A Hollow Victory. Ethics, Science, and the NIH PROMISE Study.
On the night of June 16, 2015 I received an email message from Washington DC stating, “Because of START results, they [NIH sponsored researchers] will be offering HAART to all mothers in all [research] arms in the PROMISE study.”
First an explanation of the acronyms: NIH stands for the National Institutes of Health, PROMISE stands for Promoting Maternal and Infant Survival Everywhere, START stands for Strategic Timing of Anti-Retroviral Treatment and HAART stands for Highly Active Antiretroviral Therapy.
The announcement that all HIV-infected pregnant women in the PROMISE study would be placed on HAART was a hollow victory for HIV-infected pregnant women in resource poor countries. For almost two decades it had been argued that withholding known effective antiretroviral treatment from pregnant women in order to conduct unnecessary research studies was unethical. Going as far back as 1996 it was known that early initiation of highly active antiretroviral therapy (HAART) prevented the progression of HIV to AIDS, decreased the complications of HIV infection and reduced mortality as a result of AIDS. In spite of the evidence, rather than embarking on a vigorous campaign to make HAART available to treat all HIV infected pregnant women and prevent their infants from becoming infected the pediatric HIV research community (supported by the NIH) chose to devise a false and unsubstantiated hypothesis— HIV-infected pregnant women might not respond to HAART in the same manner as all other HIV infected individuals.
However, there were several difficulties with moving forward with their proposed clinical research studies; there was no evidence from infectious disease experience or medical publications that delaying the initiation of treatment for any infection was of benefit to the patient; the study could not be performed in the US for scientific and ethical reasons; if the study were to be performed a large population of HIV infected women would be necessary. The need for scientific evidence was dismissed as not pertinent to HIV-infected pregnant women; the population issue was solved by designing studies that would enroll large numbers of vulnerable HIV-infected pregnant women in resource poor countries; the ethical issue was rejected by stating that there was no obligation to conduct studies using international standards of care guidelines in resource poor countries.
A myriad of clinical studies followed which were conducted in multiple countries employing what seemed to be an infinite variation in the drugs evaluated and the schedule of administration. All studies concluded that the earlier treatment was started and the more treatment given (three drugs was better than one or two) the greater benefit to the mother’s health and the lower the HIV transmission to the infants. But no matter how many studies were conducted over more than a decade they all seem to conclude that more studies were needed before early initiation of HAART for all HIV-infected pregnant women, symptomatic or asymptomatic, could be recommended. More than benefiting the HIV-infected pregnant women who progressed to AIDS and their infants who became infected, the conclusion that more studies were needed, seemed to provide justification for a continuous flow of funding for repetitive studies that never quite seemed to dismiss their false hypothesis.
Elsewhere studies were conducted to evaluate the impact of HAART on large populations of HIV-infected men and women (nonpregnant). None of the studies found any hint that men or women responded differently to treatment of HIV with HAART. Each study confirmed the life-saving benefits of early initiation of therapy and proved what should’ve been accepted from the very beginning— that HIV, an infection that disseminates throughout the body and penetrates every organ is no different than any other infectious disease and should be treated as soon as a diagnosis of infection is made.
On May 27, 2015 an announcement was made by NIH that the SMART study of over 4,000 men and women was stopped because of the dramatic benefit of treatment. The SMART investigators announced, “Together with data from previous studies showing that antiretroviral treatment reduced the risk of HIV transmission to uninfected sexual partners, these findings support offering treatment to everyone with HIV. http://www.niaid.nih.gov/news/newsreleases/Archive/2011/Pages/START.aspx
In contrast to the START study, the PROMISE study was a randomized clinical trial conducted in thousands of women some of whom received highly active antiretroviral therapy (HAART) during pregnancy for purposes of prevention of mother-to-child transmission (PMTCT) of HIV but “who did not otherwise meet criteria to initiate HAART for their own health.” The study was designed to determine whether continuation of HAART after delivery reduced morbidity and mortality compared to discontinuation and re-initiation of HAART. The study thus unethically withheld known effective treatment from HIV-infected women. The IMPAACT/PROMISE investigators dismissed all criticism of the ethics and science of their studies restating their original hypothesis that HIV infected might respond differently to treatment with HAART. http://www.impaactnetwork.org/studies/1077HS.asp
The announcement of the SMART study finally forced the pediatric clinical investigators to place all HIV-infected pregnant women on treatment with HAART.
There was both irony and tragedy in the announcement of the SMART study results recommending that all HIV-infected individuals (including HIV infected pregnant women) should be placed on HAART regardless of symptoms and CD4 count. The irony was that in spite of myriads of studies conducted by the pediatric clinical investigators in HIV-infected pregnant women in resource poor countries it was a study conducted in men and non-pregnant women that forced the PROMISE researchers to end their almost two decade research pursuits, driven by the false hypothesis that HIV infected pregnant women might respond differently to early initiation of HAART.
The tragedy was that the false hypothesis of the PROMISE study denied tens of thousands of HIV infected pregnant women and infants the treatment that they needed resulting in unnecessary HIV progression to AIDS, thousands of unnecessary infections of infants, hundreds of millions of dollars in scarce research funds, and delays in developing international treatment and prevention guidelines recommending HAART as standard of care for all HIV infected individuals. The appalling result of the 20 year delay in treating all HIV individuals with HAART was the unnecessary deaths of more than 2.2 million women and children.
Note: WHO estimated that from 1996 to 2014 there were approximately 600,000 deaths among HIV infected women and children each year. A conservative estimated 20% decline in deaths with HAART would have resulted in 2.2 million fewer deaths over that time period.
1- An open letter to the Presidential Commission for the Study of Bioethical Issues.
October 17, 2011. http://ethicsinhealth.org/?p=57
2- Montaner JS, Montessori V, Harrigan R, O’Shaughnessy M, Hogg R. Antiretroviral therapy: ‘the state of the art’. Biomedecine & pharmacotherapie. Mar 1999;53(2):63-72.
3- Carpenter CC, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1996. Recommendations of an international panel. International AIDS Society-USA. Jama. Jul 10 1996;276(2):146-154.
Mofenson L. Overview of Perinatal Intervention Trials Table. 2009. http://www.womenchildrenhiv.org/wchiv?page=wx-resource&root=typ&cat=02&subcat=prov&rid=20-785