Two cheers for microbicides

This year's biggest success in HIV prevention research was undoubtedly the CAPRISA 004 study on pre-exposure prophylaxis (PrEP) microbicides gel for women. The unveiling of the study results at the recent International AIDS conference in Vienna made it the toast of the town and raised the spirits of HIV/AIDS researchers, policy-makers and advocates everywhere, given the sad string of serious pitfalls and setbacks -- scientific, economic, and political -- endured over the last years. Against that dismal backdrop, a gel that over a 30-month period, used before and after sex, protected women from getting HIV by 39% sounds like manna from heaven. Colleen Farrell over at the Bioethics Forum has a good brief description of the CAPRISA study and some of its implications and limitations.

However, even one assumes that the study results will be replicated and confirmed, it is still hard not to be somewhat pessimistic about the challenges of implementing this HIV prevention strategy in the field. On paper, it has fine feminist credentials: it is female-controlled way of preventing women from getting HIV from (all-too-often-wayward) men. In reality, there are bound to be challenges to adherence, when women are not repeatedly reminded to use the gel, and particularly if men dictate when sex occurs (not an hour from now, but now). This blogger does not personally have a vagina, but can imagine that inserting gel into it before and after sex is not a particularly erotic or pleasant experience, even if doing so might be lifesaving, particularly in high HIV-prevalence settings. (Fortunately pill and other forms of PrEP are currently being tested.) In addition, I am not sure anyone knows what the long-term health effects of intermittent use of antiretroviral drugs for HIV prevention purposes are, since this is (as Ferrell puts it) a new frontier. And we are not even talking yet about the usual problems of distributive justice in developing countries -- universal access to PrEP for safe sex purposes will be a long time coming, in countries where there is still no universal access for drugs for prevention of mother-to-child transmission or for antiretroviral treatment.

Of course, we already have a pretty vivid idea of what doing nothing in the face of the HIV/AIDS epidemic amounts to. Pessimism can and only should go so far. So researchers have to soldier on, even if they come up with interventions that provide spotty protection and whose implementation raises ethical problems right, left and center. CAPRISA 004 seems to have provided an important weapon for the long and ugly battle ahead.

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.

HIV testing policy revisited

A few years ago, a colleague and I wrote a paper on some of the ethical issues surrounding proposed changes in HIV testing policy. Traditionally, HIV testing depended strongly on personal choice: if you felt you had been at risk of infection, you could (in theory) go to whatever available clinic offered HIV testing. The policy of voluntary testing and counseling (or VCT) was meant to do just that: support those who wanted to know their own HIV status. The policy change -- pursued by the World Health Organization and the Centers for Disease Control and Prevention -- involved putting greater pressure on individuals to get tested for HIV, given that (a) relatively few persons in high HIV-prevalent countries made use of VCT services and (b) antiretroviral treatment has become more available for those who test positive for HIV. 'Putting more pressure' took the form of an opt-out HIV testing policy, i.e. telling patients in clinics that they would be tested for HIV unless they choose not to be. While a more aggressive HIV testing policy could have some obvious benefits, my colleague and I were worried about possible negative repercussions that the policy might have. More precisely, the concern was less about the policy in the abstract, but what implementation of the policy might produce in settings marked by poverty, stigma, gender inequality and weak health care infrastructure.

This month's issue of the World Health Organization has a well-argued defense of 'opt-out' HIV testing policy. Michael April rests the argument on two philosophical foundations: consequentialism and what he calls 'libertarian paternalism.' On the consequentialist front, he basically argues that the positive consequences of having an opt-out testing policy outweigh the potential negative consequences. In regard to libertarian paternalism, April argues that there is nothing wrong with influencing persons to get tested for HIV by means of health policy as long as the influence does not constitute coercion and persons are thereby directed towards more health-promoting behavior than they might have otherwise.

Does the argument defuse the worries surrounding opt-out testing in poor countries in sub-Saharan Africa? Perhaps I should let the reader decide, but it is tempting to make a couple remarks. First, the consequentialist argument depends on the idea of 'weighing' potential positive consequences of opt-out testing against negative ones. Such weighing exercises in ethics are always slippery and elusive. On an individual level, it is not necessarily clear that getting tested for HIV has the best consequences, especially considering that health is not the only value at stake. (The astonishing book Three Letter Plague was centered around this theme.) If we go to a population level, and say that having opt-out testing will have overall better consequences than VCT, the consequences should (at least) be expressed in terms of lower HIV incidence. Maybe the policy will help to lower incidence, or rather, it may make a contribution as long as some other ducks are rowed up with it: presence of decent medical services (including HIV/AIDS care and availability of health care professionals), food and political security, opportunities for employment, and so on. As far libertarian paternalism goes, it seems plausible enough to say that people sometimes make decisions against their own interests, and that it can be justified sometimes to channel their behavior in more beneficial directions. But in an individual case, HIV testing conceivably might not be in a person's own interest, and hence libertarian paternalism would not be justified there. Though it sometimes makes appeals to individual self-interest, the whole argument works best at public health or population level: putting this policy in place, it is argued, will (likely) have positive overall consequences for many even if it might have negative consequences for some.

Perhaps so. On paper, the opt-out HIV testing policy has always looked promising. Our main concern was about such policies being implemented wisely and sensitively in the field, with a thorough knowledge of the cultures, communities and institutions involved, in order to avoid the best public health intentions going seriously astray.