TreatmentUpdate57, Vol. 7, No. 3 - March 1995
Sean Hosein

Despite the apparent benefit of AZT in ANRS 024/ACTG 076 (details of which appear above) many questions remain unanswered .

* TIMING OF 'TREATMENT'

It appears that HIV infection of the fetus happens late in the course of pregnancy; before, during and possibly after birth (via breast milk). In making an attempt to protect the fetus, researchers gave women oral and iv AZT, and later their infants received the drug as well. One issue arising from this research is the timing of treatment. Can shorter exposure to AZT late in pregnancy also provide the same or better protection from HIV?

* AZT: DELIVERY AND DOSE

Women in this trial received oral AZT at a dose of 500 mg/day. Can the fetus of pregnant women benefit from a reduced dose of AZT-300 mg/day? The women in the trial also received iv AZT, is this always needed? AZT is supposed to work by interfering with the viral enzyme RT (reverse transcriptase); it works only once a cell has already been infected by HIV. In experiments on health care workers and patients accidentally infected with HIV, treatment with AZT by itself or the related drug ddI and interferon-alpha has not protected people from HIV infection. As well, it is not clear what might happen to the fetus if the mother develops virus that is resistant to AZT.

* OTHER PREGNANT WOMEN

Readers cannot assume that the results from this study mean that fetuses of other pregnant HIV-infected women will 'benefit' from AZT treatment of their mother. The subjects in this trial were a "select group of women", having

- few, if any, symptoms of HIV infection - little past use of AZT - relatively high CD4+ cell counts

Based on results from ANRS 24/ACTG 076, it is not clear what might happen to the fetuses of other pregnant HIV-infected women who have lower CD4+ cell counts, used AZT for long periods of time and/or have serious symptoms.

* TOXIC FOR SOME BUT NOT OTHERS?

Results from the French-American study suggest that toxicity from AZT to infants is minor, but it is not clear what will happen to mothers and infants over the long term. Mothers may be understandably wary given the interim results from the American study ACTG 152. In that trial hundreds of infants-most aged between 3 and 30 months-received AZT or ddI or a combination of both drugs. An independent safety monitoring board recommended that the trial be stopped because babies receiving AZT alone, compared to the other 2 groups, had:

- stopped growing - more life-threatening infections - brain damage - higher rates of death

Given that 75% to 85% of pregnant HIV-infected women give birth to healthy, non-HIV-infected babies, there are concerns about giving all such women (and their fetuses) AZT. Perhaps research using less toxic drugs such as nevirapine might be useful.

* HOW DOES AZT WORK?

Doctors associated with this study do not know why AZT treatment apparently reduced the chance of HIV infection of the fetus. Experiments on baby monkeys infected with SIV suggests that AZT may delay the appearance of AIDS. Researchers think that the anti-viral effects of AZT may be the source of its benefit--but this has not been formally proven. Indeed, researchers do not have a precise and clear understanding of exactly why most babies born to HIV-infected mothers do not have HIV infection.

REFERENCES:

1. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-fetal transmission of Human Immunodeficiency Virus type 1 with Zidovudine treatment. New England Journal of Medicine 1994;331(18):1173-1180.

2. Rogers MF and Jaffe HW. Reducing the risk of maternal-infant transmission of HIV: a door is opened. [Editorial] New England Journal of Medicine 1994;331(18):1222-1223.

3. Palmer DL, Njelle BL, Wiley CA, et al. HIV-1 infection despite immediate combination antiviral therapy after infusion of contaminated white blood cells. American Journal of Medicine 1994;97:289-295.

4. Glick ME. Interim results lead to discontinuation of AZT-only study arm. Press release. February, 1995.

5. Bayer R. Ethical challenges posed by Zidovudine treatment to reduce vertical transmission of HIV. New England Journal of Medicine 1994;331(18):1223-1225.

6. Van Rompay KKA, Otsyula MG, Marthas ML, et al. Immediate Zidovudine treatment protects Simian Immunodeficiency Virus-infected new born macaques against rapid onset of AIDS. Antimicrobial Agents and Chemotherapy 1995;39(1):125-131.

7. Dabis F, Mandelbrot L, Msellati P and van de Perre P. Zidovudine to decrease mother-to-child transmission of HIV- 1: is it a good thing for developing countries? AIDS 1995;9(2):204-206.

8. Michie CA and Hyer W. When does HIV cross the placenta? Lancet 1995; 345(8948): 517-518.

9. Kesson AM, Fear WR, Williams L, et al. HIV infection of placental macrophages: their potential role in vertical transmission. Journal of Leukocyte Biology 1994;56:241-246.

10. Bryson YJ, Pangs, Wei LS, et al. Clearance of HIV infection in a perinatally infected infant. New England Journal of Medicine 1995;332(13):833-838.

11. Schwartz DH, Sharma UK, Perlman EJ and Blakemore K. Adherence of Human Immunodeficiency Virus lymphocytes to fetal placental cells: a model of maternal->fetal transmission. Proceedings of the National Academy of Sciences USA 1995; 92:978-982

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