Abstract
Over the past decade AIDS research has turned toward the use of pharmacology in HIV prevention, including pre-exposure prophylaxis (PrEP): the use of HIV medication as a means of preventing HIV acquisition in those who do not have it. This paper explores the contradictory reasons offered in support of PrEP—to empower women, to provide another risk-reduction option for gay men—as the context for understanding the social meaning of the experimental trials that appear to show that PrEP works in gay men and heterosexual couples but not single women. The PrEP debates reveal the different ideas about “demedicalization” in the earlier gay health and women’s health movements and highlight the relationship between health activism and critique of research ethics in the context of a global pharmaceutical market.
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Notes
The original letter signers included eight longstanding AIDS organizations that developed from early community activism (AIDS Action Committee of Massachusetts, AIDS Foundation of Chicago, Gay Men’s Health Crisis [New York City], National Minority AIDS Council, Project Inform, the San Francisco AIDS Foundation, Harlem United and Black AIDS Institute); one of the iPrEX trial sites (Fenway Community Health Center); two clinical trial research centers that not only had complex relationships with communities but also murky relationships to pharmaceutical companies, including either funding or overlapping board of directors membership (AIDS Research Consortium of Atlanta, with more than 275 clinical trials and recent expansion to vaccine and PrEP research, and AIDS United, whose trustees come primarily from major corporations, including Gilead Sciences); and two more recent advocacy organizations concerned with pharmacological prevention (International Rectal Microbicides Advocates and AVAC, which took a lead role in the pro-iPrEX publicity.) AVAC is concerned with “ethical delivery of new HIV preventions options,” and although they do not accept funds from drug companies or the government—their funding comes from UNAIDS, WHO, and major nonprofit donors and corporations—their very impressive board of directors is dominated by individuals involved in previous vaccine trials or who have previously worked with drug companies or as academicians on HIV trials. No AVAC board members have longstanding experience with community-based, non-pharmaceutical prevention education and none are social scientists with expertise in socio-sexual cultures.
There are about two dozen ongoing or completed randomized controlled pre-exposure prophylaxis trials, which have involved approximately 20,000 people in 15 countries, including only three high-resource countries: France, the United States and Canada. (The other 12 countries are: Cameron, Nigeria, Ghana, Thailand, Botswana, Peru, Ecuador, Kenya, Uganda, Brazil, Zimbabwe, South Africa.) The initial trials used tenofovir (brand name Viread, a Gilead product) and/or a tenofovir and emtricitabine combination (brand name Truvada, also a Gilead product that typically comes in the form of a once-a-day pill but is also available as a vaginal gel). The latest trials compare newer anti-HIV pills or alternate dosing schedules (for example, intermittent dosing before or after sex).
“The findings in this report are subject to at least five limitations. First, the trial was not large enough to evaluate the efficacy in each of these sites, and the majority of the participants were in South America; only 10 % were in the United States, making it impossible to determine effects on incidence in the United States trial sites specifically. Second, the assessment of adherence by drug-level testing was not performed for all trial participants and was performed for seroconverters at the first clinical visit in which infection was diagnosed; therefore, the findings might not reflect drugs levels at the time of infection. Third, the study does not provide information about long-term health effects of TDF/TFC in HIV-uninfected men or men who became HIV-infected while on PrEP medications. Fourth, results of drug-level testing showed that adherence measures in the trial might overstate levels of actual adherence; many of those with high level of adherence to the daily regimen by self-report, pill count, and bottles dispensed had low levels or no drug measured in their blood. Finally, sexual risk behaviour and adherence to PrEP medications among MSM taking TDF/FTC for PrEP outside of a trial setting, and with awareness of the trail results, might be different from what was observed for men in the iPrEx trial” (Centers for Disease Control and Prevention 2011, ¶2 under “Editorial Note”).
Futility means that statisticians—in these cases, the mandatory independent data monitoring committee—determine that the difference between the study groups is so small that, even by continuing the study, there will not be a result that could rise to statistical significance. Futile study closure is essentially a finding of no finding; that is, the null hypothesis—that there is no difference between the treatment group and the control group—stands. VOICE sought to confirm the results of CAPRISA, a study of vaginal tenofovir—one of the two drugs in Truvada—versus placebo. VOICE is a trial of multiple different anti-HIV formulations, in both oral and vaginal form, versus placebo. Only the tenofovir tablet arm was closed; nevertheless, it is hard to explain why a gel would show marginal utility, while an oral version did not.
