GMHC Treatment Issues, Vol. 10, No. 4 - April 1996
Dave Gilden

Four studies on mother-to-child (vertical) HIV transmission were presented at the Conference, with three so newly completed that they appeared among the event's "late breakers." These studies looked at whether higher HIV levels in blood plasma correlated with greater mother-to-child transmission. They sought to ascertain whether a threshold viral load existed below which HIV transmission did not occur. A related question was also under examination: whether an AZT-induced reduction in a woman's viral load leads to a reduced risk of her baby contracting HIV before and during birth.

The first report (abstract S25) was presented by Yvonne Bryson, M.D., of the University of California Los Angeles, and has recently been published.1 The UCLA investigators found that women who transmitted HIV to their babies prior to or during birth tended to have higher viral loads at delivery than those that did not (a median of 94,000 copies of HIV RNA per milliliter of plasma for the transmitters versus 4,600 copies/ml for the nontransmitters -- a highly significant difference). No one with a viral load below 25,000 copies/ml transmitted HIV, and a viral load at delivery of greater than 50,000 was the single best predictor of transmission among the many variables analyzed. AZT-treated nontransmitting mothers generally experienced reduced viral loads during pregnancy (an eight-fold, or 0.9 log, median decrease), and their viral loads at delivery had a distribution similar to that of untreated nontransmitters.

The three late breaker presentations were not so sanguine about viral load's predictive power. Richard A. Koup, M.D., reporting for the Pediatric AIDS Foundation's Ariel Project, described the findings that viral load was a poor predictor of HIV vertical transmission in a group of 151 pregnant women (LB2). The transmission rate in this cohort was thirteen percent. (Eighty-three percent of study participants were taking AZT.) There was a trend toward higher viral load in the HIV-transmitting mothers -- transmitting mothers' viral loads averaged 5,200 copies/ml, compared to 2,600 for the nontransmitters -- but there was a large overlap between the two groups and the difference was not quite statistically significant. Vertical transmission occurred even in women with HIV levels so low that their virus was unculturable.

The Woman Infant Transmission Study Group (WITS) also found that there was only a weak association between viral load and vertical transmission (abstract LB3). Transmission was seen at all plasma HIV levels, except under 1,000 copies/ml, and although transmitting mothers had slightly higher viral loads than nontransmitting ones at delivery, this difference was not statistically significant.

Rhoda Sperling, M.D., (abstract LB1) summarized the long-awaited virologic results from ACTG 076, a study of reducing mother-to-child HIV transmission by administering AZT to pregnant women and, starting immediately after birth, to their babies. Use of AZT in this double-blind, placebo-controlled trial reduced the rate of vertical transmission by about 70 percent (see Treatment Issues, March 1994, pages 15-16). In both the study group receiving AZT and that receiving placebo, HIV transmission took place at all detectable viral loads (but not in women with undetectable levels of HIV). The pregnant women receiving AZT saw their viral load drop by a median of only 0.2 log (37 percent), and differences in the magnitude of this reduction did not correlate with any difference in transmission rate. The 076 team concluded that the fall in HIV levels with AZT could not explain the entire decline in mother-to-child transmission of the virus. Dr. Sperling conjectured that the AZT given in 076 to the newborn babies, as a kind of immediate post-exposure prophylaxis for those babies contracting HIV during delivery, played a major role in lowering transmission rates.

One limitation of these last three studies is that the observed viral loads in the women they followed were remarkably low (the means or medians were below 10,000 copies/ml). Any differences in HIV levels were relatively small, as was any effect AZT could have on these levels.

But the measured viral loads may not have been accurate. They could have been reduced by the way blood samples were processed: the three late breaker studies all used heparin as an anticoagulant in the blood samples collected. Dr. Bryson contends that heparin results in an immediate 30 to 38 percent loss in viral load values. (Dr. Bryson's group at UCLA processed their samples mostly with EDTA.) Storage of samples could also be a problem: a delay in separating plasma from whole blood can lead to lower viral loads as can a postponement in freezing the processed samples. (The Ariel Project shipped its samples to New York for overnight processing whereas the 076 and WITS studies batch-processed their samples well after the studies were terminated.)

Finally, researchers are attempting to divide up mother-to-child transmission by stage -- during pregnancy (in utero) or during labor (intrapartum). In utero HIV transmission is considered to have taken place if the infant is PCR- or culture-positive for HIV within 48 hours after birth, according to Dr. Bryson's working definition, for example. Such early transmission seemed to be promoted by high maternal viral load in her study, as it did in the WITS. (Note that a low viral load early in pregnancy is not sufficient to establish low transmission risk since viral load can rise abruptly.)

Intrapartum transmission, a much more common occurrence than in utero, is not necessarily tied to high maternal viral load during delivery. Events during delivery that expose the baby to maternal blood or cervicovaginal secretions might promote transmission. For example, the UCLA group detected a tendency for intrapartum transmission to occur in women whose uterine membranes ruptured well in advance of delivery. This trend did not reach statistical significance, though, and the ACTG 076 investigators did not notice any correlation between vertical transmission and such "obstetrical factors." The WITS researchers are continuing to look at maternal cofactors that promote vertical transmission, and the 076 researchers are now analyzing whether the particular infectivity of a woman's HIV strain influences the risk of transmission during her pregnancy.

1 Dickover RE et al., Journal of the American Medical Association. Feb. 28, 1996; 275(8):599-605.

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