# Table of Contents
List of Tables, Figures , and Boxes

# Summary
Preexposure Prophylaxis for HIV Prevention in the United States -2013: A Clinical Practice Guideline provides comprehensive information for the use of daily oral antiretroviral preexposure prophylaxis (PrEP) to reduce the risk of acquiring HIV infection in adults. The key messages of the guideline are as follows:
 Daily oral PrEP with the fixed-dose combination of tenofovir disoproxil fumarate (TDF) 300 mg and emtricitabine (FTC) 200 mg has been shown to be safe and effective in reducing the risk of sexual HIV acquisition in adults; therefore, o PrEP is recommended as one prevention option for sexually-active adult MSM (men who have sex with men) at substantial risk of HIV acquisition (IA) 1 o PrEP is recommended as one prevention option for adult heterosexually active men and women who are at substantial risk of HIV acquisition. (IA) o PrEP is recommended as one prevention option for adult injection drug users (IDU) at substantial risk of HIV acquisition. (IA) o PrEP should be discussed with heterosexually-active women and men whose partners are known to have HIV infection (i.e., HIV-discordant couples) as one of several options to protect the uninfected partner during conception and pregnancy so that an informed decision can be made in awareness of what is known and unknown about benefits and risks of PrEP for mother and fetus (IIB)  Currently the data on the efficacy and safety of PrEP for adolescents are insufficient.
Therefore, the risks and benefits of PrEP for adolescents should be weighed carefully in the context of local laws and regulations about autonomy in health care decision-making by minors. (IIIB)  Acute and chronic HIV infection must be excluded by symptom history and HIV testing immediately before PrEP is prescribed. (IA)  The only medication regimen approved by the Food and Drug Administration and recommended for PrEP with all the populations specified in this guideline is daily TDF 300 mg co-formulated with FTC 200 mg (Truvada) (IA) o TDF alone has shown substantial efficacy and safety in trials with IDUs and heterosexually active adults and can be considered as an alternative regimen for these populations, but not for MSM, among whom its efficacy has not been studied. (IC) o The use of other antiretroviral medications for PrEP, either in place of or in addition to TDF/FTC (or TDF) is not recommended. (IIIA) o The prescription of oral PrEP for coitally-timed or other noncontinuous daily use is not recommended. (IIIA)  HIV infection should be assessed at least every 3 months while patients are taking PrEP so that those with incident infection do not continue taking it. The 2-drug regimen of TDF/FTC is inadequate therapy for established HIV infection, and its use may engender resistance to either or both drugs. (IA)  Renal function should be assessed at baseline and monitored at least every 6 months while patients are taking PrEP so that those in whom renal failure is developing do not continue to take it. (IIIA)  When PrEP is prescribed, clinicians should provide access, directly or by facilitated referral, to proven effective risk-reduction services. Because high medication adherence is critical to PrEP efficacy but was not uniformly achieved by trial participants, patients should be encouraged and enabled to use PrEP in combination with other effective prevention methods.
(IIIA)

# Introduction
Recent findings from several clinical trials have demonstrated safety 1 and a substantial reduction in the rate of HIV acquisition for men who have sex with men (MSM) 2 , men and women in heterosexual HIV-discordant couples 3 , and heterosexual men and women recruited as individuals 4 who were prescribed daily oral antiretroviral preexposure prophylaxis (PrEP) with a fixed-dose combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC). In addition, one clinical trial among injection drug users (IDU) 5 and one among men and women in heterosexual HIV-discordant couples 3 have demonstrated substantial efficacy and safety of daily oral PrEP with TDF alone. The demonstrated efficacy of PrEP was in addition to the effects of repeated condom provision, sexual risk-reduction counseling, and the diagnosis and treatment of sexually transmitted infection (STI), all of which were provided to trial participants, including those in the drug treatment group and those in the placebo group. In July 2012, after reviewing the available trial results, the U.S. Food and Drug Administration (FDA) approved an indication for the use of Truvada  (TDF/FC) "in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk" 6,7 .
On the basis of these trial results and the FDA approval, the U.S. Public Health Service recommends that clinicians evaluate their male and female patients who are sexually active or who are injecting illicit drugs and consider offering PrEP as one prevention option to those whose sexual or injection behaviors and epidemiologic context place them at substantial risk of acquiring HIV infection.
The evidence base for these recommendations is derived from a systematic search and review of published literature. To identify all PrEP safety and efficacy trials pertaining to the prevention of sexual and injection acquisition of HIV, a search of the clinical trials registry () was performed by using combinations search terms (preexposure prophylaxis, pre-exposure prophylaxis, PrEP, HIV, Truvada, tenofovir, and antiretroviral). In addition, the same search terms were used to search conference abstracts for major HIV conferences (e.g., International AIDS Conference, Conference on Retroviruses and Opportunistic Infections) for the years 2009-2013. These same search terms were used to search PubMed and Web of Science databases for the years 2006-2013. Finally, a review of references from published PrEP trial data and the data summary prepared by FDA for its approval decision 8 confirmed that no additional trial results were available.
This publication provides a comprehensive clinical practice guideline for the use of PrEP for the prevention of HIV infection in the United States. It incorporates and extends information provided in interim guidance for PrEP use with MSM 9 , with heterosexually active adults 10 , and with IDU (also called persons who injection drugs ) 11 . Currently, prescribing daily oral PrEP with TDF/FTC is recommended as one prevention option for MSM, heterosexual men, heterosexual women, and IDU at substantial risk of HIV acquisition. As the results of additional PrEP clinical trials and studies in these and other populations at risk of HIV acquisition become known, this guideline will be updated.
The intended users of this guideline include  primary care clinicians who provide care to persons at risk of acquiring HIV infection  clinicians who provide substance abuse treatment  infectious disease and HIV treatment specialists who may provide PrEP or serve as consultants to primary care physicians about the use of antiretroviral medications  health program policymakers.

