In the past few days reports from the mainstream press were distributing accusing the NIH, the White House and Boehringer Ingelheim of being implicit in allegedly improper handling of information regarding the side effects of nevirapine in a Uganda study involving single-dose nevirapine to prevent mother-to-child HIV transmission. Responses to these allegations have been forthcoming in the past two days from the NIH and Elizabeth Glazer Pediatric AIDS Foundation. Last night the manufacturer of nevirapine Boehringer Ingelheim issued a Statement regarding this development. You can find all of these reports and statements below in this order: (1) Elizabeth Glazer Foundation, (2) Boehringer Ingelheim, (3) NIH, (4) summary of Mainstream Press reports. Presumably, more information and coverage of this story will surface.
ELIZABETH GLASER PEDIATRIC AIDS FOUNDATION ON ISSUE OF PREVENTION OF MOTHER-TO-CHILD TRANSMISSION OF HIV/AIDS AND SINGLE-DOSE NEVIRAPINE
December 14, 2004
In response to an Associated Press (AP) article that revisits past questions about the drug nevirapine (NVP), the Elizabeth Glaser Pediatric AIDS Foundation is issuing this statement to clarify the scientific facts, based on the full body of evidence, regarding the use of this drug to prevent mother-to-child transmission (PMTCT) of HIV in the developing world.
The Elizabeth Glaser Pediatric AIDS Foundation supports providing the safest, most effective regimen of drugs to prevent mother-to-child transmission in all instances. In the United States and other developed world settings, mother-to-child transmission has been dramatically reduced through aggressive prevention and treatment programs that are widely available. In the developing world, due to poor infrastructure and the high cost of other regimens, nevirapine, administered as one dose to the mother at the onset of labor and one dose to the child within 72 hours of birth, is frequently the only option feasible and available. There is considerable scientific data demonstrating that this short-course nevirapine regimen is safe and effective and should continue to be used to prevent mother-to-child transmission in settings where more complex regimens are not available.
The AP article raises concerns about the safety of short-course nevirapine for prevention of mother-to-child transmission. It is important to understand that there are no data demonstrating that significant NVP-induced toxicities occur in women or infants receiving short-course nevirapine for PMTCT. Although studies have shown a risk of toxicity with long-term use of nevirapine for HIV treatment, it is scientifically inaccurate to deduce harmful effects of a short-term course of nevirapine based on studies that examine long-term, continued use of the drug.
The single-dose nevirapine regimen to prevent mother-to-child transmission has been used in hundreds of thousands of women -- both in practice and in clinical trials -- without any significant toxicity for mothers or babies. Including the HIVNET 012 study, referenced in the AP article, single-dose NVP regimen has been studied in three large, randomized, comparative, phase III clinical trials including over 1,600 HIV-infected women and their infants. PACTG 316 was a phase III, randomized, double-blind clinical trial conducted in the U.S., Europe, Brazil, and the Bahamas. The South African Intrapartum Nevirapine Trial (SAINT) trial was a phase III, randomized trial comparing a combination of drugs to single-dose nevirapine. No significant clinical or laboratory toxicity was observed in any of these three studies. In addition, reports from clinicians administering this regimen in the field confirm what these studies demonstrated: that nevirapine, when taken in a short-course for PMTCT, does not cause significant toxicity in mothers or babies.
It is true that resistance has been shown to occur in those receiving short-course nevirapine. However, to date, there is no evidence of negative clinical outcomes as a result of subsequent antiretroviral therapy. The Foundation strongly supports further research about resistance issues. We are currently partnering with the Centers for Disease Control and Prevention to examine the long-term effects of a single dose of nevirapine for prevention of mother-to-child transmission on a woman's subsequent response to ARV therapies containing nevirapine. However, in the absence of evidence of negative clinical outcomes for future treatment, it would be premature to withdraw the only safe and effective regimen to prevent mother-to-child transmission of HIV that is currently available throughout large parts of Africa and other portions of the developing world.
