------------------------------------------------------------------------

The New England Journal of Medicine -- September 18, 1997 -- Volume 337,

Number 12

SOUNDING BOARD

Unethical Trials of Interventions to Reduce Perinatal Transmission of the

Human Immunodeficiency Virus in Developing Countries

It has been almost three years since the Journal (1) published

the results of AIDS Clinical Trials Group (ACTG) Study 076, the

first randomized, controlled trial in which an intervention was

proved to reduce the incidence of human immunodeficiency virus

(HIV) infection. The antiretroviral drug zidovudine, administered

orally to HIV-positive pregnant women in the United States and

France, administered intravenously during labor, and subsequently

administered to the newborn infants, reduced the incidence of HIV

infection by two thirds. (2) The regimen can save the life of one

of every seven infants born to HIV-infected women.

Because of these findings, the study was terminated at the first

interim analysis and within two months after the results had been

announced, the Public Health Service had convened a meeting and

concluded that the ACTG 076 regimen should be recommended for all

HIV-positive pregnant women without substantial prior exposure to

zidovudine and should be considered for other HIV-positive

pregnant women on a case-by-case basis. (3) The standard of care

for HIV-positive pregnant women thus became the ACTG 076 regimen.

In the United States, three recent studies of clinical practice

report that the use of the ACTG 076 regimen is associated with

decreases of 50 percent or more in perinatal HIV transmission.

(4,5,6) But in developing countries, especially in Asia and

sub-Saharan Africa, where it is projected that by the year 2000,

6 million pregnant women will be infected with HIV, (7) the

potential of the ACTG 076 regimen remains unrealized primarily

because of the drug's exorbitant cost in most countries.

Clearly, a regimen that is less expensive than ACTG 076 but as

effective is desirable, in both developing and industrialized

countries. But there has been uncertainty about what research

design to use in the search for a less expensive regimen. In June

1994, the World Health Organization (WHO) convened a group in

Geneva to assess the agenda for research on perinatal HIV

transmission in the wake of ACTG 076. The group, which included

no ethicists, concluded, "Placebo-controlled trials offer the

best option for a rapid and scientifically valid assessment of

alternative antiretroviral drug regimens to prevent [perinatal]

transmission of HIV." (8) This unpublished document has been

widely cited as justification for subsequent trials in developing

countries. In our view, most of these trials are unethical and

will lead to hundreds of preventable HIV infections in infants.

Primarily on the basis of documents obtained from the Centers for

Disease Control and Prevention (CDC), we have identified 18

randomized, controlled trials of interventions to prevent

perinatal HIV transmission that either began to enroll patients

after the ACTG 076 study was completed or have not yet begun to

enroll patients. The studies are designed to evaluate a variety

of interventions: antiretroviral drugs such as zidovudine

(usually in regimens that are less expensive or complex than the

ACTG 076 regimen), vitamin A and its derivatives, intrapartum

vaginal washing, and HIV immune globulin, a form of

immunotherapy. These trials involve a total of more than 17,000

women.

In the two studies being performed in the United States, the

patients in all the study groups have unrestricted access to

zidovudine or other antiretroviral drugs. In 15 of the 16 trials

in developing countries, however, some or all of the patients are

not provided with antiretroviral drugs. Nine of the 15 studies

being conducted outside the United States are funded by the U.S.

government through the CDC or the National Institutes of Health

(NIH), 5 are funded by other governments, and 1 is funded by the

United Nations AIDS Program. The studies are being conducted in

Cote d'Ivoire, Uganda, Tanzania, South Africa, Malawi, Thailand,

Ethiopia, Burkina Faso, Zimbabwe, Kenya, and the Dominican

Republic. These 15 studies clearly violate recent guidelines

designed specifically to address ethical issues pertaining to

studies in developing countries. According to these guidelines,

"The ethical standards applied should be no less exacting than

they would be in the case of research carried out in [the

sponsoring] country." (9) In addition, U.S. regulations governing

studies performed with federal funds domestically or abroad

specify that research procedures must "not unnecessarily expose

subjects to risk." (10)

The 16th study is noteworthy both as a model of an ethically

conducted study attempting to identify less expensive

antiretroviral regimens and as an indication of how strong the

placebo-controlled trial orthodoxy is. In 1994, Marc Lallemant, a

researcher at the Harvard School of Public Health, applied for

NIH funding for an equivalency study in Thailand in which three

shorter zidovudine regimens were to be compared with a regimen

similar to that used in the ACTG 076 study. An equivalency study

is typically conducted when a particular regimen has already been

proved effective and one is interested in determining whether a

second regimen is about as effective but less toxic or expensive.

(11) The NIH study section repeatedly put pressure on Lallemant

and the Harvard School of Public Health to conduct a

placebo-controlled trial instead, prompting the director of

Harvard's human subjects committee to reply, "The conduct of a

placebo-controlled trial for [zidovudine] in pregnant women in

Thailand would be unethical and unacceptable, since an

active-controlled trial is feasible." (12) The NIH eventually

relented, and the study is now under way. Since the nine studies

of antiretroviral drugs have attracted the most attention, we

focus on them in this article.