1
Introduction

In sub-Saharan Africa, 10 to 30% or more of pregnant women are infected with human immunodeficiency virus type 1 (HIV-1). Mother-to-child transmission is the dominant mode by which infants and children become infected with HIV-1. In 2004 alone, about 640,000 infants and children under 15 years of age worldwide were newly infected with HIV-1, and about 510,000 died of acquired immune deficiency syndrome (AIDS). An estimated 1,700 children are born with HIV-1 infection every day owing to mother-to-child transmission. Most new infections and deaths occur in sub-Saharan Africa (UNAIDS and WHO, 2004).

A variety of interventions can reduce rates of mother-to-child transmission of HIV, from more than 20% to 2% or less. These interventions include antiretroviral treatment of pregnant women and their infants, the selective use of elective cesarean delivery, and complete avoidance of breastfeeding (UNAIDS and WHO, 2004). In a study completed in 1994, U.S. researchers showed for the first time that a three-part regimen of zidovudine (ZDV)—given to women during pregnancy and labor and delivery, and to newborns during the first 6 weeks of life—could reduce mother-to-child transmission by about two-thirds, from 25 to 8% (Connor et al., 1994). This intervention was promptly adopted programmatically in the United States and other resource-rich settings. However, the complexity and expense of this approach, which entails both oral and intravenous dosing, made it impractical for use in most developing countries and unlikely that it would be adopted in those settings. Barriers to broader availability of this and other options for reducing mother-to-child transmission



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Review of the HIVNET 012 Perinatal HIV Prevention Study 1 Introduction In sub-Saharan Africa, 10 to 30% or more of pregnant women are infected with human immunodeficiency virus type 1 (HIV-1). Mother-to-child transmission is the dominant mode by which infants and children become infected with HIV-1. In 2004 alone, about 640,000 infants and children under 15 years of age worldwide were newly infected with HIV-1, and about 510,000 died of acquired immune deficiency syndrome (AIDS). An estimated 1,700 children are born with HIV-1 infection every day owing to mother-to-child transmission. Most new infections and deaths occur in sub-Saharan Africa (UNAIDS and WHO, 2004). A variety of interventions can reduce rates of mother-to-child transmission of HIV, from more than 20% to 2% or less. These interventions include antiretroviral treatment of pregnant women and their infants, the selective use of elective cesarean delivery, and complete avoidance of breastfeeding (UNAIDS and WHO, 2004). In a study completed in 1994, U.S. researchers showed for the first time that a three-part regimen of zidovudine (ZDV)—given to women during pregnancy and labor and delivery, and to newborns during the first 6 weeks of life—could reduce mother-to-child transmission by about two-thirds, from 25 to 8% (Connor et al., 1994). This intervention was promptly adopted programmatically in the United States and other resource-rich settings. However, the complexity and expense of this approach, which entails both oral and intravenous dosing, made it impractical for use in most developing countries and unlikely that it would be adopted in those settings. Barriers to broader availability of this and other options for reducing mother-to-child transmission

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Review of the HIVNET 012 Perinatal HIV Prevention Study include poor public health and health care infrastructure, the complexity and expense of treatment, and the lack of suitable and acceptable alternatives to breastfeeding. The urgent need in sub-Saharan Africa and throughout the developing world for practical, affordable approaches to preventing mother-to-child transmission of HIV-1 has spurred studies to identify inexpensive, simple, easy-to-implement new antiretroviral regimens. HIVNET 012 was one such study. Initiated in Uganda in 1997, HIVNET 012 was designed to provide preliminary information on the comparative safety and efficacy of two relatively simple and inexpensive short courses of oral antiretroviral treatment—one involving ZDV, and the other nevirapine (NVP)—likely to be feasible in resource-limited settings. The trial was sponsored by the Division of AIDS (DAIDS) of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). The study was performed at Mulago Hospital, Makerere University, Kampala, Uganda, by investigators from the Johns Hopkins University School of Medicine and Makerere University, under the auspices of the NIAID-sponsored HIV Prevention Trials Network (HPTN, formerly HIVNET). The U.S. Food and Drug Administration (FDA) had already approved both NVP and ZDV for treating HIV in adults, and HIVNET 012 was not initially intended to collect data for formal presentation to FDA for approval of new indications for NVP. However, as a matter of policy, DAIDS required that the study be conducted under an investigational new drug application, held by DAIDS. Enrollment of pregnant women in the trial was completed in 1999, but infants continued to be followed until 5 years of age (HIVNET 012 Investigators, 2000). Two widely cited papers published in The Lancet in 1999 and 2003 reported striking results from HIVNET 012 (Guay et al., 1999; Jackson et al., 2003). The trial showed that a single dose of NVP—given to the mother at the onset of labor and to the infant within 72 hours of birth—reduced the risk of HIV-1 transmission by nearly 50% measured at 14 to 16 weeks postpartum, compared with the short-course ZDV regimen. These results catalyzed efforts to implement the single-dose NVP-based regimen for preventing mother-to-child transmission in resource-limited settings in Africa and throughout the world in an effort to stem the global pediatric HIV epidemic. Based on these published results, Boehringer Ingelheim (BI), the pharmaceutical company that manufactures NVP, decided in 2001 to submit a supplemental new drug application to FDA for preventing mother-to-child transmission.1 FDA approval of a new indication required compliance with 1   Such an application is used to add a new indication to the label of an already approved drug. While drugs may legally be used for indications not on their labels (known as “off-label

