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Prospects for Intermittent PrEP Dosing
PrEP trial results reviewed in the preceding section leave little doubt that spotty adherence to once-daily TDF/FTC imperils chances of protection from HIV. As Robert Steinbrook (Yale School of Medicine) wrote in his recent PrEP review, TDF/FTC "is not an effective morning before pill or morning after pill, to be taken as needed by uninfected persons."26 But animal studies, other research, and iPrEx itself dangle tantalizing evidence that intermittent TDF/FTC dosing -- if planned well and practiced faithfully -- could offer reliable HIV prophylaxis, at a lower cost and a lower side effect risk (Table 3).
|Table 3. Intermittent TDF/FTC PrEP Strategies Considered or Being Studied|
|Strategy||Completed on Ongoing Trial||Results|
|Subcutaneous FTC plus high-dose TDF 2 hours before and 24 hours after exposure to simian HIV (SHIV)||Tested in macaques rectally challenged weekly with SHIV27||Protected 6 of 6 macaques from 14 rectal SHIV challenges|
|Oral TDF/FTC 1, 3, or 7 days before sexual exposure and 2 hours after exposure||Tested in macaques rectally challenged weekly with SHIV28||As protective as daily TDF/FTC|
|Doubled dose of oral TDF/FTC 2 hours before or after sexual exposure||Tested in macaques rectally challenged weekly with SHIV28||Fully protective (but dose 24 hours after exposure not protective)|
|Oral TDF/FTC four times weekly||Assessed in modeling study by iPrEx investigators29||Provided intracellular drug concentrations high enough to protect as well as one dose daily|
|Oral TDF/FTC on Monday, Friday, and within 2 hours after sex versus daily dosing||Assessed in placebo-controlled trial enrolling Kenyan MSM and female sex workers31||MEMS-measured adherence 83% with daily dosing, 55% with intermittent dosing, and 26% with postsex dose|
|Oral TDF/FTC before and after sexual exposure or twice-weekly with a postsex boost||Being tested in HPTN 067, the ADAPT study32||Trial enrolling MSM in Thailand and women in South Africa|
|Two oral TDF/FTC doses within 24 hours of sex, one dose during sex, plus one dose 24 hours after sex||Being tested in ANRS IPERGAY trial33||Trial enrolling MSM in France and Canada|
MEMS, Medication Event Monitoring System; MSM, men who have sex with men.
See text for full discussion of trials and results.
CDC investigators rectally challenged macaques with simian HIV (SHIV) once weekly for 14 weeks as the monkeys received one of three daily regimens of FTC or TDF/FTC or subcutaneous FTC plus high-dose TDF given 2 hours before and 24 hours after SHIV exposure.27 All six macaques given the before-and-after subcutaneous shot remained free of HIV through the 14-week challenge period. In another study these same researchers also rectally exposed macaques to SHIV once weekly for 14 weeks, but the TDF/FTC dosing strategy was different.28 An oral dose of TDF/FTC 1, 3, or 7 days before rectal exposure and 2 hours after exposure proved as effective in forestalling infection as daily dosing. A two-dose regimen given 2 hours before or after SHIV exposure -- with doubled TDF/FTC concentrations -- proved fully protective. But a postexposure dose 24 hours after rectal challenge did not block SHIV in these monkeys.
Modeling work by iPrEx pharmacologist Peter Anderson (University of Colorado) yielded evidence that taking TDF/FTC PrEP four times a week may have protected MSM study participants virtually as well as once-daily dosing.29 Compared with placebo, daily TDF/FTC dosing hoisted intracellular drug concentrations high enough to cut HIV acquisition risk 99%, according to this model. Four doses weekly packed enough drug into cells to trim the risk 96%. But twice-weekly dosing produced intracellular drug levels high enough to lower HIV risk only 76%. iPrEx investigators and others still recommend daily TDF/FTC PrEP, however, because it offers some forgiveness for missed doses, while forgiveness with four-times-weekly dosing approaches the razor's edge.
