Nevirapine (Viramune)

Nevirapine (Viramune) 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). The enzyme reverse transcriptase converts single-stranded viral RNA into DNA. Drugs in the NNRTI class stop HIV from replicating within cells by binding near reverse transcriptase’s active site and inhibiting polymerase activity.

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 (Viramune) is able to reduce 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.

Nevirapine was licensed after three clinical trials found that the combination of nevirapine, zidovudine (AZT, Retrovir) and didanosine (ddI, Videx) 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.[ref] [ref] [ref]

Several studies have reported that triple regimens including nevirapine are as effective as protease inhibitor-containing regimens.[ref] [ref] [ref] Concerns about the potency of nevirapine in people who begin treatment with high viral load have been dispelled by these studies.[ref]

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.[ref]

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 widely used in lower- and middle-income countries.

Taking it

The standard dose of nevirapine (Viramune) 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.

Glossary

rash

A rash is an area of irritated or swollen skin, affecting its colour, appearance, or texture. It may be localised in one part of the body or affect all the skin. Rashes are usually caused by inflammation of the skin, which can have many causes, including an allergic reaction to a medicine.

liver

An essential organ involved in digestion of food and excretion of waste products from the body.

resistance

A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus.

non-nucleoside reverse transcriptase inhibitor (NNRTI)

Non-nucleoside reverse transcriptase inhibitor, the family of antiretrovirals which includes efavirenz, nevirapine, etravirine, doravirine and rilpivirine. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind to and block HIV reverse transcriptase (an HIV enzyme), preventing HIV from replicating.

therapy

Any form of treatment. Drugs, radiation, and psychiatric counselling are forms of therapy. 

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. 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.

The United States Food and Drug Administration (FDA) now recommends that if a rash with constitutional symptoms or a severe rash develops, treatment with nevirapine should be stopped. If a mild to moderate rash occurs without constitutional symptoms during the lead-in period, the nevirapine dose should not be doubled to the full dosage until the rash is gone. The lead in period of once-daily dosing should also not exceed 28 days. If the rash has not subsided, an alternative treatment should be used.[ref]

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.[ref] [ref]

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 (Viramune) are rash, nausea, fatigue, headache, vomiting, diarrhoea, abdominal pain, and muscle pain.

Approximately 16% of people starting nevirapine will get a 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. Thereafter, most people experience very few or no side-effects.

Prophylactic concurrent treatment with antihistamines during the first two weeks of nevirapine therapy has been shown to reduce the risk of rash.[ref] However, treatment with the corticosteroid prednisolone has no effect on the number of people experiencing rash, and can increase its severity.[ref] [ref]

The rash can be treated in many cases with antihistamines. Beginning treatment with nevirapine at the same time as abacavir (Ziagen) is not recommended as both drugs can cause rashes, and it can be difficult to tell which drug is causing the reaction.

Women seem to be at greater risk than men of developing the mild and severe forms of rash associated with nevirapine.[ref] [ref] [ref] [ref]

People experiencing severe rash or a rash accompanied by fever, blistering, sores in the mouth, conjunctivitis, facial swelling, muscle or joint aches, or general malaise should consult a doctor, who may advise them to stop taking nevirapine.

The US FDA in 2008 issued safety labelling revisions for nevirapine tablets and oral solution following a number of serious hepatic events and skin reactions. Hepatic failure may be linked to a hypersensitivity reaction, resulting in severe rash (~7%), fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, renal dysfunction, and only rarely, Stevens-Johnson syndrome or toxic epidermal necrolysis. Most serious adverse events in the US occurred after nevirapine treatment as part of a post-exposure prophylaxis regimen in healthcare workers.

A two-week induction stage of nevirapine at 200mg/day (150mg in children) can often reduce the occurrence of rash. If there is rash and no other symptoms, the dose should not be escalated until the rash is resolved. The lead-in time should not exceed four weeks; if rash is still unresolved, an alternative regimen is suggested.

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

In addition to rash, liver toxicity can be a problem in people beginning nevirapine. [ref] [ref] [ref] [ref] The greatest risk of liver toxicity occurs in the first six weeks of treatment. Some experts advise doing a liver panel at baseline, at week two when the nevirapine dose is increased, and then two weeks after that. The first 18 weeks on therapy require vigilance, particularly the first six weeks, which is the time of greatest risk.

For this reason, nevirapine should not be included in a post-exposure prophylaxis regimen to prevent HIV infection.[ref] Pregnant women may also be at particular risk of developing liver toxicity when starting nevirapine treatment.[ref] [ref] One sizable US study even found that while pregnancy posed a risk for liver toxicity in women, nevirapine use did not.[ref]

Less than 1% of patients in clinical trials have stopped nevirapine treatment due to liver toxicity. While elevated liver enzymes are more common in people with hepatitis co-infection, these individuals are not at increased risk of liver toxicity.

