Extended Antiretroviral Prophylaxis Lowers Risk of Mother-to-child HIV Transmission during Breast-feeding, but Early Weaning Is Detrimental

By Liz Highleyman

Antiretroviral therapy during pregnancy and delivery dramatically lowers the risk of mother-to-child HIV transmission, but infants still may become infected via breast-feeding, which is estimated to account for more than 200,000 of the 500,000 new cases of HIV infection in children each year.

While HIV positive women in industrialized countries are advised to use formula, the World Health Organization recommends breast-feeding in areas where replacement feeding is not "acceptable, feasible, affordable, sustainable and safe, for example due to lack of clean water.

Now, researchers have shown that longer prophylaxis with nevirapine (Viramune) can reduce the rate of mother-to-child transmission, but abrupt early weaning at 6 months does not offer any benefit for mothers or infants, according to 2 studies in the July 4, 2008, online edition of the New England Journal of Medicine (to appear in print July 10, 2008).

Viramune Tablet

Extended Nevirapine

In the first study, Taha Taha and colleagues enrolled women with HIV-1 infection and their breast-feeding infants in Blantyre, Malawi. At birth, the babies were randomly assigned to 1 of 3 regimens:

• A standard control regimen of single-dose nevirapine during delivery plus 1 week of zidovudine (AZT; Retrovir) for the infant after birth;

• The same regimen plus daily extended prophylaxis with nevirapine for the infant until the age of 14 weeks;

• The same regimen plus an extended dual regimen of nevirapine plus zidovudine daily for 14 weeks.

The frequency of breast-feeding was similar across the groups. The researchers used Kaplan-Meier analysis to assess the risk of HIV infection among infants who were uninfected (HIV negative by polymerase chain reaction testing) at birth.

Results:

• Among 3016 infants in the study, those in the control group had consistently higher rates of HIV infection from the age of 6 weeks through 18 months than those who received extended prophylaxis.

• At 9 months, the estimated rate of HIV infection was 10.6% in the control group, compared with 5.2% in the extended nevirapine group (P < 0.001) and 6.4% in the extended dual prophylaxis group (P = 0.002).

• There were no significant differences in HIV infection rates between the 2 extended prophylaxis regimens.

• However, rates of HIV transmission more than doubled in both extended prophylaxis groups between 9 and 24 months (during which about 15%-20% of mothers continued to breast-feed).

• Infants receiving the extended dual prophylaxis regimen had a significant increase in the number of possible drug-related adverse events (primarily neutropenia).

• By 12-15 months, the advantage with regard to HIV-free survival was no longer apparent.

• Overall mortality rates did not differ in the extended prophylaxis and control groups.

Based on these findings, the study authors concluded that, "Extended prophylaxis with nevirapine or with nevirapine and zidovudine for the first 14 weeks of life significantly reduced postnatal HIV-1 infection in 9-month-old infants."

Bloomberg School of Public Health and School of Medicine, Johns Hopkins University, Baltimore, MD; Rutgers University, Piscataway, NJ; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD; Centers for Disease Control and Prevention, Atlanta, GA; University of Malawi College of Medicine and Johns Hopkins University-College of Medicine Research Project, Blantyre, Malawi.

Early Weaning

Women in resource-limited settings are sometimes advised to stop breast-feeding completely after a few months in order to reduce the risk of HIV transmission, but the benefits of this practice are not clear, since breast-feeding lowers the risk of infant health problems such as diarrhea.

In the second report, investigators with the Zambia Exclusive Breastfeeding Study described results of a randomized trial to evaluate whether abrupt weaning at 4 months has a net benefit with regard to HIV-free survival of children.

The researchers enrolled 958 HIV positive women and their infants in Lusaka, Zambia. All the women planned to breast-feed exclusively through 4 months. Of these, 481 were randomly assigned to a counseling program that encouraged abrupt weaning at 4 months and provided free formula, while 477 were assigned to a program that encouraged continued breast-feeding for as long as the women chose.

