Two Thai studies have provided further evidence that short courses of more than one antiretroviral drug after delivery almost eliminate the risk of nevirapine resistance in mothers when it is used to prevent mother-to-child transmission, thus preserving nevirapine as an option for maternal treatment when eventually needed.
The findings were presented on Tuesday at the Sixteenth Conference on Retroviruses and Opportunistic Infections in Montreal.
In one study researchers compared a triple regimen of AZT/ddI and lopinavir/ritonavir (Kaletra) taken for one month or one week with AZT/ddI taken for one month, while in the second study another research group compared one month of postpartum AZT/ddI to a historical control group that received AZT postpartum. Both studies evaluated the regimens in women who did not need antiretroviral therapy for their own health.
This approach to preventing the development of resistance in women who receive single-dose nevirapine is called 'covering the tail'. It is designed to prevent the emergence of nevirapine resistance after a single dose. Levels of nevirapine in the blood may take at least a week to fall below the level at which resistance can still develop, giving rise to nevirapine resistance in up to 70% of women who receive a single dose. Previous studies have looked at the effect of covering this tail-off in drug levels by giving seven days of treatment with AZT, with AZT and 3TC or with tenofovir and FTC.
One of the studies (IMPAACT P1032) was a phase II open-label randomised trial with three antiretroviral treatment arms that were compared to a historic control arm. HIV-positive pregnant women were eligible if they were at 28 to 38 weeks gestation, had CD4 cell count levels greater than 250 cells/mm3, and were not planning to breastfeed or to receive antiretroviral therapy during the first eight weeks after delivery.
The study enrolled 175 women from June 2006 to June 2008, and also analysed data for 119 controls who had enrolled in another study from January 2001 to February 2003. At study entry, the women slated to receive postpartum antiretroviral therapy had higher median CD4 cell counts and lower viral loads than the women in the control arm (456 CD4 cells/mm3 versus 414 CD4 cells/mm3; 3.5 HIV RNA log10 copies versus 4.0 HIV RNA log10 copies; 25% undetectable viral load versus 8% undetectable viral load).
The women in the postpartum treatment arms all received a single intrapartum dose of nevirapine, along with either AZT (zidovudine), ddI (didanosine, Videx EC) and lopinavir/ritonavir (Kaletra) for seven days (Arm A); AZT and ddI for 30 days (Arm B); or AZT, ddI, and Kaletra for 30 days (Arm C). The women in the control arm had received prenatal AZT and a single intrapartum dose of nevirapine.
Researchers compared nevirapine resistance at two weeks postpartum and six weeks postpartum in all four study arms, using consensus sequencing and oligonucleotide ligation assay (OLA). At both of those times, each postpartum treatment arm was found to have a significantly lower incidence of new nevirapine resistance than the control arm, while not differing significantly from the other postpartum treatment arms.
At eight weeks postpartum, 8.3% of women from the postpartum treatment arms had new resistance at any time (95% confidence interval, 5% – 14%). New nevirapine resistance mutations were identified at weeks 2 or 6 in 3.6% of women in Arm A, 7.1% in Arm B and 5.3% in Arm C. There was no significant difference in the emergence of resistance between the three treatment arms, despite the fact that one of them contained a boosted protease inhibitor that might be expected to suppress viral load below the limits of detection, and so minimise the risk of resistance. However the rate of new resistance mutations was significantly lower in each of the three arms than in the historical control arm, which used data from the PHPT-2 study, a previous Thai study in which women received AZT in addition to single-dose nevirapine.
The second study (PHPT-4) also compared pregnant HIV-positive women receiving intrapartum nevirapine and postpartum antiretroviral therapy to a historical control arm, again derived from the PHPT-2 study. The postpartum treatment arm was comprised of 222 antiretroviral-naïve women with CD4 cell counts above 250 cells/mm3. They were individually matched to the controls on baseline viral load, CD4 cell count and duration of antepartum AZT use.
The treatment arm received AZT prophylaxis during the third trimester of pregnancy, then a single dose of intrapartum nevirapine followed by an AZT/ddI regimen for one month. Didanosine was dosed at either 250mg or 400mg once daily according to weight.
Didanosine was used in this study in preference to tenofovir or 3TC due to the high prevalence of hepatitis B among women in Thailand (approximately 10% of pregnant women have hepatitis B). A short course of prophylaxis containing either tenofovir or 3TC might result in a hepatitis B flare when prophylaxis ceases.
Consensus sequencing and OLA were used to assess nevirapine resistance, with samples drawn at 7 to 10 days postpartum, 37 to 45 days postpartum and 120 days postpartum. Consensus sequencing identified major non-nucleoside reverse transcriptase inhibitor resistance mutations in 10.4% of controls, but found no evidence of resistance in the treatment arm by consensus sequencing. OLA identified the K103N, G190A or Y181C mutation in 18.9% of controls, but in only 1.8% of study participants receiving postpartum antiretroviral therapy. When the results of consensus sequencing and OLA were combined, resistance mutations were found in 1.8% of postpartum antiretroviral recipients and 20.7% of controls.
The resistance results in PHPT-4 represent the lowest prevalence of drug resistance yet measured in a study of postpartum treatment, said Gonzague Jourdain of the Research Institute for Development, Thailand, reporting the results of the trial.
He said that one month of treatment with AZT/ddI postpartum could be considered where single-dose nevirapine and AZT are currently being used for prevention of mother-to-child transmission, in order to reduce the risk of nevirapine resistance. However, discussion after the presentation showed greater enthusiasm for using three-drug antiretroviral therapy to prevent mother-to-child transmission in pregnant women wherever feasible, even if the mother does not need it for her own health.
Lallemant M et al. Efficacy and safety of 1-month post-partum zidovudine and didanosine to prevent HIV-1 nevirapine resistance mutations following intrapartum single-dose nevirapine. Sixteenth Conference on Retroviruses and Opportunistic Infections, Montreal, abstract 95bLB, 2009.
Van Dyke R et al. A phase II study of the incidence of nevirapine resistance mutations in HIV-infected Thai women receiving a single intrapartum dose of NVP followed by a postpartum tail of ZDV/ddI or ZDV/ddI/LPV/r: IMPAACT P1032. Sixteenth Conference on Retroviruses and Opportunistic Infections, Montreal, abstract 95aLB, 2009.