The IOM's analysis of the design and methodology
of the 1997 drug study in Uganda, called HIVNET 012, determined that
policy-makers and other scientists can rely on the resulting data and
conclusions, despite some flaws in record keeping and procedural issues. The
data from the HIVNET 012 study, which showed that nevirapine effectively
prevents many infants from contracting HIV from their infected mothers, are
sound and reliable, said James Ware, chair of the committee that wrote the
report, and professor of biostatistics, Harvard School of Public Health, Boston.
None of the shortcomings that we discovered upon reviewing the data and
conducting our own original analysis of source documents indicates a need to
retract or discount the study's findings. Our confidence in the trial's data and
findings is based on several factors, including evidence that the study's design
was both scientifically sound and ethically implemented, that participants
adhered well to the treatment regimens, and that a high percentage of
participants remained in the study so that the effectiveness and safety of the
drug could be thoroughly assessed. Previous evaluations of HIVNET 012 left
lingering uncertainties about the trial's results, suggesting the need for a
definitive, objective review.
The IOM focused on the scientific validity of
the study's conclusions based on a close examination of how researchers from
Johns Hopkins University and Uganda's Makerere University conducted the trial.
This independent review was requested and funded by the National Institutes of
Health, which also funded the original trial in Uganda. The
committee did not evaluate the trial's oversight by the National Institutes of
Health. It also did not examine the impact of other recent studies of potential
toxicity or resistance buildup associated with the use of nevirapine either in
short- or long-term treatment of HIV-infected individuals. Because of
inconsistencies in and challenges to previous audits, the committee undertook
its own assessment of the accuracy and completeness of the trial's reporting
through a review of medical records and other primary source documents for a
subset of 49 infants involved in the trial. In addition, the committee reviewed
information provided by NIH, the original investigators, previous audits of the
trial, and other information brought to its attention. The findings of the
HIVNET 012 study previously underwent audits by Westat Corp. and by NIH's
Division of AIDS (DAIDS).
The Hopkins and Makerere researchers' conclusion
that nevirapine is effective is supported by data on rates of survival and HIV
infection among newborns in the study, the committee determined, noting that the
trial researchers accurately recorded that information in the database created
for the study. No evidence was found that the trial researchers either failed to
report or mistakenly reported the deaths of any of the infants. Regarding the
trial researchers' findings on nevirapine's safety, the committee's review of
source documents for the subset of 49 infants found that deaths,
hospitalizations, and serious adverse events observed during clinic visits also
were recorded accurately in the trial database. In some instances, however, not
all serious adverse events that occurred simultaneously were reported, and some
less-serious adverse events were underreported. However, there was no evidence
of a difference in the level of underreporting of adverse events among patients
receiving nevirapine versus those receiving zidovudine, a second AIDS drug that
also was studied in HIVNET 012. The trial investigators' comparative findings on
safety are valid, the committee said.
Questions in previous audits about whether any
adverse events had been missed stemmed from the trial investigators' use of a
narrow but acceptable interpretation of what counted as serious. The
Hopkins and Makerere researchers used hospitalization as the principal -- but
not sole * determinant to classify clinical events as serious to
take into account the high prevalence of malaria, tuberculosis, and other
concurrent health problems in Uganda. The IOM report finds that the
investigators' use of a narrow interpretation was reasonable, but it means that
other researchers may not be able to generalize the study's total rate of
adverse events to all settings. Other settings -- such as countries with lower
rates of endemic diseases -- may have different thresholds for hospitalization
and interpretations of what counts as serious.