UNAIDS estimates that 1,900 children worldwide are infected with HIV each day, the vast majority through mother-to-child transmission. Yet, services to prevent mother-to-child transmission are available to less than 10 percent of the women who need them. We must continue to work aggressively to expand access for pregnant women to scientifically-based services to prevent mother-to-child transmission and support research that will guide the very best implementation of these lifesaving programs. As one of the world's largest funders of PMTCT programs, the Foundation is committed to using the best available science to prevent as many infant infections as possible and safeguard the health of HIV-positive mothers.
In making any decision about drug regimen use, we should rely on the scientific facts. It would be premature and inappropriate to withdraw nevirapine as an option for mother-to-child transmission at a time when so many pregnant women throughout the world have no other option to save the lives of their babies. At this point in time, based on all existing scientific evidence, nevirapine should continue to be one of several interventions available to prevent mother-to-child transmission.
However, it is important to remember that safer, more effective drug regimens, including a combination of AZT and single-dose nevirapine and long-term combination therapy for the mother, exist and are already being used in some parts of the developing world. Rather than focus on withdrawing nevirapine from those who urgently need it, the entire world should focus on how we can provide the funding for infrastructure improvements, training, and drug purchase costs so that more and more women will have access to the most effective drug regimens possible. Ultimately, our goal must be for all pregnant women throughout the world to have access to the same drug therapy that is currently available in the United States and other developed nations. In the face of the worst pandemic of infectious disease in history, anything less than a full effort to save the lives of the next generation is a tragic avoidance of our fundamental responsibility.
STATEMENT From Boehringer Ingelheim
Boehringer Ingelheim provides key background on Viramune
December 15, 2004
In light of recent interest in the use of Viramune® (nevirapine), Boehringer Ingelheim (BI) provides the following background information on the drug and key events that have been revisited by the media.
Viramune has played a vital role in the fight against HIV/AIDS since its U.S. regulatory approval in 1996. The first drug in its class (non-nucleoside reverse transcriptase inhibitor), Viramune has been an important component in the effort to improve HIV drug therapy. Research supporting Viramune has helped evolve clinical management standards and has defined the current role of this drug both in chronic combination therapy and in the prevention of mother to child transmission (pMTCT) during childbirth in resource-limited settings.
Viramune for pMTCT in the developing world
The use of Viramune has been shown in clinical studies to prevent mother to child transmission of HIV infection in 40-50% of infants receiving the drug as a single-dose treatment.1 This regimen has earned the support of the public health and HIV/AIDS treatment communities, who recognize its value as an alternative option in the developing world and understand the clinical research that has clearly defined its utility in this setting.2 In resource-limited settings, single-dose Viramune is often the most feasible treatment to prevent HIV transmission from mother to child. The 2004 World Health Organization guidelines continue to recommend its use as a practical option in the developing world. 3 Through the Viramune Donation Program, BI has expanded global access to this important medication to 122 programs in 57 developing countries.
In 1997, the National Institutes of Health (NIH) requested BI's support for a study (HIVNET 012) to determine what had not yet been clearly defined: whether a simple, inexpensive, single-dose regimen of Viramune could effectively block mother-to-infant HIV transmission. BI provided support as requested by NIH and supplied the drug for a study in Uganda. Based on the very positive results of this study, BI submitted an NDA supplement to obtain an indication for pMTCT in 2001. Subsequently, BI conducted a site review of this NIH study in 2002 to assess the site's readiness for an FDA audit. The company provided preliminary findings of this site review to the NIH to signal potential issues requiring follow up. BI distributed multiple copies of its findings to key study team members at the NIH, the study's contract monitor, and Ugandan and U.S. investigators to validate our preliminary assessment and to encourage prompt correction of observed procedural deficiencies prior to the planned FDA audit.
The FDA audit was cancelled because the Ugandan study site could not correct these procedural deficiencies in the regulatory timeframe of the FDA supplement. Accordingly, BI withdrew its supplemental filing in March 2002. Following multiple reviews by NIH and the National Institute of Allergies and Infectious Diseases (NIAID), overall study conclusions regarding the safety and efficacy of single-dose Viramune in this setting have remained intact and have contributed to the evidence provided by other studies regarding the role of Viramune in pMTCT.
