To the Editors:
In the December 4, 2011 issue, the J Acquir Immune Defic Syndr Onyango-Makumbi et al report on the lack of efficacy of HIV hyper immunoglobulin (HIVIG) in pregnant women and their infants in Uganda.1 This is not surprising. Despite the lack of efficacy in a 1999 study of HIVIG (ACTG 185) performed in the United States, and the fact that a Data and Safety Monitoring Board (DSMB) had stopped the study after it had determined that no efficacy could be shown in HIV-infected pregnant women and their infants, the National Institute of Health moved forward with this study in Uganda.1,2
Before initiating the study in Uganda, there were objections voiced by scientists and clinical researchers that an experimental HIVIG product should not move forward in HIV-infected pregnant women and their infants. The reasons were ethical concerns governing clinical research in vulnerable populations and the lack of convincing in vitro and in vivo evidence of efficacy.2–6
Enthusiasm for HIVIG as an efficacious product was dampened when it was shown that typical preparations neutralized many clinical isolates of HIV-1 very poorly. This is true when the clade of the HIVIG preparation matches the test virus panel, but there is even less neutralization when the dominant clades are not matched (Clade A and D viruses dominant in Uganda; the HIVIG study preparation was not tested against clade D.) Even high concentrations of HIVIG were unable to prevent infection of monkeys with a chimeric HIV/simian immunodeficiency virus under conditions where neutralizing monoclonal antibodies clearly worked.7 Support for HIVIG as a way to interrupt mother–child transmission by treating the mother was also called into question when it was shown that antibodies had, at best, a weak effect on viral load in established infection and no significant impact on CD4 counts.3–6,8,9 The ease with which HIV-1 could escape from neutralizing antibody suggested that treatment of a mother could even be detrimental, by selecting for antibody-resistant virus variants.8 Further, unlike antiretrovirals which are required to show a statistically significant impact on viral load and CD4 counts before expanding efficacy studies, HIVIG, having failed all these criteria, the research study still moved forward in Uganda.
One of the most worrisome results of the study was the statistically significant increase in HIV infection or death (over 2 times higher in the experimental HIVIG arm) at 2 weeks in infants who received HIVIG (P = 0.03). It is possible that a larger study population might have reached a different statistical conclusion. However, the fact that the trend continued until the 6-month evaluation but not thereafter makes it more likely that the result was statistically significant. Nevertheless, both the article and the accompanying editorial dismissed the significance of the short-term increases in HIV infection and infant mortality. We believe that this attitude was imprudent, given the underlying immunology and virology. The observed short-term enhancement of HIV transmission is consistent with the known half-life of HIVIG; any biological effect it exerted would be greatest soon after administration but would diminish over time, which fits the observed pattern of transmission.1,10 Two mechanisms that might account for the increased infection which should not be dismissed lightly, include antibody-dependent enhancement of HIV infection by antibodies that do not neutralize the virus and the presence of inactivated virus and/or other antigens in the HIVIG preparation that could have stimulated infected maternal immune cells to produce increased amounts of HIV, increasing the risk of transmission to the infant.11–16 Both the article and the accompanying editorial dismissed the significance of the increase in infant mortality or HIV infection based on the 6-month evaluation (when HIVIG would no longer be present).1,17
The study violated numerous international ethical principles. The experimental product showed no convincing efficacy in the United States and yet was evaluated in Uganda. The cost of intravenous immunoglobulin (IVIG), similar to HIVIG, currently at least 25–30 times greater than the cost of generic highly active antiretroviral therapy, the difficulties in manufacturing HIVIG from multiple HIV-infected donors in Africa, separation of blood into plasma, shipping biologically hazardous blood products to Europe and back to Africa, the requirement for a cold chain, the requirement for health care workers to initiate and monitor intravenous infusions, all point to a product that has significant biohazards and would not be affordable or usable in Uganda or similar populations in other nations. This violates the ethical principle that something ought not be studied in a population which could not reasonably benefit from it. The use of a product that failed in previous studies to show efficacy in lowering viral load and increasing CD4 counts violates ethical and scientific principles that require that medical research involving human subjects be justifiable on scientific grounds. The performance of a nonminimal risk research study in pregnant women and their infants with a product that was not shown to have efficacy in a US study, was halted by the DSMB, utilized a product derived from HIV-infected individuals, and which could no longer be performed in the United States, raises additional ethical questions as to exploitation of highly vulnerable research subjects for nonbeneficial research.18,19 Additionally, the study did not take into account the possible misperceptions that might accompany the administration of a blood product obtained from HIV-infected individuals that lacked convincing efficacy, to pregnant women and their infants in Uganda, when other much less expensive and highly effective antiretrovirals could have been used.
The ethics and science of the study seem to have been reviewed by appropriate Ugandan and US Internal Review Boards. Through the Freedom of Information Act, we obtained a copy of the study approval by the Ugandan Council for Science and Technology. However, we noted that the AIDS Research Committee approval expired in 2005 although the study continued through 2006. All of the participating US institutions utilized Western Institutional Review Board, a commercial, for profit, Internal Review Board, because it is not a government agency, we were unable to obtain copies of either the protocol they reviewed or their deliberations through Freedom of Information Act.
The key question about this study is not why the DSMB did not stop it but why, given the myriad of scientific and ethical questions, was the study allowed to be implemented in vulnerable research subjects in poor nations raising issues related to the adequacy of the review process of National Institute of Health–funded clinical research studies?
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2. Stiehm ER, Lambert JS, Mofenson LM, et al.. Efficacy of zidovudine and human immunodeficiency virus (HIV) hyperimmune immunoglobulin for reducing perinatal HIV transmission from HIV-infected women with advanced disease: results of Pediatric AIDS Clinical Trials Group protocol 185. J Infect Dis. 1999;179:567–575.
3. Stiehm ER, Fletcher CV, Mofenson LM, et al.. Use of human immunodeficiency virus (HIV) human hyperimmune immunoglobulin in HIV type 1-infected children (Pediatric AIDS clinical trials group protocol 273). J Infect Dis. 2000;181:548–554.
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10. Lambert JS, Mofenson LM, Fletcher CV, et al.. Safety and pharmacokinetics of hyperimmune anti-human immunodeficiency virus (HIV) immunoglobulin administered to HIV-infected pregnant women and their newborns. Pediatric AIDS Clinical Trials Group Protocol 185 Pharmacokinetic Study Group. J Infect Dis. 1997;175:283–291.
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13. Burton DR, Hessell AJ, Keele BF, et al.. Limited or no protection by weakly or nonneutralizing antibodies against vaginal SHIV challenge of macaques compared with a strongly neutralizing antibody. Proc Natl Acad Sci U S A. 2011;108:11181–11186.
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15. Vigano A, Bricalli D, Trabattoni D, et al.. Immunization with both T cell-dependent and T cell-independent vaccines augments HIV viral load secondarily to stimulation of tumor necrosis factor alpha. AIDS Res Hum Retroviruses. 1998;14:727–34.
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19. Presidential Commission for the Study of Bioethical Issues. Moral science: protecting participants in human subjects research. 21012. 2011. Available at: http://bioethics.gov/cms/node/558
. Accessed March 27, 2012.