Review of the HIVNET 012 Perinatal HIV Prevention Study
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NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance.
This study was supported by Contract No. N01-OD-4-2139, Task Order No. 146 between the National Academy of Sciences and the National Institutes of Health. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project.
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COMMITTEE ON REVIEWING THE HIVNET 012 PERINATAL HIV PREVENTION STUDY
JAMES H. WARE, Ph.D. (Chair), Dean for Academic Affairs and Frederick Mosteller Professor of Biostatistics,
Harvard School of Public Health, Boston, MA
R. ALTA CHARO, J.D., Elizabeth S. Wilson Professor of Law and Medical Ethics and Associate Dean,
School of Law, University of Wisconsin-Madison
EZRA C. DAVIDSON, Jr., M.D., Associate Dean, Primary Care and Professor and Past Chairman,
Department of Obstetrics & Gynecology, Charles R. Drew University of Medicine and Science, Los Angeles, CA
WAFAA EL-SADR, M.D., M.P.H., M.P.A., Professor of Clinical Medicine and Epidemiology,
Mailman School of Public Health, Columbia University, and
Chief,
Division of Infectious Diseases, Harlem Hospital Center, New York, NY
MARK W. KLINE, M.D., Professor of Pediatrics, Chief of Retrovirology; Director of the AIDS International Training and Research Program; Director of the Baylor-CDC Global AIDS Technical Assistance Project; and Associate Director of the General Clinical Research Center,
Baylor College of Medicine, Houston, TX
STEPHEN W. LAGAKOS, Ph.D., Henry Pickering Walcott Professor and Chair,
Department of Biostatistics, Harvard School of Public Health, Boston, MA
J. RICHARD LANDIS, Ph.D., Professor of Biostatistics and Director,
Division of Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine
GEORGE W. RUTHERFORD, III, M.D., Professor and Director,
Institute for Global Health, University of California, San Francisco School of Medicine
CHARLES van der HORST, M.D., Professor of Medicine,
University of North Carolina-Chapel Hill
Staff
ALICIA R. GABLE, M.P.H., Study Director
ALINA BACIU, M.P.H., Program Officer
RUTH KANTHULA, M.P.H., Senior Program Assistant
SANDRA HACKMAN, Copy Editor
ROSE MARIE MARTINEZ, Sc.D., Director,
Board on Population Health and Public Health Practice
Consultants
NANCY CALLES, B.S.N., R.N., A.C.R.N.,
Baylor International Pediatric AIDS Initiative, Baylor College of Medicine, Houston, TX
TOMMY CLARK, Ph.D.,
University of California, San Francisco
DAVID W. FEIGAL, M.D., M.P.H.,
Arizona Biodesign Institute, Phoenix, AZ
MARGARET G. FERRIS, M.P.H.,
Baylor International Pediatric AIDS Initiative, Baylor College of Medicine, Houston, TX
VALERIE FLAHERMAN, M.D., M.P.H.,
University of California, San Francisco
THOMAS NEWMAN, M.D., M.P.H.,
University of California, San Francisco
LAURA SMEATON, M.S.,
Harvard School of Public Health, Boston, MA
Reviewers
This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report:
SOLOMON BENATAR, M.D., University of Cape Town, South Africa
EDMUND V. CAPPARELLI, Pharm.D., University of California, San Diego
HOOSEN COOVADIA, M.D., University of Kwazulu/Natal
SCOTT M. HAMMER, M.D., Columbia University, New York, NY
CAREL IJSSELMUIDEN, M.D., Council on Health Research for Development, Switzerland
KYUNGMANN KIM, Ph.D., University of Wisconsin, Madison
DEBRA LAPPIN, J.D., B&D Sagamore, Washington, DC
LISA RARICK, M.D., Gaithersburg, MD
PAUL VOLBERDING, M.D., University of California, San Francisco
Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations nor did they see the final draft of the report before its release. The review of this report was overseen by CHARLES C.J. CARPENTER, M.D., Brown University and GIL OMENN, M.D., Ph.D., University of Michigan. Appointed by the National Research Council and Institute of Medicine, they were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.
