Table of Contents



Tenofovir/emtricitabine (TDF/FTC) won FDA approval for preexposure prophylaxis (PrEP) after three placebo-controlled trials demonstrated that once-daily TDF/FTC lowers HIV acquisition risk in gay and bisexual men and heterosexual women and men. In the one trial that found no HIV protection with TDF/FTC PrEP in women, poor adherence largely explained that failure. Good adherence in the three successful PrEP trials enhanced the protective potential of this two-in-one, once-daily antiretroviral. Emergence of HIV resistant to FTC and/or TDF in PrEP users is unlikely -- provided that people do not start PrEP when infected with HIV and that they do not take few enough doses to become infected but just enough doses to maintain meager drug levels. Placebo-controlled PrEP trials in gay men and heterosexuals found that study participants practiced safer sex after being randomized. But communitybased research in the United States indicates that a substantial proportion of PrEP candidates would abandon condoms if they took a fairly reliable PrEP pill. Three modeling studies suggest TDF/FTC PrEP may not be cost-effective at current TDF/FTC prices with only moderate efficacy. But lower costs and higher efficacy could make PrEP cost-effective by current standards. Researchers are already testing future PrEP agents, which fall into three (sometimes overlapping) groups -- current or investigational antiretrovirals with mechanisms different from TDF and FTC, longer-acting antiretrovirals that may be taken by mouth or injection, and longer-acting antiretrovirals suffused into vaginal rings.

PrEP will protect people from picking up HIV during sex if ...

And after those ellipses one can append an armlong list starting with "if PrEPpers take their pills often enough to maintain ample drug levels in target tissues" and ending with "if randomized trial data revealed so far hold true in the real world of sex, drugs, and outrageous fortune."

Four placebo-controlled trials involving 10,521 HIV-negative people unloaded a ton of data on PrEP (preexposure prophylaxis for HIV infection) with coformulated tenofovir/emtricitabine (TDF/FTC) or TDF alone. Considering these results and other findings, the US FDA approved TDF/FTC "in combination with safer sex practices for ... PrEP to reduce the risk of sexually acquired HIV-1 in adults at high risk."1

Ten thousand sounds like a hefty number of PrEP trial participants, but it's not so big when you consider the biggest HIV risk group in the United States and countries with similar epidemics -- gay and bisexual men or, in clinical argot, men who have sex with men (MSM). The four large PrEP trials with reported data -- iPrEx,2 Partners PrEP,3 TDF2,4 and FEM-PrEP5 -- involved only 6123 men, only 3912 of them assigned to TDF/FTC or TDF alone, and only 1251 of them MSM or transgenders assigned to TDF/FTC, all in iPrEx. (iPrEx stands for Iniciativa Profilaxis Pre-exposición.)

More than half of all iPrEx men lived in Peru, while the United States contributed only 227 men to the trial, about 9% of the TDF/FTC arm and 9% of the placebo arm.2 MSM account for almost two thirds of new HIV infections in the United States every year, and young black MSM bear the brunt of this high incidence.6 Yet only 117 blacks (including 45 from South Africa) took TDF/FTC in iPrEx.2

Placebo-controlled PrEP trials reported in the past 2 years2-5 offer little or no data on several other urgent questions about this much-bruited strategy:

  • PrEP efficacy in heterosexual women outside sub-Saharan Africa
  • PrEP efficacy in heterosexual men outside sub-Saharan Africa
  • Whether US men and women will use PrEP
  • How regularly US men and women will use PrEP
  • Long-term TDF/FTC side effects in PrEP users
  • PrEP efficacy with any type of PrEP besides TDF and TDF/FTC

iPrEx,2 Partners PrEP,3 and TDF24 yielded solid evidence that TDF/FTC PrEP substantially lowers the risk of getting HIV infection from a sex partner, especially when people take the drug regularly -- as directed. But TDF/FTC did not protect high-risk Kenyan, South African, and Tanzanian women from HIV in FEM-PrEP.5 And the VOICE trial in women of South Africa, Uganda, and Zimbabwe shut down its TDF-only arm early when results showed this strategy wasn't working7 -- even though TDF alone did protect women and men from HIV in Partners PrEP.3 VOICE continued its TDF/FTC-versus-placebo faceoff, and results are expected soon. Poor adherence largely explained TDF/FTC failure in FEM-PrEP, as discussed below. What went wrong with TDF alone in VOICE will remain unknown until data from that trial are fully analyzed.

