Access to Treatment for HIV in Developing Countries

International Seminar on Access to Treatment for HIV in Developing Countries
5-6 June 1998 London, UK

Ethics of drug trials in developing countries

Dr. Philippa Musoke Mudido
Department of Paediatrics, Makerere University
Kampala, Uganda

As we are all aware, the HIV/AIDS pandemic has continued to escalate with over 30 million cases world-wide, with more than 50 % of them found in sub-Saharan Africa. Uganda is one of these countries with high seroprevalance rates (10%). Rates range from 0.1 % in the rural areas to as high as 50% in some high risk population groups (e.g. prostitutes). Despite the fact that the seroprevalence rates are dropping, they are still high in antenatal clinics, between 1.5% - 20%. Women contribute 12 million of the 30 million world-wide cases of HIV infection. 80% of them are found in Sub-Saharan Africa.

Over 1 million children are infected and every year 500,000 children are HIV infected through vertical transmission. Because of the high seroprevalence rates and high fertility rate, nine out of ten of these children are also found in Sub-Saharan Africa. The crude birth rate in Uganda is 50 per 1000 which translates to 500,000 births per year in a population of approximately 20 million. The HIV seroprevalence rates in pregnant women are 20% which translates into 100,000 HIV infected women. With HIV vertical transmission rates of approximately 30%, this means there are 30,000 HIV infected infants each year.

Prevention of HIV vertical transmission
The major breakthrough in HIV research was the prevention of vertical transmission using AZT. ACTG 076 The results were available in 1994. Starting early in pregnancy, oral AZT was given five times a day to each woman. AZT was administered intravenously during labour and oral AZT given to the mother and her infant for six weeks post delivery.

Results
The placebo arm had a transmission rate of 25% while the AZT arm had a transmission rate 8%, which is a 66% reduction in HIV transmission from mother to child.

CDC Thailand
This year in February the results from the Center for Disease Control (CDC) Thailand regimen were available. This short course AZT trial starts in the third trimester of pregnancy (at 36 weeks) with oral AZT two times a day and oral AZT administered every three hours during labour. There was no postpartum medication and none of the infants were breastfed.

Results
The placebo arm had a transmission rate 18.6% and the AZT arm had a transmission rate of 9.2%, which is a reduction of 50%. HIV perinatal intervention trials currently in Uganda.

Currently there are two main perinatal intervention trials in Uganda, which is a breastfeeding population. All placebo arms were dropped after the results of the CDC Thailand regimen were reported. PETRA This trial will look at the effect of giving the mothers AZT plus 3TC twice a day starting at 36 weeks and oral AZT and 3TC every three hours and every 12 hours respectively in labour, and for one week after birth to both the mother and her baby.

There are three arms in this study. AZT and 3TC are administered either:
i) Only intrapartum (during labour)
ii) Only intrapartum and postpartum (after birth)
iii) Starting prepartum, through intrapartum and postpartum

NVP/AZT
This trial will give the mothers either AZT or Nevirapine (NVP) in labour only and for one week postpartum to both the mother and her infant.

These shorter regimens are less expensive, easier to administer and more applicable to the developing countries. If they are found to also reduce HIV vertical transmission then they will be more convenient and affordable for the pregnant women in developing countries.

General ethics of research done in Ugandan women
Major ethical issues involved in doing research in Ugandan women is probably similar to other developing countries. Here are some of the issues that researchers will need to address when designing trials:

In the male dominated society, women often cannot make their own decisions even regarding their own health and the health of their unborn child. In Uganda, the culture demands that women bear children to be considered "complete".
Concepts of research may be foreign and difficult to comprehend. The mindset is often that hospitals and medical care are for care and treatment and not for asking questions. "If you do not know if it works, why give it to me?"
Language of the researcher is often different from the participants so the ideas will have to be translated into a foreign language and yet maintain the original concept. For example, one drug warning was translated from "nearly fatal" to the vernacular for "fatal". Research participants are often from the lower socio-economic strata and may not be able to provide even the basics for their families.
Medical care, personnel and facilities are scanty and overstretched, making extra time and detail for research difficult. The economic empowerment of the women participating in the research projects must be addressed.

