After years of legal wrangling and controversy, authorities finally approved an anti-HIV drug trial. Sharon Davis and Christina Scott report.
A clinical trial investigating ways to prevent newborns from contracting HIV through breast milk is set to proceed in South Africa, following a court judgement overruling the apparent reluctance of the country's drugs regulators to let the trial go ahead.
South Africa's Medicines Control Council (MCC) finally approved the trial last week (30 July) after a protracted battle between the MCC and paediatric HIV/AIDS researchers that ended in court.
The situation highlights problems in scaling up HIV/AIDS research in South Africa. The Sydney Declaration at the recent International AIDS Society conference in Australia (22–28 July) called for an increase in research in the developing world (see Scientists: Don't neglect HIV/AIDS research).
Research presented at the conference indicated that breastfeeding by HIV infected mothers accounts for one third of all mother-to-child HIV transmissions in the developing world.
"Many HIV-infected women in South Africa and other African countries do not have the luxurious choice of breastfeeding alternatives, and would still choose to breastfeed despite knowing the risks of HIV transmission to their babies through breast milk," said Daya Moodley, from the Nelson Mandela School of Medicine at the University of KwaZulu-Natal (UKZN) in Durban, South Africa.
In the developed world, formula milk provides a safe alternative to breastfeeding. But bottle-feeding is a risky option in many parts of Africa with poor access to clean water or electricity, and can trigger severe gastrointestinal illnesses in infants.
A US$7.5 million trial, sponsored by the US-based National Institutes of Health (NIH) and led by Moodley and her team at UKZN, aims to test the effectiveness of the antiretroviral (ARV) drug nevirapine as a treatment to block HIV infection in babies breastfed by HIV positive mothers. Nevirapine has been registered with the MCC since April 2000 for the treatment of HIV in adults, adolescents and children with HIV/AIDS.
Three hundred and fifty babies of HIV-infected mothers will be enrolled in the trial. Half the newborns will be given nevirapine and half a placebo for six months or until they stop breastfeeding. The researchers will then monitor the children for signs of HIV infection until 18 months of age. The trial has a double-blind design, meaning neither the participants or researchers know who is receiving which treatment.
South African studies into the safety of nevirapine for babies were completed in 2000 after approval about a year earlier by the MCC.
Yet it was only last week that the MCC approved the trial.
"The MCC is supposed to make a decision within three months of submission by researchers," said Quarraisha Abdool Karim of the Centre for the AIDS Programme of Research in South Africa (CAPRISA) and co-principal investigator of the global HIV Prevention Trials Network leadership group.
"This is important research. In KwaZulu-Natal and many rural areas, formula feeding is not an option. This delay in research targeted at reducing risk in some of the most vulnerable populations is outrageous," she told SciDev.Net.
The dispute between the MCC and the researchers has run for four years. The researchers first applied for MCC approval in November 2003, and the application was eventually rejected in December 2004. The MCC continued to oppose the trial despite several court orders and its own appeals committee approving the trial in February 2006.
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The MCC's main concern was the use of a placebo in the trial as a comparison for nevirapine.
Peter Eagles, chairperson of the MCC, told SciDev.Net two weeks ago (27 July) that the MCC is worried about infants in the placebo arm of the trial being exposed to HIV through breastfeeding.
But Pretoria High Court judge Willie Hartzenberg, dismissing the MCC's application for leave to appeal previous court verdicts (3 July), found the MCC's allegations that the trial would lead to the infection of babies with HIV to be unsound. He noted that the clinical trial would not place any mother or child in a position worse than they would have been without the trial.
Moodley said, "There is a misunderstanding that women will be forced to breastfeed in the trial. There is no threat of coercion of women to breastfeed and participate in the trial." Only HIV positive mothers who elect to breastfeed despite the risk of mother-to-child transmission will be enrolled in the trial.
The MCC has also questioned the use of nevirapine to prevent mother-to-baby transmission of HIV. The council told South African newspaper The Argus (30 July) that it has rejected the findings of the HIVNet012 study conducted in Uganda — regarded by researchers as the 'pivotal study' on nevirapine for single-dose use to prevent mother-to-baby HIV transmission. "We are no longer able to continue accepting HIVNet as a basis for registering nevirapine for single-dose use in preventing HIV transmission from mother to child in South Africa," Peter Eagles was quoted as saying.
