Om brugen af Nevirapine

 

Five Critical Statements on the Safety and Efficacy of Nevirapine for Mother-to-Child Transmission Prevention

24 March 2002
FOR WIDEST DISTRIBUTION

Here are five statements that affirm the safety and efficacy of nevirapine
for the prevention of mother-to-child transmission.

1. World Health Organisation (WHO) / UNAIDS Joint Press Statement

2. National Institute of Allergy and Infectious Diseases (NIAID) Statement
(NIAID is a division of the NIH)

3. Centre for Disease Control Questions and Answers about NIAID Statement

4. Elizabeth Glaser Foundation Memo, Statement and Questions and Answers
about Mother-to-Child Transmission Prevention and Nevirapine

5. Boehringer Ingelheim Statement about HIVNET 012 Trial

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JOINT WHO/UNAIDS PRESS STATEMENT

WHO AND UNAIDS CONTINUE TO SUPPORT USE OF NEVIRAPINE FOR PREVENTION OF
MOTHER-TO-CHILD HIV TRANSMISSION

Geneva, 22 March 2002 - The statement released today by the United States
National Institutes of Health (NIH), concerning some reporting and
documentation irregularities in clinical trial HIVNET012, does not warrant
any change in the recommendations issued following a WHO technical
consultation on mother-to-child HIV transmission in October 2000. This
expert group, convened by WHO on behalf of UNICEF, UNFPA, and the UNAIDS
Secretariat, concluded that the safety and effectiveness of antiretroviral
regimens, including nevirapine, in preventing mother-to-child HIV
transmission has been clearly documented and that the use of these
regimens is thus warranted for preventing mother-to-child HIV
transmission. The simplest regimen requires a single dose of nevirapine to
the mother at delivery and a single dose to the newborn within 72 hours of
birth. The NIH statement emphasized that, according to available
information, there has been no evidence the scientific data from the
HIVNET012 study demonstrating the safety and effectiveness of nevirapine
is invalid. Each year, more than 600 000 infants become infected with HIV,
mainly through mother-to-child transmission. WHO and the UNAIDS
Secretariat recommend that the prevention of mother-to-child transmission
of HIV, including antiretroviral regimens such as nevirapine, should be
included in the minimum standard package of care for HIV-positive women
and their children. We are aware of no information that would cause the
WHO and UNAIDS to change its recommendations.

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For more information, please contact Bernhard Schwartlander, WHO, Geneva
(+41 79) 689 1332, Jon LidŽn, WHO, Geneva (+41 79) 244 6006, Anne Winter,
UNAIDS, Geneva, (+41 22) 791 4577, Dominique de Santis, UNAIDS, Geneva,
(+41 22) 791 4509 or Andrew Shih, UNAIDS, New York, (+ 1 212) 584 5012.

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Statement by National Institute of Allergy and Infectious Diseases:
National Institutes of Health

March 22, 2002
STATEMENT

Review of HIVNET 012

(A Clinical Trial to Determine the Efficacy of Oral AZT and the Efficacy
of Oral Nevirapine for the Prevention of Vertical Transmission of
HIV-1 Infection in Pregnant Ugandan Women and Their Neonates)

Since 1997, funding from the National Institute of Allergy and Infectious
Diseases (NIAID), National Institutes of Health (NIH), has supported a
trial known as HIVNET 012, conducted by co-investigators at Makerere
University in Kampala, Uganda, and the Johns Hopkins University in
Baltimore, Maryland. The trial was designed to examine the effectiveness
of nevirapine (NVP) in blocking transmission of HIV from a mother to her
newborn baby by treating the mother and baby at the time of birth. NVP is
approved by the U.S. Food and Drug Administration (FDA) for the treatment
of HIV infection in adults and children. Enrollment in HIVNET012 was
completed in 1999. The results, published in Lancet in 1999, concluded
that NVP significantly reduced the risk of HIV transmission from mother to
child during the first week of life. Other studies conducted in the United
States and internationally were consistent with the results from HIVNET
012. Based on the data from these studies, a U.S. Public Health Service
Task Force currently recommends NVP as an option for prevention of
mother-to-child transmission (MTCT) for women and their newborns in the
United States who have not received antiretroviral therapy during
pregnancy.