Jonathan Volk (Department of Public Health, San Francisco) and colleagues at other institutions observed that intermittent PrEPping could improve adherence, cut costs and side effects, and make sense for people who "only perceive themselves to be at risk at certain periods (eg, weekends, vacations), and thus are not willing to take a daily pill."30 But TDF/FTC dosing just before and after sex, as in the macaque studies, will work only for people who have sex fewer than three times a week (otherwise you still need near-daily dosing) and for people who plan sex ahead of time and have TDF/FTC on hand.
To see how many MSM plan their sexual forays far enough ahead to make before-and-after dosing feasible, Volk and coworkers recruited 1013 HIV-negative men from two social networks, facebook and black gay chat (bcglive).30 Study participants were at least 18 and reported anal sex with another man in the past 12 months. They completed an online survey about sex in the past year shortly after iPrEx results became known. Most men (70%) were white, 13% were Hispanic, 8% were black, and 9% had another racial or ethnic background. More than half (56%) said they did not use a condom the last time they had anal sex, 34% had anal sex during the preceding weekend, and 36% had anal sex on a least 1 weekday in the preceding week. Half of these men (50.4%) reported no advance planning before their last sex, 8.2% reported planning only minutes in advance, and 22.4% planned only hours in advance. All told, then, 81% of these men would not benefit from a PrEP regimen that requires dosing more than a few hours before sex; but the 1 in 5 men with a more structured sex calendar may.
One completed placebo-controlled trial of intermittent PrEP -- in HIV-negative Kenyan MSM and female sex workers -- found that these people had a hard time remembering less-than-daily dosing and especially postsex dosing.31 The trial involved 67 MSM and 5 female sex workers randomized to daily TDF/FTC or to three doses -- one Monday, one Friday, and one within 2 hours after sex. Researchers monitored adherence with the Medication Event Monitoring System (MEMS), and monthly followup continued for 4 months. The study took place in late 2009, before release of iPrEx, Partners PrEP, and TDF2 results. Two thirds of study participants reported transactional sex, and nearly two thirds reported receptive anal intercourse in the past 28 days. Median MEMS adherence measured 83% with daily dosing but dropped off to 55% with intermittent dosing. Median MEMS adherence to any postsex dose was only 26%.
HPTN 067, the ADAPT study, is recruiting participants to compare two intermittent TDF/FTC PrEP schedules with daily dosing: before and after potential HIV exposure or twice-weekly dosing with a postsex boost.32 Study participants are Thai MSM and South African women. A PrEP trial that hopes to enroll 1900 MSM in France and Canada will compare placebo with two TDF/FTC pills within 24 hours before sex, one pill during the period of sexual activity, and one pill about 24 hours after sex.33 It will be interesting to see if these MSM do better planning sex than the MSM surveyed in the United States.30
At the FDA PrEP hearing, iPrEx principal investigator Robert Grant stressed that PrEP candidates should be told to take one TDF/FTC tablet daily because that's the only course that's been tested and because it's probably easier to remember than intermittent schedules. But all the PrEP studies so far -- and the recruiting intermittent trials -- involve TDF/FTC, a once-a-day drug. As detailed in the final section of this report, drug developers are hard at work devising agents that might be injected once monthly or loaded into vaginal rings that last as long.
Resistance Risk With TDF/FTC PrEP
PrEP trials so far indicate a low risk that HIV resistant to FTC or TDF will emerge in someone taking this two-in-one pill to stave off infection. The reasons are simple: If HIV-negative people take TDF/FTC PrEP on schedule, they will avoid infection, and no virus means no resistance. If HIV-negative people miss enough TDF/FTC doses and become infected, resistant virus will probably not evolve because no drug means no resistance.
