Test Shows AIDS Drug Can Protect Both Babies and Mothers

It is a decision no mother should have to make: choosing to protect her health or that of her baby. Yet that deadly predicament has appeared to arise for pregnant women infected with HIV in developing countries just as a major global push begins to make basic lifesaving antiretroviral therapy and prophylaxis available to more people.

Photo by Graham Ramsay

HIV-infected mothers in developing countries can take a single-dose AIDS drug during labor to block HIV transmission to their infants without jeopardizing their own treatment outcomes—as long as they can wait at least six months before beginning the standard therapy, report Max Essex (left), Shahin Lockman, and their colleagues.

The heartbreaking dilemma centers around a drug called nevirapine. A single dose to the mother and to the newborn has been shown to protect nearly half the babies from acquiring HIV infection during birth. But it takes only one point mutation for the sloppily replicating virus to become resistant to nevirapine and other drugs of its type. The same dose that can prevent HIV infection in the infant can make the virus resistant and the drugs ineffective for treating full-blown AIDS in the mother.

A new study may relieve women of this life-or-death quandary. If given six months or more after childbirth, the international standard triple-drug combination, which includes nevirapine, works as well in women who received a single dose during labor as it does in those who received a placebo, report Shahin Lockman and her colleagues at HSPH in the Jan. 11 New England Journal of Medicine.

“You don’t have to pit mother against baby,” said Lynne Mofenson, branch chief of pediatric, adolescent, and maternal AIDS at the National Institute of Child Health and Human Development, which funded the study. “You can both prevent the transmission and take care of maternal health.”

The analysis narrows the crucial window of clinical drug resistance in mothers who take the single-dose prophylactic during labor. In the study, antiretroviral drugs failed to block the virus from replicating in nearly half of the women who started AIDS treatment within six months compared to helping most of the women who received a placebo in childbirth.

“The results translate into very clear policy for how to treat AIDS in new mothers who receive nevirapine to protect their infants,” said senior author Max Essex, the Lasker professor of immunology and infectious diseases at HSPH and chair of the School’s AIDS Initiative. “If you can wait six months, do so. If not, treat only with combinations of drugs that do not contain nevirapine or nevirapine-related drugs.”
Even better, Mofenson said, identify pregnant women who need combination therapy and start treatment right away, as per international guidelines. This way, preventive single-dose nevirapine goes only to women who do not require therapy until much later, when viral resistance fades and the nevirapine-containing multidrug regimen is more likely to work.

Policy Building
Most of the recommendations from the study are reflected in the latest World Health Organization (WHO) guidelines to prevent mother-to-child transmission of HIV updated in August, said William Rodriguez, chief medical officer for the Clinton Foundation HIV/AIDS Initiative. Nevirapine remains the cornerstone of WHO policy for the prevention of mother-to-child transmission.

The study marks the beginning of a shift in thinking about HIV/AIDS care in developing countries from quick emergency fixes to longer term implications, Rodriguez said. Since Lockman first reported preliminary results in late 2005, others have reported similar findings in smaller observational studies in Thailand, Zimbabwe, and Zambia. Lockman’s study is the first of the bunch published in a peer-reviewed journal. “It is a landmark study—powerful and informative,” said Rodriguez, HMS assistant professor of medicine at Brigham and Women’s Hospital and Massachusetts General Hospital.

In a more tentative finding, the paper heightens concerns about nevirapine resistance in infants. Therapy failed in more drug-exposed infants than in those who had received a placebo. These first data on infant resistance need to be confirmed in larger studies before making new health policy, said Lockman, HMS assistant professor of medicine at HSPH and Brigham and Women’s Hospital, but individual practitioners may be more comfortable treating exposed infants with more costly protease inhibitors if possible.

The paper is the third in a triad of major findings to emerge from a cohort of 1,200 HIV-positive women and their infants based in Gaborone, Botswana, and three nearby villages. The original randomized trial, named Mashi after the Setswana term for milk, evaluated drugs for preventing HIV transmission before and during birth and compared formula feeding to breast feeding plus extended prophylactic infant zidovudine (AZT) for reducing infections and deaths after birth.

When mothers and infants also received AZT, the first paper in the series reported the protective effect of nevirapine worked just as well when given only to the newborn infant at birth and not to the mother in labor, an alternative strategy that can safeguard health in the baby without risking nevirapine resistance in the mother. Surprisingly, 75 percent of the transmissions occurred in utero before the nevirapine was administered to mother or child. This finding supported a decision by Botswana health leaders to provide antiretroviral drugs earlier in pregnancy, at week 28 instead of week 34. The study was led by Roger Shapiro, HMS assistant professor of medicine at Beth Israel Deaconess Medical Center, and published in the June 12, 2006, AIDS.

The second article found a higher death rate among formula-fed babies, even though they had fewer HIV infections at seven months than breast-fed infants. The relatively clean water in Botswana suggests that the formula strategy could inadvertently cause even more deaths in areas where access to clean water is more problematic. The paper was led by Ibou Thior, who until recently was the site director of the Botswana–Harvard Partnership in Gaborone, and was published in the Aug. 16, 2006, Journal of the American Medical Association.

Botswana has one of the highest HIV infection rates in the world, with about one third of its adults infected. Most of the infections are due to the most common HIV-1 subtype in southern Africa, clade C. Globally, HIV disproportionately affects women. Three quarters of young Africans with HIV are women aged 15 to 24. Last year, an estimated 530,000 infants became newly infected with HIV, mostly in developing countries.

Even as the researchers urge more effective prevention and treatment strategies in Botswana, where more than two thirds of infected pregnant women receive intervention, they face the reality that a similar proportion of women and infants in Africa receive nothing for HIV/AIDS.

“It’s almost impossible to grasp the scale of these questions that affect the lives of millions of women and men and infants worldwide,” Lockman said. “It’s the biggest pandemic in the history of the world.”

Adapting to Better Care
Botswana leaders were ahead of other African countries in rolling out prevention and treatment programs. They began with a short course of maternal and infant AZT and provided infant formula to prevent mother-to-child transmission.

All women and infants in the Mashi study received at least AZT, which has been shown to halve the rate of mother-to-child transmission. At the start, half of the mothers and infants also received the promising addition of a single dose of nevirapine, suggested to be nearly as powerful by itself by more recent studies in developing countries and hypothesized to provide significant additional protection when added to short-course AZT.

The study started before any treatment was available in Botswana, but things quickly changed, prompting several protocol modifications. All Mashi infants also began receiving nevirapine after a Thailand-based HSPH team led by Marc Lallemant reported that AZT and nevirapine were better than AZT alone at preventing mother-to-child transmission. And as soon as Botswana became the first African country to launch a free national antiretroviral therapy program in one locale, the study team added the same treatment for study participants in all four locales. Thinking ahead, Lockman and her colleagues prospectively designed a new study question into the protocol change as an observational study on a randomized cohort.

“You’re always walking an ethical tightrope to make sure you’re answering a question that is relevant and providing the best standard of care,” said Lockman. “You absolutely have to strive to do the right thing. Every effort should be made to provide effective combination treatment for HIV-infected women who need it for their own health, whenever they need it, including during pregnancy.”

—Carol Cruzan Morton

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