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Review of the HIVNET 012 Perinatal HIV Prevention Study a more stringent set of research procedures and an audit of the study site. Following a visit by BI to the Mulago Hospital study site in Kampala in November 2001, DAIDS contracted with Westat Corporation to visit the site and help HIVNET 012 staff prepare for the FDA audit, expected to occur in March 2002. In February 2002, a team from Westat visited the study site and reviewed regulatory compliance, laboratory facilities, pharmacy facilities and processes, and trial records. The Westat team reported finding multiple problems with HIVNET 012, including procedural irregularities and issues with how investigators had defined, graded, and reported serious adverse events. The Westat team also raised the possibility that the trial had not recorded some deaths that had occurred during the study, although the Westat team reported that the tests of infants’ HIV-1 status were verifiable (Chamberlin et al., 2002). Westat submitted its preliminary report to DAIDS on March 8, 2002. Based on debriefing discussions with the Westat team and FDA (although not with the investigators), DAIDS concluded that the Westat report did not contain conclusive evidence that deaths had gone unreported to the study database or to FDA (DAIDS, NIAID, 2002). The HIVNET 012 investigators, the statistical center supporting the data management and analysis of HIVNET 012 (Statistical Center for HIV/AIDS Research and Prevention, SCHARP, at the Fred Hutchinson Cancer Center in Seattle), and the contract research organization assigned to conduct regular monitoring visits to the HIVNET 012 study site (Family Health International [FHI]) developed a response to the Westat report, which they submitted to DAIDS (FHI, 2002; HIVNET 012 Investigators, 2002; SCHARP, 2002). Those responses to the Westat report clarified and corrected some of the assertions and criticisms made by Westat. Based on the findings in the Westat report, DAIDS decided to conduct its own comprehensive audit—or remonitoring—of the study to clarify the issues. BI later withdrew its application to the FDA for a supplemental indication for the use of NVP in preventing mother-to-child transmission, stating that the “NIAID and Boehringer Ingelheim review could not be completed within the remaining timeline for FDA action for the supplement” (Boehringer Ingelheim, 2002). Between July and December 2002, DAIDS conducted a comprehensive remonitoring evaluation of the HIVNET 012 site and records at Mulago Hospital. Stage I of this assessment included laboratory, pharmacy, and regulatory audits; a review of study procedures and processes; and random selection of 80 mother/infant pairs, for which DAIDS compared reporting on informed consent, birth and delivery, virology, and adverse events with     use”), drugs may be advertised and marketed only for the indications reviewed by the FDA and approved for their labels.

