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[DURBAN] South Africa’s Medicines Control Council has provoked a storm of controversy over nevirapine, widely used for preventing the transmission of HIV from pregnant women to their infants, by saying it is not satisfied with the original Ugandan trial whose results were used to register the drug.

The council has given the drug’s manufacturer, Boehringer Ingelheim, 90 days to supply further evidence of nevirapine’s safety and efficacy. If the company fails to do so, the council says that it will de-register the use of the drug for preventing mother-to-child transmission of HIV.

The Ugandan HIVNET 012 trial, conducted in 1997, was the first to demonstrate nevirapine's safety and efficacy in reducing the risk that an HIV-positive pregnant woman would pass the virus on to her baby.

It showed that a single dose of nevirapine given at the onset of labour, and a single dose given to the infant within 72 hours of birth, cut the risk of transmission to 13 per cent. The trial, whose results were published in 1999, provided the foundation study that many developing countries used to initiate programmes to prevent mother-to-child transmission of HIV.

Nevirapine was included in the World Health Organization’s Model List of Essential Medicines after consulting with a number of international agencies, which reviewed all the available evidence on the safety and efficacy of short-course anti-retroviral drugs to reduce the risk of mother-to-child transmission of HIV.

Questions about the Ugandan trials surfaced in March last year, when claims that it under-reported serious adverse events prompted an investigation by the US National Institutes of Health (NIH).

In a report published March 2003, the NIH concluded that there were documentation irregularities during the HIVNET 012 trial, as a result of which the trial on its own was not sufficient for the drug to be licensed by the Food and Drug Administration. But the report also found that nevirapine was safe and effective.

Despite this, the South African Medicines Control Council has now announced that the NIH findings indicate that the HIVNET 012 study does not meet the regulatory requirements for it to approve the use of nevirapine “as a single agent for reducing the risk of mother-to-child transmission of HIV” (the use of nevirapine in combination with other anti-retroviral medicines for the long-term treatment of people infected with HIV is not affected).

Precious Matsotso, the country’s registrar of medicines, says that the patient records of the Ugandan trial did not support the published results. Records of treatments allocated to trial participants were missing, there were inadequate records of how the drug was stored, handled and distributed, and in some cases it could not be confirmed that proper informed consent had been given.

Boehringer Ingelheim says it is puzzled by the Medicines Control Council’s request, as it submitted a report two months ago providing details of the efficacy of nevirapine for preventing mother-to-child transmission in a number of different trials and settings. The report was written by two of South Africa’s leading peri-natal HIV research scientists, James McIntyre and Glenda Grey, co-directors of the Peri-natal HIV Research Unit at Chris Hani Baragwanath Hospital in Johannesburg.

“Several other clinical trials have used a similar nevirapine dosing regimen, either alone or in combination with one or more other antiretroviral drugs,” says the report. Those only using nevirapine “confirm the level of efficacy of the HIVNET 012 study, and further demonstrate the lack of safety or toxicity concerns with this dosing”.

The nevirapine controversy is expected to dominate the South African National AIDS conference, the largest gathering of its kind in the country since the International AIDS conference in 2000. Yesterday (3 August) the conference chairman Jerry Coovadia, who holds the Victor Daitz chair of HIV/AIDS research at the University of Natal, said he had been left “breathless” by the council’s decision to question the “validity of the science around nevirapine”.

Coovadia announced that a special session of the conference would be convened on Wednesday to discuss the issue. He also called for a forum to be set up, where scientists, government officials and policy makers could discuss research findings.

“It’s not always easy to determine the best scientific evidence, and one can only decide [on the best course of action] if there is opportunity to discuss,” he says. “If not, we are going to keep making mistakes.”

Nono Simelela, the health department’s chief director in charge of HIV/AIDS, emphasises the independence of the Medicines Control Council, saying the health department could not intervene in its decisions. But she adds that she was “really taken aback by their decision”.

According to Simelela, the health department does not yet have an alternative plan for HIV-positive pregnant women should nevirapine be de-registered. But she suggests that the department might provide AZT instead.

However this would also be controversial, since although AZT is the only other drug registered in South Africa for use in preventing mother-to-child transmission of HIV, it is considerably more expensive, and requires a longer period of treatment. Its use would therefore have major resource implications for the government.

The government is also seeking legal advice on its obligations under a ruling by the constitutional court last year ordering it to provide nevirapine – or a suitable alternative – to pregnant HIV-positive women and their babies.

Tamar Kahn is the science and health correspondent for Business Day.