Exposure to a single dose of nevirapine at the time of childbirth appears to reduce the effectiveness of triple antiretroviral therapy in mothers who subsequently receive nevirapine-based regimens, especially if therapy starts less than six months after childbirth, according to findings from a major Thai study presented on Monday at the Eleventh Conference on Retroviruses and Opportunistic Infections in San Francisco.
The study, called PHPT-2, recruited 1844 pregnant HIV-positive women, and randomised them and their newborns to receive either:
- One dose of nevirapine for the mother at delivery and nevirapine within 72 hours of birth for the infant (the nevirapine/nevirapine arm).
- Nevirapine for the mother at delivery and a placebo for the infant (the nevirapine/placebo arm).
- Placebos for both mother and infant (the placebo/placebo arm).
All mothers received AZT for the last three months of their pregnancy, and all infants received AZT syrup for the first week of life. No infants were breastfed.
The placebo/placebo arm of the study was stopped after an interim analysis showed a higher rate of HIV transmission from mother to child in this arm (6.3% vs 1.1% in the nevirapine/nevirapine arm)
The final analysis of the study showed that the nevirapine/nevirapine regimen proved only slightly superior to the nevirapine/ placebo arm in reducing the rate of transmission (2.0% vs 2.8%). HIV DNA testing was carried out at birth, week 6 and months 4 and 6 to determine if the child had become infected.
A random sample of 90 women exposed to nevirapine showed that NNRTI-associated mutations were present in 18% of women tested 12 days after delivery, whilst a pharmacokinetic study showed that 77% of the women had detectable levels of nevirapine 5-15 days after delivery, and detectable levels of nevirapine were still present in one woman 19 days after delivery.
A sub-analysis of mothers who needed to start triple antiretroviral therapy with d4T/3TC/nevirapine due to CD4 counts below 250 cells/mm3 after delivery showed that women exposed to nevirapine at delivery had significantly poorer virologic responses after six months of treatment if they showed evidence of nevirapine resistance six weeks after delivery, with a trend towards poorer response also evident in women who were exposed to nevirapine without developing detectable resistance to the drug.
A quarter of women who participated in PHPT-2 needed antiretroviral treatment after delivery, and the researchers found that when virologic response was measured using an ultrasensitive viral load assay, only 34% of women with at least one nevirapine-associated mutation had viral load below 50 copies/ml after six months of treatment, compared to 75% of women not exposed to nevirapine (p=0.001). 53% of women exposed to nevirapine without evidence of resistance had viral load below 50 copies at this point, leading Professor John Mellors of Pittsburgh University School of Medicine to note that this trend mirrored results from a study presented by his group in the same session. His group found that participants in the ACTG 398 study who added efavirenz were significantly more likely to experience virologic failure if they had been exposed previously to another NNRTI, even in the absence of resistance detectable by normal assays. Using a highly sensitive resistance assay, the ACTG 398 researchers found that between 0.6% and 7% of the virus population in previously exposed patients already carried the same mutation at baseline that would later emerge upon failure of the efavirenz-containing regimen. This result would be missed by standard genotypic resistance testing, which cannot detect minority populations that comprise less than 10-20% of the total virus population in a blood sample.
Women who started treatment more than six months after delivery had a better response to treatment , suggesting that starting treatment earlier is likely to result in a sub-optimal response. Although treatment responses appeared equivalent when measured by CD4 cell response, experts argue that poorer virologic responses at six months signal higher risk of treatment failure.
Several speakers at the meeting argued that whilst single dose nevirapine treatment should be continued for the time being, it should be considered to be a transitional treatment regimen, and that HAART for pregnant women should be the preferred regimen at the very least around the time of delivery. They also emphasised that the findings should not block the roll-out of nevirapine-based HAART regimens, given that the majority of women will not receive short-course nevirapine treatment during pregnancy.
Speakers also suggested that where women need antiretroviral therapy soon after delivery, protease inhibitor-based therapy may be preferable in order to side-step the resistance problems now clearly apparent with nevirapine-based treatment.
Lallemant M et al. A randomised double blind trial assessing the efficacy of single-dose perinatal nevirapine added to a standard zidovudine regimen for the prevention of mother-to-child transmission of HIV-1 in Thailand. Eleventh Conference on Rettroviruses and Opportunistic Infections, San Francisco, abstract 40LB, 2004.
Jourdain G et al. Exposure to intrapartum single-dose nevirapine and subsequent maternal six month response to NNRTI-based regimens. Eleventh Conference on Rettroviruses and Opportunistic Infections, San Francisco, abstract 41LB, 2004.
Mellors J et al. Low frequency NNRTI-resistant variants contribute to failure of efavirenz-containing regimens. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 39, 2004.