Partly because of these mixed results -- and partly because participants in successful PrEP trials used condoms more and had fewer sex partners during the study -- not all observers are convinced that TDF/FTC should have won a PrEP license from the FDA. The National Cancer Institute's Lauren Wood, a member of the FDA Antiviral Drugs Advisory Committee that considered TDF/FTC PrEP, voted no on all three proposed indications -- for MSM, for HIV-negative people with a positive partner (HIVdiscordant couples), and for other people at risk of picking up HIV during sex.8

In the context of contradictory trial results and lower sexual risk taking during the trials, Wood explained, "I found it difficult to get a sense of the additional benefit contributed by Truvada PrEP in reducing HIV transmission and would have liked to have had the effects of PrEP confirmed in a multiple logistic regression analysis of the data."8 But Wood found herself in minorities in all three votes, which went 19 to 3 for the MSM indication, 19 to 2 with 1 abstention for the HIV-discordant couple indication, and 12 to 8 with 2 abstentions for the "other" indication.

This review will scrutinize what's known (and not known) about people who may try PrEP in the United States and countries with similar epidemics, whether HIV-negative people in the United States intend to use PrEP, FDA and Centers for Disease Control and Prevention (CDC) guidance on how to use PrEP, how often people must take TDF/FTC PrEP to protect themselves from HIV, the threat of riskier sex in PrEP users, resistance risk with inconsistent PrEP dosing, and prospects for PrEP beyond TDF/FTC.

PrEP means giving drugs to healthy people -- always a concern when one of the drugs, TDF, has wellknown and much-chronicled side effects if taken regularly by people with HIV. Whether HIV-negative people taking TDF/FTC PrEP daily -- or perhaps less often -- will end up with flagging kidney function or dwindling bone mineral density will not be known until enough people use it for a year or more. But hints can be garnered from long-term clinical studies of HIV-positive people and from what's known about likely PrEP users in the United States. A separate article in this issue of RITA! will consider risk of long-term side effects in steady PrEP use. Interviews with Robert Grant and Raphael Landovitz will provide expert advice on these and other issues.

Who Should Use PrEP?

Year after year about 50,000 people in the United States get infected with HIV. In the CDC's most recent analysis, MSM (gay/bisexual men) account for almost two thirds of these new infections, while heterosexuals who don't inject drugs account for a little more than one quarter.6 From 2006 through 2009, HIV incidence -- the new infection rate -- rose 21% in people 13 to 29 years old and climbed 34% in MSM that age. Over those years HIV incidence in 13- to 29-year-old black MSM vaulted 48% in the United States. HIV incidence has been surging among US MSM since the 1990s, the CDC figures.9

Among all African-American men -- heterosexual or MSM -- HIV incidence held steady at about 100 per 100,000 from 2006 through 2009.6 Among African-American women HIV incidence remained at about 40 per 100,000 throughout the study period, about 4 times higher than incidence among Hispanic women and about 8 times higher than incidence among white women.

CDC advice to offer opt-out HIV testing to all 13- to 64-year-old people at routine medical visits10 denotes an official stance that any sexually active person runs a risk of HIV infection. Does that mean anyone who has sex should consider PrEP? No. The CDC's 2011 PrEP interim guidance advised clinicians to confirm that a PrEP candidate "is at substantial, ongoing high risk for acquiring HIV infection"9 (Table 1). High-risk MSM, the CDC suggests, are those in regions with high HIV prevalence who often change sex partners or have concurrent partners. High-risk heterosexual women and men include those whose regular sex partners who have HIV.11 FDA prescribing information for TDF/FTC PrEP says the following factors may help clinicians pinpoint high-risk men or women:1

