Nevirapine, pregnancy and adverse events

2 April 2004. Related: Conference reports, Pregnancy, CROI 11 (Retrovirus) 2004.

Polly Clayden, HIV i-Base

There have been legitimate concerns that the serious adverse events associated with nevirapine – including rash and hepatitis – which women are at greater risk of experiencing compared to men, may be heightened in pregnancy. Due to this agent’s widespread use in pregnancy, there is potential for serious risk both to the pregnant woman and to her foetus were a serious event to develop. Three posters evaluate tolerability and toxicity of nevirapine use during pregnancy.

Kramer and colleagues from the University of Southern California, Los Angeles, performed a case note review of 125 pregnancies during the period March 1996 to November 2002 – in which women received nevirapine-containing HAART – to determine the tolerability of nevirapine in HIV-positive pregnant women according to ethnicity, CD4 and viral load [1]. Additionally the investigators analysed use in women with underlying risk factors for hepatotoxicity: chronic hepatitis B or C and alcoholism, according to duration of therapy and gestational age at initiation.

Of the group 76 (61%) were Latino and 36 (29%) were Black; 7 (6%) were co-infected with HCV and 18 (15%) with HBV. At baseline, the median CD4 count was 395 cells/mm3 and 86 women (66%) had CD4 counts <500 cells/mm3. Median HIV viral load was 4382 copies/mL with 57 (46%) women having <4000 copies/mL HIV RNA. 76 (63%) of women received nevirapine within the first 24 weeks of pregnancy with a median length of nevirapine therapy of 14 weeks (range 1 to 40); 29% were receiving nevirapine at conception. Of the 125 pregnancies, there were no transmissions (this in itself is an exciting finding).

Toxicities occurred in 17/125 (13%) women: rash in 8, elevated liver function in 6 and both in 3. The investigators reported no difference in mean baseline CD4 count between those women with or without toxicity (420 cells/mL for both, p=0.99). However, those women with CD4 >500 cells/mm3 had more frequent toxicity than those with CD4<500 cells/mm3, but this was not statistically significant (19%:  8/42 vs 11%: 9/82 p=0.22). Toxicity occurred more frequently within first eight weeks of nevirapine use, but again this did not reach statistical significance (7/ 37, 19% vs 10/87, 11%, p=0.27).

In multivariate logistic analysis, the investigators found no significant association between toxicity and ethnicity (p=0.22), baseline CD4 (p=0.14), baseline HIV RNA level (p=0.37) and duration of nevirapine use (per week increase: p=0.71 or longer than eight weeks: p=0.48). They also noted that there was no additional nevirapine toxicity among women taking nevirapine at the time of conception and who continued during pregnancy.

They concluded: “Nevirapine containing regimens provided effective treatment of our pregnant patients and contributed to our lack of perinatal transmission over the last seven years.”

A second case note review from Bershoff-Matcha and colleagues at the University of Washington was performed to investigate this group’s observation: “We anecdotally noted fewer serious adverse events among women who were initiated on nevirapine during pregnancy.” [2]

Both pregnant (n=41) and non-pregnant (n=222) women receiving nevirapine at two clinics between September 1999 and July 2003 were evaluated in this study. Demographic data, CD4 counts, viral loads, concurrent medical therapies, and serious adverse events were reviewed.

The pregnant women were younger than the non-pregnant women (mean age 28.7 years for pregnant women vs. 38.0 years for non-pregnant women). The mean CD4 counts and viral loads for the two groups were 474 cells/mm3 (range 93 to 1,290) and 52,209 copies/mL (range 49 to 296,056) for the pregnant women and 289 cells/mm3 (range 3 to 1490) and 379,119 copies/mL (range 49 to >750,000) for the non-pregnant women respectively.

Only one pregnant woman (0.4%) and 38 non-pregnant women (14.5%) from this group developed any adverse event after initiating nevirapine (OR = 8.26, 95% CI: 1.10 to 62.0, p=0.0153). The investigators reported mild adverse events (grades 1-2) in one (0.4%) pregnant woman and 21 (8.0%) non-pregnant women (p=0.1365) and serious adverse events (grades 3-4) in none of the pregnant women and 17 (6.5%) non-pregnant women (OR=7.07, 95% CI:  0.41 to 119.87, p=0.0675). They found risk of rash to be independent of race, age, CD4 count, viral load, or other medications including hormonal contraceptives, antihistamines and corticosteroids.

The investigators concluded: “Although our results are limited by small sample size, women in our study were significantly less likely to develop an adverse reaction to nevirapine when the drug was initiated during pregnancy.”

Finally the FDA presented a report of a search of their Adverse Event Reporting System (AERS) database following reports of six deaths (three in 2003) of pregnant HIV-positive women receiving antiretrovirals, due to hepatic failure [3].

This study found hepatic adverse events most commonly associated with 3TC (35 reports), AZT/zidovudine (ZDV) (34), and nevirapine (28) and to be less common with protease inhibitors (7 nelfinavir, 6 saquinavir and 5 ritonavir). There were no reports for more recently approved antiretrovirals (tenofovir, emtricitabine, atazanavir or enfuvirtide).

Rash, fever, or jaundice with increased transaminases were reported with the use of nevirapine (9), 3TC (7), and ZDV (6). Hepatic failure was reported with the use of nevirapine (6), ZDV (4), ddI (4), and d4T (4).

Five deaths were reported due to hepatic failure during pregnancy and one in the immediate postpartum period: 3 women were receiving ZDV/3TV/NVP, 2 ddI/d4T/NVP and 1 ddI/d4T/NFV. The deaths in women receiving ZDV/3TV/NVP were due to hepatic necrosis while the deaths in women receiving ddI and d4T were associated with lactic acidosis.

The investigators concluded: “The majority [of adverse events] of were reported in patients receiving ARV commonly prescribed during pregnancy (ZDV, 3TC, NVP) … Severe hepatotoxicity, including hepatic failure and death, was reported with ZDV/3TC/NVP and with regimens containing ddI and d4T. Due to limitations of AERS, it is difficult to determine if this is due to increased toxicity during pregnancy or reactions to one of the ARV or combinations of ARV.”

Comment

The findings of Kramer et al mirrors the published experience of nevirapine use in pregnancy in London (Edwards et al, HIV Medicine 2001) in which 4/30 women (13.3%) starting nevirapine during pregnancy experienced rash (2 women) or biochemical hepatitis (2 women) but otherwise nevirapine was well tolerated. It is also very encouraging to see no transmissions among the group of 125 pregnant women in this study.

The difficulties with the FDA data are the lack of numerator, potential for reporting bias and a lack of causal association. However there is real concern that nevirapine toxicities are more common in women with CD4 counts greater than 250 cells/mm3, a profile that frequently matches pregnant women receiving short courses of antiretroviral therapy to reduce the risk of mother to child transmission.

In comparison to the experience with zidovudine, lamivudine, nevirapine and nelfinavir, there is relatively little experience with other antiretroviral therapies. The benefits for the mothers and babies should not be underestimated but all antiretroviral therapy should be prescribed with care and closely monitored in pregnancy.

References:

1. Kramer F, Stek A, Du WB et al. Nevirapine tolerability in HIV-infected women in pregnancy. 11th CROI 2004, Abstract 923.
2. Bershoff-Matcha SJ, Mundy LM, and Henry JV. Adverse events to nevirapine therapy during pregnancy. 11th CROI 2004, Abstract 939.
3. Baylor M, Truffa M, and Gibbs N. Hepatic toxicity of antiretrovirals in HIV-infected pregnant women: a review of the FDA’s adverse event reporting system. 11th CROI 2004, Abstract 944.