[e-med] Etude indépendante en Ouganda sur la névirapine

["Marc Dixneuf" <Marc.DIXNEUF@sante.gouv.fr>]

Le message de ee-drug annonce que l'étude avec la névirapine dans la 
Prévention de la transmission de la mère à l'enfant conduite en Ouganda 
(HIVNET 012) a été validée par des analystes indépendants de Boston de 
Institute of Medicines of the National Academies. Il précise qu'il met fin 
aux tergiversations qui l'ont entourée.
Ce texte précise cependant que le comité n'a pas évalué l'impact d'autres 
récentes études sur la toxicité potentielle ou les mutations de résistances 
associées à la prise de névirapine en traitement court ou long. Cette 
précision se justifie parce que la Névirapine, notamment son usage dans les 
programmes de PTME, est ou a été un objet de discussions de nature très 
différentes.

D'une part, le produit a une efficacité démontrée dans la réduction de la 
TME, mais les risques de toxicité ont été avancés par le gouvernement sud 
africain pour ne pas donner accès à ce médicaments aux femmes enceintes. 
L'association Treatment Action Campaign (Afrique du Sud) s'est battue devant 
les tribunaux pour l'accès à ce médicament. Pour cette raison, le communiqué 
de presse faisant état de la validation de l'essais à fait l'objet d'une 
diffusion sur la liste de l'associaiton le dimanche 10 avril.

D'autre part, quand le produit est disponible et accessible l'efficacité du 
traitement monodose/monoprise permet de mettre en oeuvre des programmes de 
PTME utiles. Toutefois, ces programmes se limitent souvent à la prévention 
de la transmission et ne prévoient pas, quand ce serait possible, des 
programmes d'accès aux traitements pour les femmes, ce qui peut faire 
l'objet de débat : voir sur ce point l'avis du Conseil National du Sida 
(Paris) "Promouvoir l'accès aux antirétroviraux des femmes enceintes vivant 
avec le VIH/sida dans les pays du Sud": 
http://www.cns.sante.fr/htm/avis/international/24_06_04/fr_1_b.htm.]

Marc Dixneuf
Marc.DIXNEUF@sante.gouv.fr

-----Message d'origine-----

E-DRUG: HIVNET 012 Uganda nevirapine study validated by independent analysis
----------------------------------------------------------------------------
[This HIVNET 012 study was the study in Uganda that showed that perinatal 
nevirapine could prevent HIV transmission to the baby. WHO made nevirapine 
an essential drug just on this study. The study was widely discussed, also 
by politicians (e.g., the South African Minister of Health Dr Manto 
Tshabalala-Msimang) as being flawed.
The scientific results and ethical conduct of the trial have now been 
validated by an independent analysis of the Institute of Medicine of the 
National Academies.  Below is their press release.
Current PMTCT treatment proposes double or even triple ARV therapy. WB]

PRESS STATEMENT

Date: April 7, 2005
Contacts: Christine Stencel, Media Relations Officer
Megan Petty, Media Relations Assistant
Office of News and Public Information
202-334-2138; e-mail <news@nas.edu>

FOR IMMEDIATE RELEASE

Findings From Perinatal HIV Prevention Study in Uganda are Valid, New Review
Says

WASHINGTON -- A Ugandan drug trial's findings that the AIDS medication
nevirapine is effective and safe in preventing HIV transmission from mother 
to
unborn child during birth were well-supported, according to a new, 
independent
analysis by the Institute of Medicine of the National Academies. 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