guidelines include dosing algorithms for as young as newborn babies.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Preventing mother-to-child transmission

Although 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,<ref>Template:Cite journal</ref> that trial was found in an Associated Press investigation to be riddled with "sloppy recordkeeping" and possibly fraud.<ref>Template:Cite news</ref> A subsequent study in Thailand showed that prophylaxis with single-dose nevirapine in addition to zidovudine is more effective than zidovudine alone.<ref name="Lallemant">Template:Cite journal</ref> 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 <ref>The HIVNET 012 Study and the Safety and Effectiveness of Nevirapine in Preventing Mother-to-Infant Transmission of HIV, {{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and as of 2006 the FDA has not approved of such nevirapine prophylaxis.<ref>Celia Farber, "Out of Control: AIDS and the Corruption of Science" Template:Cite magazine</ref> However, supporters of HIVNET 012 experiment argued that the flaws in this experiment were largely due to bureaucratic incompetence, while the findings regarding the safety and efficacy of single-dose nevirapine from this study were scientifically solid and too important to discard.<ref name="pmid21553555">Template:Cite journal</ref> Moreover, it was argued that holding African researchers who operated under resource-poor situations to the same moral and procedural standards to their Western counterparts was unrealistic, and would further marginalize African researchers' role in the science community and impede the progress of African science.<ref>Lock, M. & Nguyen, V 2010, an Anthropology of Biomedicine, Malden, Wiley-Blackwell.</ref> Another clinical trial, Using Nevirapine to Prevent Mother-to-Child HIV Transmission During Breastfeeding, was completed in September 2013.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

A major concern with this approach is that NNRTI resistance mutations are commonly observed in both mothers and infants after single-dose nevirapine,<ref>Template:Cite journal</ref> and may compromise the response to future NNRTI-containing regimens.<ref>Template:Cite journal</ref> A short course of maternal Lamivudine/zidovudine is recommended by the U.S. Public Health Service Task Force to reduce this risk.<ref name=perinatal/>

Nonoccupational Post-Exposure Prophylaxis

Nevirapine is contraindicated for non-occupational post-exposure-prophylaxis including for pregnant and nonpregnant women due to severe liver toxicity.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Adverse effects

The most common adverse effect of nevirapine is the development of mild or moderate rash (13%).<ref name=PInfo/><ref name=ATDN>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Severe or life-threatening skin reactions have been observed in 1.5% of patients, including Stevens–Johnson syndrome, toxic epidermal necrolysis and hypersensitivity.<ref name=PInfo/>

Nevirapine may cause severe or life-threatening liver toxicity, usually emerging in the first six weeks of treatment.<ref name=PInfo/><ref name=dhhs>DHHS panel. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (May 4, 2006). (Available for download from AIDSInfo Template:Webarchive)</ref> In 2000, the U.S. Food and Drug Administration issued a black box warning on nevirapine, warning that it could cause life-threatening liver toxicity and skin reactions.<ref name="Viramune XR FDA label" /> Unacceptably high risk of serious liver symptoms in certain patient groups (women with CD4 count >250 and men >400)<ref name="2NN"/><ref>Template:Cite journal</ref> has led the U.S. DHHS to recommend the restriction of nevirapine use to those at lower risk, unless the benefit to the patient clearly outweighs the risk;<ref name=dhhs/> 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.<ref>Template:Cite journal</ref> 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.<ref name="perinatal">Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. {{#invoke:citation/CS1|citation |CitationClass=web }}. Accessed 16 November 2016.</ref>

Cases of immune reconstitution syndrome and fat redistribution have also been observed with this drug.<ref name="Viramune XR FDA label" />

The U.S. Food and Drug Administration recommends stopping nevirapine if a person experiences:<ref name="Viramune XR FDA label" />

• sign and symptoms of liver issues such as hepatitis
• increased transaminases in addition to rash or systemic symptoms
• formation of rash with systemic symptoms
• severe skin or hypersensitivity reactions

Additionally, the U.S. FDA recommends close monitoring during the first 6 weeks of therapy for the above symptoms as there is high risk during this time. Continued monitoring is recommended for up to the first 18 weeks of treatment. If a patient experiences hepatitis plus rash or other systemic symptoms, or severe hypersensitivity or skin rash, nevirapine should not be restarted.<ref name="Viramune XR FDA label" />

Drug interactions

Nevirapine is a substrate for liver CYP3A and CYP2B6 enzymes. Concomitant administration of drugs that are inhibitors of these enzymes may increase serum nevirapine levels significantly. Some examples of these drugs include ritonavir, fosamprenavir, and fluconazole. On the other hand, drugs that are inducers of these enzymes such as rifampicin may lower serum nevirapine levels.<ref name=":02">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>^[18]

In addition, concomitant use of St. John's wort (Hypericum perforatum, which has been shown to induce CYP3A4 and CYP1A2<ref>Template:Cite journal</ref>) or St. John's wort containing products may significantly lower nevirapine levels.<ref name=":02" />

Nevirapine is an inducer of cytochrome P450 isoenzymes CYP3A4 and CYP2B6. It may reduce 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.<ref name=PInfo/>

Mechanism of action

File:Nevirapine 3D.png

Nevirapine shown in ball and stick structure.

Nevirapine falls in the non-nucleoside reverse transcriptase inhibitor (NNRTI) class of antiretrovirals.<ref>Template:Cite journal</ref> 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 polymerase active site, NNRTIs bind to a hydrophobic pocket in the subdomain of p66 which is about 10 angstrom away from the active site (known as the NNRTI pocket). Therefore, this NNRTI-binding pocket will inhibit reverse transcription in a way that is distinct to the NRTIs.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

Resistance to nevirapine develops rapidly if viral replication is not completely suppressed.<ref name=INCAS_1998>Template:Cite journal</ref> The most common mutations observed after nevirapine treatment are Y181C and K103N, which are also observed with other NNRTIs.<ref name="PInfo">Viramune (nevirapine) tablets; Viramune (nevirapine) oral suspension prescribing information Template:Webarchive</ref><ref>Template:Cite journal</ref> 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. However, second generation NNRTIs like rilpivirine and etravirine are effective in treatment for HIV strains resistant to nevirapine and other first generation drugs in that same class.

History

Nevirapine was discovered by Karl D. Hargrave and colleagues at Boehringer Ingelheim Pharmaceuticals, Inc., one of the Boehringer Ingelheim group of companies. It is covered by U.S. Patent 5,366,972 Template:Webarchive 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.

Society and culture

Former U.S. President George W. Bush's PEPFAR funding of $500 million to help combat the African AIDS epidemic included nevirapine, among other medications and programs.

In South Africa, the Treatment Action Campaign successfully sued the government over its failure to make nevirapine widely available. In Minister of Health v Treatment Action Campaign the Constitutional Court of South Africa ordered the government to immediately "remove the restrictions that prevent Nevirapine from being made available for the purpose of reducing the risk of mother-to-child transmission of HIV at public hospitals and clinics that are not research and training sites [and] permit and facilitate the use of Nevirapine for the purpose of reducing the risk of mother-to-child transmission of HIV and to make it available for this purpose at hospitals and clinics when in the judgement of the attending medical practitioner acting in consultation with the medical superintendent of the facility concerned this is medically indicated, which shall if necessary include that the mother concerned has been appropriately tested and counselled."<ref name="atlantic">Template:Cite book</ref><ref name="Time">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>