  • Inconsistent or no condom use
  • Diagnosis of sexually transmitted infections
  • Exchange of sex for commodities (such as money, goods, shelter, or drugs)
  • Use of illicit drugs or alcohol dependence
  • Incarceration
  • One or more partners of unknown HIV status with any factor listed above
Table 1. Who Should Use PrEP -- And Who Should Not
People Who Might Consider TDF/FTC PrEPPeople Who Should Not Use TDF/FTC PrEP
  • People "at substantial, ongoing high risk for acquiring HIV infection"9
  • MSM in regions of high HIV prevalence who often change sex partners9
  • MSM in regions of high HIV prevalence who have concurrent partners9
  • Heterosexual men and women whose regular sex partners have HIV11
  • Heterosexual men and women and MSM with one or more of the following traits:1
    • Inconsistent or no condom use
    • Diagnosis of sexually transmitted infections
    • Exchange of sex for commodities
    • (such as money, goods, shelter, or drugs)
    • Use of illicit drugs or alcohol dependence
    • Incarceration
    • One or more partners of unknown HIV status with any factor listed above
  • Anyone without a documented HIV-negative test immediately before starting PrEP1
  • Anyone with signs or symptoms suggesting acute HIV infection unless HIV RNA assay confirms negative status1
  • Anyone reporting unprotected sex with an HIV-positive person in past month unless HIV RNA assay confirms negative status11
  • Anyone not screened for HIV at least once every 3 months1
  • Pregnant women, unless PrEP is "clearly needed"1
  • Breastfeeding women11
  • Anyone with creatinine clearance below 60 mL/min1
  • Anyone taking adefovir (Hepsera) for HBV infection1

MSM: men who have sex with men.

In an interview in this issue of RITA!, iPrEx principal investigator Robert Grant (University of California, San Francisco) argues that providers should not get bogged down sorting through the nuances of high HIV risk in PrEP candidates. He maintains that "anyone who comes forward and says they're interested in finding new ways to protect themselves and their partners from HIV should receive prevention services, regardless of whether we can easily identify a risk factor." In another interview in this issue, Raphael Landovitz (University of California, Los Angeles) notes that people who use postexposure prophylaxis (PEP) more than once are also excellent PrEP candidates.

CDC interim guidance also sanctions PrEP as "one of several options to help protect the HIV-negative partner in discordant couples during attempts to conceive."11 But a woman should use PrEP during pregnancy only if the strategy is "clearly needed" because studies of TDF/FTC cannot rule out the possibility of harming the fetus.1 Reproductive-age women should have a documented negative pregnancy test before starting PrEP and regularly during PrEP.11 However, CDC interim PrEP guidance for heterosexuals also notes that the Antiretroviral Use in Pregnancy Registry and studies of pregnant women taking TDF or FTC "indicate no evidence of adverse effects among fetuses exposed to TDF or FTC."11 Those guidelines state that breastfeeding women should not use PrEP.11

Because tenofovir saturates female genital mucosa less than it does colorectal tissue, and because TDF/FTC or TDF alone failed in the all-women FEMPrEP5 and VOICE7 trials, some worry that TDF/FTC may not protect women from HIV as well as it protects men. But the 4747-couple Partners PrEP trial, with 38% of HIV-negative partners women, found equivalent protection with either TDF or TDF/FTC in women and men.3

Of course people who have HIV -- or might have HIV -- should steer clear of PrEP. Although regularly taken TDF/FTC does a great job warding off HIV infection, it can't control established HIV infection by itself and rapidly opens the door to resistance to FTC and eventually TDF. The FDA license stipulates that clinicians should prescribe PrEP only for someone with a confirmed HIV-negative test immediately before starting PrEP.1 Prescribers should dole out enough pills for only 90 days of PrEP, and users should get retested before getting another 90-day supply.11 CDC guidance says PrEP candidates should have an HIV antibody test or fourth-generation antibody/antigen test every 2 to 3 months to confirm their negative status.9,11

Because antibody tests do not detect acute HIV infection, any PrEP candidate with symptoms or signs of acute HIV infection (fever, fatigue, myalgia, skin rash) and anyone who reports unprotected (condom-free or broken-condom) sex with an HIVpositive person in the past month should be tested (by HIV RNA assay, a nucleic acid amplification test, or the fourth-generation antibody/antigen sandwich ELISA) to spot recent infection. If symptoms of acute infection crop up during a course of PrEP, TDF/FTC should be stopped immediately until testing reconfirms that the person does not have HIV infection.1

PrEP for high-risk MSM? Yes. For high-risk heterosexuals? Yes. But what about transgenders? The American Psychological Associations defines transgender as "an umbrella term for persons whose gender identity, gender expression, or behavior does not conform to that typically associated with the sex to which they were assigned at birth."12

A systematic review leaves little doubt that people born male who consider themselves women have high rates of HIV infection.13 This analysis dissected 29 studies in the US-based HIV behavioral prevention literature that focused on male-to-female transgenders. Four studies that tested male-to-female transgenders for HIV found a prevalence of 27.7%, while 18 studies in which transgenders self-reported HIV status recorded a prevalence of 11.8%. African-American male-to-female transgenders had even higher HIV rates, whether tested for HIV (56.3%) or asked their HIV status (30.8%). Between one quarter and one half of male-to-female transgenders reported risky behaviors such as receptive anal intercourse without condoms, multiple casual sex partners, and sex work. Rates of HIV and risk behaviors were low among female-to-male transgenders.

