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.

Declaration of Helsinki redux

The Declaration of Helsinki was revised last week, apparently not to much fanfare. In fact, I could only find two news articles on the web about it (here and here), and Science published a piece about the lingering controversies surrounding the Declaration and its revisions. But other than that, the revised Declaration seems to have generated little interest, excitement or opposition. For those unfamiliar with this document, or the organization that acts as its custodian, the Declaration of Helsinki is a statement of principles concerning medical research with human participants developed by the World Medical Association (WMA). There is nothing particularly Finnish about the Declaration, only the name -- it happened to be where the WMA General Assembly first adopted it in 1964 -- but the name lends the document a certain austere, Nordic and 'internationalist' feel. This is only fitting for a document that is regarded by some as a cornerstone of research ethics with global reach.

Careful and prolonged attention is bestowed to the precise wording of the Declaration, as though the lives of millions depended on each word. So what is new about the revision? Three main changes seem to stand out:

• Registering clinical trials. Paragraph 19 of the revised Declaration states: "Every clinical trial must be registered in a publicly accessible database before recruitment of the first subject." Apparently representatives of pharmaceutical companies are unhappy with this new paragraph, because it implies that all phases of clinical trials must be registered, even phase 1 trials. They argue that such registration drives up research costs and because it involves disclosure of what research projects are doing, it could violate intellectual property rights. On the other hand, it is predictable that something would be added to the Declaration about registering clinical trials (without being specific about any phase) after the high-profile injuries to humans involved in the Northwick Park TGN1412 Phase I trial. Nevermind: the pharmaceutical industry will probably just ignor this paragraph anyway.

• The use of placebos in clinical trials. When is it ethically acceptable to have a placebo arm in a clinical trial? Paragraph 32 is meant to deal with this sticky issue, and the answer (to paraphrase) is that a new experimental intervention should be tested against the 'best current proven intervention', except when (a) no current proven intervention exists, or (b) where there are really good scientific reasons to use a placebo and where those who receive the placebo will not be subject to any risk of serious or irreverible harm. The paragraph adds: "Extreme care must be taken to avoid abuse of this option." Reports on the revision suggest that this Paragraph is really restrictive of placebo use -- which some find troubling because it could hamper the progress of science, and others find noble because it protects research participants and does not bow down to pharmaceutical industry interests. Nevermind: FDA recently implemented rules allowing applicants for new drug approvals bypass the Declaration ofHelsinki when conducting certain trials overseas.

• Post-trial benefits. The concern that research participants (particularly those in impoverished countries) ought to get something back from their participation has been growing in reserach ethics circles in recent years. There is a feeling that it is unjust for drugs to be tested on the world's poor, while the benefits of the research mostly accrue to the richer nations -- in short, the poor are good enough to be tested on, but not good enough to have access to the finished product. The new Paragraph 33 reads: "At the conclusion of the study, patients entered into the study are entitled to be informed about the outcome of the study and to share any benefits that result from it, for example, access to interventions identified as beneficial in the study or to other appropriate care and benefits." For better or for worse, this leaves the question what counts as an 'appropriate benefit' wide open. A research team could say that there were things in a study that the participants got that non-participants didn't get, and that is 'benefit' enough to fulfill the requirements of the Declaration of Helsinki. Nevermind.