MCC Decision to Deregister Nevirapine for Mother-to-Child Transmission Prevention is Disturbing and Confusing



31 July 2003


The Medicines Control Council (MCC) is one of the most important institutions in public health. Its only task is to ensure the safety, efficacy and quality of medicines in the public interest.  An independent and fearless MCC is essential to the health care system. In 1996, the MCC registered nevirapine, an anti-retroviral for the daily treatment of HIV/AIDS.  This registration was done in accordance with its statutory mandate. In April 2001, the MCC also registered nevirapine to reduce mother-to-child HIV transmission.

Regrettably, the MCC has played political games with the registration of nevirapine for mother-to-child-HIV transmission since November 1999.  Unfortunately, the MCC's questioning of science appears to coincide with the conversion of  President Mbeki and Minister Tshabalala-Msimang to HIV denialist science.  Despite their protestations, the MCC cannot deny the enormous political pressure brought to play on it during the registration process and in the MTCT court case.

Now, the MCC has rejected the Ugandan HIVNET 012 study on the prevention of mother-to-child HIV transmission.  It has stated that it will deregister nevirapine for single-dose mother-to-child transmission prevention (MTCTP) in 90 days unless the patent-holder supplies it with new data.

Many thousands of pregnant women and communities have already been confused by the forays of the MCC into the politics of medicines and anti-retrovirals. HIV/AIDS denialists misuse the MCC's authority to cause further confusion and harm in our communities. The MCC has not provided the public with any new scientific information to support it's  inexplicable position. The recent work of the MCC to register generic ARVs including nevirapine is being undermined by its fork-tongued approach.

Nurses and doctors in public hospitals and clinics around South Africa have expressed dismay at this decision because it undermines the sustainability of the public sector MTCTP programme. This programme has the potential when it is fully rolled out to prevent approximately 30,000 babies from contracting HIV every year.

Nevirapine is not the only drug that can be used to reduce mother-to-child HIV transmission. AZT and other anti-retrovirals can be used as individual drugs or in combination for this purpose. Since its inception TAC has campaigned for the use of AZT. This is slightly more expensive and complex that nevirapine. But, it is also more effective.

The TAC has for a long time called for hospitals and clinics, where capacity exists, to begin using more effective regimens than short-course nevirapine, but the reality is that many facilities will not be in a position to upgrade their programmes to better regimens for months or even years to come. It is these facilities whose MTCTP programmes will be endangered if the MCC carries out its threat.

The MCC's position contradicts a press statement by the World Health Organisation (WHO) released in July 2003 (see below) which states that short-course nevirapine for MTCTP should be part of the minimum standard of care for HIV-positive women and their children. Nevirapine can be used and is used in the United States, contrary to a popularly upheld belief frequently propagated by AIDS denialists. Short-course nevirapine is recommended by the US Public Health Service Task Force for MTCTP among HIV-positive women in labour who have had no prior therapy. It is also included on the WHO essential medicines list for both treatment and prevention purposes.


The TAC rejects this confusing and seemingly unjustified decision by the MCC without a clear public explanation of its reasons or motives.   If there is evidence that it has acted either incompetently or under political influence, there will be a dangerous loss in confidence by the public, but especially health care workers, in South Africa's medicines registration system. All the publicly available data on short-course nevirapine used for mother-to-child transmission prevention indicates that it is safe and effective. If the MCC has information to the contrary, it must make this available because of the public interest in this issue. In the meanwhile the TAC will seek legal opinion from its lawyers on how to proceed on this matter.

Evidence for the Efficacy of Short-Course Nevirapine


In a radio interview on Cape Talk (30 July 2003, 21:00-22:15 - transcript will be made available next week) the MCC chairperson, Professor Peter Eagles, stated unequivocally that that the MCC's decision is based on its concerns over the efficacy of short-course Nevirapine and not its safety. The MCC is aware of the following evidence that supports the efficacy of short-course Nevirapine:

 a. The HIVNET 012 trail conducted in Uganda found that short-course nevirapine reduced transmission by nearly half.

 b. The South African Intrapartum Nevirapine Trail (SAINT) has confirmed that short-course nevirapine (albeit with two doses to the mother, instead of one as used in Uganda) is effective.

 c. A number of trials have been (or still are being) conducted using short-course nevirapine added to other MTCTP regimens. These trials have demonstrated added efficacy due to the addition of short-course nevirapine to other standard regimens. One of these studies combined short-course AZT with short-course nevirapine and found that AZT plus nevirapine reduced transmission by about 50% over AZT alone. The Western Cape Department of Health has indicated that it intends to switch to this regimen.

 d. A study conducted at a hospital in South Africa that has been submitted for publication examined 300 babies on a  short-course nevirapine mtctp programme (women were encouraged to use formula milk as well). The study found a transmission rate of just under 9% at three months. This is much lower than  the typically seen 25 to 35% transmission rates in the absence of MTCTP. This study confirms the operational effectiveness of short-course nevirapine. (Researchers have requested confidentiality until the study is published, but the MCC is aware of their findings.)

 e. A nevirapine MTCTP programme in Lusaka, Zambia found a transmission rate at 6 weeks of slightly over 11%. This study also confirms the operational effectiveness of short-course nevirapine.

 f. An unpublished study from a hospital in Uganda implementing short-course nevirapine found a transmission rate of about 12%. Before the programme this hospital recorded a rate at 6 weeks of 20%.