About 15% of iPrEx participants, 366, identified themselves as "trans" or used female sex hormones, though few of them had sex-change surgery.14 Eleven transgenders randomized to TDF/FTC and 11 randomized to placebo became infected, a result indicating that PrEP did not work in this group. In an interview in this issue of RITA!, iPrEx principal investigator Robert Grant reported that transgenders in that trial appeared to have a tougher time with PrEP adherence than gay men, and he suggested that may explain why transgenders randomized to TDF/FTC did not have a lower HIV acquisition rate than those randomized to placebo. He stressed, though, that iPrEx didn't enroll enough transgenders to make a definitive call on this question.

Whether PrEP can block HIV in injection drug users (IDUs) also remains an unanswered question. The Bangkok Tenofovir Study, comparing once-daily TDF with placebo, enrolled 2400 IDUs and aims to have an answer in 2013.15

Because TDF may promote kidney toxicity, the FDA stipulates that no one with creatinine clearance below 60 mL/min should take TDF/FTC for PrEP.1 If creatinine clearance falls in someone taking TDF/FTC for PrEP, the FDA advises clinicians to "evaluate potential causes and re-assess potential risks and benefits of continued use" of PrEP.1

CDC experts advise clinicians to screen PrEP candidates for hepatitis B virus (HBV) infection, to vaccinate people susceptible to HBV, and to treat those infected.9,11 Hepatitis can flare when people with HIV and active HBV infection start or stop anti-HBV antiretrovirals, so HBV-positive people must be monitored closely when starting or stopping TDF/FTC PrEP. Although FDA prescribing information for TDF/FTC notes that the two-in-one pill is not licensed for chronic HBV infection,1 CDC PrEP guidance says clinicians can consider TDF/FTC for HIV prevention and HBV treatment in coinfected people.9,11

Providers should not prescribe TDF/FTC for anyone taking adefovir (Hepsera), an antiviral related to TDF, for HBV infection.1 Table 2 summarizes key screening and follow-up tests providers should perform when deciding whether to prescribe TDF/FTC PrEP, and whether to continue, according to CDC interim guidance for MSM9 and heterosexuals.11

Table 2. Test and Retest -- Screening and Follow-Up Advice for PrEP Providers9,11

Before prescribing:

  • Confirm that candidate has substantial, ongoing, high risk for acquiring HIV infection.
  • Document negative HIV antibody test(s) immediately before starting PrEP.
  • Test for acute HIV infection if candidate has symptoms consistent with acute infection.
  • Determine if women are planning to become pregnant, are currently pregnant, or are breastfeeding.
  • Counsel women that TDF/FTC safety for infants exposed during pregnancy is not fully assessed but no harm has been reported.
  • Do not prescribe PrEP for breastfeeding women.
  • Confirm that creatinine clearance is at or above 60 mL/min by Cockroft-Gault formula.
  • Screen for and treat sexually transmitted infections (STIs).
  • Screen candidates for HBV; vaccinate susceptible people; treat active infection regardless of decision to prescribe PrEP.

When prescribing PrEP:

  • In general, prescribe no more than a 90-day supply, renewable only after HIV testing confirms that person remains HIV-uninfected.
  • For people with active HBV infection, consider using TDF/FTC both for HBV therapy and for PrEP.
  • Provide risk-reduction

After PrEP has begun:

  • Every 2 to 3 months, perform an HIV antibody test and document negative result.
  • Every 2 to 3 months, assess risk behaviors and provide risk-reduction counseling and condoms.
  • Every 2 to 3 months, assess STI symptoms and, if present, test and treat for STIs.
  • Every 6 months, test for STIs even if patient is asymptomatic and treat as needed.
  • Three months after PrEP begins, then every 6 months while on PrEP, check blood urea nitrogen and serum creatinine and calculate creatinine clearance.
  • At each follow-up visit for women, conduct a pregnancy test. If woman is pregnant, discuss continued PrEP use.
  • Evaluate and support PrEP adherence at every follow-up visit -- and more often if inconsistent adherence is identified.

