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Drugs! Drugs! Drugs!
An Overview of the Approved Anti-HIV Medications

Viramune (Nevirapine, NVP)

Fall 2003/Winter 2004

Viramune (nevirapine, NVP) was the first non-nucleoside reverse transcriptase inhibitor (NNRTI) approved by the FDA, but has taken a back seat to Sustiva (efavirenz) due to the latter NNRTI's impressive results in clinical trials. New data could change that, as we find that Viramune's "poor cousin" status may more likely be the result of unfortunate research decisions rather than a lack of strength.


Background

Long before its approval in June 1996, Viramune entered the scene with a big splash in early 1993 when a Harvard medical student, Yung-Kang Chow, published an article in Nature magazine describing effects of various two- and three-drug combinations against HIV in vitro (in the test tube). Chow said that certain drug combinations -- Retrovir (AZT)/Videx (ddI)/Viramune among them -- forced the virus to mutate so much that it became unable to reproduce. The press jumped on the bandwagon and "convergent combination therapy" -- hitting the virus with multiple drugs targeted at the same point in its lifecycle -- became the buzz of the day.

Unfortunately, the experiment didn't hold up. Chow had to retract his results after it was discovered that he had inadvertently constructed a virus with mutations that made it non-infectious. Worse than that, the trial designed to test this three-drug combination in people (ACTG 241) was only open to people who had already taken Retrovir, Videx, or Hivid (ddC) for at least six months. Since many of them were resistant to these drugs, the results were not impressive -- people taking three drugs saw steeper drops in viral load than those taking only two drugs, but they all returned to starting levels within a year. The first trial of what would years later be called HAART was a disappointment. If a trial had also been done in people who had never taken antiretrovirals before, HAART might have become the standard of care in 1994 rather than in 1996. Who knows how many lives might have been saved?

One of the studies that led to Viramune's approval was BI 1046, also called the INCAS trial (Italy, Netherlands, Canada and Australia Study). Started in 1994, this trial of 151 people compared two-drug combinations to the three-drug combination of Retrovir, Videx, and Viramune. The study found that 51% of people on the three-drug combination had viral loads below 20 (a tough standard) after a year of treatment compared to 12% of those taking a Retrovir/Videx combination. But when later studies showed that about 70% of people on Sustiva combinations could maintain viral loads below 50, Viramune was viewed as second best for many years.

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That changed with the results of the 2NN study, reported early in 2003. This was a head-to-head comparison of Viramune to Sustiva (or both drugs together) when combined with Epivir (3TC) and Zerit (d4T) in 1,216 people from 17 countries who had never taken any anti-HIV drugs. After a year, the two drugs were equal in potency -- 70% of people taking either Viramune or Sustiva once a day had viral loads below 50. (65% of people taking twice-daily Viramune and 63% of those taking both drugs were below 50.) Because of this study, some treatment guidelines now place Viramune on equal footing with Sustiva as a "preferred" first regimen drug. But one study can't prove that the drugs are equally effective -- more data for longer periods of time are needed.


Side Effects

The most common side effects of Viramune are rash and liver problems. Most rashes occur during the first six weeks on therapy. In clinical trials, 17-24% of people developed a rash, and serious rashes occurred in 7% of people. Women have a higher risk of rash, as do people who are allergic to sulfa drugs such as Bactrim. To minimize the possibility of rash, people take Viramune at half-dose for the first two weeks, building up to the full dose. If a rash develops within those first two weeks, the Viramune dose shouldn't be increased until the rash goes away. People who get a rash while taking Viramune should call their healthcare provider right away and may need to stop the drug. Since Ziagen (abacavir) can also cause a rash, it's best not to start both drugs at the same time.

In November 2000, Boehringer Ingelheim, Viramune's manufacturer, sent a letter to physicians stating that the drug's warning label had been "strengthened in response to continued reports of severe, life-threatening, and, in some cases, fatal hepatotoxicity." A company-sponsored analysis of studies found that only 12% of people had any liver side effects, but other studies have found rates of severe liver problems ranging from 15-20%.

Most liver problems caused by Viramune happen within the first four months on the drug, whereas liver problems caused by other antiretrovirals usually occur later. So people starting Viramune should watch their liver function tests carefully during the first four months and continue to monitor them regularly after that. Women, people with chronic hepatitis B or C, and those with higher CD4 counts or elevated liver enzymes have a greater chance of developing liver problems. If you get any of the following symptoms, call your healthcare provider right away: flu-like symptoms; dark urine; tiredness; pale stools; nausea; lack of appetite; pain, ache, or sensitivity to touch on the right side below the ribs; yellowing of the skin or eyes (jaundice).