In practice, there was considerable overlap between the 2 groups. In the abrupt weaning group, 69% of the mothers stopped breast-feeding at 5 months or earlier, and almost all reported completion of weaning in less than 2 days. About one-third did not complete early weaning, however, and one-quarter were still breast-feeding at 12 months. In the control group, the median duration of breast-feeding was 16 months, though about one-third stopped before 12 months.

The primary outcome was either HIV infection or death of the child by 24 months.

Results:

The HIV transmission rate between 4 and 24 months was 6.2% in the abrupt weaning group compared with 8.8% in the control group (not a statistically significant difference).

In the overall cohort, there was no significant difference between the groups in the rate of HIV-free survival of the children.

68.4% of babies in the abrupt weaning group and 64.0% in the prolonged breast-feeding group survived to 24 months without HIV infection (P = 0.13).

Among infants who were still being breast-fed and were not HIV-infected at 4 months, there was no significant difference between the groups in HIV-free survival at 24 months (83.9% vs 80.7%, respectively; P = 0.27).

However, babies who were HIV-infected by 4 months had a higher mortality rate by 24 months in the abrupt weaning group compared with the extended breast-feeding group (73.6% vs 54.8%, respectively; P = 0.007).

In conclusion, the study authors wrote, "Early, abrupt cessation of breast-feeding by HIV-infected women in a low-resource setting, such as Lusaka, Zambia, does not improve the rate of HIV-free survival among children born to HIV-infected mothers and is harmful to HIV-infected infants.

The researchers suggested that breast infection (mastitis) that can occur when breast-feeding is abruptly reduced or halted may increase the risk of HIV transmission during the weaning process.

Gertrude H. Sergievsky Center and the Departments of Epidemiology and Biostatistics, Mailman School of Public Health, Columbia University, New York, NY; Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA; Lusaka District Health Management Team, University Teaching Hospital, University of Zambia, Lusaka, Zambia; U.S. Centers for Disease Control and Prevention Global AIDS Program, Lusaka, Zambia; Center for International Health and Development, Boston University School of Public Health, Boston, MA.

Editorial

In an accompanying editorial, Glenda Gray and Haroon Saloojee from the University of Witwatersrand in Johannesburg, South Africa, noted that these studies leave much to learn about optimal recommendations regarding infant feeding in resource-limited settings.

"Continued breast-feeding beyond the period of antiretroviral prophylaxis clearly affected the durability of the extended regimens [in the first study], making it difficult to recommend widespread implementation of the study strategies in populations that favor prolonged breast-feeding," they wrote. "It stands to reason that in settings where breast-feeding must be the practice for socioeconomic reasons, antiretroviral prophylaxis for infants for the duration of breast-feeding may be the logical approach."

Ultimately, they continued, "caregivers and mothers in low-resource settings will continue to select options that best suit their own cultural, economic, and psychological needs, and science will need to adapt and design strategies to meet their needs, rather than the other way around."

6/17/08

References

NI Kumwenda, DR Hoover, LM Mofenson, and others. Extended Antiretroviral Prophylaxis to Reduce Breast-Milk HIV-1 Transmission. New England Journal of Medicine. June 4, 2008 [Epub ahead of print].

L Kuhn, GM Aldrovandi, M Sinkala, and others (Zambia Exclusive Breastfeeding Study). Effects of Early, Abrupt Weaning for HIV-free Survival of Children in Zambia. New England Journal of Medicine. June 4, 2008 [Epub ahead of print].

GE Gray and H Saloojee. Breast-Feeding, Antiretroviral Prophylaxis, and HIV. New England Journal of Medicine. June 4, 2008 [Epub ahead of print].
National Institutes of Health. Findings Offer Insights into Role of Breastfeeding in Preventing Infant Death and HIV Infection in Resource Poor Countries. NIH News. June 4, 2008.