But that "probably" needs some explanation. At the FDA PrEP hearing, HIV resistance expert John Mellors (University of Pittsburgh) cautioned that there may be a grey-area TDF/FTC level that permits infection but also leaves enough circulating drug to select resistant virus (Figure 2), though Mellors added that this possibility "appears to be uncommon."
|Figure 2. Theoretical Infection-Exposure-Resistance Relationships|
Left: If someone taking TDF/FTC PrEP misses too many doses, drug levels will fall and that person may become infected with HIV. But facing little or no TDF or FTC in the newly infected person, the virus will not be pressured to evolve to mutant strains resistant to TDF or FTC. Right: If a person takes TDF/FTC PrEP regularly, levels of the drug will be high enough to prevent infection -- and without virus there can be no resistance. Center: But there may be a "zone of resistance risk" between low and high TDF/FTC levels that permits infection at drug levels still high enough to select resistant virus. (Illustration courtesy of John Mellors, University of Pittsburgh.)
So uncommon that HIV apparently did not nose out that route to resistance in PrEP trials analyzed so far. Although researchers did spot resistant virus in a few TDF/FTC takers in iPrEx,2 Partners PrEP,3 and TDF2,4 these people all appeared to have undetected HIV infection when they started PrEP. CDC PrEP guidelines stress that PrEP candidates must have a documented negative HIV antibody test "immediately before starting PrEP medication."9,11 Providers should also look for signals of acute HIV infection, which may not register on a standard antibody test.
While prescribing PrEP for someone with undetected HIV infection poses a clear resistance risk, continuing PrEP in a negative person who picks up HIV also poses a danger. PrEP trials minimized the latter possibility by testing PrEPpers for HIV once a month,2-4 Whether clinicians manage to screen PrEP users for HIV even every 2 or 3 months, as recommended,9,11 remains unknown. In a thoughtful review of PrEP pointers for providers, Douglas Krakower and Kenneth Mayer (Harvard Medical School and Fenway Institute) suggested that home HIV testing (which costs $40 per test) may prove a useful adjunct to clinical screening for PrEP users.34
Once someone starts PrEP, HIV risk counseling assumes paramount importance. CDC PrEP guidelines map out a three-pronged approach for PrEP prescribers (Table 2): (1) assess risk behaviors and provide risk-reduction counseling and condoms every 2 to 3 months, (2) assess STI symptoms every 2 to 3 months and treat STIs, (3) test for STIs every 6 months even in people with no STI symptoms. Avoiding STIs lowers HIV risk by preventing mucosal lesions that offer a portal to HIV if PrEP adherence falters.
What's the chance that someone taking TDF/FTC PrEP will pick up an HIV variant resistant to one or both of those drugs and so become infected? Low, according to a modeling study involving MSM in the United Kingdom.35 This analysis by researchers from the UK HIV Drug Resistance Database and the UK Collaborative HIV Cohort (UK CHIC) figured that population prevalence of TDF/FTC-resistant virus in infectious individuals in 2008 lay at 0.9%, and resistance levels dropped throughout the 2005-2009 study period. Population prevalence of virus resistant to FTC stood at 1.6%, and prevalence of virus resistant to FTC or TDF stood at 4.1%.
Research in the United States also shows waning rates of HIV bearing mutations that spawn resistance to TDF (K65R) or FTC (M184V/I). A study by Gilead investigators parsed resistance data in 107,231 HIV sequences filed in the database of a large reference lab from 2003 through 2010.36 Over that period prevalence of K65R fell by half, from 4.3% to 2.1%. Over the same years prevalence of M184V/I dropped even more, from 44.0% to 17.9%. Coincident with these dips, the Gilead team traced a prescription shift away from lamivudine (associated with M184V/I) plus zidovudine and toward TDF plus FTC.