# Evidence of Need for Additional HIV Prevention Methods
Approximately 50,000 people in the United States are infected with HIV each year 12 . From 2008 through 2010, HIV incidence remained stable or declined among IDU and heterosexuals of all races and Hispanic/Latino ethnicity, but incidence increased among MSM (12% increase), especially among adolescent and young adult MSM (aged 13-24 years) (22% increase) 12 . The greatest number of new HIV infections among MSM occurred in young African American MSM (4,800). In 2010, 63% of the estimated 47,500 new infections were attributed to male-male sexual activity without injection drug use, 4% to male-male sexual activity with injection drug use, 25% to male-female sexual contact without injection drug use, and 8% to injection drug use. Among the 25% of persons newly infected through heterosexual activity, 66% were African-American women and men. These data indicate a need for additional methods of HIV prevention to further reduce new HIV infections, especially (but not exclusively) among young adult and adolescent MSM of all races and Hispanic/Latino ethnicity and for African American heterosexuals (populations with higher HIV prevalence and at higher risk of HIV infection among those without HIV infection).

# Evidence of the Safety and Efficacy of Antiretroviral Prophylaxis
The biological plausibility and the short-term safety of antiretroviral use to prevent HIV acquisition in other exposure situations have been demonstrated in 2 studies conducted prior to the PrEP trials. In a randomized placebo-controlled trial, perinatal transmission was reduced 68% among the HIV-infected women who received zidovudine during pregnancy and labor and whose infants received zidovudine for 6 weeks after birth 13 . That is, these infants received both preexposure and postexposure prophylaxis. In 1995, investigators used case-control surveillance data from health-care workers to demonstrate that zidovudine provided within 72 hours after percutaneous exposure to HIV-infected blood and continued for 28 days (PEP, or postexposure prophylaxis) was associated with an 81% reduction in the risk of acquiring HIV infection  .
Evidence from these human studies of blood-borne and perinatal transmission as well as studies of vaginal and rectal exposure among animals  suggested that PrEP (using antiretroviral drugs) could reduce the risk of acquiring HIV infection from sexual and drug-use exposures. Clinical trials were launched to evaluate the safety and efficacy of PrEP in populations at risk of HIV infection through several routes of exposure. The results of completed trials published as of August 2013 are summarized below. See also Tables 2-6.

# PUBLISHED TRIALS OF ANTIRETROVIRAL PREEXPOSURE PROPHYLAXIS AMONG MEN WHO HAVE SEX WITH MEN

# IPREX (PREEXPOSURE PROPHYLAXIS INITIATIVE) TRIAL
The iPrEx study 2 was a phase 3, randomized, double-blind, placebo-controlled trial conducted in Peru, Ecuador, Brazil, Thailand, South Africa, and the United States among men and male-tofemale transgender adults who reported sex with a man during the 6 months preceding enrollment. Participants were randomly assigned to receive a daily oral dose of either the fixeddose combination of TDF and FTC or a placebo. All participants (drug and placebo groups) were seen every 4 weeks for an interview, HIV testing, counseling about risk-reduction and adherence to PrEP medication doses, pill count, and dispensing of pills and condoms. Analysis of data through May 1, 2010, revealed that after the exclusion of 58 participants (10 later determined to be HIV-infected at enrollment and 48 who did not have an HIV test after enrollment), 36 of 1,224 participants in the TDF/FTC group and 64 of 1,217 in the placebo group had acquired HIV infection. Enrollment in the TDF/FTC group was associated with a 44% reduction in the risk of HIV acquisition (95% CI, 15-63). The reduction was greater in the as-treated analysis: at the visits at which adherence was 50% (by self-report and pill count/dispensing), the reduction in HIV acquisition was 50% (95% CI, . The reduction in the risk of HIV acquisition was 73% at visits at which self-reported adherence was 90% (95% CI, 41-88) during the preceding 30 days. Among participants randomly assigned to the TDF/FTC group, plasma and intracellular drug-level testing was performed for all those who acquired HIV infection during the trial and for a matched subset who remained HIV-uninfected: a 92% reduction in the risk of HIV acquisition (95% CI, 40-99) was found in participants with detectable levels of TDF/FTC versus those with no drug detected. Generally, TDF/FTC was well tolerated, although nausea in the first month was more common among participants taking medication than among those taking placebo (9% versus 5%). No differences in severe (grade 3) or life-threatening (grade 4) adverse laboratory events were observed between the active and placebo group, and no drug-resistant virus was found in the 100 participants infected after enrollment. Among 10 participants who were HIV-negative at enrollment but later found to have been infected before enrollment, FTC-resistant virus was detected in 2 of 2 men in the active group and 1 of 8 men in the placebo group. Compared to participant reports at baseline, over the course of the study participants in both the TDF/FTC and placebo groups reported fewer total numbers of sex partners with whom the participants had receptive anal intercourse and higher percentages of partners who used condoms.

