February 11, 2004
The well-understood pharmacokinetics in pregnancy and in infants, the efficacy, and the apparent safety are attractive features. However, a rare but concerning side effect of nevirapine is a syndrome of severe hepatic injury, often with rash, that occurs early after the beginning of treatment. It can be life threatening and a few deaths have occurred. Recent studies have identified a high CD4 count and being a woman as risk factors for this syndrome, and this new information has been incorporated into the package insert (PDF). Stevens-Johnson syndrome is another rare, but serious side effect.
Against this background, it is clear we need to know more about the safety of nevirapine in different groups of women, especially those who are pregnant. Two studies provided some reassuring data. Kramer and colleagues from the University of Southern California reviewed all pregnant HIV-positive women cared for at L.A. County USC Medical Center and identified 117 women who had used nevirapine in 125 pregnancies. Most were non-white with 61% Latina and 29% black.
HIV had been diagnosed during pregnancy in 43% of the women. Since a high CD4 count is a predictor of nevirapine toxicities, it is important that 80% of the women had more than 250 CD4 cells/mL and 34% had more than 500 cells. Overall, 19/117 stopped nevirapine at some point, although three women successfully restarted. There were seven significant reactions among the 117 women. Rash occurred in three women, elevated liver enzymes occurred in three women and one woman had nausea and vomiting. None of the rashes were severe. Only one woman had grade 3 elevations of liver function tests (LFTs) and there were no episodes of severe hepatitis. Toxicity of any grade was more common among those with more than 500 CD4 cells than those with lower counts.
But are these numbers higher or lower than among non-pregnant women? We do not have a clear-cut answer, but another study, from Bersoff-Matcha at Kaiser Permanente in Washington D.C., compared 43 pregnant women treated with nevirapine with 227 non-pregnant women. The two groups were relatively comparable in everything except age (median 28 years versus 38 for the non-pregnant women). CD4 counts higher than 500 were slightly more common in the non-pregnant women (31% compared to 26%, although this was not statistically significant).
Overall, significantly fewer pregnant women had adverse events after starting nevirapine than non-pregnant women. The rates were 1/43 (2.3%) compared to 43/227 (18.9%, P = 0.007). This remained significant when controlling for age, CD4 count and race. There was also a significant difference in more serious adverse events (grade 3-4), with 0 among 43 pregnant women compared to 20 among 227 (8.8%, P = 0.05).
Rash was the most common side effect. Only one pregnant woman had a rash compared to 23 mild rashes and 17 grade 3-4 rashes among the non-pregnant group. Hepatitis occurred in five non-pregnant women; two had hepatitis with rash, which may be the most worrisome syndrome.
So, what does this mean in daily practice? In the only comparative data we have, pregnancy is not a risk factor for nevirapine toxicity among women. This needs to be confirmed in larger studies. Women are, however, at increased risk of the more severe types of nevirapine toxicity compared to men, and the women with the highest CD4 counts are at the greatest risk (PDF).
We continue to need to focus on the health of women, pregnant or not, and not just on the prevention of mother-to-child transmission. I think we can continue to use nevirapine in pregnancy, but we should be careful to warn women to be alert to rashes, abdominal pain, fever and jaundice during the first 6 weeks after beginning therapy. We must educate them to contact their healthcare provider if any of these symptoms occur. We also should remember that the combination of stavudine (d4T, Zerit) and didanosine (ddI, Videx) should not be used in pregnancy because of the risk of severe lactic acidosis.
Abstract: Nevirapine Tolerability in HIV-Infected Women in Pregnancy (Poster 923)
Authored by: F. Kramer, A. Stek, W. B. Du, A. Kovacs
Affiliations: Univ. of Southern California, Los Angeles, CA
Abstract: Adverse Events to Nevirapine Therapy During Pregnancy (Poster 939)
Authored by: S. J. Bershoff-Matcha, L. M. Mundy, J. V. Henry
Affiliations: Kaiser Permanente of the Mid-Atlantic States, Washington, DC; Washington Univ. Sch. of Med., St. Louis, MO
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