Viramune as part of combination therapy for the treatment of HIV/AIDS in the developed world
Viramune as treatment for chronic HIV/AIDS in combination with other HIV (antiretroviral) drugs has been used in more than 600,000 patient years worldwide since its approval in 1996. As knowledge about HIV infection and its treatment evolves, the understanding of Viramune's role in combination therapy also has increased, and BI continues to educate and support physicians' efforts to identify those patients most likely to benefit from treatment with Viramune.
Treatment with Viramune as part of combination therapy needs to be managed differently than the single-dose regimen administered in the developing world for pMTCT. Because HIV is a serious and life-threatening disease it requires treatment with potent medicines, all of which can cause serious adverse events. The most clinically important adverse events associated with Viramune are rash and liver-related events, which in rare cases may be severe and life threatening. The greatest risk of these events occurs within the first six weeks of therapy. Events are usually managed adequately if careful monitoring takes place throughout the course of therapy.
BI's commitment to the fight against HIV/AIDS
BI is a steadfast partner to professionals, patients, government and non-governmental organizations (NGOs) in the fight against HIV/AIDS. With our partners we are working toward a goal of ensuring that the next generation of infants in the developing world are born HIV-free. It is important that media reports preserve accuracy to ensure that people in AIDS-ravaged countries are not unnecessarily discouraged from continuing to use Viramune and other treatments to prevent the transmission of HIV during childbirth.
1. -- PACTG 316: Dorenbaum A, Cunningham CK, Gelber, RD, Culnane M, Mofensonb L, Britto P, Rekacewicz C, Newell ML, Delfraissy, JF, Cunningham-Schrader B, Mirochnick M, Sullivan JL. For the International PACTG 316 Team. Two-Dose Intrapartum/Newborn Nevirapine and Standard Antiretroviral Therapy to Reduce Perinatal HIV Transmission. JAMA 2002; 288:189-198.
-- SAINT study: Moodley D, Moodly J, Coodavia H, Gray G, McIntyre J, Hofmyer J, Nikodem C, Hall D, Gigliotti M, Robinson P, Boshoff L, Sullivan JL, for the South African Intrapartum Nevirapine Trial (SAINT) Investigators. A multicenter randomized controlled trial of nevirapine versus a combination of zidovudine and lamivudine to reduce intrapartum and early postpartum mother-to-child transmission of human immunodeficiency virus type 1. Journal of Infectious Diseases 2003;187:725-735.
2. WHO: Antiretroviral drugs for treating pregnant women and prevention HIV infection in infants: guidelines on care, treatment and support for women living with HIV/AIDS and their children in resourceconstrained settings. World Health Organization; July 2004.
3. Elizabeth Glaser Pediatric AIDS Foundation On Issue Of Prevention Of Mother-To-Child Transmission Of HIV/AIDS And Single-Dose Nevirapine [statement]. Elizabeth Glaser Pediatric AIDS Foundation; December 14, 2004.
4. NIAID & NIH: The HIVNET 012 Study and the Safety and Effectiveness of Nevirapine in Preventing Mother-to-Infant Transmission of HIV [press release]; December 14, 2004.
STATEMENT from the NIH, NIAID
Dec 14, 2004
The HIVNET 012 Study and the Safety and Effectiveness of Nevirapine in Preventing Mother-to-Infant Transmission of HIV
In 1997, a clinical trial known as HIVNET 012 was begun in Uganda to address the developing world's urgent need for safe, effective and affordable regimens to prevent mother-to-infant transmission of HIV. The study was funded by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) and conducted by co-investigators from The Johns Hopkins University and Makerere University in Kampala, Uganda.
The purpose of HIVNET 012 was to examine whether a simple, inexpensive regimen of the drug nevirapine could effectively block mother-to-infant HIV transmission. In the study, both mother and baby were treated with a single dose of nevirapine, a drug licensed for the treatment of HIV-infected adults and children in the United States.
The researchers found that this intervention reduced the risk of mother-to-infant HIV transmission by approximately 50 percent. The results of this landmark study were published in The Lancet in 1999. The HIVNET 012 nevirapine regimen subsequently has been endorsed by the World Health Organization (WHO), the Joint United Nations Programme on AIDS (UNAIDS) and other international organizations. NIAID stands by the accuracy of the results of HIVNET 012.