Recent US research also shows an ebb in transmission of resistant virus from before 2003 to 2007, though that trend may have bottomed out in 2007 and 2008.37 This analysis deciphered 1585 viral sequences from HIV-positive antiretroviral-naive people in the CNICS cohort in Birmingham, Boston, Cleveland, San Diego, San Francisco, and Seattle. Among these viral samples, 225 (14.2%) harbored one or more resistance mutations. In contrast, a European-Israeli analysis covering 2002 through 2005 charted an overall 8.4% prevalence of transmitted resistance mutations in 2687 people, with declines in protease inhibitor and nonnucleoside mutations but a stable prevalence of nucleoside-related mutations (4.7%).38
In the US cohort study prevalence of transmitted mutations dropped from 1.2 per viral sequence before 2003, to 0.76 in 2003, and gradually down to 0.22 in 2007.37 But the rate inched back up to 0.37 per viral sequence in 2008. Overall prevalence of transmitted 3TC/FTC mutations at reverse transcriptase positive M184 stood at 2.52%, compared with an overall 0.19% prevalence of TDF-related mutations a K65.
If PrEP catches on, there's no doubt that a few users will wind up with resistant virus, either because they start PrEP when already infected or get infected with enough TDF or FTC in their body to engender viral evolution to a resistant strain. How will that bump in resistance prevalence affect overall resistance prevalence? There's only one way to project an estimate: make a model. That's what Cleveland Clinic investigators did, modeling the impact of an optimistic scenario (75% PrEP efficacy, 60% coverage of the susceptible population, and 5% inadvertent PrEP use in infected people leading to emergence of resistance), a realistic scenario (50% PrEP efficacy, 30% coverage, and 10% inadvertent PrEP use), and a pessimistic scenario (25% PrEP efficacy, 15% coverage, and 25% inadvertent PrEP use).39
The model does not consider a specific PrEP agent, though the researchers say they used "resistancerelated input estimates that would be expected for a single antiretroviral drug used for PrEP such as tenofovir."39 And the model does not consider a combination PrEP agent, such as TDF/FTC. Figure 3 shows that an optimistic PrEP scenario would boost total resistance prevalence in a population of sexually active people by only 2.5% in the 10 years after PrEP rollout, a realistic scenario would hoist the resistance total 9.9%, and a pessimistic scenario would expand resistance prevalence by 42.3%. The inverse rates of infections prevented are equally dramatic.
|Figure 3. Modeling 10-Year PrEP Impact on Resistance Prevalence and HIV Prevention|
Optimistic, realistic, and pessimistic PrEP scenarios (see text for explanation) would have dramatically different impacts on additional prevalence of resistant virus in that population 10 years after PrEP rollout, according to results of a modeling study by Cleveland Clinic researchers.39 The relative impacts on HIV infections prevented would be equally striking.
For many gay men and high-risk heterosexuals, the answer to that question is yes, recent research shows. Although so-called risk compensation or disinhibition did not occur in the iPrEx and Partners PrEP trials, that finding may not translate smoothly into the hurly burly of busy sex lives.
While 60% of iPrEx MSM reported having receptive anal sex without condoms before the trial began, that rate fell to about 30% at study week 12 and stayed right there through week 144.40 When MSM entered iPrEx, 16% had an STI. During the trial STI incidence measured 12.6 per 100 person-years in the TDF/FTC arm and 12.2 in the placebo arm. About one quarter of Partners PrEP participants (27%) said they had condom-free sex in the month before enrolling, and that proportion sagged steadily to about 10% at month 30.41
But everyone knows how people behave in clinical trials may not mirror how they behave in day-to-day life, for at least three reasons. First, people who sign up for clinical trials are probably better self-motivators than people who don't. Second, iPrEx and Partners PrEP participants had A-to-Z risk counseling before the trials, then they made monthly follow-up visits where they got condoms and got reminded about shunning risk. And three, during the trials participants didn't know if TDF/FTC PrEP would work and whether they were taking the antiretrovirals or placebo. Average Jacks and Jills getting counseled quarterly (at best) and taking a drug they know works pretty well may be less prudent.
FDA product information stresses that TDF/FTC "is indicated in combination with safer sex practices for pre-exposure prophylaxis" (emphasis added), but few at-risk people will read the product information and many will combine TDF/FTC with riskier sex practices.
