Q1. What CDC studies of AZT use in pregnancy are underway in other countries?
In cooperation with host country scientists, CDC and host country collaborators are currently carrying out studies in two countries (Thailand and Cote d'Ivoire [Ivory Coast]) to examine whether or not a "short course" of oral AZT (also called zidovudine or ZDV) given to women late in pregnancy is effective for preventing perinatal (mother-to-child) transmission of HIV. Several studies with the same goal of evaluating "short course" AZT and other antiretroviral medications in pregnancy, supported by the United Nations Joint Programme on AIDS (UNAIDS) and other leading public health institutions, are either underway or planned in a number of other countries.
Q2. Why are these studies being done outside the United States?
The National Institutes of Health (NIH) sponsored an AIDS clinical trial in the United States, ACTG-076, that was concluded in early 1994 after it demonstrated that the risk of perinatal transmission of HIV could be reduced by as much as two-thirds (25% to 8%) by giving HIV-positive pregnant women AZT throughout their pregnancy (orally for 16 to 24 weeks) and childbirth (intravenously) and by giving it to their newborns for six weeks after birth. This regimen has become "standard of care" in the United States; and, as a direct result, there has been a dramatic decrease in HIV infections and reported AIDS cases among children in this country.
However, the 076 regimen is currently not used, and is probably not affordable, in the developing world where annual national health budgets are often less than $10 per person. The cost of the drugs alone for the 076 regimen are at least eighty times that amount. The "short course" AZT regimen now being investigated involves giving oral AZT only in the last four weeks of pregnancy and during labor. This regimen is estimated to cost roughly $50. If this trial demonstrates effectiveness in reducing perinatal HIV transmission, it is clear that this new regimen would be a far more feasible option for women in developing world. Throughout most of the developing world where millions of women are infected with HIV, pediatric AIDS is a very serious and growing problem. Perinatal HIV transmission is the number one cause of pediatric AIDS. Infection rates among women in the general population of many countries are far higher than in the United States. In some African countries, more than 1/3 of women of childbearing age are HIV-infected. In Cote d'Ivoire, approximately 12-14% of women in the general population are infected with HIV. In Thailand, the rate of infection in the general population is somewhat lower but varies by location in the country. In the absence of cost effective therapy, we can expect about 25% of children born to HIV infected mothers to be infected themselves.
The CDC-sponsored studies are being carried out in CDC-supported field stations, representing long-term collaborations between CDC and the host country health ministry. These collaborations have, for a number of years, focused on public health issues of importance to both the host country government and to the United States.
Q3. Can the research detect any side effects of taking AZT during pregnancy?
Yes, in the current studies as in the earlier studies, an extensive search for side effects is being carried out. In the previous clinical trial (076), the only side effect detected for the mother was a reduction in the red blood cell count of treated pregnant women, which disappeared after the end of pregnancy without any specific treatment. This effect was thought to be related to the total time the women were taking AZT. Because the women in the current "short course" studies are only receiving four weeks of AZT rather than the 6-24 weeks in the earlier study (076), any effect on red blood cell count should be minimal. Short-term side effects in the infants born to mothers receiving AZT in the 076 study were also mild, and were limited to reversible anemia. The risk of AZT for women who are already anemic is unknown.
There is a theoretical risk of rare long-term side effects; therefore, researchers will continue to follow both the women and their children to ensure that if there are any long-term side effects, they are quickly detected. These concerns about possible adverse effects is a strong argument for the inclusion of an untreated control group in the studies. Recently, two laboratory studies in the United States examined the question of whether AZT may cause cancer in the offspring of pregnant mice exposed to various doses of the drug. The first study was designed to determine if AZT, when given in extremely high doses to pregnant mice, could result in cancer of their offspring. Researchers found, not surprisingly, that when AZT is given in these high doses to pregnant mice, it can cause tumors in the liver, lung, and genital tract of their infants. The second study examined the long-term outcomes in the offspring of mice when given doses of AZT that replicate the level of in the blood of pregnant women following the 076 treatment regimen. This study used much lower doses of AZT, and found no increase in tumors. The relationship between the doses of AZT used in these studies and those used in clinical practice in humans is not well understood. Mice metabolize AZT very differently than humans. Since very few drugs have been studied in mice, researchers are uncertain if the outcomes of either of these mice studies have any relevance to human beings.
Q4. Did CDC address these mice studies at all in the current trials?
Yes. This information became available and was reviewed by an expert NIH panel in January, 1997. In the interest of providing full disclosure to trial participants, CDC Institutional Review Board (IRB) granted permission to modify the consent forms to include information about both of the AZT and pregnant mice studies.