The simple and cost-effective nevirapine regimen has been used in developing countries to prevent HIV infection in thousands of infants; it represents a major public health advance and is one of the true success stories in HIV prevention.
The results of HIVNET 012, including the safety and effectiveness of the nevirapine regimen, have been subjected to multiple reviews. In every instance, the initial conclusions of the HIVNET 012 investigators have been found to be correct. In addition, findings of other studies conducted in the United States and internationally have consistently supported the results of HIVNET 012.
Because of the striking results of HIVNET 012, in 2001 the manufacturer of nevirapine decided to apply to the U.S. Food and Drug Administration (FDA) for an expanded indication for nevirapine in the United States to include use of the drug to prevent mother-to-infant transmission of HIV. As part of the evaluation of the HIVNET 012 trial for this new indication, the conclusions of HIVNET 012 were re-affirmed as valid. Certain aspects of the collection of some of the primary data, however, did not strictly conform to FDA regulatory requirements. For this reason, the study could not serve as a single pivotal trial leading to an expanded indication.
As noted above, NIAID and NIH initiated several reviews and re-reviews of HIVNET 012. These reviews identified procedural flaws in the study that led NIAID to implement improvements in the conduct of clinical research it supports both in the United States and abroad. We understand that certain previously recognized criticisms of the conduct of HIVNET 012 have re-emerged, but stress strongly that throughout multiple reviews, the overall conclusions regarding the safety and efficacy of single-dose nevirapine in this setting have remained intact.
Moreover, NIH has contracted the Institute of Medicine (IOM), part of the National Academy of Sciences, to conduct an additional independent review of HIVNET 012. The results of the IOM review are anticipated in March 2005. NIAID is confident that the previous conclusions regarding the integrity of the HIVNET 012 data will be upheld.
The reduction of perinatal HIV transmission by the use of the readily accessible, inexpensive nevirapine regimen studied by the HIVNET 012 investigators represents a major public health advance for developing countries. No new data exist to suggest that current recommendations regarding use of this regimen should be changed, and we urge clinicians and policymakers to continue to heed the current WHO and UNAIDS guidance on single-dose nevirapine.
Media inquiries can be directed to the NIAID OCPL media group at 301-402-1663.
NIAID is a component of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on transplantation and immune-related illnesses, including autoimmune disorders, asthma and allergies.
Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
Office of Communications and Public Liaison
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD 20892
U.S. Department of Health and Human Services
MAINSTREAM PRESS REPORTS
NIH Official Rewrote Safety Report on Nevirapine Use in Pregnant Women To Change Conclusions, Remove Negative Information
[Dec 15, 2004]
Dr. Edmund Tramont, director of the National Institute of Allergy and Infectious Diseases Division of AIDS, rewrote a safety report on the use of the antiretroviral drug nevirapine in pregnant women in order to change its conclusions and remove negative information about the drug, the AP/Boston Globe reports (Solomon, AP/Boston Globe, 12/15). In March 2002, NIH received data from a Ugandan study testing whether nevirapine can reduce the risk of mother-to-child HIV transmission that prompted the agency to suspend the trial for more than a year and warn Uganda's government of the risks associated with the drug when used in pregnant women. According to documents obtained by the Associated Press, poor record keeping might have caused an underreporting of severe reactions to the drug, including deaths. The documents also show that Tramont and other NIH officials regarded the problems with the trial as exaggerated and did not immediately report safety concerns about the drug to FDA.