Specific drug trial issues
One major issue involved in these sorts of drug trials is the autonomy of the pregnant women and the right to make the final decisions affecting her life and that of her baby. The question must be addressed, does the baby come before the mother? Is what is best for the baby, the best for her? Sometimes these are in conflict. Mothers often say "You have found out that I am HIV infected and you are giving me drugs to prevent transmission to the baby, but what about me?" The mother has the right to decide what is best for her and her baby.

In addition, what happens if the father of the baby does not want the intervention? The mother must have autonomy regardless of her husband's wishes. Other major issues are those around privacy and confidentiality. Privacy is necessary during pre-test and post test counselling, during HIV screening and while receiving the results, which can be difficult in a busy antenatal clinic. There should not be a special room set aside for HIV related work, since women or records which visit that room can be branded HIV infected. All records must be kept confidential, not only from other mothers but other medical personnel.

Drug packaging and scheduling
Drug preparation, packaging and dosing schedule must be made convenient for the mothers. The preparation should be appropriate for the hot humid climate where the majority of mothers do not have access to refrigeration. The drug should be packaged so that her privacy may be protected if her drugs are accidentally exposed to the family or neighbours (i.e. without markings or names which let others know of her HIV status). Also, is the drug so large that the mother cannot store it away and conceal it? The drugs must be chosen with dosing schedules that can fit into the women's schedule and thus avoid a large non-compliance issue. If a woman rises early and works all day away from home, it will be more difficult for her to take medications two or three times a day.

Placebo versus no placebo in drug trials
Currently all maternal to child HIV interventions in Uganda will not have a placebo arm. However placebo studies in the developing countries were not unethical. Where a new treatment is tried in a new setting and where the standard of care is low or non-existent then the use of placebos cannot be considered unethical.

Good medical care
In developing countries where the health budget is so low and the majority of the population cannot afford even the basics, provisions must be built into the research project providing good medical care and follow-up. This includes routine care, nutrition, obstetrics, immunisations, growth monitoring and sick visits. This also includes access to non study drugs when required for free or reduced cost. Most of these women may have no insurance or other means of paying for this medical care. It is recommended that these women are given continued access to basic health care for free or at reduced cost after the study period. After participating and providing answers to questions raised, there is a need for the women to directly benefit from the results

Priorities for ongoing drug trials: Good research practices
In conclusion, what are some of the priorities we see in Uganda that will make research beneficial not only to the researcher but also to the individual participants. There needs to be adequate initial and follow up counselling at the level appropriate to the participant. It is crucial to spend a lot of time explaining to the mother what is involved in her participation in the trial. Attempt to get informed consent, not just a signature or a thumb print on paper. In an effort to enrol large numbers of women, there can be an overload in these requirements. Adequate follow up and networking for patients to be in contact with researchers and with other organisations which could be of benefit to them. The provision for the women post study needs to be addressed. Are these mothers left hanging or will there be something for them, such as access to research drugs or other benefits, after the study is over?

Other provisions to the mothers during the study should be taken into account, for both ethical reasons and for increasing compliance. One suggestion is to provide transport for the clinic visits, since often the women cannot afford the price of public transport and the walk might be considerable. A midday snack of porridge or bread for the women and their infants is another suggestion, especially when they travel or have to spend long hours in the clinic. When infants are sick, arranging that they be seen at no cost outside regularly scheduled hours. And researching other sources of funding for drugs for the mothers. Can donations be solicited to pay for them?

Social support
During the study, there needs to be an overriding concern for the individuals and their medical, social, emotional needs. Many of these women when empowered can raise themselves up and their families. This empowerment can be assisted via the provision of small micro-enterprise loans or training in basic health, hygiene, and nutrition. These things are often taken for granted but there also needs to be the provision of revenues to sustain these programmes. One may prevent HIV transmission but if both the mother and her infant die because no other provisions have been made then it will all be to no avail. We have to provide more than just drugs.

Discussion:
In response to a question, Dr Musoke Mudido agreed that it was unethical to conduct a clinical trial in a country if subsequently the results could not be implemented in that country.