Q5. What are the risks that the specific HIV strain infecting women in these studies will become resistant to AZT as a result of the exposure to AZT for the four-week period of the study?
In the already completed 076 trial described earlier, in which women took AZT for 6-24 weeks, a very small number (about 3 %) of the women taking AZT were shown to have developed AZT-resistant organisms. Because development of AZT resistance seems to be related in part to the amount of time a person takes AZT, the risk of development of AZT resistance in a study involving only four weeks of AZT is felt to be even lower. Nevertheless, these studies will monitor for AZT resistance.
Q6. 076 was carried out using a placebo (non-drug substance) for about half the women. Since we now know that the 076 AZT regimen reduces the risk of perinatal transmission, what is the justification for doing the current studies with placebo controls?
A placebo control will provide the best scientifically valid and credible comparison to confirm the efficacy and safety of short course AZT under developing country conditions. When planning trials of short-course AZT, a WHO-sponsored consultation concluded that placebo controlled studies were by far the best alternative for a study design. Historical controls were specifically considered unreliable, as were women not in antenatal care, or delivering in a different city.
Scientific studies usually compare new treatments with the standard treatment for a given setting. The initial trial answered the question, "Does AZT, when given for 6-24 weeks in pregnancy, result in less perinatal HIV transmission than among untreated women in the United States and France?" What the earlier study found to be effective was not simply the drug AZT but a specific regimen of an oral AZT dose taken 5 times per day for 16-24 weeks, plus intravenous AZT at the time of delivery plus oral AZT to children for the first 6 weeks of life. We are not using that regimen in the current studies because, although those results have changed the standard of care in the United States and other industrialized countries, the standard of care for treating HIV-infected pregnancies in most developing countries remains "no intervention." The intent in the current studies is to answer the question which is most relevant for public health decision makers in developing countries, "Does AZT, when given at this specific dose for four weeks, result in a lower perinatal HIV transmission rate compared to untreated women." There is consensus at WHO, UNAIDS, and in countries where these trials are being conducted that the full regimen of 076 could not currently be implemented as standard of care.
Another reason that placebo trials have been recommended is because it is necessary to change multiple parameters from the original 076 regimen, including dose, frequency of dosing, duration of treatment, and mode of treatment. As stated earlier, the changes are necessary in order to ensure that the potential new regimen is safe, practical, and economically feasible in developing countries. A placebo trial is the most scientifically valid way to determine the effect of these changes. Moreover, a placebo design (for example the design that is being used in Thailand) allows for a "streamlined study" which can provide an answer within 1-2 years after the start of the study. This is a very important consideration for host countries involved in the research; since there is not now a practical perinatal HIV prevention option for millions of poor HIV infected pregnant women in these countries.
In addition, in order to identify any adverse effects associated with use of AZT in this shorter dosing schedule in these new populations where pre-existing anemia and other diseases are more common than in the U.S., women taking AZT (and their children) need to be compared with women (and their children) not taking AZT. This essential search for side effects can only be done if some women do not receive AZT.
Q7. What about a study design that compares short course AZT regimen with 076?
A study design that compares a short AZT regimen with the long 076 AZT regimen would not meet the study objectives, in other words, it would not answer the question, "Does short course AZT work to prevent perinatal transmission?" Although with this design one could determine if the efficacy of the short AZT regimen is equivalent to that of the long regimen ( a question of interest to decision-makers in the United States but is far less relevant to the developing countries) this would not indicate whether the short AZT regimen was better than the currently available intervention, (nothing at all). With this design, one could also determine if the two regimens were equivalently efficacious, but because of statistical considerations, this would require an extremely large study that would take a relatively long time to complete and depending on the outcome still might not provide the appropriate data needed for policy making.
An additional problem with using this design to evaluate the safety of the new intervention is that it would be impossible to determine whether AZT was responsible for any side effects that might occur in trial participants. Because this new regimen could be taken by millions of women in a short period of time, clear information about the occurrence of side effects is critical for decision makers in developing countries.
Q8. Why aren't "historical" controls or comparison with already known rates of transmission reliable?
Historical controls are unreliable because mother-to-child transmission rates vary and are not predictable, with 12%-32% transmission found in industrialized countries and 25%-48% in developing countries. Transmission rates are known to vary within the same country and even in the same places over time.
Historical controls are not comparable with short-course AZT candidates due to inclusion, in most studies, of women without antenatal care, those delivering prematurely, and those with anemia and other illnesses. Some of these conditions, which are associated with HIV transmission, are criteria for excluding women from these studies. Delivery practices have changed for HIV-infected women, at least in Thailand, with more known infected women avoiding pregnancy, choosing to terminate, or being delivered by Caesarian section.