Finally, Viramune can cause a severe allergic reaction called Stevens-Johnson syndrome in about 1% of people. Those who have this reaction should not restart Viramune, since that could be life threatening.


Drug Interactions

Viramune can lower levels of the protease inhibitors Fortovase (saquinavir) and Crixivan (indinavir), but this can be addressed by adding low-dose Norvir (ritonavir). Viramune should not be taken with Nizoral (ketoconazole), since it can lower levels of Nizoral significantly. It can also lower levels of methadone up to 36% and lead to symptoms of withdrawal, so people taking methadone may need a dose increase if they take Viramune. Viramune can also lower levels of Viagra (sildenafil), so the Viagra dose may need to be increased to achieve the same result. St. John's wort (hypericum) can lower levels of Viramune, so they should not be taken together. Viramune can lower levels of the oral contraceptives norethindrone and ethinyl estradiol, so other methods of birth control should be used.


When to Consider It

Because of the results of the 2NN study, the British, French, and New York State HIV treatment guidelines place it on an equal footing with Sustiva as a first-line therapy (the U.S. Department of Health and Human Services guidelines do not). The very different side effects of these two drugs may be the main factor in making a personal choice if you're considering a starting regimen that includes an NNRTI.

A number of studies have shown that people can switch to Viramune from a protease inhibitor and keep their viral load below detection, but only if they are not already resistant to other NNRTIs. Most studies have found that people who switch to Viramune from a protease inhibitor see cholesterol and triglyceride levels improve. It's questionable if switching to Viramune will improve body shape changes -- some trials have reported improvement, but most have not.


Good to Know

  • Viramune is one of only a few antiretrovirals with the ability to cross the blood-brain barrier. This ability makes the drug effective against HIV in the brain and central nervous system and may help prevent neurological disease like dementia. It's important to include at least one antiretroviral that crosses the blood-brain barrier in your combination.

  • Once-a-day Viramune has been studied with good results, but has not yet been reviewed by the FDA.

  • Viramune is not recommended for post-exposure prophylaxis (after a needlestick or unprotected sex) because the risk of short-term liver problems outweighs the potential benefit.


Mother-to-Child Transmission

Viramune made big news in 1999 with the HIVNET 012 study in Uganda, which gave a single dose of Viramune to HIV-positive pregnant women during labor and a single dose to infants immediately after birth. The study found that this lowered the risk of transmission by half. That's not as good as PACTG 076, which showed that Retrovir taken during pregnancy lowered the risk by two-thirds, but it's still impressive, especially since this approach is very cheap. Unfortunately, almost 20% of the women in HIVNET 012 developed resistance to Viramune, and other studies have found that up to 75% of women and 46% of infants will develop resistance to Viramune. Some people have questioned the ethics of using Viramune this way since it may impact future treatment options for both mother and child. A recent commentary in The Lancet suggests adding other antiretrovirals in the hopes of avoiding widespread resistance to all of the NNRTIs. A trial adding single-dose Viramune to standard Retrovir treatment during pregnancy did not show any additional benefit.


Pregnancy

Viramune is classified as an FDA pregnancy category C drug. No damage to the fetus was seen when the drug was given to pregnant rats and rabbits. But its safety in pregnant women has not been studied long-term, so it should be used during pregnancy only if the benefit justifies the risk to the mother and fetus. The Antiretroviral Pregnancy Registry has not reported an increase in the prevalence of birth defects when Viramune was used during the first trimester. In fact, the prevalence of birth defects was only 2%, compared to an overall prevalence of 3.1%.


Dose

400 mg a day taken as one 200-mg tablet twice a day, with or without food. For the first two weeks, the dose is one 200-mg tablet once a day. There is a liquid form of Viramune for pediatric use, which is dosed according to weight. For children ages 2 months to 8 years, the dose is 7 mg/kg twice a day (4 mg/kg once a day for the first two weeks). Over 8 years old, the dose is 4 mg/kg twice a day (once a day for the first two weeks). No one should take more than 400 mg a day.

FDA Approval: 1996

Manufacturer: Boehringer Ingelheim Pharmaceuticals

Patient Assistance Program: 800-274-8651





  
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This article was provided by AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.
 

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