If he started PrEP, one Los Angeles gay man told researchers, "I could engage in more risky behavior because I now have that extra layer of confidence and protection."19 Another proposed that he "would probably end up thinking well, after taking [PrEP] for a while, like a month or two, I would probably feel like okay I can stop using condoms because it would've built up in my body apparently." But one man said if his provider prescribed PrEP, "I would not negate condoms just because I was on the pill. I would still take that extra precaution."
In this pre-iPrEx study of 50 MSM in HIV-discordant partnerships, almost two thirds said they would probably engage in riskier sex behaviors if they had 90% effective PrEP, a level close to the 92% recorded in iPrEx men with detectable drug in plasma.19 Almost as many men, 60%, predicted they would abandon condoms if they started PrEP. This is a small study and included only members of discordant partnerships, so the findings may not apply to all gay and bisexual men in the United States. But the results suggest PrEP prescribers will have hard work keeping PrEP users sheathed in latex.
In a larger study 630 substance-using MSM in Chicago, Los Angeles, New York, and San Diego fielded questions about a theoretical PrEP pill before anyone knew what iPrEx would find.42 One third of these men (34.1%) would feel free to forgo condoms during insertive anal intercourse if PrEP were effective "at least half the time or more but not [effective] almost always or always" -- roughly paralleling the overall iPrEx efficacy result. The same midrange level of PrEP would encourage 15% of these men to abandon condoms during receptive anal sex. Even higher proportions of men said they would have unprotected receptive anal sex (28%) or unprotected insertive anal sex (51%) with PrEP that protected them from HIV "less than half the time." Compared with white men, black and Latino MSM were more willing to rely on less effective PrEP to avoid condom use.
A post-iPrEx online survey of 1155 US MSM recruited from facebook and black gay chat (bcglive) found that a 44%-effective PrEP pill (overall efficacy in iPrEx) would not change condom use in 75% of respondents -- and 51% said they had unprotected anal intercourse the last time they had sex.43 Another 7% said they would use condoms less often with 44% effective PrEP, 8% claimed they would use condoms more often, and 10% said they wouldn't use PrEP. One third of these men felt they would face increased pressure to shun condoms if they took PrEP. Almost three quarters of respondents (73%) were white, while 7% were black and 12% Hispanic.
Two studies offer some insight into how PrEP may affect risk behavior in heterosexual men and women. One survey involved 235 men and 125 women considered at high risk of HIV infection while attending a Chicago HIV clinic. Fifty-four men (23%) and 17 women (14%) said PrEP would make them use condoms less, while 109 men (47%) and 74 women (59%) said they would use condoms at the same rate with PrEP.16 But only 38% of men and 33% of women reported using condoms all or most of the time during vaginal sex, and only 25% of men and 19% of women used condoms all or most of the time during anal sex. On the brighter side, only 54 men (23%) and 7 women (6%) foresaw having more sex partners if they took PrEP.
A similar 2009-2010 survey in a South Carolina STI clinic quizzed 225 men and 174 women, 89% of them black and 90% identifying themselves as heterosexual.17 One third of survey respondents (32%) somewhat agreed that they or their partner would find it "very difficult to both use condoms and take daily pills to prevent HIV infection." On the other hand, 38% strongly disagreed with that statement. Men were 3 times more likely than women to foresee difficultly with simultaneous PrEP and condom use.
But at the end of the day should anyone be surprised that people who don't use condoms much -- if at all -- would suddenly start using them if they had a pretty good PrEP pill? PrEP candidates -- people with "substantial, ongoing high risk for acquiring HIV infection"9 -- have that high risk precisely because condoms rarely show up on their shopping lists. As South African HIV prevention researchers Salim and Quarraisha Abdool Karim observed in an essay on these questions, "PrEP is most appropriate for the target populations where condom use is low or non-existent."44
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