Q9. Couldn't you use historical controls, even if they are scientifically less pure?
In most places where efficacy trials are feasible, either insufficient or no historical data exist to serve as a comparison, regardless of their comparability. In Cote d'Ivoire, an earlier observational study had only 89 fully evaluable mother-child pairs, a number far too small to serve as a control group. Even fewer historical data exist elsewhere in Africa.
Q10. Do you believe these perinatal prevention studies are ethical?
Yes. One of the most important ethical considerations in conducting clinical trial research is that participants in the research should not receive less care than would be available to them if they were not involved in the research. Since in Thailand and Ivory Coast AZT is not currently available for perinatal HIV prevention, the placebo-controlled trial design is consistent with that principle.
1) The studies meet the traditional ethical criteria of: a) respect for autonomy, b) beneficence (doing good), c) non-maleficence (doing no harm), d) justice.
2) No available medications available to the populace are withheld.
3) No medications are being withdrawn.
4) Women are not asked to stop using any traditional medicines or treatments.
5) Women are clearly told that the AZT regimen might or might not be effective. Women are clearly told about possible risks of AZT.
6) Women were clearly told that some would receive AZT and others would not.
7) Women are clearly told that they would be put into one group or the other by chance and that neither they nor their doctors would know which group they were in. The studies are consistent with U.S. and international ethical standards, approved by ethical review committees, monitored by a Data and Safety Monitoring Board, and endorsed by numerous responsible research institutions around the world, including the UNAIDS program. Given our ability to address this critical issue, it could be considered unethical not to undertake studies that can convincingly show efficacy and therefore realistically and rapidly make perinatal prevention a possibility in the developing world.
Q11. What ethical procedures and safeguards are in place for protecting the participants in CDC's two current perinatal AZT studies?
Before deciding about entering the studies, women who are potential study participants are provided information about HIV and AIDS, about the intent of the study and about possible risks and benefits for them and their children. It is clearly explained to the women involved that some would receive AZT and others would receive a placebo, a similar capsule without active medication; and that there would be no way for them to tell which group they are in. Women must give informed consent before participation begins. The plans for the studies and the consent forms have been reviewed and approved by the Institutional Review Board at CDC and by the equivalent human subject protection groups in the countries in which the studies are being carried out. CDC IRB approval is renewed on a regular basis, after careful review of the side effects data from the studies and consideration about access of the women to alternative methods for preventing perinatal HIV transmission. In addition, the ongoing study results are examined every six months by a Data Safety and Monitoring Board at the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. This group is charged with the responsibility of monitoring study results and stopping the studies before completion if either the benefits or risks are greater than expected.
Q12. When is it ethical to do studies overseas that could not be done in the United States?
The International Ethical Guidelines for Biomedical Research Involving Human Subjects was prepared by the Council for International Organizations of Medical Sciences, in collaboration with the World Health Organization. It indicates (Guideline #8) that "Diseases that rarely or never occur in economically developed countries or communities exact a heavy toll of illness, disability or death in some communities that are socially and economically at risk of being exploited for research purposes. Research into the prevention and treatment of such diseases is needed and, in general, must be carried out in large part in the countries and communities at risk." This guideline further states that the research carried out in these settings "should be responsive to the health needs and priorities of the host countries."
Q13. What are the benefits to the subjects in the trials and to the host countries?
The women and their children benefit from knowing their HIV status and from the counseling they receive related to it. They also receive somewhat enhanced care during labor and delivery plus 18 months of medical follow-up, including well baby and mother check-ups, childhood immunizations, and enhanced access to and care in the event of illness. In addition, half the women receive the short course AZT regimen that may or may not provide prevention benefits.
The countries gain the experience and training related to operating HIV counseling and testing services. If efficacy is shown, they will have cost-benefit data on which to base policy decisions regarding mother-to-child HIV prevention plus the experience of administering short-course AZT in pregnancy.
Q14. What is the rationale for studying AZT monotherapy in the developing country perinatal HIV studies?
AZT is the only antiviral drug known to reduce perinatal HIV transmission. Although some studies using a combination of AZT and another antiviral drug called 3TC have started, the safety of drugs other than AZT (including 3TC) when taken during pregnancy remains to be demonstrated. At the time that the current studies were being planned, we did not feel that there was sufficient evidence for the safety of other antiviral drugs to allow us to advocate their use. In addition, a demonstration of the efficacy of a combination of two or three drugs in preventing perinatal transmission would not directly address the needs of most HIV-infected women living in developing countries, i.e., identification of a relatively simple and inexpensive way to reduce perinatal HIV transmission.