Chasela CS, Hudgens MG, Jamieson DJ, et al. Maternal or infant antiretroviral drugs to reduce HIV-1 transmission. N Engl J Med. 2010 Jun 17;362(24):2271-81.
Antiretroviral therapy (ART) used during pregnancy, labor, and delivery results in a large and statistically significant decrease in the risk of HIV infection in infants born to HIV-infected mothers.(1, 2) Ongoing risk of transmission occurs during breastfeeding, but this risk is reduced by extended postpartum maternal or infant use of ART.(3, 4) Studies have not directly compared the prophylactic effectiveness of these two treatment options.
To measure the efficacy of a maternal, triple-drug ART regimen of infant nevirapine (NVP) prophylaxis for 28 weeks during breastfeeding to reduce postpartum HIV transmission
Antenatal clinics in Lilongwe, Malawi
Randomized controlled trial
Pregnant women and adolescent girls aged ≥14 years who are at ≤30 weeks' gestation, who have CD4 cell counts of ≥250 cells/mm3, hemoglobin levels of ≥7 g/dL, alkaline aminotransferase levels ≤2.5 times normal, and who have no other pregnancy-related complications, prior ART use, or serious infection. Infants must have weighed at least 2000 grams at birth, and mother and infant could not have any condition in which ART was contraindicated.
The rate of HIV transmission at 28 weeks among all randomized infants and infants not found to be infected at two weeks; HIV-free survival by 28 weeks among infants without infection at two weeks
The treatment group consisted of maternal treatment with a single tablet of zidovudine-lamivudine twice daily
plus NVP once daily for two weeks and twice daily until 28 weeks post-delivery. After 39 women were
randomized to this regimen, the NVP was replaced with nelfinavir twice daily and given to the next 146 women.
The remaining women randomized to the maternal treatment group were then given lopinavir and ritonavir. This
change was in response to the Food and Drug Administration black-box warning for women receiving this
regimen with CD4 counts >250 cells/mm3. The infant treatment group received NVP doses that increased with
age. Adherence was measured by maternal self-report at five follow-up visits.
Mothers and infants were followed at 1, 2, 4, 6, 8, 12, 18, 21, 24, 28, 32, 36, 42, and 48 weeks after birth. A
complete blood count and chemical analyses, including levels of alanine aminotransferase, were obtained from
mothers and infants at delivery and at 2, 6, 12, 18, 24, 28, 36, and 48 weeks. Specimens were collected from
mothers at screening and at weeks 4 and 8 of pregnancy. Infants were tested for HIV-1 infection at birth and at
2, 12, 28, and 48 weeks by polymerase chain reaction. Positive specimens were confirmed by retesting at the
next visit. If an infant was lost to follow-up or died before a confirmatory test was obtained, a second specimen
from the same day was tested at a reference laboratory. Specimens with discrepant test results at the local
laboratory were retested at the reference laboratory. Final infection status was determined by review of test
results by investigators who were unaware of study-group assignments.
Women were instructed to breastfeed their infants exclusively then to rapidly wean at 24-28 weeks. Treatment
was continued until the infants were weaned or at 28 weeks if weaning had not yet occurred.
The probability of each endpoint was estimated using the Kaplan-Meier method. Hazard ratios were calculated
using Cox proportional hazards models with adjustments for potential confounders. Infants were censored when
they reached the endpoint, or at last HIV-negative test or 28 weeks, whichever came first.
At the fourth interim analysis by the data safety monitoring board, enrollment into the control group was stopped.
At this time, 668 of the planned 806 mother-infant pairs had been assigned to the control group. Women who
were assigned to the control group were censored at the time they were switched to an intervention group. P
values <0.025 were considered statistically significant. A more stringent P value was used to account for multiple
There were 3572 HIV-infected pregnant women who underwent screening, and 3109 (87%) of these were eligible for the study. Ninety percent of the eligible women delivered live infants and 2382 of these women met the secondary enrollment criteria. Thirteen mothers declined participation, leaving 2369 mother-infant pairs for randomization.
The demographic characteristics and laboratory results were similar among assignment groups. Twelve percent of mother-infant pairs in each group were lost to follow-up.
Risk of infection was similar at two weeks, but among infants who were HIV-negative at two weeks, the risk of infection was higher in the control group (reference group) (5.7%, 95% confidence interval [CI]: 4.1-8.0) than in the maternal treatment group (2.9%, 95% CI: 1.9-4.4) or the infant treatment group (1.7%, 95% CI: 1.0-2.9). Among all infants, the difference in the estimates of HIV transmission between the control and infant treatment groups was significant (P=0.01) by six weeks and between control and maternal treatment groups was close to significant (P=0.04) at 12 weeks and significant (P=0.01) at 18 weeks.
There were 37 infant deaths between randomization and week 28, of which eight were among HIV-infected infants. There were 23 deaths between two and 28 weeks; nine occurred in the maternal treatment group and seven in the control group. Among infants who were HIV-1-negative at two weeks, the estimated risk of infection or death by 28 weeks was 7.0% in the control group (reference group), 4.1% in the maternal-regimen group, and 2.6% in the infant-regimen group. Among all randomized infants, the proportion that had died or was HIV-1- positive by 28 weeks was 12.3% (95% CI: 10.0-15.2) in the control group (reference group), 9.6% (95% CI: 7.7- 11.8) in the maternal regimen group, and 7.1% (95% CI: 5.5-9.1) in the infant-regimen group.
After adjustment for prognostic factors, the risk of HIV infection or death by 28 weeks was significantly lower among infants in the treatment group (relative hazard [RH] 0.34, 95% CI: 0.20-0.59) and mothers in the treatment group (RH 0.56, 95% CI: 0.35-0.90).
Both maternal and infant ART significantly reduces the risk of HIV transmission during breastfeeding with a greater reduction of risk with infant treatment.
The findings from this study support others that have documented reduced postnatal HIV transmission with extended maternal or infant treatment,(5, 5) but this study goes further by demonstrating that infant treatment has a greater protective effect than maternal treatment. However, maternal ART is likely to improve maternal health while also reducing HIV transmission. Women with CD4 counts <350 cells/mm3 should receive treatment for HIV infection, both to reduce their risk of HIV-related morbidity and mortality and to reduce peri- and postnatal transmission. For women with less advanced disease, either maternal or infant treatment should be provided.
- Lallemant M, Jourdain G, Le Coeur S, et al. Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of
HIV-1 in Thailand. N Engl J Med. 2004;351:217-28.
- Achievements in public health: reduction in perinatal transmission of HIV infection- United States, 1985-2005. MMWR Morb Mortal Wkly Rep
- Kilewo C, Karlsson K, Ngarina M, et al. Prevention of mother-to-child transmission of HIV-1 through breastfeeding by treating mothers with triple antiretroviral therapy in Dar es Salaam, Tanzania: the Mitra Plus study. J Acquir Immune Defic Syndr. 2009;52:406-16.
- Peltier CA, Ndayisaba GF, Lepage P, et al. Breastfeeding with maternal antiretroviral therapy or formula feeding to prevent HIV postnatal motherto- child transmission in Rwanda. AIDS. 2009;23:2415-23.
- Bedri A, Gudetta B, Isehak A, et al. Extended-dose nevirapine to 6 weeks of age for infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: an analysis of three randomized controlled trials. Lancet. 2008;372:300-13.