AIDS TREATMENT NEWS Issue #207, September 16, 1994
Rae Trewartha

* This trial (AIDS Clinical Trials Group [ACTG] 076) targeted a very specific group of pregnant HIV-positive women who had relatively high T-helper cell counts (greater than or equal to 200), and who had had less than 6 months previous AZT or other anti-retroviral treatment. Now many other women need to make decisions about taking AZT during their pregnancies, and it is unclear how the trial results relate to their own particular circumstances.

* Is the full study regimen necessary? The women in the trial took AZT starting at between 14 and 34 weeks of gestation and continuing through the pregnancy; then they took AZT intravenously during labor; and, finally, their babies were given AZT for the first six weeks of life. Sometimes the complete protocol is not feasible, due to cost or other concerns; and it is impossible to tell from the study whether a lesser regimen would be effective. This point has particular relevance to studies which suggest that many babies may be infected during the birth process.(6)

* What about the possibility, in the years ahead, of long-term adverse effects to the babies? The babies showed very little evidence of side-effects attributable to AZT, but there is no research available on the long-term effects of administering AZT to children, either pre- or post-natally.(2)

* Is the mother's viral load, or the fact that she may have been on AZT, or other HIV treatments for her own health, for a length of time, a factor in the perinatal transmission rate?

* How does taking AZT as a preventative measure affect its usefulness when either the mother or baby may need to take it as a health measure in the future?

* Will AZT work as well for subsequent pregnancies as it does for the first?

* Is this trial result likely to be used to invoke legislation to mandate testing of all pregnant women?

While health care providers need to be aware of all the issues involved in advising pregnant women about the effects of AZT, there are many questions which are unanswerable with the present, available information.

On August 5, 1994 the U.S. Public Health Service published recommendations for the administration of AZT to pregnant women and their babies. In these recommendations [see note] they are careful to point out that, "the results of this study are directly applicable only to HIV-infected women with characteristics similar to those of the women who entered the study, and the long-term risks of ZDV [AZT] used in this manner are not known."(1) For this group of women the recommendations are that the woman's health-care provider should advocate the full ACTG Protocol 076 regimen. This regimen -- modified as appropriate for the woman's stage of pregnancy -- is also recommended for any HIV-infected woman who is more than 14 weeks pregnant and has not shown previous adverse reactions to AZT, with the provision that health-care providers present all women with the necessary information on the risks and benefits of the therapy. This information should be presented in a manner that will enable the woman to make an informed decision -- free from coercion.

The recommendations conclude by noting that "The information on which these recommendations are based is incomplete, and additional information is needed to optimize use of AZT for this purpose."(1) For instance, the recommendations note that the "Use of AZT during pregnancy could be associated with the development of AZT-resistant virus, which may lessen the drug's therapeutic benefit for the woman when it is needed for her own health," and suggests that because of this concern "considerations for the woman's future health care should include the availability of alternative drugs for treatment of HIV infection."(1) This may, of course, also be a problem for the future health of the babies who are HIV- infected.

The Lancet, in an editorial entitled "Zidovudine for mother, fetus, and child: hope or poison?",(2) points out that there have been no placebo-controlled trials of AZT in children, and says that "the most worrisome aspect" of the trial results is the lack of information about "the possibility of long-term adverse affects on children exposed to zidovudine during fetal life, especially since the vast majority would not have been infected anyway." This may be true in England where the risk of perinatal transmission is approximately 14.4%,(3) however this risk rises to 25% in the U.S.(4) and 45% in parts of Kenya.(3) In the U.S., that 25% transmission rate accounts for 88% of all pediatric AIDS cases -- approximately 1,750 babies are born HIV-infected each year.(5)

Our knowledge regarding the links between the viral load of the mother and the subsequent rate or severity of infection of her infant is confusing and inadequate at this point. A study in Zaire(6) reported that highest risk appeared to be associated with high CD8+ and low CD4+ lymphocyte counts or a positive test for p24 antigen, but that in women with none of these factors inflammation of the placental membrane was the main risk factor; these factors appeared to be neither synergistic nor additive. In women who manifested none of the above risks the rate of perinatal transmission was as low as 7% while it ranged as high as 71% for other women in the study. The researchers noted that high viral load is consistent with late and early stages of HIV infection, so that recently-infected pregnant women, who are likely to be unaware of their HIV status, may be at high risk for transmitting the virus to their babies. It is difficult, however, to reconcile the implications of these findings with current recommendations which do not allow the administration of AZT to pregnant women until the 14th week of pregnancy (unless it is indicated for their own health).(1)