# US MSM SAFETY TRIAL
The US MSM Safety Trial 1 was a phase 2 randomized, double-blind, placebo-controlled study of the clinical safety and behavioral effects of TDF for HIV prevention among 400 MSM in San Francisco, Boston, and Atlanta. Participants were randomly assigned 1:1:1:1 to receive daily oral TDF or placebo immediately or after a 9-month delay. Participants were seen for follow-up visits 1 month after enrollment and quarterly thereafter. Among those without directed drug interruptions, medication adherence was high: 92% by pill count and 77% by pill bottle openings recorded by Medication Event Monitoring System (MEMS) caps. Temporary drug interruptions and the overall frequency of adverse events did not differ significantly between TDF and placebo groups. In multivariable analyses, back pain was the only adverse event associated with receipt of TDF. In a subset of men at the San Francisco site (n=184) for whom bone mineral density (BMD) was assessed, receipt of TDF was associated with small decrease in BMD (1% decrease at the femoral neck, 0.8% decrease for total hip) 20 . TDF was not associated with reported bone fractures at any anatomical site. Among 7 seroconversions, no HIV with mutations associated with TDF resistance was detected. No HIV infections occurred while participants were being given TDF; 3 occurred in men while taking placebo, 3 occurred among men in the delayed TDF group who had not started receiving drug; 1 occurred in a man who had been randomly assigned to receive placebo and who was later determined to have had acute HIV infection at the enrollment visit.
Daily oral PrEP with TDF/FTC is recommended as one HIV prevention option for sexuallyactive MSM at substantial risk of HIV acquisition because the iPrEx trial presents evidence of its safety and efficacy in this population, especially when medication adherence is high. (IA)

# PUBLISHED TRIALS OF ANTIRETROVIRAL PREEXPOSURE PROPHYLAXIS AMONG HETEROSEXUAL MEN AND WOMEN

# PARTNERS PREP TRIAL
The Partners PrEP trial 3,21 was a phase 3 randomized, double-blind, placebo-controlled study of daily oral TDF/FTC or TDF for the prevention of acquisition of HIV by the uninfected partner in 4,758 HIV-discordant heterosexual couples in Uganda and Kenya. The trial was stopped after an interim analysis in mid-2011 showed statistically significant efficacy in the medication groups (TDF/FTC or TDF) compared with the placebo group. In 48% of couples, the infected partner was male. HIV-positive partners had a median CD4 count of 495 cells/L and were not being prescribed antiretroviral therapy because they were not eligible by local treatment guidelines. Participants had monthly follow-up visits and the study drug was discontinued among women who became pregnant during the trial.
Adherence to medication was very high: 98% by pills dispensed, 92% by pill count, and 82% by plasma drug-level testing among randomly selected participants in the TDF and TDF/FTC study groups. Rates of serious adverse events and serum creatinine or phosphorus abnormalities did not differ by study group. Modest increases in gastrointestinal symptoms and fatigue were reported in the antiretroviral medication groups compared with the placebo group, primarily in the first month of use. Among participants of both sexes combined, efficacy estimates for each of the 2 antiretroviral regimens compared with placebo were 67% (95% CI, 44-81) for TDF and 75% (95% CI, 55-87) for TDF/FTC. Among women, the estimated efficacy was 71% for TDF and 66% for TDF/FTC. Among men, the estimated efficacy was 63% for TDF and 84% for TDF/FTC. Efficacy estimates by drug regimen were not statistically different among men, women, men and women combined, or between men and women. In a Partners PrEP substudy that measured plasma TDF levels among participants randomly assigned to receive TDF/FTC, detectable drug was associated with a 90% reduction in the risk of HIV acquisition. TDF-or FTC-resistant virus was detected in 3 of 14 persons determined to have been infected when enrolled (2 of 5 in the TDF group; 1 of 3 in the TDF/FTC group) 8 . No TDF or FTC resistant virus was detected among those infected after enrollment. Among women, the pregnancy rate was high (10.3 per 100 person -years) and rates did not differ significantly between the study groups.

# TDF2 TRIAL
The Botswana TDF2 Trial 22 , a phase 2 randomized, double-blind, placebo-controlled study of the safety and efficacy of daily oral TDF/FTC, enrolled 1,219 heterosexual men and women in Botswana, and follow-up has been completed. Participants were seen for monthly follow-up visits, and study drug was discontinued in women who became pregnant during the trial. Among participants of both sexes combined, the efficacy of TDF/FTC was 62% (22%-83%). Efficacy estimates by sex did not statistically differ from each other or from the overall estimate, although the small number of endpoints in the subsets of men and women limited the statistical power to detect a difference. Compliance with study visits was low: 33.1% of participants did not complete the study per protocol. However, many were re-engaged for an exit visit, and 89.3% of enrolled participants had a final HIV test. Among 3 participants later found to have been infected at enrollment, TDF/FTC-resistant virus was detected in 1 participant in the TDF/FTC group and a low level of TDF/FTC-resistant virus was transiently detected in 1 participant in the placebo group. No resistant virus was detected in the 33 participants who seroconverted after enrollment.
Medication adherence by pill count was 84% in both groups. Nausea, vomiting, and dizziness occurred more commonly, primarily during the first month of use, among those randomly assigned to TDF/FTC than among those assigned to placebo. The groups did not differ in rates of serious clinical or laboratory adverse events. Pregnancy rates and rates of fetal loss did not differ by study group.

