The trial, known as the South African Starting Antiretroviral Therapy at Three Points in Tuberculosis Therapy (SAPIT), was led by Professor Salim Abdool Karim, Deputy Vice-Chancellor of the University of KwaZulu-Natal.
Writing in the latest edition of the SA Medical Journal, the doctors argue that the study delivered a lower standard of care to these patients than treatment guidelines recommended by South African Department of Health.
The doctors include Professors Gary Maartens, Ian Sanne, and Graeme Meintjies; head of the SA HIV Clinicians’ Society Prof Francois Venter; Harvard Medical School’s Dr Krista Dong and Rocio Hurtado and public health doctors from hospitals in Gauteng, the Western Cape and KwaZulu-Natal.
The SAPIT study enrolled TB-HIV infected patients with CD4 counts below 500, assigning them randomly to three groups. The first group started ARVs within four weeks of TB therapy and the second, within four weeks of finishing the intensive phase of TB therapy (after two months of TB treatment).
But patients in the third group (the “sequential arm) started ARVs within four weeks after the completing TB treatment, which meant that their ARV treatment was delayed by at least six months. Twenty seven people (12.7 percent) died in the “sequential arm”, mostly patients with CD4 counts below 200. This was double the deaths in the other two groups (5.8 percent) which integrated TB treatment and ARVs.
The trial stopped recruiting patients for the third group after the pattern of deaths was established by the Data Safety Monitoring Board (DSMB). However, Professor Abdool Karim points out that initially more deaths took place in the integrated arm of the trial.
“Most of the deaths in the sequential arm only happened after six to ten months when all patients had already finished their TB treatment. In other words, the benefit of combining TB treatment and ARVs took some months to emerge,” explained Abdool Karim.
But the trial’s critics argue that trial’s sequential arm was offering sub-standard care, as the SA treatment guidelines at the time of the trial (2004) recommended that patients with CD4 counts of less than 200 should “complete two months of TB therapy” before starting ARVs while those with CD4 counts below 50 should simply show that they were “tolerating TB treatment” before starting ARVs.
“Patients with CD4 counts below 200 would have been better off had they been given the prescribed standard of care in the South African health system at the time rather than enrolled into the sequential arm of the SAPIT study,” argue the group.
They dismiss the SAPIT investigators’ argument that doctors in the study were able to start ARVs at any stage if the patients’ condition deteriorated.
“We do not accept that this ensures patient safety, as patients with low CD4 counts may appear relatively well one day and then deteriorate rapidly with life-threatening conditions such as bacterial infections or pneumocystis pneumonia. It may be too late at this point to intervene with anti-retroviral therapy, which works by suppressing viral replication, resulting in improvement of CD4 count and function. This takes months to achieve in most patients.”
They argue that the SAPIT study should have been conducted on people with CD4 counts of between 200 and 500: “We believe that it was predictable that patients with advanced disease (CD4 counts below 200) would experience higher mortality if ART was deferred for a long period and that these patients should not have been enrolled.”
The trial has split the usually close HIV/AIDS research field, of which Professor Abdool Karim is a leading figure. Debate has been raging since the trial was first published in the New England Journal of Medicine earlier this year.
However, a number of prominent researchers have supported the trial.
“The criticisms of SAPiT are unjustified, in my view, and represent a retroactive application of the very knowledge that the study generated,” said Dr Richard Chaisson, a world renowned TB expert, Professor of Medicine and International Health Director of the Johns Hopkins University Centre for Tuberculosis Research in Baltimore.
“In our clinics here in Baltimore, almost all clinicians opted to wait until TB therapy was completed before starting ART to avoid complications. Most clinicians believed that a delay in starting treatment was not detrimental. In fact, a mantra of the time was ‘ART is never an emergency, but TB therapy is’. The SAPiT study clearly showed that earlier initiation of ART was safe and lifesaving.”
The SAMJ group argue that the ethics committees in the country need to be strengthened, and recommend the establishment of a registry of independent researchers to help ethics committees to evaluate the design of clinical trials.
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