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Thai nevirapine study reports final results
Providing mothers and newborns with a single dose of nevirapine, in addition to AZT treatment, significantly reduces the rates of mother-to-baby transmission of HIV, according to the final results of a study conducted in Thailand and published in the July 15th edition of the New England Journal of Medicine. However, the women who received the single dose of nevirapine were less likely to achieve a viral load below 50 copies/ml when they subsequently started a nevirapine-based HAART regimen, according to a study involving the same population published in the same edition of the NEJM. Nevertheless, no difference was seen in CD4 cell gain or mortality between the women provided with single dose nevirapine during labour and the women who subsequently started HAART.
The findings of these studies were originally presented to the Conference on Retroviruses and Opportunistic Infections (CROI) in early 2004 and were reported on aidsmap.com at the time here.
Since 1999 HIV-positive pregnant women in Thailand have been provided with treatment to prevent mother-to-child transmission of HIV. This involves AZT during the final trimester of pregnancy, an intravenous dose of AZT during labour, and the provision of a dose of AZT to the newborn. Women are also instructed not to breastfeed. Nevertheless, the rate of mother-to-baby transmission of HIV is 6%. Investigators wished to see if adding a single dose of nevirapine for the mother during labour, and the infant shortly after birth, reduced this rate of mother-to-child transmission.
Investigators designed a randomised, double-blind, placebo controlled trial which recruited 1844 HIV-positive pregnant Thai women between 2001 and 2003. In addition to standard AZT therapy, the women were randomised into one of three treatment arms. In the nevirapine-nevirapine arm the mother was provided with a single dose of nevirapine during delivery and the infant with a single dose of the drug between 48 and 72 hours after birth. In the nevirapine-placebo arm the women were provided with a single dose of nevirapine during labour, but the infant received a placebo 48 to 72 hours after birth. In the placebo-placebo arm both the mother and infant were given a placebo.
Infants were considered to be infected with HIV if two separate PCR tests were positive. Data were also collected on the safety of nevirapine use in both the mothers and infants.
Baseline characteristics for the women were broadly similar across all three arms of the study. AZT therapy was started at a median of 28.7 weeks of gestation, with women receiving a median of 9.7 weeks of prophylactic AZT treatment. Median CD4 cell count was 372 cells/mm3, and median viral load was 10,000 copies/ml.
Interim analysis was performed in May 2002, at which point investigators stopped recruitment to the placebo-placebo arm. Transmission rates were 1.1% in the nevirapine-nevirapine arm, 2.1% in the nevirapine-placebo arm, but 6% in the placebo-placebo arm (p < 0.001).
In the final analysis, transmission rates were 1.9% in the nevirapine-nevirapine arm and 2.8% in the nevirapine-placebo arm.
No severe nevirapine rashes were seen in women, and although 9.4% of women had elevated liver function, none had seriously abnormal liver function. One woman experienced an allergic reaction to nevirapine, the only serious adverse reaction attributed to the drug.
Rash caused by nevirapine was observed in 15.9% of infants at day ten, and 7.5% at day 45. No infant had seriously elevated liver enzymes, and no serious adverse events in the babies were attributed to nevirapine use.
“This study demonstrates the high efficacy of adding a single dose of nevirapine in the mother, with or without a dose in the infant, to oral [AZT] prophylaxis for the reduction in perinatal transmission of HIV” comment the investigators. On the basis of these findings the Thai health ministry now recommends that HIV-positive women, on top of AZT treatment, should receive a dose of nevirapine on arrival at hospital to give birth and that infants receive a dose of the drug as soon as possible after birth.
Another study looked at whether providing a single dose of nevirapine had significant consequences for the future antiretroviral therapy of the mothers enrolled in this study.
Of the 1844 women recruited a total of 269 women with a CD4 cell count below 250 cells/mm3 began a HAART regimen including nevirapine after birth. Blood samples were obtained ten days after delivery to look for resistance mutations. Viral load was measured at baseline, and then after three and six months of HAART.
A total of 221 of the women had received a single dose of nevirapine during delivery. The remaining 48 women had not.
After six months of nevirapine-based HAART, 49% of women who had received the the single dose of nevirapine during delivery had a viral load below 50 copies/ml compared to 68% of women who did not (p = 0.03). Mutations conferring resistance to NNRTIs were detected in the blood samples obtained ten days after delivery of 32 women. The most frequent mutations were K103N, G109A and Y181C. A viral load below 50 copies/ml was achieved by 38% of women with these mutations at month six, compare to 52% of women treated with nevirapine at delivery who did not develop these mutations.
A viral load above 35,000 copies/ml at baseline (p < 0.001), and exposure to nevirapine during delivery (p = 0.01) were all associated with virological failure at six months.
CD4 cell count increased by a median of 120 cells/mm3 across the study population, with no significant difference seen between women who received nevirapine during delivery and those who did not.
No serious liver-related side-effects were seen in the study population, 5% of women who had received nevirapine during delivery and 10% who had not develop rash. Two women died, both of whom had taken nevirapine during delivery, but neither death was associated with nevirapine use.
“We found that, among HIV-infected women who began taking a nevirapine-based regimen after delivery, intrapartum exposure to nevirapine was associated with a significant decrease in the rate of virologic suppression at six months,” conclude the investigators. However they add that, “clinical and immunologic outcomes after six months of therapy did not differ significantly between the women who had received intrapartum nevirapine and those who had not received it.”