A recent study(7) has suggested that HIV-positive pregnant women who experience complications during delivery have better chances for delivering a healthy baby if they quickly undergo a cesarean section. Results showed that the risk factor for perinatal HIV infection increased when babies experienced complications either during vaginal or cesarean births, but the risk was reduced from 25% for babies born vaginally with no complications, to 19% for babies born by cesarean section with no complications. This result is supported by research on births of twins to HIV-infected mothers, which showed that first-born twins were more likely than second-born to be HIV-infected; a finding which led the researchers to hypothesize that "a substantial proportion of HIV-1 transmission occurs as the first twin encounters the cervix and the birth canal."(8) They, thus, suggested that "measures such as cleansing of the birth canal and cesarean delivery before membrane rupture" should be studied to determine their usefulness in reducing perinatal transmission of HIV. As the birth process is obviously such a high-risk factor in this transmission, it appears that this is another area which requires more study in regard to the use of AZT as a preventative measure.

The July 1994 issue of State AIDS Reports(5) reviews legislation enacted in the area of HIV/AIDS and pregnant women. Many states have requirements that women be offered free and anonymous testing but none have so far made this mandatory. Michigan, however, requires doctors to offer testing to all pregnant women, but this law does create exemptions in cases where women will not give their written consent, or their physician considers testing medically inadvisable. The National Resource Center on Women and AIDS, at the Center for Women Policy Studies, plans to convene a "surveillance think tank" to study this issue.

While there are obvious concerns, and many areas that require further study and research regarding the prevention of perinatal HIV transmission, the good news from ACTG 076 is that it appears to provide a method of prevention which could reduce this transmission rate to 8.3%, which would mean 1100 fewer babies per year born HIV infected in the U.S. As The Lancet editorial points out, this "could have far greater implications for children born to HIV-positive women than any treatment for HIV-infected children themselves in the foreseeable future."(2) Above all, however, it must be reiterated that high-quality prenatal care is the major necessity for healthy babies. Researchers writing in the American Journal of Public Health on maternal-infant HIV transmission comment, "As in many other aspects of maternal- child health, prenatal care is critical. Early identification and monitoring of high-risk pregnancies may be beneficial. Unfortunately, many HIV-infected women still do not receive adequate prenatal care."(7)

[Note: The Recommendations (reference 1. below) are available from The National AIDS Hotline, phone 800/342-2437; Spanish, 800/344-7432.]

References

1. Recommendations of the U.S. Public Health Service Task Force on the use of zidovudine to reduce perinatal transmission of human immunodeficiency virus. Morbidity and Mortality Weekly Report. August 5, 1994; volume 43, number RR-11.

2. Zidovudine for mother, fetus, and child: hope or poison? Lancet. July 23, 1994; volume 344, number 8917, pages 207- 209.

3. Wara D. Pediatric AIDS: Part 2 perinatal transmission and early diagnosis. AIDS Clinical Care. March 1993; volume 5, number 3, page 21.

4. Denison, Rebecca. Update: AZT & pregnant women. WORLD. April 1994; page 4.

5. Bowleg, L. HIV/AIDS testing, counseling or treatment? Tackling thorny issues for pregnant women. State AIDS Reports. July 1994; volume 7, number 5, pages 1-2.

6. St. Louis ME, Munkolenkole K, Brown C, Nelson AM, Manzila T, Batter V, and others. Risk for perinatal HIV-1 transmission according to maternal immunologic, virologic, and placental factors. Journal of the American Medical Association. June 9, 1993; volume 269, number 22, pages 2853- 2859.

7. Kuhn L, Stein ZA, Thomas PA, Singh T, and Tsai W-Y. Maternal-Infant transmission and circumstances of delivery. American Journal of Public Health. July 1994; volume 84, number 7, pages 1110-1115.

8. Goedert JJ, Duliege A-M, Amos CI, Felton S, Biggar, RJ, and The International Registry of HIV-exposed Twins. High risk of HIV-1 infection for first-born twins. Lancet. December 14, 1991; volume 338, number 8781, pages 1471-1475.

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