An examination of the data to support an extension of the indication for
the use of NVP to include prevention of MTCT was recently begun. Although
no evidence has been found that the conclusions of HIVNET 012 are invalid
or that any trial participants were placed at an increased risk of harm,
certain aspects of the collection of the primary data may not conform to
FDA regulatory requirements. A comprehensive effort to access the primary
data has begun to determine the applicability of the data collection
processes to these regulatory requirements.

The reduction in perinatal transmission by the use of NVP, an accessible,
inexpensive regimen, represents a major public health advance in
resource-poor settings and NIAID believes there is no reason for programs
implementing this life-saving regimen to change their practices.

NIAID is committed to ensuring the highest standards of patient safety,
investigator conduct and accountability, and regulatory cooperation in all
clinical trials carried out in the United States and abroad.

NIAID is a component of the NIH. NIAID supports basic and applied
research to prevent, diagnose, and treat infectious and immune-mediated
illnesses, including HIV/AIDS and other sexually transmitted diseases,
illness from potential agents of bioterrorism, tuberculosis, malaria,
autoimmune disorders, asthma and allergies.

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Prepared by:
Office of Communications and Public Liaison
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD 20892
Press Office: (301) 402-1663

CDC Media Q&A
Response to NIAID Statement on HIVNET 012 March 21, 2002

What is your reaction to the NIAID statement regarding the problems with
HIVNET012?

Based on the press statement, the NIAID preliminary review revealed no
evidence that the scientific data produced during the study is invalid or
that trial participants were placed at increased risk of harm. The
reduction of perinatal transmission by an accessible, inexpensive regimen
represents a major public health advance in resource poor settings, and
CDC believes that there is no reason for other programs implementing this
life-saving regimen to change their practice. In addition to the HIVNET
012 trial, several other trials have evaluated the safety and/or efficacy
of single dose NVP for perinatal HIV prevention, and it has been
demonstrated to be both safe and effective.

Does this change recommendations for the U.S. of NVP for perinatal
prevention in the U.S?

No, at this point, based on the information we have, the NIAID review has identified no problems that would warrant a change in the PHS
Recommendations for the Use of Antiretroviral Drugs in Pregnant
HIV-1-Infected Women for Maternal Health and Interventions to Reduce
Perinatal HIV-1 Transmission in the U.S. (www.hivatis.org)." Because
HIV-infected women present at varying times during pregnancy, with varying
levels of prenatal care and previous antiretroviral treatment, these
guidelines present multiple clinical scenarios. For HIV-infected women
who do not present for care until they are in labor and who have had no
prior antiretroviral therapy, one of the recommended treatment regimens is
the single dose NVP regimen for themselves and their babies.

It will of course be important for NIAID to complete their review. If any
problems are identified regarding the single-dose NVP regimen for
prevention of mother-to-child HIV transmission, the USPHS perinatal task
force will review the data and current recommendations. Additionally,
both domestic and international mother-to-child prevention programs would
be reviewed for appropriate guidance. At present, the benefit of NVP in
preventing mother-to-infant HIV transmission has been clearly documented and available data indicate that this is a safe, inexpensive and effective regimen. Therefore, CDC continues to support NVP as one of four options for reducing perinatal HIV transmission among women who learn of their HIV-infection late in the course of pregnancy or during labor. Does this change the recommendations for use of NVP for perinatal HIV prevention in
the developing world? WHO and UNAIDS are the agencies responsible for
making recommendations for the use of preventive regimens in the
developing world. CDC and NIH provide technical consultation as they
develop their guidelines, but questions regarding any changes in
recommendations should be directed to them. At present, UNAIDS and WHO,
based on a review of safety and efficacy data from several large clinical trials, have concluded that single-dose NVP for the mother and the infant is safe and effective for the prevention of perinatal HIV transmission and
do recommend its use in the developing world.

