American Foundation for AIDS Research, October 2003
Kristen Kresge

Each year over 800,000 children are infected with HIV. The source of infection: an HIV-positive parent. In South Africa alone, 100,000 children a year are born to HIV-infected mothers. Nine years after the prevention of mother-to-child transmission (MTCT) of HIV gained research prominence, an alarming number of new infections still occur.

Transmission can occur at three points: during pregnancy, birth or breast-feeding. The risk for infection ranges from 13% to 60%, depending on the population studied. Previous clinical studies, including ANRS 1201 in Africa, found that a combination of AZT and nevirapine reduced transmission rates during birth to as low as 5%. MTCT trials have made major strides in lowering risk through birth. But researchers like François Dabis—who led ANRS 1201—believe that this rate could decline further.

Current MTCT prevention concentrates mostly on post-partum transmission through breast-feeding. The 2nd IAS Conference on HIV Pathogenesis and Treatment in Paris ushered in further advances in this area and was a prime focus of the meeting.

Breast-feeding accounts for 44% of overall HIV transmission, according to Dr. Ruth Nduati, of the University of Nairobi in Kenya. The likelihood of transmitting virus through breast milk directly correlates with the mother's disease status and viral load: the higher the viral load in the bloodstream, the more virus found in breast milk. Studies have found that in HIV-infected women, 80% of breast milk samples test positive for the virus.

In richer countries, HIV-infected mothers will feed their babies formula to lower or eliminate risk of transmission. But this is not always practical in the developing world. Even in the urban centers of Uganda, where women can afford formula and have access to clean water, many still choose to breast-feed. This is due to the stigma associated with not breast-feeding, according to Dr. Pius Okong, a gynecologist from St. Francis Hospital in Kampala, Uganda. "If a mother doesn't breast-feed, it's a sign of HIV infection," said Okong. Even if formula is an option, "not everybody has the courage to use it," he added.

There may now be a safer approach for women who breast-feed, based on results of the SIMBA study (abstract LB7)—Stopping Infection from Mother-to-child via Breast-feeding in Africa. Clinicians gave mothers AZT and ddI, and their babies either 3TC or nevirapine, from birth until one month after breast-feeding stopped; the women breast-fed the babies for six months. Treating the babies at the same time that they received HIV-infected breast milk reduced the transmission rate to just 1%. (The study found no difference between the nevirapine and 3TC arms in the 397 children studied.) These results were strikingly lower than transmission rates in previous MTCT trials, which hovered around 15%. "If you are going to breast-feed, it's also possible to protect the baby," said Okong.

This prevention strategy requires a recommendation by the World Health Organization before it is widely practiced. But Joep Lange, current president of the IAS and lead author on the study, advises implementing the strategy immediately. "It's helpful in settings where breast-feeding is the norm," said Lange. "I recommend we get our act together and treat people who need medicine."

A major advantage to the SIMBA study's strategy was that it spared the mother from taking nevirapine, once regarded as the gold standard for preventing MTCT. Though the single non-nucleoside is by far the most convenient, and perhaps affordable, it strictly limits women's treatment options.

This is because nevirapine resistance develops quickly in the mother. In study PHPT-2, also presented at IAS, 19% of Thai women who received a single nevirapine dose during labor had resistance mutations associated with the drug (abstract 62). These included K103N, G190A and Y181C, which also confer resistance to the other non-nucleoside efavirenz. Clinicians have yet to determine how long such resistance persists, how it limits the mother's therapy options or impacts preventing transmission of HIV from the mother to her future children.

Despite the advantage of sparing nevirapine use, the SIMBA study had a few weaknesses. At delivery, the women had very mild HIV disease, with an average CD4 count of 428 and viral load of 400 copies/mL. Their mild disease status resulted from their receipt of drug therapy beginning 36 weeks into their pregnancy. Without knowing their viral loads at the time therapy was initiated, it remains unclear how effective this strategy would be in women with more established HIV infection.

Another shortcoming is the limited time that the women breast-fed—an average of three to four months—thanks to intense counseling by trial coordinators who encouraged early weaning. Whether or not this early weaning is practical or culturally acceptable outside of clinical studies is another issue.

According to Lange, the cost should not be a stumbling block to implementation. Babies received an equivalent to two bottles of medicine. "The actual price is virtually nothing. It's extremely cheap and it's extremely simple," he said.

The exact price tag for this strategy may rest with GlaxoSmithKline and Bristol-Myers Squibb. It is hoped that low-cost, generic versions of their drugs might be made available. Nevirapine (Viramune) has been provided free since July 2000 by its manufacturer, Boehringer Ingelheim, in an effort to support MTCT programs in developing countries. But in fact, few have actually taken advantage of Boehringer's offer. MTCT researchers speculate this is partly due to lack of infrastructure and getting the word out to health care workers. "It's a lack of community mobilization around MTCT in these areas," said Dabis, of the University of Bourdeaux. "We need to move in the same direction at a faster pace."

While current drug combinations are being studied, other options, such as formula feeding, are also being explored. A study from South Africa presented by Dr. David Coetzee of the University of Cape Town found that when formula was provided free to 113 women in the Western Cape, 95% chose not to breast-feed at all (abstract 220). He attributed the study's success to focus groups that provided support for the women. But the practicality of this study is limited by the cost of formula and the incomes of the families involved. In that area, 71% of the women had fresh drinking water in their homes. This is uncommon elsewhere, and is another barrier to formula feeding.

The ultimate answer is for all women in developing countries to have continued access to anti-HIV drugs long after delivery, a missing component of most MTCT trial designs. In addition to drastically lowering transmission rates, it increases their chances of surviving long enough to care for their offspring. "Even better would be to treat the mothers," said Lange. "Why not take the risk down to zero?"

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