Unequal Care Sustains Vertical Transmission Rate
The 6th Conference on Retroviruses and Opportunistic Infections reported considerable progress in eliminating mother-to-infant HIV transmission in this country, while the struggle to reduce such transmission in the developing world is only beginning. A major report at the conference concerned the PETRA Study, a multinational effort to assess the potency of regimens considerably shorter than the U.S. standard. That standard is based on the ACTG 076 trial protocol, which mandates the usage of AZT starting between the 14th and 34th weeks of pregnancy and continuing intravenously during pregnancy and in the newborns for six weeks after delivery. The treated cohort in 076 experienced an 8.3% rate of mother-to-child (vertical) transmission, two-thirds lower than the 25.5% transmission rate in the placebo cohort.
Vertical Transmission Plummets in the U.S.
Great strides have indisputably been made in reducing the risk of vertical transmission in the U.S. over the past several years. These were reviewed by Dr. Lynne Mofenson of the National Institutes of Health in her talk at the 6th Retrovirus Conference (symposium lecture S6). Rates of screening pregnant women for HIV and the likelihood of HIV-positive mothers following the 076 protocol have been steadily increasing in the U.S., with the expected concomitant drop in transmission rates: In 1996 the rate of transmission had fallen to 2.8 per 100,000 births, down from 8.2 per 100,000 only three years earlier. In fact, only 298 infants in the U.S. acquired HIV in 1997. Predictably, this decline has been inequitably distributed, with many women still lacking the basic prenatal care necessary for optimal maternal and fetal health. Dr. Mofenson presented data suggesting that approximately 15% of HIV-positive women do not have adequate prenatal health care, and that women who inject drugs are particularly likely not to have prenatal care.
Very positive data also came out of two small studies of women taking highly active antiretroviral therapy (HAART) during pregnancy. There were no cases of HIV transmission among the 89 and 48 infants thus far delivered and tested in the studies, and rates of illness and birth defects in the infants were similar to other babies in their communities (posters 686 and 687, respectively). The data indicate that women who wish to take protease inhibitors for their own health can remain on their therapy with little to no risk to their infants. These two studies are small, though, and their duration is too limited to catch problems that might crop up only after the infants had further developed.
Poster 687 included follow-up data on 19 women in Los Angeles taking nevirapine, the only nonnucleoside reverse transcriptase inhibitor (NNRTI) studied, which suggested that its use, like that of the protease inhibitors, was rarely marked by severe complications. Thus women who wish to avoid using protease inhibitors when pregnant have a viable NNRTI option. This contrasts with the newest NNRTI, efavirenz, which has been found to cause severe birth defects in monkeys and should never be used during pregnancy.
Another study (poster 685) examined data from 497 women enrolled in PACTG 185 and found that HIV-positive women (including those on AZT) were no more likely to have preterm birth or low birth-weight babies than other women. Traditional factors such as multiple gestation, prior preterm birth, pre-eclampsia (a dangerous maternal syndrome consisting of high blood pressure, swelling and/or kidney malfunction), alcohol use, and cigarette use are equally valid predictors of adverse pregnancy outcome among both HIV-positive and HIV-negative women.
On the other hand, it is clear that Cesarean sections do lead to serious complications in significant numbers of women with HIV. Two large multicenter American studies (posters 683 and 684, which analyzed data from 1,119 and 497 women, respectively) found similar results: Nonelective Cesarean sections (that is, C-sections performed after the onset of labor or the rupture of membranes) were associated with complications (such as inflammation of the uterine membranes, urinary tract infections, and wound infections) in over 40% of the women in each study. Those women who had elective C-sections had fewer complications, but still significantly more than in women who had had either natural or assisted vaginal births.