Will CDC continue to support its use in developing nations?

The reduction of perinatal HIV transmission by an accessible, inexpensive regimen represents a major public health advance in resource poor settings and there is no reason for programs implementing this life-saving regimen
to change their practice. Both WHO/UNAIDS recommendations and a USPHS
perinatal task force review of available safety and efficacy data conclude that NVP has been demonstrated to significantly reduce the risk of
perinatal HIV transmission (by 40 to 50%), and available data demonstrate
an excellent short-term safety profile for this single dose regimen when
given to mothers at labor onset and to their newborns. Therefore, CDC
continues to support the use of NVP as part of perinatal HIV prevention
programs in the developing world. If any problems are identified
regarding the single-dose NVP regimen for prevention of mother-to-child
HIV transmission, CDC would, of course, review the data and both domestic
and international mother-to-child prevention programs for appropriate
guidance.
Upon what data were the U.S. and international recommendations based?

In addition to the safety and efficacy data reported in the HIVNET 012
trial, a South African clinical trial (SAINT) of 660 mother/infant pairs
who received NVP has reported similar efficacy and short-term safety data.
In the US, two studies have provided data supporting the safety of
single-dose NVP: a Phase I safety study of NVP in 17 mother/infant pairs
(PACTG 250) and a large phase III clinical trial (PACTG 316) in which more than 600 women and their infants received a single dose of NVP in addition to other antiretroviral drugs during pregnancy.
Is CDC conducting other studies using NVP?
Yes, CDC is currently conducting studies in the U.S. and Thailand that use single-dose NVP for perinatal HIV prevention. The U.S. study, MIRIAD, is
evaluating the use of rapid HIV testing in women who present for delivery
without knowledge of their HIV status. Women who are found to be infected
will be treated according to the PHS Recommendations for the Use of
Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health
and Interventions to Reduce Perinatal HIV-1 Transmission in the U.S.
(www.hivatis.org)." One of the four recommended treatment regimens for
women who are HIV-infected, in labor and not on antiretroviral therapy is
a single dose of NVP to the mother and her infant. The Thailand study
looks at the safety and feasibility of providing single dose NVP to Thai
women and their infants along with short-course ZDV.

Will CDC studies be stopped?

No. CDC has no studies of NVP at the Uganda trial site under NIH review.
Because the NIAID review of this site revealed no evidence that the
scientific data on the safety or efficacy of NVP is invalid, there is no
reason to suspend other studies of NVP at this time. It is of course
important for NIAID to complete their review. If any problems are
identified regarding the single-dose NVP regimen for prevention of
mother-to-child HIV transmission, CDC would review the data and take
appropriate action.

Memo, Statement and Q&A by Elizabeth Glaser Foundation

M E M O R A N D U M

TO: Members of the Board of Directors

FROM: Kate Carr and Catherine Wilfert, MD DATE: March 20, 2002

RE: Nevirapine and FDA

We are writing to provide you with information regarding the supplementary
application of Boehringer Ingelheim (BI) to the FDA for US approval of
nevirapine (Viramune) for the prevention of mother-to-child transmission.
Today it was announced that this application has been withdrawn because of the need for additional information which will be required to prepare a
complete application to the FDA. The NIH contracted with auditors to
examine data from the study to support the manufacturer's application to
expand Food and Drug Administration (FDA) approval for use of the drug to
prevent mother-to-child transmission of HIV. The initial review
recognized some reporting and documentation irregularities at the site of the HIVNET 012 trial in Kampala, Uganda. A comprehensive follow-up review will be initiated.

