Nevirapine

Nevirapine is an anti-HIV drug that reduces the amount of virus in the body. Anti-HIV drugs such as nevirapine slow down damage to the immune system and prevent the occurrence of AIDS-defining illnesses.

Nevirapine belongs to a class of drugs known as non-nucleoside reverse transcriptase inhibitors (NNRTIs). NNRTIs stop the activity of HIV’s reverse transcriptase enzyme, which is needed to copy the genetic code of HIV into a form that can be inserted into human cells.

Nevirapine is manufactured by Boehringer Ingelheim under the trade name Viramune. Nevirapine was licensed in the European Union in February 1998, and in the United States in June 1996. Numerous generic versions of nevirapine are available as a single drug or as part of a three-drug fixed-dose combination.

An extended-release formulation of nevirapine that can be taken once daily was approved in the European Union in 2011 and the United States in 2012 (Viramune XR). Generic extended-release formulations of nevirapine are also available.

Effectiveness

Nevirapine reduces HIV-1 viral load and increase CD4 cell counts in the majority of people when taken in combination with at least two other antiretroviral drugs. Nevirapine is not active against HIV-2. Men should not start treatment with nevirapine if their CD4 cell count is above 400 and women should not start treatment with nevirapine if their CD4 cell count is above 250, as this increases the risk of potentially dangerous side effects. See Side effects below for further information.

Nevirapine was licensed after three clinical trials found that the combination of nevirapine, zidovudine (AZT) and didanosine (ddI) brought about greater decreases in viral load and increases in CD4 cell counts than zidovudine and didanosine taken without nevirapine in people who had not taken antiretroviral therapy before. The triple combination also led to fewer cases of HIV disease progression. (d'Aquila) (Montaner, 1998) (Floridia)

Several studies have reported that triple regimens including nevirapine are as effective as protease inhibitor-containing regimens. (Squires) (Guardiola) (Chen)

Numerous randomised trials and observational studies have compared nevirapine and efavirenz. A systematic review and meta-analysis of 38 studies found that efavirenz-based first-line antiretroviral treatment was significantly less likely to lead to virologic failure than nevirapine-based treatment (RR 0.85 [0.73-0.99]) and was more likely to achieve virologic suppression. (Pillay)

Nevirapine is no longer recommended as a preferred option for first-line antiretroviral treatment in British, European, United States or World Health Organization guidelines, but owing to its low cost, it is still used in some lower- and middle-income countries as an alternative to efavirenz.

Taking it

The standard dose of nevirapine is one 200mg tablet per day for the first 14 days on therapy, and afterwards 200mg twice daily or one 400mg extended-release tablet once daily.

During the first two weeks on nevirapine, only one tablet should be taken once a day, to allow the body to establish safe levels of the drug, so reducing the risk of developing a serious rash or other side effects. Full-dose nevirapine should be started after a rash has gone away; if the rash does not resolve within 28 days, an alternative agent to nevirapine should be used instead.

Nevirapine can be taken with or without food and at the same time as other anti-HIV drugs.

Nevirapine is also available as an oral suspension at a dose of 10mg/ml, which can be used by children weighing less than 50kg, and people who cannot take tablets.

Those who wish to interrupt or stop nevirapine-based treatment should stop taking the nevirapine component of their regimen five days before the nucleoside reverse transcriptase inhibitor (NRTI) backbone. Since nevirapine has a long half-life and a low genetic barrier to resistance, stopping all the drugs at the same time could cause diminishing effects of nevirapine to persist much longer than those of the NRTIs, leading to the emergence of NNRTI resistance mutations. (Mackie) (Muro)

If nevirapine therapy is stopped for any reason for more than seven days, the lead-in dosing of 200mg a day for 14 days should be used when the drug is resumed.

Individuals with hepatitis C/HIV co-infection may have elevated levels of nevirapine in the blood. Nevirapine is not advised for use in people with moderate or severe liver impairment.

Side effects

The commonest side effects experienced by people taking nevirapine are rash, nausea, fatigue, fever, headache, vomiting, diarrhoea and abdominal pain. People taking nevirapine may also develop a low level of granulocytes, a type of white blood cell.

At least one in ten people starting nevirapine will get a mild rash in the form of red blotches, itchy lumps, and/or speckles on the skin. This usually appears after one to four weeks of treatment and goes away after two to four weeks. The rash can be treated in many cases with antihistamines. Thereafter, most people experience very few or no side effects.

Less than one in a hundred people experience a severe rash that may be accompanied by fever, skin blistering, mouth sores, facial swelling, shortness of breath, abdominal pain, malaise and muscle or joint pain. Nevirapine should be stopped immediately and medical advice sought if a severe rash develops.

Women seem to be at greater risk than men of developing the mild and severe forms of rash associated with nevirapine. (Antinori) (Bersoff-Matcha) (de Luca) (Mazhude)

Nevirapine treatment should also be stopped if an increase in liver enzymes (transaminases) is accompanied by nausea, loss of appetite, fatigue, abdominal pain, yellowing of the whites of the eyes, dark greenish-brown urine, yellowing of the skin (jaundice), and greyish or white stools.

