Review of the HIVNET 012 Perinatal HIV Prevention Study

Committee on Reviewing the HIVNET 012 Perinatal HIV Prevention Study

Board on Population Health and Public Health Practice

INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington, D.C.
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Review of the HIVNET 012 Perinatal HIV Prevention Study Review of the HIVNET 012 Perinatal HIV Prevention Study Committee on Reviewing the HIVNET 012 Perinatal HIV Prevention Study Board on Population Health and Public Health Practice INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Review of the HIVNET 012 Perinatal HIV Prevention Study THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001 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. Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); http://www.nap.edu. International Standard Book Number 0-309-09651-0 Library of Congres Control Number 2005931056 For more information about the Institute of Medicine, visit the IOM home page at www.iom.edu. Copyright 2005 by the National Academy of Sciences. All rights reserved. Printed in the United States of America. The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.

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Review of the HIVNET 012 Perinatal HIV Prevention Study “Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES Adviser to the Nation to Improve Health

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Review of the HIVNET 012 Perinatal HIV Prevention Study THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Wm. A. Wulf is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Review of the HIVNET 012 Perinatal HIV Prevention Study 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

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Review of the HIVNET 012 Perinatal HIV Prevention Study 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

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Review of the HIVNET 012 Perinatal HIV Prevention Study 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

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Review of the HIVNET 012 Perinatal HIV Prevention Study 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.

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Review of the HIVNET 012 Perinatal HIV Prevention Study 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-

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Review of the HIVNET 012 Perinatal HIV Prevention Study 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

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Review of the HIVNET 012 Perinatal HIV Prevention Study Contents     EXECUTIVE SUMMARY   1      References,   10 1   INTRODUCTION   11      Charge to the Committee,   14      Study Process,   15      Framing of the Committee’s Deliberation,   16      References,   17 2   OVERVIEW OF HIVNET 012   18      Results,   20      Key Events during HIVNET 012,   22      References,   26 3   STUDY DESIGN, TREATMENT ASSIGNMENT, AND ADHERENCE TO STUDY REGIMENS   27      Background,   27      Choice of Uganda as Study Site,   28      Choice of Drug Regimens,   29      Eligibility Criteria,   31      Design and Implementation of the Randomization Procedures,   31      Sample Size,   35      Statistical Methods,   36      Drug Management,   37

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Review of the HIVNET 012 Perinatal HIV Prevention Study      Drug Packaging and Handling Before Enrollment,   37      Drug Handling After Enrollment and Dosing,   38      Reviews of Pharmacy Procedures,   39      Adherence,   42      References,   44 4   EFFICACY AND SAFETY   48      Design of Efficacy and Safety Endpoints,   48      Primary Endpoints,   48      Study Implementation with Regard to the Endpoints,   51      Laboratory Data,   51      Identifying Serious Adverse Events,   51      Recording Serious Adverse Events,   54      Record Keeping at the HIVNET 012 Site,   55      Co-Enrollment into a Vitamin A Study,   56      Impact of Flooding and Other Natural Phenomena on Study Records,   57      Committee’s Review of the Completeness and Accuracy of Efficacy and Safety Endpoints,   58      Methods of Committee’s Review,   59      Survival Status,   60      HIV-1 Status,   62      Completeness and Timeliness of Reporting HIV-1 Positivity to the SCHARP Database,   63      Capture of Adverse Events, Serious Adverse Events, and Hospitalizations,   63      Hyperbilirubinemia,   67      Appropriateness of Toxicity Tables,   67      Incidence of Hyperbilirubinemia in HIVNET 012,   68      Comparisons to Other Perinatal HIV Prevention Studies Using NVP and AZT,   69      References,   70 5   REVIEW OF ETHICAL ISSUES   73      The Investigational New Drug Application,   76      Compliance with Requirements for Institutional Review Boards,   82      The Use of a Placebo Arm,   85      Compliance with Informed Consent,   89      References,   95 6   RESPONSE TO THE CHARGE TO THE COMMITTEE   98      Findings Regarding the Study Design,   99

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Review of the HIVNET 012 Perinatal HIV Prevention Study      Findings Regarding the Implementation of the Study,   101      Findings Regarding Data Collection and Quality Control,   103      Findings Regarding the Study Conclusions,   106      References,   107     APPENDIXES     A   AGENDAS OF INFORMATION-GATHERING MEETINGS   109      Meeting One, September 30, 2004,   109      Meeting Three, January 4, 2005,   112 B   COMPARISONS TO OTHER PERINATAL HIV PREVENTION STUDIES USING NVP AND AZT   113      Introduction,   113      Methods,   113      Criteria for Considering Studies for This Review,   113      Identification of Studies,   114      Statistical Methods,   115      Results,   115      Nevirapine,   115      Zidovudine,   120      Discussion,   125      References,   127 C   COMMITTEE BIOGRAPHIES   130 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,   21 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,   23 2.3   Numbers (percentages) of Women and Infants with Adverse Events, by Study Arm,   24 2.4   HIVNET 012 Timeline,   25 3.1   Shipments of Study Drug,   40 4.1   Serious Adverse Events in HIVNET 012 Infants,   53 4.2   Serious Adverse Events in HIVNET 012 Mothers,   53

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Review of the HIVNET 012 Perinatal HIV Prevention Study 4.3   Infant Adverse Events Found Only in the Source Documents,   64 4.4   Infant Clinical Serious Adverse Events Found Only in the Source Documents,   65 B.1   Description and Outcomes of Included Studies (NVP arms only),   116 B.2   Excluded Studies (NVP arms),   121 B.3   Description and Outcomes of Included Studies (ZDV arms only),   122 B.4   Excluded Studies (ZDV-only arms),   125 Box 1.1   Charge to the Committee,   15