Tuesday, September 21, 2010

The SAPIT trial on trial

HIV and TB, tragically, to go well together. TB is the most common opportunistic infection to arrive when HIV has compromised the body’s immune system. Especially in sub-Saharan Africa, patients who are diagnosed with TB are routinely tested for HIV, and often are found HIV-positive. To compound the misfortune, current effective treatments for TB and HIV are not entirely compatible: starting HIV-positive patients with tuberculosis on antiretroviral treatment can lead to a number of complications, both in terms of toxicities and in terms of adherence (i.e. dual treatment involves taking different drugs daily for a long time). It is important, therefore, to have a clear understanding of the optimal time at which to start antiretroviral treatment with TB patients.

This is what the SAPIT study (South African Starting Antiretroviral Therapy at Three Points in Tuberculosis Therapy) in South Africa attempted to do, and their results were recently published in the prestigious New England Journal of Medicine. But the means taken to answer this important question – the study design – has been a topic of heated debate inside and outside South Africa since March. The design of the study included a sequential arm in which HIV-positive patients would start antiretroviral therapy only after they completed TB treatment or retreatment, a period of six or eight months respectively. This is a long time without antiretroviral therapy, particularly for those patients with advanced disease and low CD4 counts. The results of the study indicate significantly higher mortality in the sequential arm in the study than other arms where antiretroviral treatment was initiated earlier.

The burning ethical question is: was it predictable that those in the sequential arm of the study would experience greater mortality than those in the other arms that started antiretroviral treatment earlier? If the answer is no, the SAPIT study generated new and useful information about late initiation of antiretroviral treatment in this population. If the answer is yes, then the study violated the principle of equipoise, as enshrined in numerous ethical guidelines and regulations.

The SAPIT researchers and their defenders argue that at the time the study took place, little was known about mortality rates for HIV-positive, TB patients who were not on antiretroviral therapy. Accusations about violating equipoise are, from this perspective, criticisms based on hindsight. But a recent article in the South African Medical Journal, authored by some 20 scientists and activists, is having none of it. The authors present the evidence on mortality among patients similar to those in the sequential arm of the SAPIT trial, as was available when the trial was being conducted, as well as (generally underwhelming) evidence about complications of combining TB and HIV treatment. Their findings strongly suggest that those in the sequential arm of the SAPIT trial were given less than the clinical ‘standard of care’.

It is not easy to predict the fallout of the study, now that it is a large blip on the ethics radar. Certainly the South African ethics committees that approved the study are feeling awkward, and the relationship between (some) AIDS researchers and advocates may be strained. The fact that US investigators seemed to be involved in the study (enough to be considered authors) without the study having been reviewed in the US, raises questions about either the regulation of global health research, or the ethics of authorship, or both. The SAMJ article suggests (diplomatically) that the South African ethics committees are simply overwhelmed, but it may more simply a matter of committees inadequately judging a complicated case.

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