According to Moodley, "The local and international scientific committee, funding agencies and support staff involved in the clinical trial have been preparing intensively to ensure that we will be able to provide clear scientific evidence on the efficacy and safety of the drug regimen in children in the trial."
"This clinical trial, like other drug trials, includes intensive laboratory and clinical monitoring for potential side effects and benefits of nevirapine in children," she adds.
Hoosen 'Jerry' Coovadia, of the UKZN medical school and one of the research team, said, "The South African government has been rightly worried about research which is inappropriate for the developing world. They have accused external agencies of abusing vulnerable populations."
"But here is a study specifically addressing a problem of predominantly African children, which would be of benefit to many poor children in the developing world," he told SciDev.Net.
"[The trial] will help reduce a substantial proportion of the 300,000 children globally who are infected each year through HIV infected breast milk. [The MCC] held us back on something which could have saved lives."
Following the Pretoria High Court hearing, Judge Hartzenberg ordered the MCC to approve the trial immediately (3 July). The judge stated that the actions of the MCC were "obstructive" and said that the medical evidence refuted the council's allegations that the research would encourage HIV infection in newborns.
But weeks after the court's decision, Maryann Francis, a spokesperson from the UKZN, confirmed that the clinical trials were still on hold (24 July). She said the MCC had recently requested additional documentation — including informed consent paperwork, insurance certificates, ethics committee approvals and financial declaration of sponsorship from the NIH — before the trials at Durban's Prince Mshiyeni Hospital could proceed.
Peter Eagles told SciDev.Net that the MCC's request for more paperwork was legitimate because, since the council decided not to approve the trial, they "did not request the normal documentation required" at the time. However, the researchers say copies of the documentation were supplied earlier and have repeatedly gone missing at the MCC.
Coovadia said they sent the paperwork demanded by the MCC to the State Attorney on 26 July.
That same week Peter Eagles said the council was still considering further legal action, seeking to oppose the decision by Judge Hartzenberg, despite being refused permission to appeal. "We are not happy with the [judge's] decision, and our lawyers are looking into this," he told SciDev.Net.
But last week the MCC decided to approve the trial. It is not known what prompted the MCC to take the decision after a month's delay following the court verdict. The MCC did not respond to queries about this.
The situation in South Africa
The MCC's stance has led to claims of unscientific behaviour from HIV/AIDS health workers and activists. There are fears that MCC scientists have caved in to pressure to adopt the stance of South Africa's ruling African National Congress party, denying that HIV is the cause of AIDS and refuting the scientific consensus on the use of ARV drugs.
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South Africa's stance on
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Although South Africa has one of the highest HIV/AIDS infection rates in the world, president Thabo Mbeki has gone on record as saying that he knows no one with HIV. South Africa's health minister, Manto Tshablala-Msimang, has encouraged people to tackle the disease by eating beetroot, lemons and olive oil. The South African health department has also repeatedly raised concerns about the effectiveness and cost — as well as the alleged toxicity — of ARVs.
HIV/AIDS health workers and activists are particularly concerned at the MCC's failure to act against unproven 'cures' that have not gone through safety and efficacy tests, but are nevertheless peddled by a number of businesses and individuals. These include Matthias Rath, a German physician operating in South Africa who advocates herbs and vitamins as a viable alternative to ARVs. The MCC did not respond to queries about these allegations.
Nathan Geffen of the South African AIDS activist non-governmental organisation, the Treatment Action Campaign, says the MCC has refused to act against the "illegal distribution of medicines" by a number of other businesses and individuals profiting from unproven herbal "pseudo-cures".
"Yet in [the case of the nevirapine trial], the MCC has acted against the advice of experts and its own appeal committee and attempted to block an ethical trial of a proven medicine with the potential to save the lives of many children," Geffen told SciDev.Net.
Trials of nevirapine in babies are already underway elsewhere in Africa. A trial in Kampala, Uganda, involves 125 newborns at Mulago hospital, and a second at a clinic in Chitungwiza, Zimbabwe, has around 75 infant participants.
A third trial is expected to begin soon in Tanzania. But without the fourth — the South African trial — there was a risk that the project would not have enough participants to render it statistically significant.
Daya Moodley and her team hope to begin the trial within two months. "Our struggle was not intended for the financial gain of this project but the mere fact that we would provide important evidence of a way of protecting thousands of children from HIV if breastfed by their HIV-positive mothers."