Risk of resistance with nevirapine-containing HAART after pregnancy, even when stopped correctly

Women with a wide variety of HIV-1 subtypes, including B, B/G, F2 and G, who take nevirapine-containing HAART during the third trimester of their pregnancy in order to prevent mother-to-child transmission, are at risk of developing resistance to both non-nucleosides and nucleoside analogues, even after discontinuing nevirapine five days prior to the rest of their HAART combination, according to a small retrospective cohort study from Dublin, Ireland, published in the latest issue of the journal, AIDS.

The ‘Irish HIV in Pregnancy Guidelines’ recommend that women who do not require antiretroviral therapy for their own health commence HAART in the third trimester of pregnancy and discontinue once the baby is born. All women attending the HIV antenatal clinic at St James Hospital, Dublin, who began HAART on or after 28 weeks of pregnancy, discontinued HAART after delivery, and returned for genotypic resistance resting, were eligible for this study.

The majority (92%) of the women in this small cohort were from sub-Saharan Africa, and a wide variety of HIV-1 subtypes were seen: most were subtypes C (36%), B (31%) or G (13%), but D, CRF05/DF, F2, B/G and B/D were also found.

Although 50 women were eligible, only 39 reverse transcriptase sequences were actually generated; genotypic resistance tests were unable to be carried out in nine of the women because their viral loads were below 500 copies/ml and because the pol gene was not amplifiable in two of the women.

Of the 39 women for whom sequences were obtained, 28 had taken AZT, 3TC and nevirapine; ten had taken AZT, 3TC and nelfinavir, and one woman, who had taken AZT/3TC in a previous pregnancy and had acquired the M184V mutation, took AZT, ddI and nevirapine.

Eight women switched from nevirapine to nelfinavir, three due to side-effects (rash and/or abnormal liver enzymes) and five after concern was raised about nevirapine’s toxicity in pregnancy at the 2003 IAS meeting in Paris. Since then, nevirapine's manufacturer, Boehringer Ingelheim has issued advice warning of an increased risk of liver toxicity in women with a CD4 cell count above 250 cells/mm³.

The women spent a median of 70 days on HAART (ranging from three to 114 days) and the median viral load reduction was 1.76 log₁₀ copies (ranging from 0 to 2.74). Viral load was less than 1,000 copies/ml in 31 of the 32 women who had results available at their 36^th week of pregnancy; the other woman had a viral load of 12,788 copies/ml. Of the seven women who had no viral load results available, three were very late presenters, three delivered before the final appointment, and one was a non-attender.

The median time from stopping HAART to genotypic resistance testing was 42 days, although one woman did not return until 198 days after giving birth. This may underestimate the number of mutations detected in this study. Women taking nevirapine-containing HAART were asked to stop nevirapine immediately after giving birth and continue with the remainder of the regimen for another five days. This was reiterated to, and by, the delivering obstetrician. However, no formal adherence assessment was undertaken.

Seven primary reverse transcriptase mutations were detected in five (13%) of the women, all of whom were taking AZT/3TC/nevirapine, and all of whom were antiretroviral naive prior to this pregnancy.

• Patient 1 (subtype B) took HAART for 84 days, had a viral load of 73 copies/ml at delivery and subsequently developed the V106A mutation.
• Patient 2 (subtype B/G) took HAART for 56 days, had a viral load of less than 400 copies/ml at delivery and subsequently developed the Y181C, G190A and T215S mutations.
• Patient 3 (subtype F2) took HAART for 26 days, did not have a viral load available at time of delivery and subsequently developed the M184V mutation.
• Patient 4 (subtype F2) took HAART for 95 days, changed from nevirapine to nelfinavir after 59 days when she had a viral load of less than 50 copies/ml, remained undetectable at delivery and subsequently developed the K101E mutation.
• Patient 5 (subtype G) took HAART for 13 days, did not have a viral load available at time of delivery and subsequently developed the T181C mutation.

Although all women were protease inhibitor naive prior to this pregnancy, 35 protease sequences were generated, all of which were found in the women taking nevirapine-containing HAART. Six (17%) were the M36I mutation, which may be a naturally occurring mutation present in non-B subtypes, and may predispose to failure of protease inhibitor (PI)regimens through the emergence of the L90M mutation. Two further PI mutations were seen: L101 in two women, and K20R in one woman.

The women in whom no mutations were found did not differ from those in whom mutations developed with respect to pre-treatment CD4 count and viral load, duration of HAART, pre-delivery viral load or time from stopping HAART to genotypic resistance testing.

Mutations were not detected in the ten women who took nelfinavir-containing HAART, but the authors note this may be due to the small sample size.

Since no baseline genotypic data were available for the women in this study, mutations may have already been present prior to HAART. To date, little is known about the baseline resistance profiles of non-B subtypes. Even less is known about how the non-B subtypes will evolve in the presence of antiretroviral drugs and the impact this will have on response to therapy. In addition, resistance may occur spontaneously and there are conflicting data on the prevalence of naturally occurring mutations within non-B subtypes.

The authors conclude by saying that “this study suggests that the strategy of using triple antiretroviral in pregnancy may not protect drugs with known low-genetic barriers [to resistance] such as nevirapine, and the clinical implications of this remains to be seen.”

The British HIV Association (BHIVA) will be announcing their revised pregnancy guidelines at their Spring conference in Dublin in April, and the March issue of NAM’s monthly newsletter AIDS Treatment Update will be previewing the guidelines in det