Another concern about HIVNET 012 focused on
whether cases of jaundice -- or hyperbilirubinemia -- among infants in the study
were underreported. While the study investigators reported only one infant with
abnormal levels of bilirubin, a subsequent safety report issued by DAIDS
initially stated that there were 63 cases of elevated bilirubin. DAIDS later
retracted the safety report as incorrect. The IOM committee, based on its own
analysis, determined that the DAIDS safety report initially used an incorrect
upper limit of the normal range for bilirubin levels in newborns. When the
correct upper limit is applied, the trial data confirm the original HIVNET 012
investigators' findings and the subsequent DAIDS retraction. Overall, the
Hopkins and Makerere researchers conducted the trial ethically and in accordance
with U.S. and international standards for research and management of patient
care, the IOM report says. Although there were some problems with full
documentation of compliance with all the requirements for the trial, the
committee determined that the HIVNET 012 study was designed and implemented with
approval from the boards that oversaw the trial's design and protocols that the
researchers enrolled women only after they gave free and informed consent and
that fathers were involved in the consent process when they were reasonably
available.
Blood tests that detected the presence of
nevirapine in mothers and infants and other data showed that trial participants
received the right drug and there was a high level of adherence to the treatment
regimens, the committee found. It also noted that trial investigators achieved
high rates of retention and follow-up among participants. The committee found no
reason that medical journals should revise or retract articles that reported on
the efficacy and safety of nevirapine for reducing mother-to-child transmission
of HIV based on the HIVNET 012 trial. The Institute of Medicine is a private,
nonprofit institution that provides health policy advice under a congressional
charter granted to the National Academy of Sciences. A committee roster follows.
A pre-publication version of Review of the
HIVNET 012 Perinatal HIV Prevention Study is available from the National
Academies Press tel. 202-334-3313 or 1-800-624-6242 or on the Internet at http://www.nap.edu.
Reporters may obtain a pre-publication copy from the Office of News and Public
Information (contacts listed above).
INSTITUTE OF MEDICINE
Board on Population Health and Public Health
Practice
Committee on Reviewing the HIVNET 012 Clinical
Trial James H. Ware, Ph.D. (chair) Dean for Academic Affairs, and Frederick
Mosteller Professor of Biostatistics School of Public Health Harvard University
Boston
R. Alta Charo, J.D.
Elizabeth S. Wilson Professor of Law and
Bioethics University of Wisconsin Law School and Medica1 School, and Associate
Dean University of Wisconsin Law School Madison
Ezra C. Davidson Jr., M.D.
Associate Dean of Primary Care, and
Professor of Obstetrics and Gynecology
Charles R. Drew University of Medicine and
Science Los Angeles
Wafaa El-Sadr, M.D., M.P.H., M.P.A.
Director
Center for Infectious Diseases Epidemiologic
Research, and Professor of Clinical Medicine and Epidemiology Mailman School of
Public Health Columbia University New York City
Mark W. Kline, M.D.
Professor of Pediatrics
Chief of Retrovirology
Director, AIDS International Training and
Research Program Director, Baylor-CDC Global AIDS Technical Assistance Project
and Associate Director of General Clinical Research Center Baylor College of
Medicine Houston
Stephen W. Lagakos, Ph.D.
Henry Pickering Walcott Professor of
Biostatistics and Chair Department of Biostatistics School of Public Health
Harvard University Boston
J. Richard Landis, Ph.D.
Professor of Biostatistics, and
Director, Division of Biostatistics
Department of Biostatistics and Epidemiology
School of Medicine University of Pennsylvania Philadelphia
George W. Rutherford III, M.D.
Salvatore Pablo Lucia Professor of Preventive
Medicine Professor-in-Residence of Epidemiology, Preventive Medicine,
Pediatrics, and Family and Community Medicine Head, Division of Preventive
Medicine and Public Health and Interim Director of Institute for Global Health
University of California San Francisco
Charles van der Horst, M.D.
Professor of Medicine and Associate Chief
Division of Infectious Diseases School of Medicine University of North Carolina
Chapel Hill, and Visiting Professor University of the Witwatersrand
Johannesburg, South Africa
INSTITUTE STAFF
Alicia R. Gable, M.P.H.
Study Director
Rose Marie Martinez, Sc.D.
Director, Board on Population Health and Public
Health Practice
(Source: e-drug, April 7, 2005)
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