# FEM-PREP TRIAL
The FEM-PrEP trial 23 was a phase 3 randomized, double-blind, placebo-controlled study of the HIV prevention efficacy and clinical safety of daily TDF/FTC among heterosexual women in South Africa, Kenya, and Tanzania. Participants were seen at monthly follow-up visits, and study drug was discontinued among women who became pregnant during the trial. The trial was stopped in 2011, when an interim analysis determined that the trial would be unlikely to detect a statistically significant difference in efficacy between the two study groups.
Adherence was low in this trial: study drug was detected in plasma samples of <50% of women randomly assigned to TDF/FTC. Among adverse events, only nausea and vomiting (in the first month) and transient, modest elevations in liver function test values were more common among those assigned to TDF/FTC than those assigned to placebo. No changes in renal function were seen in either group. Initial analyses of efficacy results showed 4.7 infections per 100/ personyears in the TDF/FTC group and 5.0 infections per 100 person-years in the placebo group. The hazard ratio 0.94 (95% CI, 0.59-1.52) indicated no reduction in HIV incidence associated with TDF/FTC use. Of the 68 women who acquired HIV infection during the trial, TDF or FTC resistant virus was detected in 5 women: 1 in the placebo group and 4 in the TDF/FTC group. In multivariate analyses, there was no association between pregnancy rate and study group.

# PHASE 2 TRIAL OF PREEXPOSURE PROPHYLAXIS WITH TENOFOVIR AMONG WOMEN IN GHANA, CAMEROON, AND NIGERIA
A randomized, double-blind, placebo-controlled trial of oral tenofovir TDF was conducted among heterosexual women in West Africa -Ghana (n = 200), Cameroon (n = 200), and Nigeria (n = 136) 24 . The study was designed to assess the safety of TDF use and the efficacy of daily TDF in reducing the rate of HIV infection. The Cameroon and Nigeria study sites were closed prematurely because operational obstacles developed, so participant follow-up data were insufficient for the planned efficacy analysis. Analysis of trial safety data from Ghana and Cameroon found no statistically significant differences in grade 3 or 4 hepatic or renal events or in reports of clinical adverse events. Eight HIV seroconversions occurred among women in the trial: 2 among women in the TDF group (rate=0.86 per 100 person-years) and 6 among women receiving placebo (rate, 2.48 per 100 person-years), yielding a rate ratio of 0.35 (95% CI, 0.03-1.93; P=0.24). Blood specimens were available from 1 of the 2 participants who seroconverted while taking TDF; standard genotypic analysis revealed no evidence of drug-resistance mutations.

# VOICE (VAGINAL AND ORAL INTERVENTIONS TO CONTROL THE EPIDEMIC) TRIAL
VOICE (MTN-003) 25 was a phase 2B randomized, double-blind study comparing oral (TDF or TDF/FTC) and topical vaginal (tenofovir) antiretroviral regimens against corresponding oral and topical placebos among 5,029 heterosexual women enrolled in eastern and southern Africa. Of these women, 3,019 were randomly assigned to daily oral medication (TDF/FTC, 1,003; TDF, 1,007; oral placebo, 1,009). In 2011, the trial group receiving oral TDF and the group receiving topical tenofovir were stopped after interim analyses determined futility 26 . The group receiving oral TDF/FTC continued to the planned trial conclusion.
After the exclusion of 15 women later determined to have had acute HIV infection when enrolled in an oral medication group and 27 with no follow-up visit after baseline, 52 incident HIV infections occurred in the oral TDF group, 61 in the TDF/FTC group, and 60 in the oral placebo group. Effectiveness was not significant for either oral PrEP medication group; 49%% for TDF (hazard ratio  1.49; 95% CI, 0.97-2.29) and 4.4% for TDF/FTC (HR, 1.04; 95% CI, 0.73-1.49) in the modified-intent-to-treat analysis.
Face-to-face interview, audio computer-assisted self-interview, and pill-count medication adherence were high in all 3 groups (84%-91%). However, among 315 participants in the random cohort of the case-cohort subset for whom quarterly plasma samples were available, tenofovir was detected, on average, in 30% of samples from women randomly assigned to TDF and in 29% of samples from women randomly assigned to TDF/FTC. No drug was detected at any quarterly visit during study participation for 58% of women in the TDF group and 50% of women in the TDF/FTC group. The percentage of samples with detectable drug was less than 40% in all study drug groups and declined throughout the study. In a multivariate analysis that adjusted for baseline confounding variables (including age, marital status), the detection of study drug was not associated with reduced risk of HIV acquisition.
The number of confirmed creatinine elevations (grade not specified) observed was higher in the oral TDF/FTC group than in the oral placebo group. However, there were no significant differences between active product and placebo groups for other safety outcomes. Of women determined after enrollment to have had acute HIV infection at baseline, two women from the TDF/FTC group had virus with the M184I/V mutation associated with FTC resistance. One woman in the TDF/FTC group who acquired HIV infection after enrollment had virus with the M184I/V mutation; No participants with HIV infection had virus with a mutation associated with tenofovir resistance.
In summary, although low adherence and operational issues precluded reliable conclusions regarding efficacy in 3 trials (VOICE, FEM-PrEP and the West African trial) 27 , 2 trials (Partners PrEP and TDF2) with high medication adherence have provided substantial evidence of efficacy among heterosexual men and women. All 5 trials have found PrEP to be safe for these populations.
Daily oral PrEP with TDF/FTC is recommended as one HIV prevention option for heterosexually-active men and women at substantial risk of HIV acquisition because these trials present evidence of its safety and 2 present evidence of efficacy in these populations, especially when medication adherence is high. (IA).