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 _post_exposure 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
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

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
StrategyCompleted on Ongoing TrialResults
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 SHIV27Protected 6 of 6 macaques from 14 rectal SHIV challenges
Oral TDF/FTC 1, 3, or 7 days before sexual exposure and 2 hours after exposureTested in macaques rectally challenged weekly with SHIV28As protective as daily TDF/FTC
Doubled dose of oral TDF/FTC 2 hours before or after sexual exposureTested in macaques rectally challenged weekly with SHIV28Fully protective (but dose 24 hours after exposure not protective)
Oral TDF/FTC four times weeklyAssessed in modeling study by iPrEx investigators29Provided 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 dosingAssessed in placebo-controlled trial enrolling Kenyan MSM and female sex workers31MEMS-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 boostBeing tested in HPTN 067, the ADAPT study32Trial 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 sexBeing tested in ANRS IPERGAY trial33Trial 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
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
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
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

How Much Will PrEP Cost, and Who Will Pay?

TDF/FTC PrEP isn't cheap. lists monthly tabs ranging from $580 to $3180 for brand-name Truvada. Even if PrEPpers take TDF/FTC only 4 days a week, for example, at a cost of $20 per pill that adds up to $4160 a year, and at list price the cost would be much higher. If a person doesn't have insurance that will pay the bill, Douglas Krakower and Kenneth Mayer write, "out-of-pocket expenses are likely to be prohibitive for many high-risk persons."34 Gilead Sciences set up a PrEP Medication Assistance Program for "eligible HIV-negative adults in the United States who do not have insurance," their Website says. People can find out if they qualify by calling 1-855-330-5479 Monday through Friday between 9:00 AM and 8:00 PM Eastern time.

Los Angeles clinical investigators Theodoros Kelesidis and Raphael Landovitz estimate that "the cost of providing [TDF/FTC] PrEP to the 100,000 most at-risk people in the US could exceed $1 billion each year at current retail prices, which would exceed the CDC's current HIV prevention budget just with this intervention alone."45 Three studies tried to reckon the preventive power and cost-effectiveness of TDF/FTC PrEP among gay and bisexual men in the United States.

A 2008 modeling study of PrEP in US MSM figured the cost of once-daily TDF/FTC -- plus monitoring and care -- at $11,740 per person annually, and drug costs made up 91% of that tally.46 This model devised by Imperial College London investigators aimed to figure HIV cases prevented and cost-effectiveness of daily TDF/FTC PrEP among MSM in New York City over the course of 5 years. They figured costs based on the average wholesale cost of coformulated TDF/FTC in 2007. The model weighed different combinations of protection mechanism, efficacy, adherence, and population coverage. The researchers also modeled the impact of the three R's -- risk compensation, resistance, and renal impairment.

A PrEP program targeting 25% of high-risk New York City MSM would prevent 4% to 23% of the 19,510 infections predicted in the 5-year window.46 More than half of averted infections would involve men not taking PrEP but protected because of lowered HIV prevalence in the community. Across the range of input assumptions, TDF/FTC PrEP proved costeffective 75% of the time at a threshold of $50,000 per quality-adjusted life year (QALY) gained and 87.5% of the time at a threshold of $100,000 per QALY gained.

In 2009 researchers from Yale School of Medicine and other institutions calculated cost-effectiveness in MSM across the United States, with a base-case assumption of 50% TDF/FTC efficacy and a monthly cost of $753.47 This model also factored in the potential impact of differences in efficacy and risks of resistance, toxicity, and behavioral disinhibition.

In an MSM population averaging 34 years in age, daily PrEP would cut lifetime HIV infection risk from 44% to 25% and boost life expectancy modestly from 39.9 to 40.7 years.47 But at a steep cost of $298,000 per QALY saved, TDF/FTC PrEP would not be cost-effective in the base-case model. Cost per QALY saved dropped substantially to $107,000 if PrEP efficacy rose from 50% to 90% (about the rate among men with detectable drug levels in iPrEx), to $114,000 if drug costs got halved, and to $189,000 if the target population age fell to an average 20 years. But in an "extreme toxicity scenario," cost per QALY saved soared to $1.5 million. These investigators concluded that "with improvements in efficacy, targeting, or pricing, [TDF/FTC PrEP] may ... be cost-effective by current US standards."

