National Academies Press: OpenBook
Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×

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

Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×

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.

Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×

“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

Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×

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

Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×

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

Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×

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

Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×

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

Page viii Cite
Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×

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.

Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×

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-

Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×

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

Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×
Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×
   

 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

Page xiii Cite
Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×

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

Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×

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

Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×
Page R1
Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×
Page R2
Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×
Page R3
Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×
Page R4
Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×
Page R5
Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×
Page R6
Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×
Page R7
Page viii Cite
Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×
Page R8
Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×
Page R9
Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×
Page R10
Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×
Page R11
Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×
Page R12
Page xiii Cite
Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×
Page R13
Suggested Citation:"Front Matter." Institute of Medicine. 2005. Review of the HIVNET 012 Perinatal HIV Prevention Study. Washington, DC: The National Academies Press. doi: 10.17226/11264.
×
Page R14
Next: Executive Summary »
Review of the HIVNET 012 Perinatal HIV Prevention Study Get This Book
×
Buy Paperback | $49.00 Buy Ebook | $39.99
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

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. The HIVNET 012 trial was designed to provide preliminary information on the comparative safety and efficacy of two relatively simple and inexpensive short courses of oral antiretroviral treatment likely to be feasible in resource-limited settings.

The resulting report identified some problems with procedures and documentation, but concluded that these issues did not compromise the results of the study. However, these issues have led to public scrutiny and continued controversy. Review of the HIVNET 012 Perinatal HIV Prevention Study critically and objectively evaluates the study's design and conduct, and assesses the impact of the initial procedural issues on the validity of the overall findings and conclusions of the trial.

  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    Switch between the Original Pages, where you can read the report as it appeared in print, and Text Pages for the web version, where you can highlight and search the text.

    « Back Next »
  6. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  7. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  8. ×

    View our suggested citation for this chapter.

    « Back Next »
  9. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!