Adherence low because of fears about HIV and the drugs intended to prevent it.
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In the last analysis, the reasons for a negative outcome of an HIV prevention trial came down to people and their attitudes about the virus and the drugs intended to prevent it.
The so-called VOICE trial (for Vaginal and Oral Interventions to Control the Epidemic)tested several ways of preventing HIV acquisition among women in Africa.
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None had a significant impact on the risk of catching HIV, according to Jeanne Marrazzo, MD, of Harborview Medical Center in Seattle, and colleagues.
The outcomes were both disappointing and surprising, they write in the Feb. 5 issue of TheNew England Journal of Medicine -- disappointing because such interventions are desperately needed and surprising because other trials had shown efficacy as long as the medications were used.
In the VOICE trial, 91% of participants remained on study and -- on the basis of returned product counts -- adherence to the study drugs was 86%. As well, self-reported adherence was 88% to 90%, Marrazzo and colleagues reported.
Unfortunately, the latter data was false -- random blood testing suggested the true rate of adherence was less than 40%, the researchers found.
A central issue for future prevention trials, Marrazzo and colleagues concluded, is to find better ways of monitoring adherence and to understand why some people will enroll in trials but not follow the protocols.
The trial has been "eye-opening for all of us involved in HIV prevention, particularly on trials focused on meeting the needs of women," Marrazzo said in a statement.
"We need to better understand women's perceived motivations for participating in a trial but, more importantly, what products they will want to use," she said.
The trial tested three active treatments with two placebo arms:
- Oral tenofovir (Viread). This arm of the trial, with 1,007 participants, was ended prematurely for futility in September 2011. There were 52 infections among those in the active arm.
- Oral tenofovir/emtricitabine (Truvada). Among the 1,003 women in the study, there were 61 infections.
- Tenofovir vaginal gel. Of the 1,007 women in this arm of the trial, 61 acquired HIV. The section of the study was also stopped for futility, in November 2011.
- Placebo pills were given to 1,009 women; there were 60 infections.
- Gel placebo was given to 1,003 women; there were 70 infections.
Analysis suggested that the effectiveness of the tenofovir pills was minus 49.0% with a hazard ratio for infection of 1.49, compared with minus 4.4% for tenofovir/emtricitabine (HR of 1.04) and 14.5% with the gel (HR of 0.85).
None of the effects reached statistical significance.
The findings are consistent with the placebo-controlled FEM-PrEP trial in which women at risk of HIV were given tenofovir/emtricitabine -- there was no significant benefit, probably because adherence was in the range of 40%.
But they contrast with outcomes among women in the Partners-PrEP trial, which found reductions in the risk of HIV acquisition of 71% with tenofovir and 66% with tenofovir/emtricitabine. But adherence in that study was good, Marrazzo and colleagues noted.
"It is well established that medications don't work if they are not taken, which probably explains why no difference in efficacy was observed between the active-drug and placebo groups," commented Michael Saag, MD, of the University of Alabama Birmingham.
The disparity between reported and actual adherence is the "striking finding" of the VOICE trial, Saag argued in an accompanying editorial, noting that a large number of women gave misleading reports and some actively removed drugs from their allotment to give the impression they had been taken.
"The question that emerges is this," he wrote: "why did the participants go to such lengths to create the appearance that they were taking medications when they were not?"
Marrazzo and colleagues made an attempt to answer that question, they reported late last year, by interviewing several dozen former participants.
They found that many women were afraid to use the medications, either because they feared toxicity or because they were worried about being falsely labeled as having HIV.
Interestingly, Marrazzo and colleagues noted, the VOICE participants who were most likely to adhere were similar, in age and marital status, to women in the Partners-PrEP trial.
That trial enrolled sero-discordant couples, in which both partners were aware that one had HIV and there was mutual support for using the medications.
In the VOICE trial, being married, older than 25, and having more than one child predicted finding tenofovir in blood samples, they reported, and finding the drug in blood tests was associated with a lower risk of HIV.
For instance, among gel users who had tenofovir detected at the first quarterly checkup, the risk of acquiring HIV was significantly lower than among those who did not: the HIV incidence per 100 person-years was 1.9 versus 6.1, with an adjusted hazard ratio of 0.34, which was significant at P=0.02.
The researchers said similar results were obtained when participants were stratified on the basis of whether tenofovir was ever or never detected.
The study was supported by the NIH. Marrazzo did not make any disclosures. Two authors disclosed relationships with Gilead Sciences, which manufactures tenofovir. No other disclosures were made.
Saag disclosed relevant relationships with Gilead, Merck, BMS, Viiv, Janssen, AbbVie, and Boehringer Ingelheim.
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