# PUBLISHED TRIAL OF ANTIRETROVIRAL PREEXPOSURE PROPHYLAXIS AMONG INJECTION DRUG USERS

# BANGKOK TENOFOVIR STUDY (BTS)
BTS 5 was a phase 3 randomized, double-blind, placebo-controlled study of the safety and efficacy of daily oral TDF for HIV prevention among 2,413 IDUs in Bangkok, Thailand. The study was conducted at drug treatment clinics; 22% of participants were receiving methadone treatment at baseline. At each monthly visit, participants could choose to receive either a 28-day supply of pills or to receive medication daily by directly-observed therapy. Study clinics (n=17) provided condoms, bleach (for cleaning injection equipment), methadone, primary medical care, and social services free of charge. Participants were followed for 4.6 years (mean) and received directly-observed therapy 87% of the time.
In the modified intent-to-treat analysis (excluding 2 participants with evidence of HIV infection at enrollment), efficacy of TDF was 48.9% (95% CI, 9.6-72.2; P = .01). A post-hoc modified intent-to-treat analysis was done, removing 2 additional participants in whom HIV infection was identified within 28 days of enrollment, including only participants on directly observed therapy who met pre-established criteria for high adherence (taking a pill at least 71% of days and missing no more than two consecutive doses), and had detectable levels of tenofovir in their blood. Among this set of participants, the efficacy of TDF in plasma was associated with a 73.5% reduction in the risk for HIV acquisition (95% CI, 16.6-94.0; P = .03). Among participants in an unmatched case-control study that included the 50 persons with incident HIV infection and 282 participants at 4 clinics who remained HIV uninfected, detection of TDF in plasma was associated with a 70.0% reduction in the risk for acquiring HIV infection (95% CI, 2.3-90.6; P = .04).
Rates of nausea and vomiting were higher among TDF than among placebo recipients in the first 2 months of medication but not thereafter. The rates of adverse events, deaths, or elevated creatinine did not differ significantly between the TDF and the placebo groups. Among the 49 HIV infections for which viral RNA could be amplified (of 50 incident infections and 2 infections later determined to have been present at enrollment), no virus with mutations associated with TDF resistance were identified. Among participants with HIV infection followed up for a maximum of 24 months, HIV plasma viral load was lower in the TDF than in the placebo group at the visit when HIV infection was detected (P = .01), but not thereafter (P = .10).
Daily oral PrEP with TDF/FTC (or TDF alone) is recommended as one HIV prevention option for IDUs at substantial risk of HIV acquisition because this trial presents evidence of the safety and efficacy of TDF as PrEP in this population, especially when medication adherence is high. (IA)

# Identifying Indications for PrEP
Taking a sexual history is recommended for all adult and adolescent patients as part of ongoing primary care, but the sexual history is often deferred because of urgent care issues, provider discomfort, or anticipated patient discomfort. This deferral is common among providers of primary care 29 , STI care, 30 and HIV care  .
Routinely taking a sexual history is a necessary first step to identify which patients in a clinical practice are having sex with same-sex partners, which are having sex with opposite-sex partners, and what specific sexual behaviors may place them at risk for, or protect them from, HIV acquisition. The clinician can introduce this topic by stating that taking a brief sexual history is routine practice, go on to explain that the information is necessary to the provision of individually appropriate sexual health care, and close by reaffirming the confidentiality of patient information.

# ASSESSING RISK OF SEXUAL HIV ACQUISITION
Because offering PrEP is currently indicated for MSM at substantial risk of HIV acquisition, it is important to consider that although 76% of MSM surveyed in 2008 in 21 US cities reported a health care visit during the past year 34 , other studies reported that health care providers do not ask about, and patients often do not disclose, same-sex behaviors 35 .
Box A1 contains a set of brief questions designed to identify men who are currently having sex with men and to assess a key set of sexual practices that are associated with the risk of HIV acquisition. In studies to develop scored risk indexes predictive of incident HIV infection among MSM 36,37 (see Providers' Supplement, Section 5), several critical factors were identified.
BOX A1: RISK BEHAVIOR ASSESSMENT FOR MSM 36 Box A2 contains a set of brief questions designed to identify women and men who are currently having sex with opposite-sex partners (heterosexually active) and to assess a key set of sexual practices that are associated with the risk of HIV acquisition as identified both in PrEP trials and epidemiologic studies  .
In the past 6 months:
 Have you had sex with men, women, or both?  (if men or both sexes) How many men have you had sex with?  How many times did you have receptive anal sex (you were the bottom) with a man who was not wearing a condom?  How many of your male sex partners were HIV-positive?  (if any positive) With these HIV-positive male partners, how many times did you have insertive anal sex (you were the top) without you wearing a condom?  Have you used methamphetamines (such as crystal or speed)?

