At the 13^th International AIDS Conference in Durban, updates on mother-to-child-transmission (MTCT) strategies told a tale of two worlds. In one world, the race to prevent transmission has been almost won; in the other, the most effective regimens still leave women and newborns at loggerheads with a virus that uses every misstep to its advantage. Where there is access to HAART, more and more pregnant women are starting or remaining on combination therapy with good results. The most pressing concerns are the unknown long-term effects to children exposed to these drugs in utero and the risks of developing drug-resistant virus. In the developing world, studies of simple drug regimens have reported dramatic effects on rates of transmission at the time of delivery. They hardly eliminate all transmission, though, and there is troubling evidence that their benefits may be eroded when women breast-feed their infants.

The Promise of Short Regimens

James McIntyre, of Chris Hani Baragwanath Hospital in Johannesburg, presented the much-anticipated results of the 617-infant South African Intrapartum Nevirapine Trial (SAINT). This trial compared giving AZT and 3TC to the mother during labor and to the baby for the following seven days to a very short course of nevirapine – one dose to the mother during labor plus one dose to both newborn and mother one to two days after birth. In line with last year's Ugandan study, HIVNET 012, SAINT found that simple nevirapine regimens resulted in reduced MTCT rates of 12% to 14%, as measured six to 12 weeks after birth.

One-year data from HIVNET 012 showed that seven out of 30 (23%) women who received a single dose of nevirapine acquired resistance mutations, including K103N, the point mutation that renders HIV essentially unsusceptible to all approved non-nucleoside reverse transcriptase inhibitors (NNRTIs). These mutations become undetectable 13 to 18 months after delivery. Both the short duration of dosing and the relative fitness of wild-type HIV compared to K103N-mutated strains probably contribute to the virtual elimination of the NNRTI-resistant HIV. Minor undetectable populations of NNRTI-resistant HIV may still be present, but the prevailing opinion at the conference was that the very short nevirapine courses would still be safe for use in repeated pregnancies.

It remains to be seen how nevirapine will affect the treatment options of women in developing countries should antiretroviral drugs become available through the standard health-care system or clinical trials. During ongoing treatment with nevirapine or other non-nukes, even a small subpopulation of resistant virus could re-emerge and pose problems over time. Although potent anti-HIV combination regimens remain a distant, hypothetical prospect for most women in the developing world, widespread nevirapine MTCT programs are possible, and their effects deserve close monitoring.

One option, where the resources are available, is to offer both AZT and nevirapine, reserving nevirapine for women diagnosed late in pregnancy. Another, suggested by University of Alabama at Birmingham researcher Sten Vermund, is to reserve NNRTIs for pregnancy and to move forward with adult therapy solely in the form of protease inhibitors and nucleoside analogs (also known as NRTIs). "If nevirapine is used in the wider community for HIV care, then community resistance could be a sizable problem," states Vermund. "This is why I believe that policy makers at UNAIDS and in ministries of health should consider NRTI/PI combinations as the standard for care where affordable and reserve NNRTIs for MTCT." Ruling out an entire class for adult treatment may not be an option, considering cost, toxicities, underlying resistance profiles, and the fact that the NNRTI efavirenz (Sustiva), which offers once-daily dosing, is an attractive option for simplified regimens.

News on NRTI-based regimens came from BMS 094, a study presented by McIntyre's colleague, Glenda Gray. BMS 094 looked at the efficacy of four different regimens for prevention of MTCT, including a previously untested dual NRTI combination: d4T, ddI, ddI/d4T, and AZT. All four regimens were given from weeks 34 to 36 of pregnancy through week 6 of the infants' life. At six weeks postpartum, the rates of transmission in the four arms were 4.2%, 1.9%, 2.0% and 6.3%, respectively. All four regimens cost between $60 and $100 per mother-child pair. The study has not yet yielded data on resistance patterns or long-term rates of transmission.

There was an average -1.2 log (94%) reduction in mother's viral load during the 094 trial's relatively extended course of therapy. One-third of the women studied had less than 400 copies/mL at the time of delivery. The reduction in viral load may have led to the superior results in this trial. BMS 094 and similar studies could be useful in designing innovative treatment strategies. One widely discussed option proposed using short-course antiretroviral therapy to reduce viral load, followed by a therapeutic vaccine to stimulate immune-based viral control.

Breast-feeding Controversy

Data on the efficacy of antiretroviral therapy given during pregnancy and at the time of delivery tells only part of the story about transmission risk. One Kenyan study by Ruth Nduati estimated that 44% of all HIV infection in breast-fed children is acquired through mother's milk. The clearest example of this came from the southern African PETRA study, which looked at rates of transmission in 1802 infants. The trial, also headed up by Gray and McIntyre, measured the efficacy of AZT/3TC when administered to mother and baby in three different schedules: from week 36 of pregnancy through the first week after delivery; during labor and the week afterward; or during labor only. A control arm received only placebo. At six weeks, rates of transmission varied from 9.2% in women who started therapy at week 36 to 19.2% in the placebo arm. By 18 months, this spread had narrowed considerably. Although a trend favoring treatment persisted, there was no significant difference in rates of transmission among the four arms, including the placebo one. Some 70% of infants in the study were breast-fed, and researchers concluded that this factor alone accounted for "the loss of efficacy in all regimens."