Reference
Lallemant M et al. Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand. NEJM 351: 217-228, 2004.
Jourdain G et al. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. NEJM 351: 229-240, 2004.
The findings of these studies were originally presented to the Conference on Retroviruses and Opportunistic Infections (CROI) in early 2004 and were reported on aidsmap.com at the time here.
Since 1999 HIV-positive pregnant women in Thailand have been provided with treatment to prevent mother-to-child transmission of HIV. This involves AZT during the final trimester of pregnancy, an intravenous dose of AZT during labour, and the provision of a dose of AZT to the newborn. Women are also instructed not to breastfeed. Nevertheless, the rate of mother-to-baby transmission of HIV is 6%. Investigators wished to see if adding a single dose of nevirapine for the mother during labour, and the infant shortly after birth, reduced this rate of mother-to-child transmission.
Investigators designed a randomised, double-blind, placebo controlled trial which recruited 1844 HIV-positive pregnant Thai women between 2001 and 2003. In addition to standard AZT therapy, the women were randomised into one of three treatment arms. In the nevirapine-nevirapine arm the mother was provided with a single dose of nevirapine during delivery and the infant with a single dose of the drug between 48 and 72 hours after birth. In the nevirapine-placebo arm the women were provided with a single dose of nevirapine during labour, but the infant received a placebo 48 to 72 hours after birth. In the placebo-placebo arm both the mother and infant were given a placebo.
Infants were considered to be infected with HIV if two separate PCR tests were positive. Data were also collected on the safety of nevirapine use in both the mothers and infants.
Baseline characteristics for the women were broadly similar across all three arms of the study. AZT therapy was started at a median of 28.7 weeks of gestation, with women receiving a median of 9.7 weeks of prophylactic AZT treatment. Median CD4 cell count was 372 cells/mm3, and median viral load was 10,000 copies/ml.
Interim analysis was performed in May 2002, at which point investigators stopped recruitment to the placebo-placebo arm. Transmission rates were 1.1% in the nevirapine-nevirapine arm, 2.1% in the nevirapine-placebo arm, but 6% in the placebo-placebo arm (p < 0.001).
In the final analysis, transmission rates were 1.9% in the nevirapine-nevirapine arm and 2.8% in the nevirapine-placebo arm.
No severe nevirapine rashes were seen in women, and although 9.4% of women had elevated liver function, none had seriously abnormal liver function. One woman experienced an allergic reaction to nevirapine, the only serious adverse reaction attributed to the drug.
Rash caused by nevirapine was observed in 15.9% of infants at day ten, and 7.5% at day 45. No infant had seriously elevated liver enzymes, and no serious adverse events in the babies were attributed to nevirapine use.
“This study demonstrates the high efficacy of adding a single dose of nevirapine in the mother, with or without a dose in the infant, to oral [AZT] prophylaxis for the reduction in perinatal transmission of HIV” comment the investigators. On the basis of these findings the Thai health ministry now recommends that HIV-positive women, on top of AZT treatment, should receive a dose of nevirapine on arrival at hospital to give birth and that infants receive a dose of the drug as soon as possible after birth.
Another study looked at whether providing a single dose of nevirapine had significant consequences for the future antiretroviral therapy of the mothers enrolled in this study.
Of the 1844 women recruited a total of 269 women with a CD4 cell count below 250 cells/mm3 began a HAART regimen including nevirapine after birth. Blood samples were obtained ten days after delivery to look for resistance mutations. Viral load was measured at baseline, and then after three and six months of HAART.
A total of 221 of the women had received a single dose of nevirapine during delivery. The remaining 48 women had not.
After six months of nevirapine-based HAART, 49% of women who had received the the single dose of nevirapine during delivery had a viral load below 50 copies/ml compared to 68% of women who did not (p = 0.03). Mutations conferring resistance to NNRTIs were detected in the blood samples obtained ten days after delivery of 32 women. The most frequent mutations were K103N, G109A and Y181C. A viral load below 50 copies/ml was achieved by 38% of women with these mutations at month six, compare to 52% of women treated with nevirapine at delivery who did not develop these mutations.
A viral load above 35,000 copies/ml at baseline (p < 0.001), and exposure to nevirapine during delivery (p = 0.01) were all associated with virological failure at six months.
CD4 cell count increased by a median of 120 cells/mm3 across the study population, with no significant difference seen between women who received nevirapine during delivery and those who did not.
No serious liver-related side-effects were seen in the study population, 5% of women who had received nevirapine during delivery and 10% who had not develop rash. Two women died, both of whom had taken nevirapine during delivery, but neither death was associated with nevirapine use.
“We found that, among HIV-infected women who began taking a nevirapine-based regimen after delivery, intrapartum exposure to nevirapine was associated with a significant decrease in the rate of virologic suppression at six months,” conclude the investigators. However they add that, “clinical and immunologic outcomes after six months of therapy did not differ significantly between the women who had received intrapartum nevirapine and those who had not received it.”
Reference
Lallemant M et al. Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand. NEJM 351: 217-228, 2004.
Jourdain G et al. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. NEJM 351: 229-240, 2004.
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