In 2012 Stanford University researchers modeled the infection risk and cost-effectiveness of TDF/FTC PrEP in the general population of US MSM 13 to 64 years old and in certain MSM subgroups.48 The basecase scenario set TDF/FTC PrEP efficacy at 44% -- the overall iPrEx result. Dispensing PrEP to 20% of US MSM would trim the new-infection rate by 13% and add 550,166 QALYs over 20 years at $172,091 per QALY gained. For high-risk MSM with an average of 5 partners per year, PrEP would cost only $50,000 per QALY gained, but prescribing PrEP to all high-risk US MSM for 20 years would balloon healthcare costs $75 billion over current outlays. If the daily cost of TDF/FTC dropped to $15 or PrEP efficacy lay above 75% (as it did in adherent iPrEx men), PrEP for the general US MSM population would cost less than $100,000 per QALY gained. One might formulate the following bottom line from all three studies: PrEP could prevent many HIV infections in US gay and bisexual men over the next decade or so, but it costs a lot and may not be cost-effective at current TDF/FTC prices and if PrEP has only moderate efficacy. But lower costs and higher efficacy -- including levels achieved by adherent men in iPrEx -- could make PrEP costeffective by current standards.

And who will pay for PrEP? Insurance companies will pay, iPrEx investigator Robert Grant affirmed in an interview in this issue. "The payers in the United States have decided not to require HIV testing results before paying for antiretroviral medications," he noted, "and they do realize this means they are paying for PrEP." Of course many people with the highest risk of HIV infection do not have insurance.

Prepping for PrEP's Future

Years from now, healthcare providers and others in the know will look at TDF/FTC PrEP the way they look at zidovudine today -- as an esteemed bellwether that may retain some niche function. Drug developers and clinical investigators are already well along in refining and testing new PrEP agents they hope will be more protective, safer, and easier to take than a once-a-day TDF/FTC pill.

So far future PrEP hopefuls fall into three (sometimes overlapping) groups -- current or investigational antiretrovirals with mechanisms different from TDF and FTC, longer-acting antiretrovirals that may be taken by mouth or injection, and longer-acting antiretrovirals suffused into vaginal rings (Figure 4).

Figure 4. Three Options for Future PREP Agents
Figure 4. Three Options for Future PREP Agents Researchers are hard at work devising and testing PrEP agents that could improve on the activity, durability, and tolerability of TDF/FTC. (Pill and needle/syringe photos from Wikimedia Commons. Intravaginal ring photo from International Partnership for Microbicides.

Falling into the first category, the CCR5 antagonist maraviroc thwarts HIV infection at an earlier step in the viral replication cycle than reverse transcriptase inhibitors like TDF and FTC. NEXT-PrEP (HPTN 069) is a US double-blind placebo-controlled trial aiming to enroll 400 MSM and 200 heterosexual women to compare the 48-week safety and tolerability of daily maraviroc, maraviroc/FTC, maraviroc/TDF, and TDF/FTC.49

Nonnucleoside reverse transcriptase inhibitors are well known for their long half-lives, a property Janssen hopes to exploit in long-acting formulations of rilpivirine (TMC278LA) and dapivirine (TMC120). A study of a single intramuscular TMC278LA injection recorded high concentrations in plasma, genital tract fluid, and vaginal tissue of 27 HIV-negative women studied in London.50,51

A single 600-mg intramuscular injection of rilpivirine suspended in nanoparticles remained in circulation for 84 days in 10 HIV-negative women and 6 HIV-negative men tested by the same investigators.52 Vaginal tissue concentrations of rilpivirine were slightly lower than cervicovaginal fluid levels, but concentrations in male rectal tissue were higher than in rectal fluid. A phase 1/2 study of TMC278LA for PrEP ended early because of "additional safety information."53

Long-acting dapivirine is being studied both as a directly applied vaginal gel and in a vaginal ring, either alone54 or with maraviroc.55 Ideally, such rings could be inserted once a month, as contraceptive vaginal rings are today. In a double-blind placebocontrolled trial of a monthly dapivirine vaginal ring, 280 healthy, HIV-negative, sexually active women tolerated the ring well, and no serious safety concerns related to the ring arose.56 Two parallel phase 3 placebo-controlled trials of dapivirine are testing a once-monthly dapivirine ring in more than 5000 African women.57

Three studies have tested antiretrovirals in intravaginal rings inserted in sheep -- the protease inhibitor saquinavir,58 tenofovir plus maraviroc,59 and the integrase inhibitor raltegravir.60


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