Jerome A. Singh is at the Centre for the AIDS Programme of Research in South Africa and the Howard College School of Law, University of KwaZulu–Natal, Durban, South Africa, and the University of Toronto Joint Centre for Bioethics, Toronto, Ontario, Canada. Edward J. Mills is at the Centre for International Human Rights Law, University of Oxford, United Kingdom, and the Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.
The authors declare that they have no competing interests.
The dramatic protests that shut down trials of tenofovir as pre-exposure prophylaxis against HIV may prove damaging in our fight against the HIV pandemic.
New approaches to HIV/AIDS prevention are urgently needed to stem the estimated 5 million new infections that occur worldwide each year. One such promising, novel intervention has been the proposed use of the oral antiretroviral drug tenofovir (Viread) as a pre-exposure prophylaxis (PREP) in high-risk groups (for example, uninfected women who have high-risk commercial sex). However, emerging opposition has 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. This could prove damaging in the long term.
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. This unfortunate prospect raises questions about responsible media reporting, responsible conduct on the part of investigators and activists, and what should be done to avert or repair damaging trial-related disputes in the future.
In July 2004, increasing pressure from activist groups and affiliated non-governmental organizations persuaded the Cambodian Prime Minister to halt the initiation of a PREP trial of tenofovir among Cambodian commercial sex workers [
The dramatic protest against the Cambodian trial at the XV International AIDS Conference in Bangkok, Thailand, caught the world's media attention [
(Photo: Act Up–Paris)
(Photo: Act Up–Paris)
More recently, in February 2005, a similar trial in Cameroon, led by Family Health International (FHI), was halted by the Minister of Public Health. The activist group Act Up–Paris (
Protest should be carried out in a responsible manner.
An independent inquiry, commissioned by the Cameroon Ministry of Public Health, reported on February 23, 2005, that they now require more regular reporting and a formal study site accreditation for a satellite hospital clinic [
On March 11, 2005, FHI made the announcement that the Nigerian arm of the tenofovir PREP trial will discontinue prematurely. FHI closed the trial voluntarily, because it determined that the study team was unable to comply with the required operational and laboratory procedures at the level necessary for conducting this study. The ability to meet these standards is critical for ensuring the safety of participants and the quality of the data from the study. This decision was made in conjunction with FHI's external, independent Data and Safety Monitoring Committee. More than 100 participants had been randomized. The announcement came as a disconcerting blow to the already fragile network of trials.
Activists and ethicists argue about the contentious issue of the standard of care in randomized trials [
Guideline 29 of the Helsinki Declaration states that interventions should be tested against the best prophylactic interventions available [
In response, investigators claim that the tenofovir PREP trials were developed collaboratively with the host countries to meet relevant ethical standards. In West Africa, formative research studies with the community of participants helped to design the informed-consent instrument, to identify the preferred sites of receiving health care, and to identify sources of stigma, which the investigators tried to reduce.
Act Up–Paris and other activist groups report that they plan to continue protests against other tenofovir trials taking place elsewhere in the world (
NIH, National Institutes of Health.
As of March 2005, there are at least six ongoing or planned human clinical trials of tenofovir as PREP (
Recent protests by the Thai Drug Users Network and other Thai AIDS advocacy groups, opposing the recent approval of a tenofovir prophylaxis trial funded by the US Centers for Disease Control and Prevention (CDC) among intravenous drug users (IDUs), should be setting off alarm bells for the trial investigators concerned. Thai activists cite ethical flaws in the trial design and a lack of community involvement on the part of the trialists. The activists argue that withholding the provision of clean injection equipment is an ethical violation, saying that clean equipment is a standard prevention tool akin to condoms, which are offered to trial participants in other countries who are chosen for their high-risk sexual behaviours.
