www.hivandhepatitis.com

In high-income countries, HIV positive pregnant women are advised to use a complete ART regimen regardless of CD4 cell count and to not breast-feed their infants. In resource-limited countries, pregnant women with higher CD4 cell counts still often receive the ACTG 076 regimen of zidovudine (AZT; Retrovir) during pregnancy and labor, and for the infant for 6 months after birth. A single dose of nevirapine (Viramune) may also be used, though this can promote drug resistance in the mother.

Due to competing risks related to unclean water and inadequate nutrition, the World Health Organization recommends that HIV positive mothers should breast-feed exclusively for 6 months if replacement feeding is not "acceptable, feasible, affordable, sustainable, and safe." But the rate of HIV transmission during breast-feeding reaches about 9% after 18 months.

Charles Chasela and fellow investigators with the BAN Study Group evaluated whether antiretroviral treatment during breast-feeding -- either for the mother or for the baby -- can help reduce the likelihood of mother-to-child HIV transmission.

The analysis included 2369 HIV positive mothers in Malawi with a CD4 count of at least 250 cells/mm³. Women with anemia or pre-existing liver impairment, and those who had previously used antiretroviral drugs during pregnancy, were excluded. All women received oral single-dose nevirapine during labor followed by zidovudine/lamivudine (Combivir) for both mothers from the onset or labor and babies from birth, continuing for 7 days.

Mother-infant pairs were randomly allocated into 3 groups after the first week. In the first group, mothers were treated for 28 weeks with zidovudine/lamivudine plus nevirapine, which was replaced with nelfinavir (Viracept) and then lopinavir/ritonavir (Kaletra) for women recruited later (after studies showed nevirapine could cause hypersensitivity reactions in women with CD4 counts > 250 cells/mm³); infants received no therapy.

In the second group, infants were treated with nevirapine monotherapy for 28 weeks (increasing from 10 mg daily for the first 2 weeks to 30 mg daily starting at week 19); mothers received no treatment. In the control group, neither mothers nor infants received antiretroviral drugs during breast-feeding but received nutritional supplements (enrollment in this arm was halted early).

Mothers were counseled to breast-feed exclusively for 6 months, then wean the baby rapidly between 24 and 28 weeks, since studies have shown that mixed feeding of breast milk and alternative foods increases HIV transmission risk.

The primary outcome was the number of infants who became infected with HIV after 2 months of age, indicating that transmission occurred during breast-feeding rather than during gestation or delivery.

Results

• Overall, 5.0% of infants were found to be HIV infected at 2 weeks.
• Between 2 and 28 weeks, the risk of infection was higher in the control group (5.7%) than in either the maternal treatment group (2.9%; P = 0.009) or the infant treatment group (1.7%; P < 0.001).
• In an analysis that included all randomized infants regardless of infection status at 2 weeks, the risk of HIV infection at 28 weeks was 10.9%, 8.2%, and 6.0%, respectively.
• Similarly, the combined risk of infant HIV infection or death between 2 and 28 weeks was higher in the control group (7.0%) than in the maternal treatment group (4.1%; P = 0.02) or the infant treatment group (2.6%; P < 0.001).
• Among all infants regardless of HIV status at 2 weeks, the risk of infection or death was 12.3%, 9.6%, and 7.1%, respectively.
• Mothers receiving combination therapy during breast-feeding were more likely to develop neutropenia (6.2%) than women in the infant treatment group (2.6%) or the control group (2.3%).
• 1.9% of infants treated with nevirapine for 28 weeks developed hypersensitivity reactions.

Based on these findings, the investigators concluded, "The use of either a maternal antiretroviral regimen or infant nevirapine for 28 weeks was effective in reducing HIV-1 transmission during breast-feeding."

"The protective efficacy against HIV-1 transmission from 2 to 28 weeks was 74% for infant nevirapine and 53% for the maternal antiretroviral regimen," they elaborated in their discussion. "Infants also had significantly increased HIV-1-negative survival with both interventions, with a trend toward increased benefit when the drug regimen was administered directly to the infant."

"Health care providers and mothers can ultimately choose the option that best suits their cultural, economic, and individual needs, since there is now evidence for 2 effective options to prevent the transmission of HIV-1 to infants from their mothers during breast-feeding in resource-limited countries," they added.

Another study reported in the same issue also demonstrated the benefits of treating mothers during breast-feeding, though here treatment was started during pregnancy and did not include an extended infant treatment arm.

The Mma Bana study included 560 HIV positive pregnant women in Botswana who had a CD4 cell count above 200 cells/mm³. Starting at 26 to 34 weeks of pregnancy and continuing through infant weaning at 6 months, they were randomly assigned to receive either zidovudine/lamivudine/abacavir (Trizivir combination pill) or else lopinavir/ritonavir plus zidovudine/lamivudine; in addition, 170 women with a CD4 cell count < 200 cells/mm³ started zidovudine/lamivudine plus nevirapine. All infants received single-dose nevirapine after delivery and zidovudine for 4 weeks.

More than 95% of women in all study arms achieved undetectable viral load. The overall rate of mother-to-child HIV transmission was very low at 1.1% -- in fact, it was among the lowest ever seen in randomized studies of ART during pregnancy and breast-feeding in resource-limited settings -- and did not differ significantly between the Trizivir (2.1%) and lopinavir/ritonavir (0.4%) arms. While 6 transmissions occurred during pregnancy, 2 cases occurred during breast-feeding in the Trizivir arm.

In an accompanying editorial, Lynne Mofenson from the Pediatric, Adolescent and Maternal AIDS Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development summarized the clinical implications of the 2 studies.

"To maximally reduce transmission, antiretroviral regimens must start during pregnancy," she wrote. "In the BAN study, which did not include an antepartum regimen, in utero transmission was 5.0% as compared with 0.9% in the Mma Bana Study."

"In the BAN control group, the risk of postnatal infection was highest between 2 and 12 weeks of age," she continued. "During this early high-risk period, the infant regimen reduced postnatal transmission by 86.1% (from 3.6% in the control group to 0.5%), while the maternal regimen reduced transmission by 52.8% (from 3.6% in the control group to 1.7%)...This early difference in efficacy probably reflected the time required for the triple-drug regimen to suppress the maternal viral load. Therefore, in women presenting late or during labor, the use of nevirapine in infants may be particularly critical to prevent early postnatal infection."

University of North Carolina Project, Lilongwe, Malawi; University of North Carolina, Chapel Hill, CD; Principia, Chapel Hill, NC; Centers for Disease Control and Prevention, Atlanta, GA.

6/18/10

References

CS Chasela, MG Hudgens, DJ Jamieson, and others (BAN Study Group).
Maternal or Infant Antiretroviral Drugs to Reduce HIV-1 Transmission. New England Journal of Medicine 362(24): 2271-2281 (Abstract). June 17, 2010.

RL Shapiro, MD Hughes, A Ogwu, and others. Antiretroviral Regimens in Pregnancy and Breast-Feeding in Botswana. New England Journal of Medicine 362(24): 2282-2294 (Abstract). June 17, 2010.

LM Mofenson. Protecting the Next Generation -- Eliminating Perinatal HIV-1 Infection (Editorial). New England Journal of Medicine 362(24): 2316-2318. June 17, 2010.