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Review of the HIVNET 012 Perinatal HIV Prevention Study source documents.2,3 Stage II included a review of source documents for the remaining 565 mothers and 567 infants. The remonitoring team also examined the completeness of reporting on adverse events and information on study safety. In its resulting report, DAIDS identified some problems with procedures and documentation, but concluded that these issues did not compromise the results of the study. Thus, the report indicated that the HIVNET 012 trial’s conclusions regarding safety and efficacy were supported (DAIDS, NIAID, 2003). In 2003, after the DAIDS review and publication by the investigators of 18-month results from the trial which supported earlier findings (Jackson et al., 2003), DAIDS hired a director for its new Office of Policy in Research Operations, an office responsible for monitoring the quality and conduct of all DAIDS-sponsored clinical trials. This individual criticized the remonitoring of HIVNET 012 in his presentation to this committee, and his concerns have received media attention (Associated Press, 2004a; Associated Press, 2004b). Although the trial has been the subject of several reviews, as noted, no definitive document in the public domain critically and objectively evaluates the study’s design, conduct, results, and validity. This has led to uncertainty among public health and medical professionals—as well as political circles and the broader HIV-1-affected communities—regarding the use of NVP for preventing mother-to-child transmission (Cohen, 2004). Given continuing controversy surrounding the trial, NIH asked the Institute of Medicine (IOM) to conduct an independent review of the trial. CHARGE TO THE COMMITTEE The IOM Committee on Reviewing the HIVNET 012 Perinatal HIV Prevention Study convened to address a number of questions related to the trial. Box 1-1 contains the full charge to the committee. Some of these questions (such as numbers 2 and 6) ask the committee to render a finding on a specific issue. Overall, however, the questions focus on whether the scientific validity and results of the HIVNET 012 trial as reported in the scientific literature can be upheld. 2   Source documents included all clinical forms completed for each participant at the time of scheduled and unscheduled visits to the study clinic, and staff abstractions developed based on hospital admissions forms, before those became available to study staff. 3   The audit reviewed 25,000 data points from the study database on a random sample of 80 mother/infant pairs stratified by location (including Old Mulago and New Mulago enrollees—see Chapter 3) and infant mortality status.

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Review of the HIVNET 012 Perinatal HIV Prevention Study BOX 1.1 Charge to the Committee The IOM committee will address methodological and data interpretation questions related to protocol design, data collection, record keeping, quality control, and analysis. The committee will assess the impact of these issues on the validity of the overall findings and conclusions of the trial. The IOM committee is charged with addressing the following questions related to HIVNET 012: Was the protocol design appropriate? Does the fact that, in many cases, there were no informed-consent forms from the fathers cause enough significant concern to invalidate the conclusions? Are there results available (published or unpublished) of assays of drug levels and should consideration be given to what, if any, impact they might have on the conclusions? Was the protocol followed sufficiently to conclude that the data are sustainable? Was the quality control sufficient to uphold the conclusions? A certain number of documents were destroyed by a natural disaster. Is this a significant deterrent to drawing conclusions? Can the integrity of the data be sustained in view of the deficiencies of the data collection, and the consistency of its recording? Are the conclusions supportable by the data? Is there any reason to suggest the need to retract the publications or to revise the conclusions?a a   NIH initially asked the committee to examine resistance to NVP and the implications for its use. At the time of the trial, little was known about NVP resistance. Although a number of studies have since examined the issue, the committee considered a review of NVP resistance outside its mandate, which focused on the HIVNET 012 trial. NIH therefore withdrew this question from the committee’s charge. STUDY PROCESS The committee relied on a variety of means to gather information to address its charge. It held two information-gathering meetings that were open to the public. The first—held September 30 and October 1, 2004—focused on an overview of the HIVNET 012 trial, the NIH remonitoring effort, and information on the safety and efficacy of other clinical trials involving the use of NVP to prevent mother-to-child transmission. (See Appendix A for the agenda of that meeting.) The second information-gathering meeting, held January 4–5, 2005, focused on the quality of record keeping and other processes used during the study. (See Appendix A for the agenda of that meeting.) The committee also held a closed session November 4–5, 2004. The committee also had numerous conference call meetings after the January meeting.

