Tenofovir and the ethics of clinical trials

It seems to me hare-brained, or worse, to attempt to prevent “HIV infection” with the same drugs with the same dangerous “side”-effects as would be used to treat the actual illness IF one ever became “infected”; and being “infected”, IF illness actually ensued after an average of 10 years of symptom-free existence. So the clinical trials of tenofovir for “PreP (pre-exposure prophylaxis for HIV prevention)” appear to me to be thoroughly misguided. After all, over the years there have been various initiatives for treatments to be interrupted periodically precisely because of those “side” effects that many patients simply can’t tolerate; and, for that reason, every now and again the mainstream view has swung back to deferring treatment as long as possible.

Nevertheless, the obsession with antiretroviral drugs continues. In how many clinical trials, would you guess, does tenofovir feature, for treatment or for prophylaxis?

The information is on-line. For tenofovir, there are listed 118 clinical trials (including not yet recruiting, recruiting, active & not recruiting, completed, and one each withdrawn and enrolling by invitation only)  .

The most troubling aspect of clinical trials, of course, is that they are experiments on human beings. Therefore common sense and decency suggest that the conceivable benefits from the knowledge possibly gained should outweigh indisputably the dangers to which the human guinea-pigs are exposed. A seemingly obvious corollary is that all potential human guinea-pigs should be informed in the most complete and honest possible manner about the dangers they would expose themselves to, as well as the possible benefits to them and to humankind at large.

In First-World countries, these considerations have led to regulations that make clinical trials increasingly onerous and expensive, and clinical trials are more and more frequently carried out in places where the regulations are not quite so protective of the potential guinea-pigs. Thus it becomes possible in Africa to do experiments to find out whether the tiny cost of feeding malnourished people is a useful adjunct to very expensive antiretroviral treatment [Drugs or food?, 25 December 2007 ; Food is good for children, 8 January 2008 ], or whether the minimal cost of de-worming children helps to slow the spread of “HIV infection” or progression to AIDS better than just those very expensive antiretroviral drugs[Are intestinal worms good for us? Are they good for Africans? For African children?, 30 December 2007 ; Parasitic worms are *not* good for you!, 24 July 2008 ].

Occasionally, though, some troublemakers who are not even AIDS Rethinkers or HIV Skeptics draw attention to rather unsatisfactory circumstances in clinical trials outside First-World countries. Thus certain proposed trials of tenofovir for PreP among prostitutes had been called off :
“activist groups, including Act Up-Paris have ‘halted the progress of at least two important clinical trials of tenofovir as PREP and brought negative attention to tenofovir, somewhat similar to that visited on thalidomide more than four decades ago,’ say two researchers in an essay in the open access global health journal PLoS Medicine” [that essay is Singh JA, Mills EJ (2005). The abandoned trials of pre-exposure prophylaxis for HIV: What went wrong? PLoS Med 2(9): e234].
“But Jerome Singh, of the Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, and Edward Mills of the Department of Clinical Epidemiology and Biostatistics, McMaster University, Canada, argue that ‘if tenofovir is someday proven to be clinically efficacious as a PREP, today’s irresponsible reporting and activism surrounding tenofovir could cause those in need to snub the drug if, or when, it becomes licensed for use as a PREP.’”

That concern was underscored by “Joep Lange, who was the President of the International AIDS Society at the time . . . . ‘Activist groups have now managed to derail several PREP trials, arguably the most important studies for those at high risk of acquiring HIV infection around the globe.’ Lange is highly critical of the tactics used by those who have managed to shut down the PREP trials. ‘The methods of these specific activist groups,’ he says, ‘are uninformed demagogy, intimidation, and ‘AIDS Exceptionalism’, the last in the sense that they exploit their HIV-positive status to get away with behavior that would not be accepted from others.’”

What was that “uninformed demagogy” and “intimidation” displayed by, for example, Act-UP Paris? Here it is:

“the end justifies the means?