# BOX A2: RISK BEHAVIOR ASSESSMENT FOR HETEROSEXUAL MEN AND WOMEN
In addition, for all sexually active patients, clinicians may want to consider reports of diagnoses of bacterial STIs (chlamydia, syphilis, gonorrhea) during the past 6 months as evidence of sexual activity that could result in HIV exposure. For heterosexual women and men, sex without a condom (or its correct use) may also be indicated by recent pregnancy of a female patient or sexual partner of a male patient.
Clinicians should also briefly screen all patients for alcohol abuse 41 (especially before sexual activity) and the use of illicit non-injection drugs (e.g., amyl nitrite, stimulants). 42,43 The use of these substances may affect sexual risk behavior 44 , hepatic or renal health, or medication adherence, any of which may affect decisions about the appropriateness of prescribing PrEP medication. In addition, if substance abuse is reported, the clinician should provide referral for appropriate treatment or harm-reduction services acceptable to the patient.
Lastly, clinicians should consider the epidemiologic context of the sexual practices reported by the patient. The risk of HIV acquisition is determined by both the frequency of specific sexual practices (e.g., unprotected anal intercourse) and the likelihood that a sex partner has HIV infection. The same behaviors when reported as occurring in communities and demographic populations with high HIV prevalence or occurring with partners known to have HIV infection, are more likely to result in exposure to HIV and so will indicate greater need for intensive riskreduction methods (PrEP, multisession behavioral counseling) than when they occur in a community or population with low HIV prevalence (see  or /).
After assessing the risk of HIV acquisition, clinicians should discuss with the patient which of several effective prevention methods (e.g., PrEP, behavioral interventions) 45 will be pursued. When supporting consistent and correct condom use is feasible and the patient is motivated to achieve it, high levels of protection against both HIV and several STIs 46,47 are afforded without the side effects or cost of medication. A clinician can support consistent condom use by providing brief clinical counseling (see Providers' Supplement, Section 7), by referring the patient to behavioral medicine or health education staff in the clinical setting, or by referring the patient to community-based or local health department counseling and support services.

# In the past 6 months:
 Have you had sex with men, women, or both?  (if opposite sex or both sexes) How many men/women have you had sex with?  How many times did you have vaginal or anal sex when neither you nor your partner wore a condom?  How many of your sex partners were HIV-positive?  (if any positive) With these HIV-positive partners, how many times did you have vaginal or anal sex without a condom?
Reported consistent ("always") condom use is associated with an 80% reduction in HIV acquisition among heterosexual couples 48 . However, inconsistent condom use is less effective, 37,49 and studies have reported low rates of recent consistent condom use among MSM 50 and other sexually active adults 51 . Especially low rates have been reported when condom use was measured over several months rather than during most recent sex or the past 30 days 52 . Therefore, unless the patient reports confidence that consistent condom use can be achieved, additional HIV prevention methods, including the consideration of PrEP should be provided while continuing to support condom.
A patient who reports that 1 or more regular sex partners is of unknown HIV status should be offered HIV testing for those partners, either in the clinician's practice or at a confidential testing site (see zip code lookup at /).
Lastly, for any regular sex partner reported to be HIV-positive, clinicians should determine whether the partner is receiving antiretroviral therapy and whether a recent evaluation indicates an undetectable viral load. In addition to the known health benefits of viral load suppression, a recent clinical trial (HPTN 052 53 ) demonstrated that viral load suppression is highly, but not completely, protective against HIV transmission to a heterosexual partner (96% reduction). No similar trial has been done with MSM in HIV-discordant couples, so it is unknown how much viral load suppression reduces HIV transmission among partners who are MSM. Persons who know they have HIV infection may not be in care, may not be receiving antiretroviral therapy, may not be receiving highly effective regimens, may not be adherent to their medications, or for other reasons may not have viral loads that are associated with the least risk of transmission to an uninfected sex partner 54 .  56 substantial proportions of IDU report sharing syringes (34%) and sharing injection equipment (58%). In addition, in NHBS and epidemiologic studies conducted with IDU, most IDU report sexual behaviors that also confer risk of HIV acquisition 57 . Because of the efficacy and safety demonstrated in the PrEP trial with IDU, providing PrEP to those who report injection behaviors that place them at substantial risk of acquiring HIV infection could contribute to HIV prevention for IDU at both the individual and the population level.
Although current evidence is insufficient for a recommendation that all patients be screened for injection or other illicit drug use, the US Preventive Services Task Force recommends that clinicians be alert to the signs and symptoms of illicit drug use in patients. 26 Clinicians should determine whether patients who are currently using illicit drugs are in (or want to enter) behavioral, medication-assisted, or in-patient drug treatment. For persons with a history of injecting illicit drugs but who are currently not injecting, clinicians should assess the risk of relapse along with the patients' use of relapse prevention services (e.g., a drug-related behavioral support program, use of mental health services, 12-step program).
Box A3 contains a set of brief questions that may help identify persons who are injecting illicit drugs, and to assess a key set of injection practices that are associated with the risk of HIV acquisition as identified in the PrEP trial with IDU 5 and in epidemiologic studies 56,58 . PrEP or other HIV prevention should be integrated with prevention and clinical care services for the many health threats IDU may face (e.g., hepatitis B and C infection, abscesses, septicemia, endocarditis, overdose) 59 . In addition, referrals for drug treatment, mental health services, and social services may be indicated 59 .

