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15 July 2004

Facts About Nevirapine are Simple - But Unnecessary Confusion Endangers Lives


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"Sections 27(1) and (2) of the Constitution require the government to devise and implement within its available resources a comprehensive and co-ordinated programme to realise progressively the rights of pregnant women and their newborn children to have access to health services to combat mother-to-child transmission of HIV. ...
The policy for reducing the risk of mother-to-child transmission of HIV as formulated and implemented by government fell short of compliance with the requirements ...
3.    Government is ordered without delay to ...   [r]emove the restrictions that prevent nevirapine from being made available for the purpose of reducing the risk of mother-to-child transmission of HIV at public hospitals and clinics that are not research and training sites. ...
4. The orders made in paragraph 3 do not preclude government from adapting its policy in a manner consistent with the Constitution if equally appropriate or better methods become available to it for the prevention of mother-to-child transmission of HIV."
    -    Constitutional Court Judgment, 5 July 2002


The Treatment Action Campaign welcomes the recommendation of the Medicines Control Council that a combination of antiretrovirals be used to prevent mother-to-child transmission transmission of HIV instead of the current protocol in the public sector which uses just one antiretroviral, nevirapine. Combination regimens are more effective than the current single-dose nevirapine regimen. However, it is crucial, as well as a legal obligation of government, that health facilities currently implementing the single-dose nevirapine regimen are allowed to continue doing so until they have the capacity to upgrade to combination regimens. The Department of Health must as soon as possible ensure health facilities are given the resources they need to upgrade to the combination regimens.

Statements attributed to the Minister of Health, Manto Tshabalala-Msimang, at the International AIDS Conference in Bangkok have caused unnecessary public confusion about nevirapine. The Minister should have used the occasion to talk about the benefits of the South African mother-to-child transmission prevention programme, which has saved many lives and is possibly the largest in the world. She also could have announced that her department is considering improving the current regimen. Instead, public confidence in the current single-dose nevirapine regimen has  been undermined needlessly.

Pregnant women need to be able to choose whether or not to participate in the mother-to-child transmission prevention programme based on clear public messages. Since there are many benefits to the programme, it is important to encourage participation by explaining the facts clearly and correctly. This is the purpose of the remainder of this statement.
  • The single-dose nevirapine regimen for mother-to-child transmission prevention involves a pregnant HIV-positive woman taking a single dose of nevirapine when she is in labour and the child taking a single dose of nevirapine syrup shortly after birth. There are minor variations in the size of the dose. According to all available evidence, this regimen is safe and effective for mother-to-child transmission prevention. Since its implementation in South Africa, it has prevented HIV-infection in thousands of children.
  • A strain of the virus that is resistant to nevirapine has been detected in a large minority of women after they use the single-dose nevirapine regimen. Scientists are not sure, but this might mean these women will not be able to use nevirapine or antiretrovirals in the same class as nevirapine (such as efavirenz) effectively as part of triple-drug therapy for their own treatment, or for mother-to-child transmission prevention if they have a subsequent pregnancy. This is called drug resistance. It has been known to be an issue with single-dose nevirapine since before the mother-to-child transmission prevention Constitutional Court case between the TAC and the Minister of Health. This resistance issue does not affect the safety of nevirapine. (Technical Note: Scientists are not certain of how prevalent resistance is after single-dose nevirapine or what its consequences are for being able to use nevirapine in the future. In studies, a form of the virus resistant to nevirapine is found in the blood of between 30 to 50% of women who have used a single-dose nevirapine regimen. There is also evidence, presented at the Thailand conference, that the resistant strain of the virus is no longer detected in all except 14% of  women six months after they took the single-dose.)
  • Other more complex regimens using nevirapine and other antiretrovirals are more effective at reducing mother-to-child transmission. Any combination of antiretroviral therapy can result in resistance but the best combination of medicines for reducing transmission from mother to child and avoiding resistance would be to use three antiretroviral medicines (known as triple-drug combination therapy) where medically indicated.  With the introduction of treatment for AIDS into the South African public health service, it makes sense to keep as many antiretroviral drug options as possible open to pregnant HIV-positive women for when they later develop AIDS. Therefore switching the mother-to-child transmission protocol to one which is more effective and results in less resistance is sensible.
  • With regard to drug resistance, the problems encountered with antiretrovirals are quite similar to resistance problems encountered with anti-viral, anti-fungal and antibiotic medicines. (Technical Note: The extremely fast rate of reproduction and mutation of HIV renders it more challenging to deal with than most other viral, fungal and bacterial infections.)
  • In the Western Cape Province, a combination of AZT and nevirapine is used to prevent mother-to-child transmission prevention. This regimen is more effective than single-dose nevirapine (see the abstract from the New England Journal of Medicine copied below this statement). Nevertheless, there are other, even better, regimens.
  • The Minister of Health suggested in Bangkok that the TAC forced government to adopt the single-dose nevirapine regimen. It is true that the TAC forced government to implement a country-wide mother-to-child transmission prevention programme by taking the Minister of Health to court. This action has saved the lives of thousands of children. However, it is not true that the TAC forced the government to adopt the single-dose nevirapine regimen for mother-to-child transmission prevention. This regimen was the Department of Health's choice for the mother-to-child transmission prevention pilot sites implemented in 2001. It was known even then that more effective regimens existed, usually involving AZT. But for reasons not made clear, the single-dose nevirapine regimen was chosen. This was arguably a reasonable choice though; single-dose nevirapine is simple to administer and a good starting point for the rollout of a mother-to-child transmission prevention programme. The Constitutional Court judgment, quoted at the beginning of this statement, states that nevirapine or other appropriate methods may be used. 
  • TAC's stance, as articulated in numerous media interviews as well as written statements, has consistently been that regimens other than the single-dose nevirapine can be introduced into the public sector wherever possible (e.g. see TAC's statements on 26 July 2000,8 August 2000,2 October 2001, 25 October 2001 and 31 July 2003 as well as the court papers in the mother-to-child transmission prevention case).
  • Where there is a current lack of capacity in a clinic, the single-dose nevirapine regimen is the minimum acceptable regimen for mother-to-child transmission  prevention. But where such lack of capacity exists, clinics must be given the resources they needs to upgrade. Also, where an HIV-positive woman presents late to an antenatal clinic (e.g. during labour), single-dose nevirapine might be the only regimen available to her.
  • Transmission due to the method of infant feeding (breast-feeding versus formula) should not be confused with the safety and efficacy of single-dose nevirapine or any other regimen. However, the TAC endorses the World Health Organisation stance on this issue, which, greatly abbreviated, is that HIV-positive pregnant women should receive accurate counselling on the matter and then make their own choice.
Since the Minister's statement in Bangkok, the TAC has received calls from members of the public wanting to know if they should stop using nevirapine as part of their triple-drug antiretroviral therapy. We have also been asked if nevirapine should stop being used as part of mother-to-child transmission prevention. The answer to both these questions is obviously no. Clearly such confusion is concerning.