These observations, taken together with the smaller studies mentioned above that found that none of the women on highly active antiretroviral therapy transmitted HIV to their infants, greatly confuse the C-section debate. The New England Journal of Medicine, in a rare prepublication release, recently announced the findings of a meta-analysis of numerous earlier studies indicating that C-sections halve the rates of vertical transmission. Potential harm to the mother must not be overlooked in the zeal to prevent perinatal transmission.
Short Course Therapy in Africa
As presented by Dr. Joseph Saba of UNAIDS (symposium lecture S7), the good news from PETRA is that much shorter courses of therapy can provide substantial benefits. This randomized, placebo-controlled trial measured the efficacy of a regimen of AZT/3TC (at the standard twice-daily 300 mg and 150 mg doses, respectively) given before birth (starting at 36 weeks of pregnancy), during labor and/or after birth. Treatment was provided for one week postpartum to both the child and the mother, to ensure a supply of antiretrovirals in the mother's milk. The study, which was conducted in South Africa, Tanzania and Uganda, was quite large, with 1,357 infants evaluated.
The use of AZT/3TC beginning at week 36 and continued until one week after birth proved the most effective regimen, reducing the risk of transmission by 50% (from 17.2% in the placebo arm to 8.6% of treated women), an impressive drop, especially considering that 69% of the women breast-fed. Breast-feeding results in significant further HIV transmission after the one-week postpartum treatment period. (It is also worth noting that the rate of transmission in the placebo group is somewhat lower than is usually found. The researchers are themselves somewhat puzzled by this and are looking for explanations.) The group that took AZT/3TC during birth and for a week afterward saw transmission drop by 37% (down to 10.6%), but taking the combination only during birth seemingly had no effect (transmission rate of 17.6%).
These results do not quite measure up to those seen in ACTG 076, in which the mothers did not breast-feed. The African data do provide significant hope for women who are first tested only during labor, as well as for women in those countries where the price of the longer regimen may be prohibitive.
A bit less hopeful was the data from the French ANRS 049a study (slide presentation 268), which evaluated the reduction in transmission among predominantly breast-feeding African women who took AZT monotherapy beginning between the 36th to 38th weeks of pregnancy and through the first 8 days after birth. This short regimen reduced transmission by 38% (from 27.5% in the placebo arm to 18% of those treated), suggesting both that giving infants AZT is beneficial and that breast-feeding continues to be a risk factor for transmission.
The results of these studies raise the question of whether women in poor countries with high HIV rates should be encouraged to breast-feed. In her symposium talk on breast-feeding, Dr. Andrea Ruff of Johns Hopkins discussed the need to recognize the complexities surrounding making recommendations about breast-feeding, including the need to analyze local sociocultural norms and values, and the availability and safety of replacement formula.
Basic Information Still Lacking
Other presentations at the 6th Retrovirus Conference served mostly to reveal the extent of our continuing ignorance. The most glaring examples are the lack of understanding of the exact means by which mother-to-child transmission occurs and the mechanism by which antiretrovirals act to inhibit this. It is clear that infants are being infected with drug-resistant HIV, but a French study of 30 infants who were infected despite AZT therapy reported that AZT resistance was found in only 20% of infected infants (poster 238). A study from the New York City Department of Health found only that premature birth (less than 37 weeks of pregnancy) and lower maternal CD4 count were significant predictors of treatment failure among 38 infants infected despite AZT therapy (poster 239). And a study of 74 women on short-term ritonavir monotherapy succeeded in positively affecting CD4 count and viral load far more than the 076 regimen without the slightest reduction in vertical transmission rates (poster 241).
Finally, several problems have appeared concerning 3TC: A French study of 200 pregnancies found that starting AZT/3TC at the 32nd week, and continuing in the neonate for six weeks, reduced vertical transmission to just 2.6%, versus 6.5% for AZT alone (slide presentation 267). But two of the infants developed a rare fatal neurological disorder. Also, the HIV in 39% of the mothers acquired 3TC resistance. The implications of 3TC for infant health and mothers' future treatment options are two more issues that require further investigation.
This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.