Foreword
Mother-to-child transmission of HIV-1 afflicts hundreds of thousands of children every year, especially in parts of the world such as sub-Saharan Africa, where HIV infection is prevalent and resources are limited. This tragic reality has spurred researchers to search for an effective, safe, and inexpensive treatment that could reduce the risk of perinatal HIV transmission.
At a time when many countries had no affordable, easy-to-use options for preventing perinatal HIV transmission, the 1999 publication of preliminary results from the HIVNET 012 trial offered great hope. This study found that a short-course of oral nevirapine given to the mother during delivery and to the child after birth could substantially reduce the risk of mother-to-child transmission of HIV-1 infection. A number of countries in Africa and elsewhere subsequently adopted the HIVNET 012 regimen as the standard of care in their national perinatal HIV prevention programs.
Since the original publication and a second publication with more complete findings from HIVNET 012, questions have arisen in the scientific and medical communities and have been reported by the media about the conduct of the HIVNET 012 study. It was in this context that the Institute of Medicine was approached by the National Institutes of Health (NIH) to conduct an independent review of the HIVNET 012 trial.
The Institute of Medicine convened a panel of nine members who possess significant breadth and depth of expertise in pertinent fields, including clinical trials methodology, law, ethics and regulation, pediatric HIV/AIDS care, biostatistics, epidemiology, clinical treatment of HIV, and pre-
vention. The committee members were selected because they are leading authorities who could conduct an independent, rigorous assessment of the evidence. The committee’s charge was to assess the scientific validity of the findings and conclusions of the HIVNET 012 trial, including a review of methodological and data interpretation questions, and aspects of protocol design, data collection, recordkeeping, quality control, and analysis.
The committee’s report does not contain an evaluation of the National Institutes of Health, nor does it examine either NIH’s handling of the HIVNET 012 trial or the process of research oversight at NIH. These important matters were never part of the task assigned to this committee. Simply put, their report presents the committee’s best, evidence-based judgment about the scientific validity of the HIVNET 012 study findings and conclusions.
By conducting this independent scientific assessment of a controversial and consequential clinical trial, the committee and its staff have performed a valuable public service. Their report deserves to be read carefully by anyone who seeks to understand the scientific validity of the HIVNET 012 trial. More generally, the systematic approach taken by the committee serves as a model for critical, scientific review of any clinical trial.
Harvey V. Fineberg
President, Institute of Medicine
TABLES AND BOX
Tables
2.1 |
Numbers (percentages) of Infants with HIV-1 Infection and HIV-1 Infection or Death at Ages 1–3 Days, 6–8 Weeks, and 14–16 Weeks, by Study Arm, |
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2.2 |
Numbers (percentages) of Infants with HIV-1 Infection and HIV-1 Infection or Death at Ages 12 and 18 Months, by Study Arm, |
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2.3 |
Numbers (percentages) of Women and Infants with Adverse Events, by Study Arm, |
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2.4 |
HIVNET 012 Timeline, |
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3.1 |
Shipments of Study Drug, |
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4.1 |
Serious Adverse Events in HIVNET 012 Infants, |
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4.2 |
Serious Adverse Events in HIVNET 012 Mothers, |
4.3 |
Infant Adverse Events Found Only in the Source Documents, |
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4.4 |
Infant Clinical Serious Adverse Events Found Only in the Source Documents, |
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B.1 |
Description and Outcomes of Included Studies (NVP arms only), |
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B.2 |
Excluded Studies (NVP arms), |
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B.3 |
Description and Outcomes of Included Studies (ZDV arms only), |
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B.4 |
Excluded Studies (ZDV-only arms), |
Box
1.1 |
Charge to the Committee, |