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Who's Prepared to Make PrEP Work?

Winter 2012

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Table of Contents


Introduction

Abstract

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

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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.1Table 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.
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This article was provided by The Center for AIDS. It is a part of the publication Research Initiative/Treatment Action!. Visit CFA's website to find out more about their activities and publications.
 

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