A statement by NIH indicates "no evidence that the scientific data
produced during the study is invalid or that trial participants were
placed at increased risk of harm. The reduction of perinatal transmission
by an accessible inexpensive regimen represents a major public health
advance in resource poor settings and NIAID believes that there is no
reason for other programs implementing this life-saving regimen to change
their practice." The Elizabeth Glaser Pediatric AIDS Foundation continues
to support the use of nevirapine to prevent mother-to-child transmission
of HIV in resource poor settings. Short-term safety and tolerance of
single dose nevirapine has been demonstrated in multiple clinical trials.
Efficacy of the intervention has been established and documented in the
SAINT trial in addition to HIVNET 012. A technical review conducted by
WHO which was released in November, 2001 also clearly indicates that based
on proven safety and efficacy nevirapine may be used in programs to
prevent MTCT.

We have attached the statement from NIH as well as an overview document
which we have prepared. Please contact us with any questions or concerns.

Press Statement

The Elizabeth Glaser Pediatric AIDS Foundation supports the use of
nevirapine to prevent mother-to-child transmission of HIV in resource poor
countries based on recommendations of the WHO and the NIH, peer reviewed
results published in established medical publications, and experience
gained through our Call to Action Project. The Foundation has provided
grants to over 100 health care sites in 13 countries to implement programs
to prevent mother-to-child transmission of HIV using several established
interventions, including nevirapine programs in resource poor settings,
where they have the potential to significantly lower the risk of
transmitting HIV from a mother to her child.

Q & A

Why are programs to prevent mother to child transmission of HIV so
critical?

Effective means to reduce mother to child transmission (MTCT) can have a
substantial impact on the HIV/AIDS epidemic as UNAIDS estimates that
800,000 new infections occurred in children under 15 years of age in
2001. Over 90% of these newly infected children live in Sub-Saharan Africa
and 95% of these children were infected through MTCT. What interventions
are available to prevent MTCT?

Provision of antiretroviral drugs to a pregnant woman and her newborn can
substantively reduce the transmission of virus from a mother to her
child. In developed nations with access to combination antiretroviral
therapy and to replacement feeding, transmission has been reduced to
1-2%. The feasible and simpler drug regimens, including AZT
administered for 4 weeks prior to delivery, AZT/3TC and nevirapine (NVP)
administered at the onset of labor and to the newborn for one week, and a
two-dose regimen of NVP given once to a pregnant woman during labor and
once to her infant at 48-72 hours of age, have been shown to substantively
reduce perinatal transmission.

How do we know NVP works?

In 1999, results of a joint Uganda/U.S. clinical trial known as HIVNET 012
indicated that an easy to administer, single-dose regimen of nevirapine,
given once to the pregnant woman during labor and once to her infant in
the first three days of life, could reduce the risk of transmission of HIV
from mother to child by 47 percent. These results were subject to
peer-review and published in the Lancet. (Guay LA, Musoke P, Fleming T, et al. HIVNET 012 randomized trial. Intrapartum and neonatal single-dose
nevirapine compared with zidovudine for prevention of mother-to-child
transmission of HIV-1 in Kampala, Uganda, Lancet 1999.) Subsequently, the
SAINT study in South Africa confirmed the efficacy of nevirapine
equivalent to that of AZT/3TC. We are not aware of any evidence that
refutes or diminishes the data in these studies or the conclusions drawn
from it.

What are the benefits of using nevirapine?

A two-dose regimen of NVP, given once to a pregnant woman during labor and
once to her infant at 48-72 hours of age, could reduce the risk of
transmission by almost 50%. NVP is simple as the drug can be given by
mouth and under direct observation. Mothers can take the drug
confidentially. The drug does not require refrigeration. It is
inexpensive and even obtainable free of charge through a donation
program. NVP is the only regimen administered as simply as two doses of
medicine. The documented ability of CTA sites to deliver this
intervention is twice as efficient as sites choosing to use a more complex
regimen such as 4 weeks of AZT. Is nevirapine safe for use in preventing
MTCT?

