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Will at-Risk Men and Women Use TDF/FTC PrEP?
Before TDF/FTC won PrEP approval and before most PrEP trial results became widely known, limited research addressed awareness of PrEP and likely use by gay and bisexual men and heterosexual men and women in the United States or countries with similar epidemics.
Two published surveys of HIV risk perception and PrEP awareness in heterosexual US men and women visiting sexually transmitted infection (STI) clinics found inverse correlations between actual HIV risk and self-perceived risk -- and moderate interest in PrEP, depending on how the question was asked.16,17 Both of these surveys were completed, however, before publication of iPrEx results,2 before release of the two key PrEP efficacy studies in African heterosexuals,3,4 and before approval of TDF/FTC PrEP.
An anonymous survey of 494 people attending a Chicago STI clinic found that 409 (83%) had a high risk of HIV infection (by predefined criteria).16 While 63% of the study group were men, 70% were black, and 88% were heterosexual. Median age stood at 30 years. Among 359 heterosexual high-risk participants in this August-to-October 2010 survey, 301 (84%) thought they had low or no risk of HIV infection. Although this group had a good understanding of HIV transmission, fewer than 20% reported consistent condom use during vaginal, oral, and anal sex.
Among the 359 high-risk heterosexual participants, 299 (83%) said they would take a pill for PrEP, including 84% of men and 82% of women.16 But lower proportions would take a PrEP pill once a week (76%) or once a day (63%). Half of these people (51%) said they would don condoms as often with PrEP as without, while 23% said they would wear condoms more with PrEP and 20% would use condoms less with PrEP. People with lower education levels were 5 times more likely to express no interest in PrEP (adjusted odds ratio [aOR] 4.97, 95% confidence interval [CI] 1.26 to 19.67, P = 0.02). People with low HIV risk perception tended to declare no interest in PrEP (P = 0.10).
A similar survey of 225 men and 174 women visiting a South Carolina STI clinic in 2009 and 2010 included 358 people who answered a question about PrEP knowledge.17 Median age of this study group stood at 24.5, 89% were black, and 90% identified themselves as heterosexuals. As in the Chicago study, clinic attendees with a higher risk of HIV infection thought they had a lower risk. Specifically, compared with people who had 1 sex partner in the past 3 months, those with 2 to 4 partners were more than twice as likely to disagree with the statement "I believe I am at risk of getting HIV" (P = 0.0003).
One third of these South Carolina residents (32%) somewhat agreed with the statement, "If I had to it would be very difficult for me (or my partner) to both use condoms and take daily pills to prevent HIV infection," while a slightly higher proportion (38%) strongly disagreed with that statement.17 Compared with women, men were almost 3 times more likely to agree that simultaneous condom and PrEP use would be tough (adjusted odds ratio 2.78, P < 0.001). Gay and bisexual men had almost a 7 times higher chance of knowing about PrEP than heterosexuals in 2011 (OR 6.7, 95% CI 1.70 to 26.1).
Research dating back a half-decade suggests that US gay and bisexual men relish the possibility of PrEP more than high-risk heterosexuals -- though some postPrEP approval evidence does not bear out that suggestion. A survey of 227 HIV-negative men in the Boston area, 46% of them white, found that only 43 (19%) had heard of PrEP in 2007, though 1 pioneer had already tried it.18 But after researchers explained PrEP and its preventive potential, 168 men (74%) averred that they would adopt this then-novel strategy.
A 2009 (pre-iPrEx) survey of 50 Los Angeles gay and bisexual men in 25 HIV-discordant couples found that 40 (80%) voiced "positive and enthusiastic comments regarding this new prevention strategy," although they did not expressly state their willingness to take a daily PrEP pill.19 Most of these men (80%) belonged to a racial or ethnic minority, one third reported unprotected receptive anal intercourse, and two thirds reported unprotected insertive anal intercourse. These men frankly admitted one of the reasons they found PrEP appealing was the opportunity to avoid HIV and condoms at the same time. If PrEP were available, one study participant predicted, condom use "would probably change dramatically, 100% less use, more than likely." These same men evinced some shrewd concern about potential barriers to ready PrEP use, including cost, possible side effects, risks posed by missing doses, and needing a prescription and a negative HIV test.20
An Internet survey of US MSM conducted early in 2011, after release of iPrEx results, determined that 83% of HIV-negative men claimed they would use a PrEP product with 44% efficacy21 -- the overall protective effect found in iPrEx. A US Internetbased survey of 398 at-risk gay men before iPrEx results became known and 4558 men after iPrEx results showed that only 12.5% of men in the preiPrEx group and 19% in the post-iPrEx group knew about PrEP.22 But once researchers explained PrEP to these men, 76% in the pre-iPrEx contingent and 78.8% in the post-iPrEx set expressed interest in using PrEP.