By early 2002, medical safety specialists, an NIH auditor and the drug's manufacturer Boehringer Ingelheim all cited "widespread" problems with the nevirapine research in Uganda -- including a failure to receive participants' consent about changes in the study, administration of incorrect doses, and delays and underreporting of fatal and life-threatening reactions to the drug, according to the Associated Press. Because of the reported problems, NIH suspended the research for 15 months from spring 2002 to summer 2003 in order to review the trial and take corrective steps (Kaiser Daily HIV/AIDS Report, 12/14). One report reviewing the Ugandan study -- which was conducted by Dr. Betsy Smith, a medical officer under Tramont -- in January 2003 said that the research had "incomplete or inadequate safety reporting" and that patient records were "of poor quality and below expected standards of clinical research," according to the AP/Globe. Because of the reported problems, Smith "urged" NIH not to make "sweeping conclusions" about nevirapine based on the research in Uganda, the AP/Globe reports. "Safety conclusions from this trial should be very conservative," Smith wrote. However, Tramont asked to review Smith's report before it was submitted to authorities, including FDA. "I need to see the primary data -- too much riding on this report," Tramont wrote on Jan. 23, 2003. The report was published and sent to FDA a few weeks later with a new conclusion and without Smith's recommendations, according to the AP/Globe. Tramont's version of the report concluded that the Ugandan study "has demonstrated the safety of single-dose nevirapine for the prevention of maternal-to-child transmission. Although discrepancies were found in the database and some unreported (adverse reactions) were discovered, ... these were not clinically important in determining the safety profile." According to the AP/Globe, Tramont said he had written the report after his staff began inquiring how Smith's report was changed.
During the 15-month suspension of the Ugandan study, Dr. Jonathan Fishbein, a specialist hired by NIH to improve the agency's research practices, wrote in a message to Tramont that he was "not convinced that the [trial] site is indeed prepared to become active." Fishbein added that he should be allowed to review the site's capabilities and safety monitoring abilities before the study resumed or NIH would be "toothless" in its efforts to rectify the situation, according to the AP/Globe. However, Tramont "dismissed" Fishbein's and other safety monitors' concerns, saying he believed they did not fully comprehend HIV/AIDS, according to the AP/Globe. "I want this restriction lifted ASAP because this site is now the best in Africa run by black Africans, and everyone has worked so hard to get it right as evidenced by the fact that their lab is now certified," Tramont wrote in response to Fishbein on July 8, 2003. After the research resumed, Tramont sent a message to his staff "ordering the end of an 18-month-long debate" over the validity and safety of the Ugandan research, the AP/Globe reports. The trial "has been reviewed, remonitored, debated and scrutinized. To do any more would be beyond reason. It is time to put it behind us and move on," Tramont wrote in an e-mail dated July 13, 2003 (AP/Boston Globe, 12/15). Fishbein recently released to journalists and members of Congress "thousands" of documents regarding the the nevirapine trial, and he is seeking whistleblower status, according to USA Today (Sternberg, USA Today, 12/15).
Tramont, NIH Reaction
According to the AP/Globe, Tramont has taken "responsibility" for the decisions to alter Smith's report and resume the Ugandan study, citing his "four decades of medical experience and argu[ing] that Africans in the midst of an AIDS crisis deserved some leniency in meeting U.S. safety standards." Although NIH officials have acknowledged that Tramont rewrote the report and overruled his staff by resuming the trials, they said he did so because of his experience and an "honest difference of opinion" with safety specialists, the AP/Globe reports. They added that Tramont had no financial interest in nevirapine and that the Ugandan study began "well before" he joined NIH in 2001, according to the AP/Globe. Dr. Clifford Lane, acting deputy director of NIAID, said that staff members who raised objections "were part of a large team of which Dr. Tramont was the head, and it is important that the people involved in that team should express their opinion and there should be discussion." Lane added that an internal NIH review concluded that Tramont did not engage in scientific misconduct. The National Academy of Sciences also is reviewing the Ugandan study. NIH believes that it "helped save hundreds of thousands of African [infants] by allowing" single-dose nevirapine use, Lane said, according to the AP/Globe. However, after reopening the trial site, Tramont received "a blunt reply" from DAIDS Deputy Director Jonathan Kagan, the AP/Globe reports. "I think we are cutting off our noses to spite our face here," Kagan wrote to Tramont, adding, "We should not be motivated by political gains, and it's dangerous for you, of all people, to be diminishing the value of our monitors" (AP/Boston Globe, 12/15).
ABCNews' "World News Tonight" on Tuesday reported on the nevirapine trial. The segment includes comments from Salih Booker, executive director of Africa Action; NIAID Director Anthony Fauci; Fishbein; and Lane (Ross, "World News Tonight," ABCNews, 12/14). A video excerpt of the segment is available online in RealPlayer.