It is difficult to assess the impact of the U.S. political battle in 1987 in which U.S. Senator Jesse Helms, a Republican from North Carolina, succeeded in passing a rider attached to the U.S. AIDS funding bill that prohibited the government from funding groups or programs that “promote homosexuality and promiscuity.” This had a chilling effect, not only in the United States but also in developing countries, where overall lack of funding for any form of health promotion made countries dependent on money from USAID and other donor agencies. AIDS groups in the United States and abroad were threatened with losing all of their funding if they did not abide by this mandate in their prevention efforts. Having succeeded with “no homo promo,” as activists of the day called the Helms Amendment, right-wing activists attached a regulation to USAID monies denying AIDS-related funding to groups and countries that permitted abortion. While virtually all policy-makers assert that “prevention has failed,” it might better be argued that dynamic prevention campaigns have largely not been attempted.
MSMGF sided with the Open Letter writers in support of allowing the FDA to proceed with a special review of PrEP for gay men only; however, this fell short of an actual endorsement of PrEP. Like many groups, MSMGF has been cautiously supportive of PrEP as a complement to condom-use for those at “high risk,” although as we will show, there is no clear definition of who that actually is. It will be interesting to track the positions of organizations like MSMGF, which have been highly critical of government funding and policy, as the real cost of PrEP comes under greater scrutiny and once it becomes clear whether any international aid organizations will step in to shoulder that cost or whether PrEP, whatever its utility, will remain out of reach except for the wealthy.
See Patton (2011) for a critique of the human rights issues involved in the emerging global consensus of aggressive HIV testing, followed by aggressive treatment of those believed likely to transmit the virus to others. This article contains a lengthy bibliography of works critical of the science and pragmatics of the “seek and treat” branch of the “treatment as prevention” movement that, along with PrEP, proposes a new solution to the epidemic organized around pharmacological intervention.
Although the hepatitis fear has become relegated to the stuff of AIDS conspiracy theories, in 1984 the idea that the vaccine trial subjects had somehow been given a mutant virus merited serious attention by the CDC, which in December published results on why this was unlikely (Centers for Disease Control and Prevention 2011).
Sero-sorting is the practice of having sex—of whatever variety—only with persons of like status. Although many safe-sex advocates viewed the practice as rife with communication problems—research showed that seropositive older men believed seronegative younger men would ask for a condom, while seronegative younger men believed seropositive older men would offer them a condom—it was clear that, by the early 1990s, the mainstream message to “know your partner” had evolved into a faith in disclosure that was the new norm in gay communities. Other strategies included “positioning” in anal sex so that seropositive men were not inserters with seronegative men and, of course, avoiding anal sex except under defined circumstances—dubbed “talk, test, test, trust”—in one Australian campaign.
The history of trials of different combinations of anti-HIV medications and at different points is a whole book in itself, including scandals related to drug side effects in infants, development of resistance in mothers, and the implications of product dumping. These issues alone should have given pause to any leap from the probable success of drugs in MTC to the likelihood that either seek-and-treat interventions or PrEP were a scientific slam-dunk. The U.K. charity AVERT, which has worked on this issue for decades, is probably the first place to start to trace this history. For a discussion of the controversial HIVNET 012 trial of nevirapine, which ignited controversy about potential cover up of drug toxicity and resulted in an NIH hearing on scientific conduct in 2005, see Adam 2005.
The regional breakdown for iPrEX, showing the number and percentage of subjects in the treatment and then the placebo group, is as follows: Lima, Peru 470 (38)/470 (38); Iquitos, Peru 230 (18)/230 (18); Guayaquil, Ecuador 150 (12)/150 (12); Rio de Janeiro, Brazil 147 (12)/147 (12); São Paulo, Brazil 39 (3)/37 (3); San Francisco, California 70 (6)/70 (6); Boston, Massachusetts 43 (3)/44 (4); Chiang Mai, Thailand 57 (5)/57 (5); Cape Town, South Africa 45 (4)/43 (3). The majority of the PrEP efficacy trials are offshore trials (see note 2). The history and rationales for offshore trials is another extremely complex area. In general, offshoring—which has increased so dramatically over the last five years that there are consulting companies to help determine the “optimal” location for a trial—is research that is conducted outside the probable catchment area for the drug’s future distributions and/or in places other than the countries that regulate the conduct of the drug companies and their university collaborators. The best single work on the history and problems—scientific and ethical—of offshoring is Andriana Petryna’s (2009) When Experiments Travel: Clinical Trials and the Global Search for Human Subjects. For a sample of the consulting world, see “Make Your Move: Taking Clinical Trials to the Best Location” (http://www.atkearney.com/index.php/Publications/make-your-move.html).