The above demonstrates unequivocally that the available evidence indicates that short-course nevirapine is effective for MTCTP.

The MCC's Concerns


HIVNET 012


In the above-mentioned radio interview, Professor Eagles stated that the MCC is unsatisfied with the conduct of the HIVNET 012 trial in Uganda and therefore no longer considers this evidence of the efficacy of short-course nevirapine. The facts however are as follows:


 a. The MCC registered short-course nevirapine for MTCTP  without expressing any concerns about the documentation from the HIVNET 012 trial in 2001.

 b. The US based Food and Drug Administration (FDA), which is the MCC's equivalent body in the US, returned an application for registration for short-course MTCTP to the patent-holder because the HIVNET 012 trial's documentation was not kept (nor ever intended to be kept) at the standards required by the FDA. The FDA arguably has the most arduous documentation requirements of any medicine regulatory authority in the world. The MCC does not have the same documentation requirements and registers many medicines that the FDA does not. This is a rational attitude in a country like South Africa which has a less litiguous environment than the US and significantly worse health issues. Nevertheless, the MCC has a justified reputation for requiring high-standard documentation. Surely, we must assume that the MCC was satisfied with the documentation supplied to it regarding the HIVNET 012 trial before it registered short-course nevirapine for MTCTP.

 c. The National Institutes of Health who conducted the HIVNET 012 trial, commissioned an independent audit of the trial to address concerns raised about the documentation and conduct of the trial. This audit found that although there were some irregularities in the documentation (which is common in many trials), nothing they found cast doubt on the findings of the safety and efficacy of nevirapine. The criticisms of the audit related to standards of patient consent and unreported adverse events  unrelated to nevirapine (such as malaria and one child being born with an extra digit). Professor Eagles stated that it is on the basis of this audit's findings that the MCC has made its decision not to consider HIVNET 012 as evidence of the efficacy of short-course nevirapine.  Yet, the MCC's decision contradicts the finding of the audit. If anything the audit has added to the confidence we can have in the HIVNET 012 trial.

 d. In the radio interview, Professor Eagles first used the FDA's decision not to register short-course nevirapine to justify the MCC's decision. It was then pointed out to him that the MCC registers many medicines that the FDA does not register. He denied this. But when specific examples of such medicines were pointed out to him, he began arguing that the MCC is an independent body that does not take its cue from the FDA. Surely Professor Eagles cannot have it both ways unless rational argument is to be suspended. As it happens, we concur with his view that the MCC most certainly should be an independent body and that although it should consider FDA opinion, it should not base decisions primarily on FDA concerns about documentation requirements.

SAINT


The MCC has also cast doubt in the past on the findings of SAINT (see the affidavit by Jonathan Levin of the MCC in the MTCTP court case on the TAC website). It argued that SAINT was setup to demonstrate the superiority of nevirapine over short-course AZT/Lamivudine. The trial failed to establish this and since it was not set up as an equivalence trial, its findings on the efficacy of short-course nevirapine cannot be inferred.

This is an unduly picky argument which fails to consider that the slightly better efficacy of the AZT/Lamivudine arm was not considered statistically significant, but more importantly that the nevirapine results (12.3%) were far better than placebo results from other trials (such as PETRA) and data on transmission rates where no intervention has taken place.  Even in Levin's affidavit (and when he gave testimony at a parliamentary hearing on this issue) he acknowledges that short-course nevirapine is effective. His argument is merely that it is not as effective as found in the HIVNET 012 trial.

TAC members learnt from scientists and lawyers that the MCC should take into account all available evidence and that it is not obliged to consider only the findings of trials in isolation from each other. It should also consider operational experience and comparisons of results between trials. Frequently the MCC makes decisions doing just this and frequently the MCC is alerted to flaws in trials, but yet accepts their overall results on the balance of evidence. Clearly, given the available evidence, it is not doing so here. It actually seems to be doing the opposite: trying to find ways to cast doubt on the findings of essentially well-conducted scientific trials.


Professor Eagles's Contradictions


In the Cape Talk interview, Professor Eagles denied that the WHO had issued a statement directly supporting short-course nevirapine, but the WHO statement (see below) was read out to him over the air. Professor Eagles contradiction regarding the FDA has already been pointed out. Furthermore the following package insert was read out to Professor Eagles from a registered flu relief medicine package insert:

"Vitamin C (ascorbic acid) has been claimed to be an essential factor in building up the patients resistance to infections as well as speeding their recovery rate."

It is clear then that the MCC allows package inserts to indicate claims where there is some evidence, even if that evidence is not overwhelming. We argue that the available evidence that short-course nevirapine is effective is overwhelming. If the MCC has some doubts over nevirapine's efficacy, surely it must allow manufacturers of the medicine to state that the balance of evidence demonstrates that nevirapine is effective for the purposes of mother-to-child transmission prevention. Professor Eagles offered no adequate response to this argument.