The science of mother-to-child transmission, as with any other active scientific endeavour, is evolving and improving all the time. It is possible that a few years from now better options for preventing mother-to-child transmission will become available; this would not negate the validity of decisions taken today based on the best available science. It is essential that government conveys accurate scientific information to the public without causing confusion. There are currently a number of good antiretroviral regimens for preventing transmission, albeit that some are better than others. HIV-positive pregnant women must be offered at least one of these regimens, preferably the best one withing government's available resources.

[END OF STATEMENT]

The abstract below, published in the New England Journal of Medicine a few days ago, adds further weight to the evidence of the efficacy of nevirapine as part of an AZT regimen.

Here is the NEJM abstract:

Published at www.nejm.org July 9, 2004 (10.1056/NEJMoa033500)

http://content.nejm.org/cgi/content/abstract/NEJMoa033500

Single-Dose Perinatal Nevirapine plus Standard Zidovudine to Prevent
Mother-to-Child Transmission of HIV-1 in Thailand
Marc Lallemant, M.D., Gonzague Jourdain, M.D., Sophie Le Coeur, M.D.,
Ph.D., Jean Yves Mary, Ph.D., Nicole Ngo-Giang-Huong, Pharm.D., Ph.D.,
Suporn Koetsawang, M.D., Siripon Kanshana, M.D., Kenneth McIntosh, M.D.,
Vallop Thaineua, M.D., for the Perinatal HIV Prevention Trial (Thailand)
Investigators

 ABSTRACT

Background Although zidovudine prophylaxis decreases the rate of transmission of the human immunodeficiency virus (HIV) type 1 substantially, a large number of infants still become infected. We hypothesized that the administration, in addition to zidovudine, of a single dose of oral nevirapine to mothers during labor and to neonates would further reduce transmission of HIV.

Methods We conducted a randomized, double-blind trial of three treatment regimens in Thai women who were receiving zidovudine therapy during the third trimester of pregnancy. In one group, mothers and infants received a single dose of nevirapine (nevirapine-nevirapine regimen); in another, mothers and infants received nevirapine and placebo, respectively (nevirapine-placebo regimen); and in the last, mothers and infants received placebo (placebo-placebo regimen). The infants also received one week of zidovudine therapy and were formula-fed. The end point of the study was infection with HIV in the infants, established by virologic testing.

Results Between January 15, 2001, and February 28, 2003, a total of 1844 Thai women were enrolled. At the first interim analysis, the independent data monitoring committee stopped enrollment in the placebo-placebo group. Among women who delivered before the interim analysis, the as-randomized Kaplan-Meier estimates of the transmission rates were 1.1 percent (95 percent confidence interval, 0.3 to 2.2) in the nevirapine-nevirapine group and 6.3 percent (95 percent confidence interval, 3.8 to 8.9) in the placebo-placebo group (P<0.001). The final per-protocol transmission rate in the nevirapine-nevirapine group, 1.9 percent (95 percent confidence interval, 0.9 to 3.0), was not significantly inferior to the rate in the nevirapine-placebo group (2.8 percent; 95 percent confidence interval, 1.5 to 4.1). Nevirapine had an effect within subgroups defined by known risk factors such as viral load and CD4 count. No serious adverse effects were associated with nevirapine therapy.

Conclusions A single dose of nevirapine to the mother, with or without a dose of nevirapine to the infant, added to oral zidovudine prophylaxis starting at 28 weeks' gestation, is highly effective in reducing mother-to-child transmission of HIV.

Notice: To coincide with presentations at the 15th International AIDS Conference, this article was published at www.nejm.org on July 9, 2004. It will appear in the July 15 issue of the Journal.

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