But according to a CDC fact sheet, participating IDUs will be offered follow-up in a methadone drug-treatment program, and will receive bleach and instructions on how to use it to clean needles [
HIV/AIDS advocacy and other activist groups have openly criticized those involved in protesting these trials for what was seen as callous behaviour on their part. Most investigators and advocates for patients with HIV/AIDS laud the past work of activist groups in attracting the world's attention to the HIV epidemic. Indeed, activism can undoubtedly play an important role in ensuring that researchers and sponsors maintain ethical standards. However, activism should be based on informed opinion and communication.
Activism should be based on informed opinion.
In May 2005, the Bill and Melinda Gates Foundation brought together activist, advocacy, and research groups to discuss future tenofovir trials. In an effort to engage stakeholders, the meeting sought resolution and clarifications to the standards of care and prophylaxis in planned provision. The meeting identified the many rumors and miscommunications that had existed in the reporting of the closed trials. It exemplified the necessity for early interventions to promote communication, in order to prevent partisan behaviour among stakeholders.
The rapidly collapsing tenofovir trial network shows that a lack of communication between activists, participants, and researchers can lead to suspicion, speculation, and, ultimately, damaging outcomes. While clinical trial investigators have increasingly begun to involve stakeholder groups in medical decision-making and trial planning, this gesture must go beyond mere tokenism. Investigators should engage in pre-trial “preventative diplomacy”. This celebrated dispute resolution mechanism is often used in political contexts but could find useful application in the research arena, too. While anything intended to keep a conflict from worsening might be described as “preventative”, preventative diplomacy involves “proaction” rather than reaction and emphasizes that crises can be better addressed before or as they emerge rather than when they have already deepened and widened.
Instruments that may be used to prevent the emergence or escalation of disputes culminating in trial suspension include the following: (1) the establishment of early warning mechanisms (such as a community liaison officer), (2) fact finding missions (these may establish that the operational reality does not resonate with protocol schedule), (3) confidence-building measures (such as the inclusion of activist groups in community advisory boards), (4) engaging the media, and (5) education (particularly on important issues such as therapeutic misconception, compensation for study-related injuries, and post-trial benefits). The development of a forum for identifying mutual interests and concerns, while still invoking reciprocity and transparency, may identify early concerns.
The investigators from the PREP trials report that they did involve activist and advocacy groups in designing the trials, but say that they were unsuccessful in addressing the wider activist community. Investigators should not merely encourage the involvement of activist groups in future prevention trials—they must make a genuine attempt to address their concerns. Such an approach may have averted the trial closures.
The world desperately needs efficacious HIV prevention and therapy. If tenofovir is shown to be an effective PREP agent, it will become a powerful tool in the fight against AIDS, but it will need to be delivered alongside behavioural interventions, condoms, clean needles, HIV testing, and access to HIV treatment. The ethics of the aforementioned Cambodian and Cameroonian tenofovir trials will likely remain forever contentious. The operations of the Nigerian trial remain a continuing issue, concerning how to assure research quality meets international standards in resource-poor settings. However, the important lesson to be learned from these experiences is that investigators, sponsors, participants, members of the study community, government authorities, and activist groups must actively engage at all stages of a trial to ensure that the study is conducted in a manner that is beneficial to, and respectful of, the participants, while remaining scientifically sound.
Stakeholders must rise above ideological differences and keep their eye on the ultimate goal: combating AIDS. If disputes arise, they must meaningfully commit themselves to addressing the issues expeditiously and in a manner that is conducive to ongoing dialogue and a sustainable relationship. A failure to do otherwise will frustrate attempts to combat AIDS and needlessly prolong the suffering of those in need.
The authors are indebted to Dr. Ross Upshur, Dr. Jim Lavery, Beth Robinson, Lori Heise, Dr. Kim Shafer, Prof. Bebe Loff, Mitchell Warren, Dr. Ward Cates, and Act Up–Paris. The opinions expressed in this paper are solely those of the authors. This work is based on an ongoing policy analysis of the tenofovir trial closures.
Centers for Disease Control and Prevention
Family Health International
intravenous drug user
pre-exposure prophylaxis