The simplest way to reduce the risk of transmission through breast milk is through formula feeding. This strategy eliminates exposure to HIV, but it also means that infants do not receive the nutritional and immunological benefits of breast milk. Kenyan researcher Ruth Nduati and her colleagues presented data on rates of mortality in 401 breast- and bottle-fed infants born to HIV-infected women. At 12 months and again at two years, there was no significant difference in rates of mortality between these infants. At three months, infants randomized to the formula-feeding arm had higher rates of diarrhea and dehydration. Although the added diarrhea did not translate into higher mortality rates, it did underscore the need for access to adequate supplies of formula and clean water, as well as continued monitoring and support of mother and child.

Nduati also presented the first study to examine the impact of breast-feeding on maternal, rather than infant, mortality, reminding the audience, "Replacement feeding is an important option for women as well as children." Women who breast-fed lost more weight than those who formula fed and were three times more likely to die. Controlling for other factors, the Kenyan team concluded that 86% of the deaths was attributable to breast-feeding. Their ongoing research will attempt to confirm these results and identify underlying metabolic and nutritional causes.

South African researcher Anna Coutsoudis highlighted the complicated issues involved in feeding choices. In follow-up data to her 1999 report in The Lancet, Coutsoudis again found that infants who received a mixture of bottle- and breast-feeding were at a higher risk of mortality than those who were exclusively breast- or bottle-fed. Infants who were exclusively breast-fed for up to six months had no more risk of contracting HIV than those who were never breast-fed.

This unexpected, controversial result came from a retrospective analysis of a 536-infant study of the effect of vitamin A supplements in reducing MTCT (no protective benefit was observed). Since the trial was not a breast-feeding study, its results may be flawed by confounding factors that remain unaccounted for. One major criticism of Coutsoudis' analysis is that the mothers who exclusively breast-fed may have been healthier in some way. Most importantly, their viral loads may have been lower. Coutsoudis maintains that viral loads were similar regardless of feeding method among the subset of mothers in whom she checked. Still, mastitis and other breast conditions may well have been greater in the mixed breast-feeders than the exclusive ones. Such inflammation can provide a route for HIV to enter breast milk in greater quantities.

Coutsoudis argued that the apparent protection conferred by exclusive breast-feeding could be explained by reduced digestive tract inflammation in the infants. They were not exposed to the allergens and contaminants present in reconstituted formula and other liquids given the mixed-fed babies. Extra inflammation possibly present in these babies' digestive systems could make them more susceptible to the HIV even though their total intake of breast milk was less.

HAART Safety

Current U.S. guidelines recommend that pregnant women start or remain on whatever anti-HIV regimen is best for their own health. Not surprisingly, this translates into increasing numbers of women giving birth on highly active antiretroviral therapy (HAART) combinations. The overall experience has been good. Data from the U.S. observational study known as the Women and Infant Transmission Study (WITS) showed that rate of transmission was inversely correlated with the number of drugs a woman was taking. Rates of transmission for women on AZT monotherapy were roughly 7.7%. The figure dropped to 1.1% for women on HAART. The researchers concluded that HAART provided "an independent protective effect" regardless of viral load levels at delivery. In a Puerto Rican cohort presented by Carmen Zorrilla, there was no transmission – and no significant side effects – in women taking HAART or AZT/3TC during pregnancy.

One note of alarm came from Patrizio Lorenzi's Swiss Mother+Child HIV Cohort Study. Two years ago, Lorenzi and his colleagues set off alarms with initial reports of unusually high rates of adverse events in pregnant women and newborns on HAART. In the Durban update, Lorenzi's most striking finding was an increased risk of premature delivery in women taking HAART as compared to those on AZT or no HAART at all. Twenty-eight percent of women on combination therapy delivered prematurely, as opposed to 17% on AZT and 14% in the group that received no drugs at all. Lorenzi's first study prompted a National Institutes of Health review of women who gave birth on HAART. The report concluded that HIV itself may increase women's risk of delivering prematurely and that protease inhibitors did not increase that risk.

Findings presented at Durban again contradicted Lorenzi's observations. In Zorrilla's cohort, for example, there was an average prematurity rate of 20 percent across all the arms of the trial. However, the Swiss research is a useful reminder that careful ongoing study of HAART is needed to determine the extent of short- and long-term risks to mother and child.

Additional HAART further encourages the evolution of drug-resistant HIV. Several studies at the International AIDS Conference looked at the relationship between resistance-conferring mutations and rates of transmission. A U.S. study of that correlation found that 12 of 24 women who transmitted HIV to their babies had NRTI or NNRTI resistant virus. Eight out of 23 (35%) infected infants also had resistant virus, and all except one infant had HIV resistance patterns resembling that found in their mothers. Not surprisingly, there was a threefold increase in risk of transmission linked to AZT resistance. Additional risk factors for transmission included low CD4 counts, high viral load and having started on AZT prior to pregnancy.

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