The risk of severe reaction to nevirapine is greatest during the first six weeks of treatment and you should watch out for signs of skin or liver reaction during the first 18 weeks of treatment.

If severe hepatic, skin, or hypersensitivity reactions occur, nevirapine therapy should not be resumed. There are cases of hepatic injury even after discontinuation. 

Previously untreated women with CD4 counts above 250 and men with CD4 counts above 400 are at greater risk of hepatic toxicity. European studies show that people with undetectable viral load and higher CD4 counts who switch to nevirapine do not have an increased risk of hepatic toxicity. (de Lazzari) (Wolf)

Beginning treatment with nevirapine at the same time as abacavir is not recommended as both drugs can cause rashes, and it can be difficult to tell which drug is causing the reaction.

High-density lipoprotein (HDL or ‘good’) cholesterol may rise in people taking nevirapine and overall, nevirapine appears to have a better lipid profile than efavirenz. (van der Valk) (van Leth, The Lancet) (van Leth, PLOS Med)

Resistance

As with all other anti-HIV drugs, strains of HIV that are resistant to nevirapine may emerge after a period of treatment. The emergence of drug-resistant strains coincides with a fall in the effectiveness of the drug.

A single mutation in the reverse transcriptase gene is sufficient to bring about resistance to nevirapine. The commonest nevirapine-associated mutations are K103N, Y181C, G190A and Y188L. (Uhlmann) (Richman) Other nevirapine-associated mutations include V106A, Y188C, G190S and M230L.

Once resistance to nevirapine has developed, it is very likely that the virus will also be resistant to the NNRTI efavirenz. (Antinori) (Casado) Conversely, previous exposure to an NNRTI may cause a person to fail a nevirapine-based regimen, even where standard resistance tests indicate that no NNRTI resistance is present.

Drug interactions

People taking nevirapine should not take the following drugs:

• Rifampicin, due to lowered rifampicin levels. People requiring tuberculosis treatment should switch to efavirenz.
• Hypericin (St John’s wort), which can reduce blood levels of nevirapine, possibly causing resistance.
• Ketoconazole (Nizoral), due to lowered ketoconazole levels.
• The protease inhibitor atazanavir/ritonavir or the integrase inhibitor elvitegravir/cobicistat.
• The NNRTIs doravirine, rilpivirine, efavirenz or etravirine.

People taking nevirapine should also take non-standard doses of the following drugs, or take them with caution:

• Clarithromycin levels are reduced by nevirapine.
• Fluconazole (Diflucan) can cause the concentration of nevirapine to double, increasing the risk of side effects. It should be used with caution. (Geel)
• The dose of itraconazole should be increased.
• Methadone hydrochloride (Methadose) levels are reduced by nevirapine, people taking both drugs should be closely monitored for withdrawal symptoms, and the methadone dose adjusted if necessary. (Stocker) (Altice)
• The dose of lopinavir/ritonavir (Kaletra) should be increased.
• Warfarin levels are reduced by nevirapine.

Nevirapine may also reduce levels of beta-blockers and steroids. It also reduces the levels of hormonal contraceptives other than DMPA and these should not be used as the sole means of birth control. (Mildvan)

Children

Nevirapine is licensed in Europe and the United States for the treatment of HIV infection in infants and children. In 2008, the US FDA advised that babies and children should receive nevirapine dosing according to body surface area rather than weight. (Klein)

Recommended oral dosing during the lead-in (or induction) stage is 150mg per m² of body surface area once daily for 14 days. Following induction, the same dose is given every 12 hours. Younger children may require a higher dosage (e.g. 200mg per metre² of body surface area twice daily), as clearance in children under the age of nine is faster than it is in older children or adults. The maximum daily limit should not exceed 400mg.

Nevirapine appears to be safe, effective and well tolerated in children from birth and is recommended as an alternative third agent in combination with two NRTIs for antiretroviral treatment for children up to six years of age in Europe. (PENTA 2019)

British HIV Association guidelines recommend that infants born to mothers living with HIV who have unknown or detectable viral load at the time of delivery should receive two weeks of nevirapine combined with four weeks of zidovudine and lamivudine as post-exposure prophylaxis. (BHIVA 2020)

Pregnancy

Nevirapine is no longer recommended as a component of antiretroviral therapy during pregnancy. (BHIVA 2020) Studies of the risk of nevirapine-related adverse events in pregnancy show contradictory findings for liver toxicity but an increased risk of severe rash. (Ford) (Ouyang) (Dube)

Treatment with nevirapine during labour has also been shown to reduce vertical transmission of HIV. (Guay) Single-dose nevirapine for mothers with HIV at delivery is only recommended if women are not on antiretroviral treatment at the time of delivery, and should be accompanied by intravenous zidovudine, together with immediate initiation of oral zidovudine, lamivudine and raltegravir. (BHIVA 2020)