Gilead Sciences is headquartered in Foster City, California. Antiretrovirals constitute a major part of its sales, and a significant part of its nearly 20 percent increase in sales comes from Atripla, Truvada, and Compera/Eviplara, the most commonly used “one-a-day” pills against HIV, which are all anchored by the Gilead product tenofovir. For actual product sales numbers, see http://www.gilead.com/pr_1688123 (Gilead Sciences 2012).
Few lay people understand what a confidence interval is, and researchers only recently began routinely reporting them. Simply put, confidence interval indicates the accuracy of a given estimate (interval) and the probability that this result is correct (confidence level). Confidence levels are often set at 95 percent, while narrower intervals show more accuracy in the result. In this case, the CI is the upper and lower limit of the percentage differences between those who contracted HIV while on placebo and those who contracted HIV while on PrEP at a 95 percent confidence level. So the statement should read, “there is a 95 percent chance that the true difference falls between the lower and upper limit.” In other words, the true difference between HIV transmission rate of the placebo group and the PrEP group could be as little as 15.4 percent and as high as 62.6 percent, given the 95 percent confidence level.
These quick recalculations cannot take account of the fact that each individual is in the study for somewhat different lengths of time due to becoming infected or dropping out for other reasons. Thus, while the study ran for 144 weeks, the median length any individual was in the study was 62.4 weeks. The researchers could have calculated an infection rate based on the average of each individual case, but instead they use aggregates. The figures presented here are merely annualized aggregates.
Just to give an idea of the intensity of involvement in the lives of the 2,499 participants, this trial involved 55,000 screening or follow-up visits, in which there were more than 500 cases of syphilis treated; 44,000 visits for HIV testing and counseling; and approximately 500,000 condoms distributed. In addition, participants received a total of 1.3 million tablets of Truvada. For an idea of what that would amount to for people living with HIV, this is about enough drugs for 200 HIV-positive people for a little less than 20 years each. Of course, most people will not take Truvada for 20 years because, for about a third, Truvada will stop working within a few years. If such a person lives in a medium- or high-resource country, he or she will be switched to another drug. The current estimate for median effectiveness of first-line drugs in general is about three years, so the numbers of drugs given out during the iPrEX trial represent first-line therapy (a drug used to failure) for about 1,100 people.
A previous essay (Patton 2011) explored the history of the fragile consensus among gay and prostitute rights activists, nations, transnational NGOs, and pharma to develop a universal access program that has been incrementally successful in getting HIV drugs to people who need them. This essay shows how the rapid shift toward “treatment as prevention,” which introduces the concept of a “population viral load” as the object of pharmaceutical attention, transforms an epidemiological simulation (“population”) into the repository of a “right”—not to “health for all” understood as access to care for real people (which would include prevention, certainly), but “health for all” understood as an abstract world free from disease, in this case, AIDS, measured in terms of “population viral load.” This displaces rights discourse from a consideration of vulnerable individuals and their communities and shifts it onto the right of the simulation to have its viral load reduced through pharmacological suppression of virus in the “components” within it that (who) are already infected with HIV. As our local experience with “Seek and Treat to Optimize AIDS Prevention” as well as “Test and Linkage to Care Plus” (the “plus” being treatment) in cities in the United States is quickly demonstrating, the frenzy of testing everyone possible has resulted already in: the elimination of pre-test counseling (viewed as a “barrier” to test-taking and ignoring its role in educating and supporting people in their efforts to practice safe sex and safe drug use); the elimination of confidentiality laws; pressure to override patients’ wishes regarding when to go on treatment; and, if recent trends in New York and British Columbia law continue, the criminalization of recalcitrant HIV-positive persons who either fail to take their medications properly or continue to practice sex deemed unsafe.
iPrEX is dominated by young men, spread unequally across the treatment and placebo groups: 18–24 yrs 591 (47)/662 (53); 25–29 yrs 274 (22)/241 (53); 30–99 yrs 249 (20)/224 (18); greater than 40 years 137 (11)/121 (10). France is currently recruiting for a PrEP study of teenagers.
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Patton, C., Kim, H.J. The Cost of Science. Bioethical Inquiry 9, 295–310 (2012). https://doi.org/10.1007/s11673-012-9383-x
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DOI: https://doi.org/10.1007/s11673-012-9383-x