The trial conducted by FHI in Cameroon, Nigeria and Ghana, financed by BBG with the logistic support of Gilead does not seem to us to provide a satisfactory response to all our questions. Provision for psychosocial support and the means implemented to promote condom use are clearly insufficient, even ridiculous: only 5 counselors and one doctor for 400 prostitutes, no access to the female condom, despite it being much easier for the prostitutes to use in negotiating with their clients. However, scientifically speaking, cases of contamination are ‘needed’ for the trial results to be ‘interesting’.
If all precautions were taken with regard to prevention and supervision, it is certain that the trial would have to recruit a much larger study population so that a difference in contamination rates between the placebo and tenofovir groups would be statistically significant. . . .
The heart of the dossier is not so much an ethical/scientific conflict, as an ethical/economic duel. In this sense also, if recruitment for the trial did not target a population already ‘forced’ to take risks, it would be necessary to considerably increase the number of participants and consequently the cost of the trial… By holding this trial in Africa, Gilead and the BBG Foundation know that they will find a population that is vulnerable both materially and in terms of practices, women willing to let them carry out a trial at minimal cost. It is then, really a question of money . . . .

when hypocrisy rhyme with economy

The tenofovir DF trial expects to provide follow-up and access to treatment for sexually transmitted diseases (STD). This plan may appear generous. In fact, it is nothing more than a means of building the prostitutes’ loyalty and minimizing the risks of their dropping out. Moreover, it so happens that follow-up tests are required for the scientific validation of the trial. Setting the amount allowed for expenses at 2,750 Fcfa shows an extraordinary level of cynicism. In fact, a rapid calculation shows us that this amount was figured to cover transportation expenses on the one hand (500 F for the taxi) and the prostitutes’ lost income on the other hand (2,150 F for two tricks, minimal fee in Douala).
What will happen to prostitutes who are found to HIV-positive during pre-enrolment testing? We don’t know, but we can imagine. In Cameroon, the promoter plans to refer women who become HIV-positive during the trial to the system of access to care and treatments set up in this country by NGOs and the government. While it is true that in Cameroon, treatment access is less difficult than in other African countries, it remains uncertain. It is estimated that one million people are infected with HIV, i.e. a prevalence of 15% (according to all of our interlocutors, this figure is an underestimate), and that 40,000 people are in urgent need of antiretrovirals (currently only 10, 000 are under treatment). It is therefore particularly shameful that Gilead; which is donating the tenofovir and placebo for the trial has not also arranged to provide free antiretrovirals to participants who need them.
. . .
In the future; the design of this type of trial must be discussed with the patient associations in the host country. We hold Gilead and the BBG Foundation responsible for the lives of the women included in the trial.”

Those words from Act-UP Paris may be strong, but they are hardly “uninformed demagogy” or “intimidation”. And it isn’t only in Africa, and it’s not only AIDS activists who object; similar ventures in Thailand brought criticism from Doctors Without Frontiers, who also contradict Joep Lange’s assertions [Chua et al., The Tenofovir Pre-Exposure Prophylaxis Trial in Thailand: Researchers Should Show More Openness in Their Engagement with the Community, PLoS Med. 2005 October; 2(10): e346]:

“The key community groups that have expressed concerns about the tenofovir trial in Thailand are the Thai Drug Users Network (TDN) and the Thai AIDS Treatment Advocacy Group (TTAG)  . . . . These community groups, which can justifiably claim to represent Thai drug users, are well informed about the trial, but their objective concerns have been ignored by the trial investigators. Contrary to the assertion of Joep Lange [2] “that the investigators did consult intensely with community groups concerned”, TDN and TTAG were not consulted about the trial design and conduct until a very late stage, after several attempts to engage with the investigators had been rebutted. TDN and TTAG had attempted to constructively engage with the investigators since October 2004; they confined their statements of concern to private letters and meetings with the investigators, until the matter was made public in a Lancet editorial in March 2005 [3].
. . . .
We believe that the disagreements surrounding the tenofovir trial in Thailand would have been avoided if the investigators had set out to engage the community more openly, and if the wealth of established knowledge among community members could have contributed enormously to the success of the trial design and implementation. TDN and TTAG have made recommendations . . .  that represent a constructive way for this trial to move forward. Mechanisms that ensure systematic involvement of legitimate representatives of the affected community as partners in research are the only way to ensure that future trials will proceed in a more productive way.”

[2] Lange, J. We must not let protestors derail trials of pre-exposure prophylaxis for HIV. PLoS Med. 2005;2:e248
[3] [Anonymous] The trials of tenofovir trials. Lancet. 2005;365:1111.

(In Thailand, the trial was to enroll drug abusers. A central issue concerned providing drug abusers with clean needles. That would be required under the spirit of the Helsinki Declaration, but the US Government bans funding for such a procedure; and the penalties in Thailand against drug abuse are so severe that participants in any such trial would need specific protection against prosecution under those laws.)