If moderate or severe abnormalities in liver enzymes occur, nevirapine should be interrupted, only to be restarted when liver enzyme levels return to baseline. Nevirapine can start again at an initial dose of 200mg a day and liver enzymes should be closely monitored. The dose should be increased to 400mg a day with caution after extended monitoring.

In early 2004, Boehringer Ingelheim updated their safety warning based on a retrospective review of safety data. They stated that women with CD4 counts above 250 cells/mm3 were at 12-fold greater risk of nevirapine-related liver toxicity than men and that women with CD4 cell counts above this level who are new to treatment should start nevirapine with caution, as should men with CD4 cell counts above 400 cells/mm3. This warning remains in the prescribing information. However, several subsequent studies have reached different conclusions.  One prospective cohort study of women in Zambia, Thailand and Kenya found that abnormal liver function tests at baseline, not CD4 cell counts, best predicted severe liver damage and associated rash in the first 24 weeks after starting antiretroviral therapy including nevirapine.[ref]

European data suggest that it is safe for people who have experienced good increases in their CD4 cell counts on another antiretroviral regimen to subsequently switch to nevirapine even when the CD4 count is above the level recommended for initiating treatment with the drug.[ref] [ref] Based on these data, the European Medicines Agency has advised that people with HIV who have an undetectable viral load can safely switch to nevirapine at any CD4 cell count.

Symptoms of liver toxicity include nausea, loss of appetite, fatigue, liver tenderness or swelling, malaise, yellowing of the whites of the eyes, dark greenish-brown urine, yellowing of the skin (jaundice), and greyish or white stools.

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. [ref] [ref] [ref]

Resistance

As with all other anti-HIV drugs, strains of HIV that are resistant to nevirapine (Viramune) 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.[ref] [ref] 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 (Sustiva).[ref] [ref] Conversely, previous exposure to an NNRTI may predispose 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 (Viramune) should not take the following drugs:

  • Hypericin (St John’s wort), which can reduce blood levels of nevirapine, possibly causing resistance.
  • Ketoconazole (Nizoral), due to lowered ketoconazole levels.

Taking nevirapine with a protease inhibitor reduces the concentration of the protease inhibitor in the blood. The non-nucleoside reverse transcriptase inhibitor etravirine is more suitable for combining with a protease inhibitor.

Combining efavirenz with nevirapine and etravirine, the other NNRTIs, is not recommended due to an increased frequency of side-effects.[ref]

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

  • Amoxicillin (Amoxil) levels are increased by nevirapine, increasing the risk of side-effects.
  • Doxycycline (Vibramycin / Vibramycin-D) levels are reduced by nevirapine.
  • Erythromycin (Erymax / Erythrocin / Erythroped / Erythroped A) levels are increased by nevirapine, increasing the risk of side-effects.
  • Felodipine (Plendil) 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.[ref]
  • Griseofulvin (Grisovin) levels are reduced by nevirapine.
  • 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.[ref] [ref]
  • Metronidazole (Flagyl / Flagyl S / Metroyl) levels are reduced by nevirapine.
  • Nifedipine (Adalat) levels are reduced by nevirapine.
  • Quinidine sulphate (Kinidin Dureles) levels are reduced by nevirapine.
  • Sildenafil (Viagra) levels are increased by nevirapine, and it should be taken at a reduced dose of 25mg.
  • Tadalafil (Cialis) levels are increased by nevirapine, and it should be taken at a reduced dose.
  • Theophylline levels are reduced by nevirapine.
  • Vardenafil (Levitra) should be taken at a lower dose in people taking nevirapine.
  • Warfarin levels are reduced by nevirapine.

Nevirapine may also reduce levels of beta-blockers and steroids. It also reduces the effectiveness of oral contraceptives and alternative forms of birth control are recommended.[ref]

Children

Nevirapine (Viramune) 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 receive nevirapine dosing according to body surface area rather than weight.[ref]

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, although no large, randomised studies comparing a nevirapine-based regimen to other regimens have been reported.[ref] [ref] [ref] Side-effects are similar in children and adults.[ref]

Pregnancy

Nevirapine (Viramune) is safe for use in pregnant women.[ref] [ref] However, the use of nevirapine in pregnant women poses an elevated risk of liver toxicity, which has been fatal to mothers and foetuses.[ref] [ref] There is also evidence that blood levels of nevirapine are reduced in pregnant women, which may increase chances of developing resistance.[ref]

Treatment with nevirapine during labour has also been shown to reduce mother-to-baby transmission of HIV.[ref]  Later studies have demonstrated that single doses of nevirapine during labour, with or without a dose for the infant after birth can further reduce the risk of transmission when added to a course of zidovudine treatment.[ref] [ref] However, maternal exposure to nevirapine compromised subsequent triple therapy including nevirapine, even in women who did not have detectable NNRTI resistance.[ref] [ref] [ref] [ref] Consequently, in February 2004, the World Health Organization recommended that short-course regimens of nevirapine monotherapy not be used when standard regimens are available. This was due to the risk of nevirapine resistance and because zidovudine in combination therapy reduced transmission to a greater extent than nevirapine alone.[ref]

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