The single-dose NVP regimen has been studied in 3 large, randomized,
comparative, phase III clinical trials comprising over 1,600 HIV-infected
women and their infants and no significant clinical or laboratory toxicity has been observed. In these controlled clinical trials, it was concluded (and reported in the WHO technical consultation) that the benefits of
these drugs in reducing mother to child HIV transmission greatly outweigh
any potential adverse effects of drug exposure.
In addition to HIVNET 012, what studies have been done on nevirapine?

There have been two phase I studies and two phase III clinical trials
focusing on the prevention of MTCT of HIV using NVP. NVP was first
administered as a single dose to 38 pregnant women and their infants in
two phase I studies, one performed in the U.S., involving 17 mother-infant
pairs (Pediatric AIDS Clinical Trials Group [PACTG] protocol 250) and the
other in Uganda, involving 21 mother-infant pairs (HIVNET 006).

The single-dose NVP regimen has also been studied in 3 large, randomized,
comparative, phase III clinical trials comprising over 1,600 HIV-infected
women and their infants. In HIVNET 012, single-dose NVP was compared with
an ultra-short intrapartum/1 week infant AZT regimen in Uganda. PACTG 316
was a phase III, randomized, double-blind clinical trial conducted in the
U.S., Europe, Brazil and the Bahamas where 642 randomized women and their
infants received the single-dose NVP regimen and 628 randomized women and
their infants received a placebo. The SAINT trial was a phase III
randomized comparative trial conducted in South Africa where a randomized
group of 654 mothers were given a single dose of NVP at onset of labor and a second dose at 48 hours postpartum; their infants received a single 48
hour NVP dose. (Daya Moodley on behalf of SAINT Investigators team,
abstract LbOr2 presented at the 13th International AIDS Conference,
Durban, South Africa, July 2000)

What is known about the long-term effects of nevirapine on infants?

Nevirapine has been approved by the FDA for regular use in adults since
1996 and children 2 months and older since 1998. While more research on
this issue is encouraged, there are no indications that a single dose
regimen of NVP will have long-term effects on infants. We are following
the recommendations of WHO and the NIH to continue implementation of
single-dose NVP programs in resource poor settings, where it has the
potential to significantly impact the perinatal HIV epidemic.

Has nevirapine been approved for any applications by the FDA?

In 1996, the FDA approved the use of NVP combination with nucleoside
analogues to treat adults with HIV infection who have experienced clinical
and/or immunological deterioration. It was the ninth drug approved by the
FDA for the treatment of people with HIV infection. In 1998, NVP was
approved for use in children over the age of 2 months.

Boehringer Ingelheim Comments on HIVNET 012 Trial

Ridgefield, CT, March 22, 2002--Boehringer Ingelheim is aware that
questions have been raised regarding reporting and documentation in a
study conducted in Uganda for prevention of the transmission of HIV from mother-to-child during birth called HIVNET 012. The study, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID),
Bethesda, Maryland, and conducted by Johns Hopkins University and Makerere
University, evaluated the use of the Boehringer Ingelheim drug VIRAMUNE¨
(nevirapine). Study data from the HIVNET 012 trial were
part of a pending supplemental NDA submitted by Boehringer Ingelheim in
support of this indication in the U.S.

The study results, published in the British medical journal, The Lancet,
concluded that nevirapine significantly lowered the risk of HIV
transmission from mother to child during the first weeks of life.
Extensive data from other trials support the safety of nevirapine in
mothers and infants in this setting.

NIAID is vigorously undertaking a comprehensive review of all the data
collected in the course of the study. Boehringer Ingelheim has offered to
support NIAID in this effort and is confident that the results of this
review will confirm the positive conclusions published in The Lancet.
However, since this NIAID and Boehringer Ingelheim review could not be completed within the remaining timeline for FDA action for the
supplement, Boehringer Ingelheim has notified the FDA of its decision to
withdraw the U.S. sNDA for prevention of mother-to-child transmission at
this time.

Boehringer Ingelheim continues to support the use of nevirapine and will
continue to offer the drug to developing countries for the prevention of mother-to-child transmission of HIV as part of the VIRAMUNE Donation
Programme.

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