For this second study, men were recruited from a multinational social networking site for MSM.22 Age averaged 40.2 in the pre-iPrEx group and 39 in the post-iPrEx group. Respective proportions of whites were 82.1% and 84.0%. Only 2.2% and 3.2% were black. Only about 6.5% of men had only a high school education or less. Multivariate analysis determined that interest in using PrEP was associated with older age (OR 1.01, 95% CI 1.00 to 1.02, P = 0.01), self-perceived risk of HIV infection (OR 1.20, 95% CI 1.13 to 1.27, P < 0.0001), and unprotected anal intercourse with one or more male partners (versus no anal intercourse) (OR 1.41, 95% CI 1.11 to 1.79, P = 0.004). Notably, men aware of postexposure prophylaxis had 45% lower odds of being interested in PrEP (OR 0.55, 95% CI 0.43 to 0.71, P < 0.0001).
The apparent appeal of PrEP to MSM, compared with high-risk heterosexuals, could reflect their greater awareness of this strategy through personal and digital networking. The University of Cincinnati's Judith Feinberg, who chaired the FDA hearing on TDF/FTC PrEP, worried whether PrEP will be "limited to persons who are well-informed and have good insurance, rather than reaching those at highest risk?"23
But now that PrEP is a prescribing reality, anecdotal evidence suggests few at-risk people in the United States are rushing to start a once-daily prophylactic pill. In an interview following this article, UCLA's Raphael Landovitz says he's had two referrals of PrEP candidates, and his colleagues in Los Angeles report a similarly meager flow of "early adopters." In an interview immediately following this article, iPrEx principal investigator Robert Grant reports that perhaps one provider in every clinician audience he talks to about PrEP across the country has started prescribing. These experiences suggest that MSM enthusiasm for PrEP in preapproval surveys may not carry over to everyday practice -- at least not right away. Raphael Landovitz suggests men may be waiting for a PrEP regimen that does not require daily dosing.
Whether MSM actually use TDF/FTC PrEP when someone puts it in their hand may depend on age and education. Analysis of tenofovir or FTC intracellular concentrations in iPrEx (in which 9% of participants lived in the United States) found measurable levels in 25 of 65 men (31%) under 25 year old and in 31 of 68 (46%) who were 25 or older.24 Eight of 30 men (27%) with less than a secondary education had detectable drug inside cells, compared with 43 of 103 men (42%) with secondary or higher education. And adherence has a big impact on how well PrEP works, as the next section describes.
PrEP Protects Men and Women -- but Adherence Is Critical
Two consistent themes emerged from the four recent and fully reported placebo-controlled PrEP trials -- iPrEx,2 Partners PrEP,3 TDF2,4 and FEM-PrEP5: TDF/FTC PrEP cuts the risk of picking up HIV during sex, and it cuts that risk more when people take TDF/FTC regularly.
In FEM-PrEP, the one trial that failed to find protection from HIV with TDF/FTC PrEP, adherence largely (though probably not entirely) explained that failure.5 This study of 2120 HIV-negative women in Kenya, South Africa, and Tanzania ended early when interim analysis tallied 33 HIV infections in the TDF/FTC group and 35 in the placebo group. Self-report and pill counts indicated good adherence, but drug-level testing did not. Measuring tenofovir and FTC in plasma samples with an assay that has a lower limit of 0.25 ng/mL, FEM-PrEP researchers considered 10 ng/mL of tenofovir as evidence that a woman had taken TDF in the past 48 hours. Among women assigned to TDF/FTC who became infected with HIV, only 7 of 27 (26%) met that target at the beginning of the infection window, and only 7 of 33 (21%) met the target at the end of that window. Among women assigned to TDF/FTC who did not become infected, only 27 of 78 (35%) met the tenofovir target level at the beginning of the infection window, and only 35 of 95 (37%) did at the end of the window.
