CDC/Thai Vertical Transmission Results Silence Critics and Pave Way for Prevention of Millions of Infections Worldwide
But who will bear the cost?
Four years ago, results of ACTG 076 showed that HIV-infected pregnant women treated with a complex regimen of AZT (100 mg five times daily during the third trimester of pregnancy, intravenous AZT (1 mg/kg/hour) during delivery, and oral treatment of the newborn infant (2 mg/kg every 6 hours) for the first 6 weeks of life) could cut the rate of maternal-fetal HIV transmission by two-thirds (from 22.6% to 7.6%). This regimen, however, is prohibitively expensive -- about $800 per patient -- and largely unrealistic in many developing-world settings where pregnant women often do not enter the healthcare system until late in pregnancy and where delivery rooms may lack the capacity to deliver intravenous medication. Now, results from a controversial AZT-vs.-placebo study conducted in Thailand have shown that a much less onerous (and less expensive) preventive protocol can produce nearly the same results. Spencer Cox reports.
Around the globe, more than 1,600 infants are born infected with HIV every day. And without effective preventive therapy, 5-10 million children will become infected with HIV through perinatal transmission before the year 2000 -- 90% of them in the so-called developing world. But it is precisely in these impoverished countries hardest hit by HIV that the potential of the "076 regimen," as it has come to be called, has been least realized.
In an attempt to address this reality in the wake of the 076 results, officials from the World Health Organization (WHO), the United Nations, the National Institutes of Health (NIH) and the Centers for Disease Control (CDC) gathered in Geneva in June 1994 to design perinatal transmission trials suitable for the developing world. In the absence of any standard of care, they settled on comparing different courses of AZT to placebo. Almost from the outset, there was controversy. Since that time, 18 randomized, controlled trials of interventions to prevent perinatal HIV transmission have begun which are to evaluate a variety of interventions: antiretroviral drugs such as AZT (usually in regimens less expensive or complex than the ACTG 076 regimen), vitamin A and its derivatives, intrapartum vaginal washing, and HIV immune globulin. These trials involve a total of more than 17,000 women from the following countries: Ivory Coast, Uganda, Tanzania, South Africa, Malawi, Thailand, Ethiopia, Burkina Faso, Zimbabwe, Kenya and the Dominican Republic.
Last month, the first of these studies (co-sponsored by the Ministry of Public Health of Thailand and the U.S. Centers for Disease Control and Prevention) to produce results was completed in Thailand where a short course of orally administered AZT given during the last 3-4 weeks of pregnancy was reported to result in a 50% reduction in the rate of mother-to-infant HIV transmission (from 18.6% to 9.2%). The MOPHT/CDC study marks a watershed in the ability to begin controlling HIV transmission in regions where more costly, lengthy antiretroviral courses are simply not feasible. The regimen used in the Thai study costs an estimated $50-$80 per patient -- or less than one tenth the cost of the 076 regimen. These results should lead to the immediate provision of AZT to all HIV-infected pregnant women who wish to use it to interrupt vertical transmission anywhere in the world.
While a 50% reduction in infection rates is impressive, many AIDS researchers and activists believe that new studies suggest the potential for still more effective means of preventing vertical HIV transmission. On-going studies looking at combinations of relatively inexpensive drugs, such as nevirapine and lamivudine (3TC), for example, are likely to show even greater potency. The use of AZT in pregnancy also carries with it at least the theoretical risk of rare long-term side effects in the infant. Once the drug becomes routinely prescribed for millions and millions of HIV-infected pregnant women, little-reported side effects could emerge which have not been seen among the comparatively small number of women-infant pairs treated in industrialized nations. While high-doses of AZT administered to pregnant mice have been shown to cause tumors in the liver, lung and genital tract of their offspring, AZT doses which are believed to more closely replicate the 076 regimen have not resulted in an increased cancer risk.
A number of vertical transmission studies in the developing world, including the MOPHT/CDC Thai study, have been criticized by New England Journal of Medicine editor Marsha Angell and by the consumer advocacy group Public Citizen. "The Declaration of Helsinki requires control groups to receive the 'best' current treatment, not the local one," Angell wrote in a September 18th editorial. "The shift in wording between 'best' and 'local' may be slight," she continued, "but the implications are profound." Public Citizen's Peter Lurie and Sidney Wolfe protested to Health and Human Services secretary Donna Shalala and argued that it would be just as scientifically valid -- albeit more expensive -- to compare a short course of AZT to the longer 076 regimen. Alongside Angell's New England Journal editorial they cautioned that, "Residents of impoverished, post-colonial countries... must be protected from potential exploitation in research. Otherwise, the abominable state of health care in these countries can be used to justify studies that could never pass ethical muster in the sponsoring country."
Critics charged that the use of a placebo control was ethically comparable to the Tuskeegee syphilis experiment, in which therapy for syphilis was withheld from a group of impoverished black men so that scientists could observe the natural history of the disease. Supporters of the placebo control, however, argued that use of a placebo was the fastest, most efficient way to obtain unambiguous information that would be of greatest value in the Third World -- and to identify regimens that were likely to be less effective than the 076 regimen. Dr. Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania (who argued against the placebo design), says the Tuskegee analogy is inappropriate if only because the Alabama men were falsely told that they were getting treatment. The New England Journal controversy led to the resignation of AIDS experts Dr. David Ho and Dr. Catherine Wilfert from the Journal's editorial board.
But without the placebo control we might have never known that short-course AZT is effective -- and whether the treatment is doing more harm than good. Over 500,000 infants are born with HIV each year. And now -- just over one year after the trial began -- we know that short-course AZT has the potential to prevent HIV infection in at least half of these cases -- saving millions of lives in the next few years. Placebos are needed no longer -- in this or any of the other on-going mother-infant transmission studies. In fact, in the second of the two CDC/UNAIDS collaborative perinatal HIV transmission studies (being conducted in Abidjan, Ivory Coast), all pregnant women previously receiving placebo have been offered the short-course AZT regimen.
Given these stunning study results, Glaxo-Wellcome should begin to make AZT available to poor countries for a substantially reduced price -- or give the drug away for free, as Merck did with its drug for African river-blindness. While the new, short-course regimen costs only one-tenth what the 076 regimen costs, this is still approximately eight times what most developing nations spend annually on health care per patient. It is clear that only a cooperative venture between local governments, the World Health Organization, private industry and advocates for people with HIV/AIDS will allow us to gain maximum benefit from these important findings.
|Comparing the Two Regimens|
|Prepartum||Oral AZT 100 mg/q5h final 12 weeks of pregnancy||Oral AZT 250 mg/BID last 3-4 weeks of pregnancy|
|Intrapartum||I.V. AZT 1 mg/kg/hr until delivery||No treatment|
|Postpartum||AZT syrup to newborn 2 mg/kg q6h for 6 weeks||No treatment|
|Risk of Transmission||7.6%||9.2%|