We will make the transcript of this interview available once we have obtained the tapes from Cape Talk.

MCC Must Re-establish Public and Health-Care Worker Confidence


The MCC's decision has caused a crisis of confidence in its competence and independence. It can however take steps to rectify this. Either it must produce convincing evidence that most of the data supporting the effectiveness of short-course nevirapine is significantly flawed or it must retract its decision to deregister short-course nevirapine for MTCTP in 90 days unless the patent-holder produces more evidence of the medicine's effectiveness. The TAC would welcome either of these two  routes. Furthermore, we believe that the irrational views on HIV purveyed by the Minister of Health, has demonstrated the need for a review of  the current legislation whereby the Registrar of Medicines is appointed (and can be removed) by the Minister of Health.

Short-course nevirapine is by no means the best way to conduct MTCTP, but it has offered hope to hundreds of thousands of mothers, nurses and doctors. It would be scandolous if this hope is eroded by unscientific, politically influenced decisions.

[END OF TAC STATEMENT]


World Health Organisation Statement

Nevirapine for the Prevention of Mother to Child Transmission of HIV


WHO reconfirms its support for the use of nevirapine to prevent mother-to-child transmission of HIV.


July 2003
 
The Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda has recently released the final report (dated March 2003) from the reassessment of the trial procedures and results in the HIVNET 012 trial conducted in Uganda1. This trial, the first to demonstrate the safety and efficacy of nevirapine to prevent mother-to-child transmission (MTCT) of HIV, was started in Uganda in 1997 and the results were published in 19992. A single dose of nevirapine given at onset of labour plus a single dose to the newborn within 72 h of birth reduced the risk of HIV transmission down to 13%, almost 2-fold lower than a short course of zidovudine started during labour. Concerns about the trial were raised in March 2002 when claims emerged that certain serious adverse events had not been properly reported. The Division issued a statement with the final report that concludes: "In summary, the re-monitoring of the study determined that nevirapine, 200mg orally given to the mother at delivery and 2mg/kg given to the neonate within 72 hours, is safe and effective. However, the conduct of the study lacked the necessary documentation to support a request to the FDA to consider this study as a stand alone pivotal trial." Nevirapine has been registered in the USA, countries of the European Union and numerous other countries for the treatment of AIDS (in combination with other antiretroviral agents), and is also registered for MTCT prevention in many countries worldwide. Nevirapine is recommended by the US Public Health Service Task Force for MTCT prevention among women in labour who have had no prior therapy3 and is included for both treatment and MTCT prevention purposes in the WHO Model List of Essential Medicines, which is updated on a regular basis.
In October 2000, WHO in partnership with UNAIDS, UNICEF and UNFPA, convened a technical consultation to review all available evidence on the safety and effectiveness of short-course antiretroviral drug-based interventions to reduce the risk of MTCT4. The consultation concluded that all regimens which had been shown to be safe and effective in controlled clinical trials could be used in MTCT-prevention programmes. These regimens included zidovudine alone or in combination with lamivudine, as well as nevirapine.
Since the consultation, further research conducted in South Africa has demonstrated the safety and efficacy of nevirapine as well as the zidovudine and lamivudine combination5.
Scaling-up MTCT-prevention programmes in resource-limited settings to reach more HIV-positive mothers and prevent any further infants being infected with HIV is a major challenge, to which many governments, non-governmental organizations, international aid agencies and WHO are committed. While nevirapine is only one of several regimens which has been shown to be safe and effective, the low cost and simplicity of use of the regimen makes it particularly attractive.
Recommendations
WHO continues to support the use of nevirapine in MTCT-prevention programmes. WHO agrees with the National Institutes of Health report and the accompanying statement, which emphasize that there is no evidence that the scientific data from the HIVNET012 study demonstrating the safety and efficacy of nevirapine are invalid. Each year, about 800,000 infants become infected with HIV, mainly through mother-to-child transmission. WHO and its partner United Nations agencies recommend that MTCT prevention using antiretroviral regimens such as nevirapine should be included in the minimum standard package of care for HIV-positive women and their children. WHO is not aware of any information that should lead to a change in this recommendation.
 
References
1.  www.niaid.nih.gov/daids/Prevention.htm
2. Guay LA, Musoke P, Fleming T, Bagenda D, Allen M, Nakabiito C, Sherman J, Bakaki P, Ducar C, Deseyve M, Emel L, Mirochnick M, Fowler MG, Mofenson L, Miotti P, Dransfield K, Bray D, Mmiro F, Jackson JB. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999;354:795-802.
3. Public Health Service Task Force. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1 Infected women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States, June 16, 2003. (http://AIDSinfo.nih.gov)
4. www.who.int/reproductive-health/rtis/MTCT_consultation.en.html
5. 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.
 
Contact
For further information please contact:
Dr Tim Farley
Department of Reproductive Health and Research
E-mail: FarleyT@who.int
or
Dr Isabelle de Zoysa
Department of HIV/AIDS
E-mail: DeZoysaI@who.int

[END OF WHO STATEMENT]

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