# LABORATORY TESTS AND OTHER DIAGNOSTIC PROCEDURES
All patients whose sexual or drug injection history indicates consideration of PrEP and who are interested in taking PrEP must undergo laboratory testing to identify those for whom this intervention would be harmful or for whom it would present specific health risks that would require close monitoring.

# HIV TESTING
HIV testing and the documentation of results are required to confirm that patients do not have HIV infection when they start taking PrEP medications. For patient safety, HIV testing and should be repeated at least every 3 months (before prescriptions are refilled or reissued). This requirement should be explained to patients during the discussion about whether PrEP is appropriate for them.
The Centers for Disease Control and Prevention (CDC) and the US Preventive Services Task Force recommends that MSM, IDUs, patients with a sex partner who has HIV infection, and others at substantial risk of HIV acquisition undergo an HIV test at least annually or for those  Have you ever injected drugs that were not prescribed to you by a clinician?  (if yes), When did you last inject unprescribed drugs?  In the past 6 months, have you injected by using needles, syringes, or other drug preparation equipment that had already been used by another person?  In the past 6 months, have you been in a methadone or other medication-based drug treatment program?
 Adult person  Without acute or established HIV infection  Any injection of drugs not prescribed by a clinician in past 6 months AND at least one of the following  Any sharing of injection or drug preparation equipment in past 6 months  Been in a methadone, buprenorphine, or suboxone treatment program in past 6 months  Risk of sexual acquisition (also evaluate by criteria in Box B1 or B2)
with additional risk factors, every 3-6. 60 However, outside the context of PrEP delivery, testing is often not done as frequently as recommended. 61 At a minimum, clinicians should document a negative antibody test result within the week before initiating (or reinitiating) PrEP medications.

# ACUTE HIV INFECTION
In the iPrEx trial, drug-resistant virus developed in 2 persons with unrecognized acute HIV infection at enrollment and for whom TDF/FTC had been dispensed. These participants had negative antibody test results before they started taking PrEP, tested positive at a later study visit, and PCR (polymerase chain reaction) on stored specimens from the initial visit detected the presence of virus. When questioned, most of the 10 acutely infected participants (8 of whom had been randomly assigned the placebo group) reported signs and symptoms consistent with a viral syndrome 2 . Both acutely infected patients to whom TDF/FTC had been dispensed had the M184V/I mutation associated with emtricitabine resistance, but not the K65R mutation associated with tenofovir resistance 2 . Among participants who were dispensed PrEP medication in the US MSM Safety Trial and in the Partners PrEP, TDF2, and VOICE trials (see Table 6), the M184V mutation, developed in several persons who were enrolled and had started taking medication with unrecognized acute HIV infection but K65R developed in only one (in the TDF2 study). However, no mutations emerged in persons who acquired infection after baseline.
In the one trial with very low medication adherence that has published its resistance testing results, the emtricitabine resistance mutation, but not the K65R mutation was found in a few persons with incident infection after baseline (4 persons in the FEM-PrEP trial).
PrEP is indicated for MSM, heterosexual men and women, and IDUs who report injection or sexual behaviors that place them at substantial risk of HIV acquisition. Therefore clinicians should suspect acute HIV infection in persons known to have been exposed recently (e.g., a condom broke during sex with an HIV-infected partner, relapse to injection drug use with shared injection equipment). In addition, clinicians should solicit a history of nonspecific signs or symptoms of viral infection during the preceding month or on the day of evaluation (Table 7) in all PrEP candidates with a negative or an indeterminate result on an HIV antibody test. Optional adjustment for low actual body weight 71 If the actual body weight is less than the IBW (ideal body weight) use the actual body weight for calculating the eCrCl.

# Optional adjustment of high actual body weight 71
Used only if the actual body weight is 30% greater than the IBW. Otherwise, the IBW is used.

# HEPATITIS SEROLOGY
Sexually active adults (especially MSM), and persons who inject illicit drugs, are at risk of acquiring HBV infection 74 and hepatitis C virus (HCV) infection 75 . Vaccination against HBV is recommended for all adolescents and adults, especially for MSM 76 . Therefore, HBV and HCV infection status should be documented by screening serology before TDF/FTC is prescribed as PrEP (see Table 8). Those patients determined to be susceptible to HBV infection should be vaccinated.
In addition, both TDF and FTC are active against HBV. This has 2 implications for PrEP use. First, if patients with active HBV infection stop taking these medications, liver function must be closely monitored because reactivated HBV infection can result in hepatic damage 77 . In addition, a recent study demonstrated a lower rate of incident HBV infections among HIV-infected MSM whose treatment regimens included TDF or lamivudine (closely related to FTC) than among men whose regimens did not contain these drugs (0.7 vs 6.7 infections per 100 person-years). 78