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Review of the HIVNET 012 Perinatal HIV Prevention Study Committee members and staff also obtained information from NIH, DAIDS, Johns Hopkins and Ugandan investigators, Westat, FHI, SCHARP, and others. The committee reviewed study protocols, manuals on operating procedures, key reports on audits and site visits, informed-consent forms, and documents on the randomization procedures used in the study. The committee also undertook a limited review of source records, case report forms, and the analytic database for a sample of study participants. FRAMING OF THE COMMITTEE’S DELIBERATION Early in its deliberations, the committee concluded that the validity of the trial’s findings ultimately rested on the following elements: (1) the integrity of the study design, treatment assignment, and treatment adherence; (2) the completeness and accuracy of efficacy and safety data; and (3) the study’s adherence to ethical principles for conducting clinical research. The first element encompasses the soundness of the scientific design, including the treatment setting, treatment regimen, eligibility criteria, randomization procedures, sample size, and drug delivery and adherence. The second element includes information on HIV-1 infection, the survival of infants, and adverse events (serious and non-serious). The third element focuses on the integrity of the procedures used to protect human subjects. The committee’s approach was informed by the recognition that study design and conduct must be assessed from the perspective of scientific validity and global standards for protecting human subjects. In Chapter 2, the committee provides more detail on how researchers conducted HIVNET 012 and a brief overview of the key events that occurred during and after the trial. In Chapters 3, 4, and 5, the committee evaluates the three critical elements of the study and offers its findings. In Chapter 6, the committee provides its overall assessment of the validity of the trial. Readers familiar with the controversy surrounding HIVNET 012 should be aware that the committee’s review was limited to an assessment of whether the integrity of the data from the trial is sufficient to support its findings. The committee was not involved in any investigation of NIH personnel, nor in allegations and litigation regarding cover-up of study deficiencies. The executive branch and Congress are investigating these matters. The committee’s charge also does not include a review of recent reports concerning the potential toxicity of NVP as part of a long-course triple-drug therapy used to treat adult patients.

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Review of the HIVNET 012 Perinatal HIV Prevention Study REFERENCES Associated Press. 2004a. NIH Researcher Seeks Whistleblower Protection: Fishbein Reported Concerns About AIDS Research. [Online] Available at http://www.msnbc.com/id/6707616/. Accessed December 14, 2004. Associated Press. 2004b. NIH Dismissed Concerns About AIDS Treatment: White House Stands by US Decision to Send Drug to Africa. [Online] Available at: http://www.msnbc.msn.com/id/6707600/. Accessed December 14, 2004. Boehringer Ingelheim. 2002. Boehringer Ingelheim Comments on HIVNET 012 Trial. [Online] Available at http://www.boehringer-ingelheim.com/corporate/asp/news/ndetail.asp?ID+224. Accessed June 24, 2004. Chamberlin J, Gustavson SA, Hensley M, Lander S. 2002. Site Visit Report, Kampala, Uganda, February 18-28, 2002. Westat Corporation, MD. Cohen J. 2004. HIV transmission. Allegations raise fears of backlash against AIDS prevention strategy. Science 306(5705):2168-2169. Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O’Sullivan MJ, VanDyke R, Bey M, Shearer W, Jacobson RL, Jimenez E, O’Neill E, Bazin B, Delfraissy J, Culnane M, Coombs R, Elkins M, Moye J, Stratton P, Balsley J, for The Pediatric AIDS Clinical Trials Gropu Protocol 076 Study Group. 1994. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. New England Journal of Medicine 331(18): 1173-1180. DAIDS, NIAID (Division of AIDS, National Institute of Allergy and Infectious Diseases). 2003. HIVNET 012 Monitoring Report. DAIDS, NIAID. 2002. DAIDS Summary of March 19 Westat Debriefing. FHI (Family Health International). 2002. Response to DAIDS by FHI on Westat Inspection Report for HIVNET 012—Kampala, Uganda—Conducted February 18-28, 2002. Guay LA, Musoke P, Fleming T, Bagenda D, Allen M, Nakabiito C, Sherman J, Bakaki P, Ducar C, Deseyve M, Emel L, Mirochnick M, Fowler MG, Mofenson L, Miotti P, Dransfield K, Bray D, Mmiro F, Jackson JB. 1999. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 354(9181): 795-802. HIVNET 012 Investigators. 2002. Summary Sheet of Major Inaccuracies in the Westat Report. HIVNET 012 Investigators. 2000. Protocol HIVNET 012: Amendment II. Extended Mother and Child Follow-Up. Jackson JB, Musoke P, Fleming T, Guay LA, Bagenda D, Allen M, Nakabiito C, Sherman J, Bakaki P, Owor M, Ducar C, Deseyve M, Mwatha A, Emel L, Duefield C, Mirochnick M, Fowler MG, Mofenson L, Miotti P, Gigliotti M, Bray D, Mmiro F. 2003. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial. Lancet 362(9387):859-868. SCHARP (Statistical Center for HIV/AIDS Research and Prevention). 2002. Response to Westat Site Visit Report. UNAIDS (Joint United Nations Programme on HIV/AIDS) and WHO (World Health Organization). 2004. AIDS Epidemic Update. [Online] Available at http://www.unaids.org/wad.2004/report.html. Accessed March 4, 2005.