Why did FEM-PrEP women take their PrEP pill so irregularly? One reason seems to be that enrollees did not think they had a high risk of HIV infection. Nearly three quarters of women (70%) believed they had no or low risk of HIV infection in the coming month when asked to rate risk at the baseline visit, as did 74.8% at the last follow-up visit.5 Yet these women averaged 3.7 vaginal sex acts in the past week and 1.9 sex acts without a condom in the past week. All women had one or more vaginal sex acts in the past 2 weeks or more than one sex partner in the past month. The researchers speculated that this perception of minimal risk may account for the low adherence observed. These investigators concluded that they "were unable to accurately assess the effect of TDF-FTC on HIV acquisition or safety because of low study drug adherence, which may be an indication that a daily pill-taking regimen will be difficult for some populations."5
Among 29 heterosexual women and men who became infected in Partners PrEP despite assignment to TDF or TDF/FTC, only 9 (31%) had detectable tenofovir in plasma at the visit when they tested positive.3 In contrast, 82% of 902 plasma samples from a randomly selected 198 PrEP takers who did not become infected had detectable tenofovir concentrations. Detectable versus undetectable tenofovir was associated with a relative HIV risk reduction of 86% in people assigned to TDF and 90% in people assigned to TDF/FTC (Figure 1). For comparison, overall risk reductions were 67% with TDF PrEP and 75% with TDF/FTC PrEP.
|Figure 1. Adherence Matters in PrEP Impact|
When tenofovir and/or FTC could be detected in plasma of Partners PrEP3 or iPrEx2 participants randomized to study drugs (versus placebo), calculated protection from HIV infection was higher than in overall protection results in those trials.
In TDF2, 2 of 4 people randomized to TDF/FTC who became infected had detectable tenofovir and FTC in plasma at the visit just before HIV seroconversion.4 In contrast, among 69 PrEP takers who did not become infected, 55 (80%) and 56 (81%) had detectable tenofovir and FTC in samples matched by date with the 4 PrEP takers who did get infected. Geometric mean plasma levels in seroconverters versus nonseroconverters were 0.3 versus 30.6 ng/mL for tenofovir (P = 0.007) and 0.5 versus 103.3 ng/mL for FTC (P = 0.009).
The impact of PrEP adherence on protection also proved telling in iPrEx men and transgender women who have sex with men.2 Overall, TDF/FTC PrEP lowered HIV acquisition risk 44%. iPrEx investigators measured tenofovir and FTC levels in everyone assigned to TDF/FTC who became infected and in a matched subset of PrEP takers who remained free of HIV. People with detectable drug levels had a 92% lower risk of HIV acquisition than did those with undetectable levels (Figure 1). iPrEx investigators found that protective concentrations of TDF and FTC continue rising through the first 3 weeks of PrEP use. iPrEx investigator Robert Grant explained in an interview in this issue of RITA!, "If people want the maximum level of protection" from TDF/FTC PrEP, he advised, "they should take it daily."
An FDA analysis presented at the agency's PrEP hearing found that iPrEx participants with measureable intracellular drug concentrations had an 87.5% lower HIV risk than participants taking placebo.25 Remember that only 9% of iPrEx participants lived in the United States. When the iPrEx team measured tenofovir diphosphate levels in blood cells, they found the drug in 94% of US men versus 43% of non-US men, a highly significant difference (P < 0.001).
CDC interim guidance stresses that iPrEx results "provide strong evidence that support for adherence to the prescribed medication regimen must be a routine component of any PrEP program."9 The two sets of CDC guidance -- for gay or bisexual men9 and heterosexual men and women11 -- both advise clinicians to provide adherence counseling when PrEP begins and to check adherence at every follow-up visit, or more often if poor adherence becomes apparent. In approving TDF/FTC for PrEP, the FDA ordered Gilead Sciences, the manufacturer, to run a trial evaluating adherence and how it affects HIV risk, emergence of resistant virus, and side effects. "An effective tool used incorrectly or inconsistently is reduced to an ineffective tool," cautioned Lauren Wood, an FDA PrEP panelist who voted against a PrEP license for TDF/FTC.8
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