July 15, 2004
J. McIntyre reported for the Treatment Options Preservation Study team on the addition of short-course zidovudine/lamivudine (AZT/3TC, Combivir) to nevirapine for 4 or 7 days, to determine whether post-partum maternal HIV-1 resistance can be avoided in treatment-naive pregnant women. This was a prospective, open-label, randomized, 3-arm study comparing single-dose nevirapine, single-dose nevirapine plus 4 days of zidovudine/lamivudine, and single-dose nevirapine plus 7 days of zidovudine/lamivudine for the prevention of MTCT. The study design was based on Uganda's HIV NET 012 data.
The primary endpoint was the percentage of mothers with new non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations identified by genotypic sequencing of specimens collected within 6 weeks of delivery. Secondary endpoints included the percentage of infants with HIV-1 infection at 6 weeks, HIV-infected infants with NNRTI resistance mutations in their virus, late resistance mutations in mothers and infants at 6 weeks, and safety measurements for mothers and infants through 6 weeks.
The study is being conducted in South Africa, with 300 mother-infant pairs, each assigned to 1 of 3 treatment groups. Single-dose nevirapine was given to the mother as 200 mg during active labor; infants were given a 2-mg/kg dose 24-48 hours after delivery. In the 4- and 7-day zidovudine/lamivudine arms, mothers were also given twice-daily zidovudine/lamivudine (zidovudine 300 mg/lamivudine 150 mg) during labor, and infants were given zidovudine 12 mg/lamivudine 6 mg twice daily within 6 hours of birth. Mothers were followed up at 2 and 6 weeks with safety assessments, plasma HIV viral loads and population sequencing for recognized NNRTI resistance genotypes. Follow-up was continued if resistance was found. Infant HIV-1 transmission was determined by HIV DNA and RNA at birth, 2 weeks and 6 weeks, with safety assessments and appropriate genotyping and follow-up of NNRTI-resistant virus if found.
Results were reported on the first 61 mothers with 6-week follow-up and population sequencing (n = 18 for single-dose nevirapine only; n = 20 for 4-day nevirapine plus zidovudine/lamivudine; and n = 23 for 7-day nevirapine plus zidovudine/lamivudine). Mothers had a mean age of 26 years, with 1 prior live birth. The median CD4+ cell count at entry was 318 cells/mm3, and the median viral load was 32,600 copies/mL. All isolates were clade C. Population sequencing was performed on specimens with viral loads of at least 1,500 copies/mL, with no baseline drug resistance found in any of the samples. Studies of minority drug-resistant populations of virus using differential polymerase chain reaction and confirmed by clonal sequencing are in progress.
Specimens taken at 2 and 6 weeks post-delivery respectively showed NNRTI resistance in 8/14 (57.1%) and 8/15 (53.3%) mothers in the single-dose nevirapine only arm; 0/6 (0%) and 1/20 (5%) in the 4-day nevirapine plus zidovudine/lamivudine arm; and 0/7 (0%) and 3/22 (13.6%) in the 7-day nevirapine plus zidovudine/lamivudine arm. There was no statistically significant difference in the development of NNRTI resistance mutations between the zidovudine/lamivudine arms, but there was a significant difference between the single-dose nevirapine only and combined zidovudine/lamivudine arms.
The proportion of mothers who developed resistance any time after baseline was 9/18 (50%) with single-dose nevirapine only, compared with 4/43 (9.3%) in both nevirapine plus zidovudine/lamivudine arms (P = .001). The most commonly observed NNRTI resistance mutations were K103N (8), Y181C (7), Y188C (4), A106V (3), M106V (3) and K103E (1). Twenty-one mutations occurred in the single-dose nevirapine only arm, compared to only 5 in the combined nevirapine plus zidovudine/lamivudine arms. No nucleoside reverse transcriptase inhibitor (NRTI) mutations, including 184, were detected. Infant viral resistance data was not reported.
Among 68 infants eligible for evaluation (not all belonging to the 61 mothers studied), intrauterine transmission was observed in 4, with 1 additional infant experiencing peri/post-partum transmission in the single-dose nevirapine only arm. Serious adverse events were reviewed for all 156 mother-infant pairs in the study, with no treatment-related serious adverse event concerns identified. Ten mothers had serious adverse effects, none treatment related. Twenty-two infants had serious adverse effects (12 on single-dose nevirapine only and 10 in the nevirapine plus zidovudine/lamivudine arms), with only 1 case of possible drug-related jaundice in an infant on nevirapine plus zidovudine/lamivudine and 2 infant deaths, neither of which was drug- or HIV-related.
Given the significant 5-fold decrease in resistance afforded by the addition of zidovudine/lamivudine, the single-dose nevirapine only arm was closed on June 4, 2004. Both nevirapine plus zidovudine/lamivudine arms of the study continue with adjusted sample sizes.
While single-dose nevirapine is effective in decreasing MTCT of HIV, single-dose nevirapine plus zidovudine/lamivudine may be a feasible and cost-effective way to significantly decrease the subsequent development of drug-resistant maternal HIV-1. The optimal duration of zidovudine/lamivudine is yet to be determined.
Intriguing data was presented in 2 related studies at this conference. Cressey et al1 reported that a single 200-mg dose of nevirapine during labor can produce maternal drug levels selecting for resistance for 3 to 4 weeks afterward. Morris et al2 showed that the K103N and Y181C mutations persist in 35% of women and 65% of infants at 6 months post-delivery, and are associated with higher HIV viral loads and lower CD4+ cell counts. No data was presented on the M184V mutation, which may be an important determinant of the length of zidovudine/lamivudine dosing. More data is yet to come from this study, and the political and scientific controversies regarding the use of nevirapine for the prevention of MTCT are sure to continue.
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