# Providing PrEP

# GOALS OF PREP THERAPY
The ultimate goal of PrEP is to reduce the acquisition of HIV infection with its resulting morbidity, mortality, and cost to individuals and society. Therefore clinicians initiating the provision of PrEP should  Prescribe medication regimens that are proven safe and effective for uninfected persons who meet recommended criteria to reduce their risk of HIV acquisition  Educate patients about the medications and the regimen to maximize their safe use  Provide support for medication-adherence to help patients achieve and maintain protective levels of medication in their bodies  Provide HIV risk-reduction support and prevention services or service referrals to help patients minimize their exposure to HIV  Provide effective contraception to women who are taking PrEP and who do not wish to become pregnant  Monitor patients to detect HIV infection, medication toxicities, and levels of risk behavior in order to make indicated changes in strategies to support patients' long-term health

# INDICATED MEDICATION
The medication proven safe and effective, and currently approved by FDA for PrEP in healthy adults at risk of acquiring HIV infection, is the fixed-dose combination of TDF and FTC in a single daily dose (see Table 9). Therefore, TDF/FTC is the recommended medication that should be prescribed for PrEP for MSM, heterosexually active men and women, and IDU who meet recommended criteria. Because TDF alone has been proven effective in trials with IDU and heterosexually active men and women, it can be considered as an alternative regimen for these specific populations. As PrEP for MSM, TDF alone is not recommended because no trials have been done, so the efficacy of TDF alone for MSM is unknown. In addition to the safety data obtained in PrEP clinical trials, data on drug interactions and longer-term toxicities have been obtained by studying the component drugs individually for their use in treatment of HIV-infected persons. Studies have also been done in small numbers of HIVuninfected, healthy adults (see Table 10).

# No data WHAT NOT TO USE
No antiretroviral regimens should be used for PrEP other than a daily oral dose of TDF/FTC, or a daily dose of TDF alone as an alternative only for IDU and heterosexually active adults.
Other medications and other dosing schedules have not yet been shown to be safe or effective in preventing HIV acquisition among otherwise healthy adults and are not approved by FDA for PrEP.  Do not use other antiretroviral medications (e.g., 3TC), either in place of, or in addition to, TDF/FTC or TDF.  Do not use other than daily dosing (e.g., intermittent, episodic , or other discontinuous dosing)  Do not provide PrEP as expedited partner therapy (i.e., do not prescribe for an uninfected person not in your care).

# TIME TO ACHIEVING PROTECTION
The time from initiation of daily oral doses of TDF/FTC to maximal protection against HIV infection is unknown. There is not scientific consensus on what intracellular concentrations are protective for either drug or the protective contribution of each drug in specific body tissues. It has been shown that the pharmacokinetics of TDF and FTC vary by tissue 80 .
Data from exploratory pharmacokinetic studies conducted with HIV-uninfected men and women does provide preliminary data on the lead-time required to achieve steady state levels of tenofovir diphosphate (TFV-DP, the activated form of the medication) in blood (PBMCs ), rectal, and vaginal tissues 81,82 . These data suggest that maximum intracellular concentrations of TFV-DP are reached in blood after approximately 20 days of daily oral dosing, in rectal tissue at approximately 7 days, and in cervicovaginal tissues at approximately 20 days. No data are yet available about intracellular drug concentrations in penile tissues susceptible to HIV infection to inform considerations of protection for male insertive sex partners.

# MANAGING SIDE EFFECTS
Patients taking PrEP should be informed of side effects among HIV-uninfected participants in clinical trials (see Table 5). In these trials, side effects were uncommon and usually resolved within the first month of taking PrEP ("start-up syndrome"). Clinicians should discuss the use of over-the-counter medications for headache, nausea, and flatulence should they occur. Patients should also be counseled about signs or symptoms that indicate a need for urgent evaluation (e.g., those suggesting possible acute renal injury or acute HIV infection).

# CLINICAL FOLLOW-UP AND MONITORING
Once PrEP is initiated, patients should return for follow-up approximately every 3 months. Clinicians may wish to see patients more frequently at the beginning of PrEP (e.g., 1 month after initiation, to assess and confirm HIV-negative test status, assess for early side effects, discuss any difficulties with medication adherence, and answer questions.
All patients receiving PrEP should be seen as follows:
 At least every 3 months to o Repeat HIV testing and assess for signs or symptoms of acute infection to document that patients are still HIV negative (see Figure) o Repeat pregnancy testing for women who may become pregnant o Provide a prescription or refill authorization of daily TDF/FTC for no more than 90 days (until the next HIV test) o Assess side effects, adherence, and HIV acquisition risk behaviors o Provide support for medication adherence and risk-reduction behaviors o Respond to new questions and provide any new information about PrEP use  At least every 6 months to o Monitor eCrCl  If other threats to renal safety are present (e.g., hypertension, diabetes), renal function may require more frequent monitoring or may need to include additional tests (e.g., urinalysis for proteinuria)  A rise in serum creatinine is not a reason to withhold treatment if eCrCl remains 60 ml/min.  If eCrCl is declining steadily (but still 60 ml/min), consultation with a nephrologist or other evaluation of possible threats to renal health may be indicated. o Conduct STI testing recommended for sexually active adolescents and adults (i.e., syphilis, gonorrhea, chlamydia) 83  At least every 12 months to o Evaluate the need to continue PrEP as a component of HIV prevention OPTIONAL ASSESSMENTS

# BONE HEALTH
Decreases in bone mineral density (BMD) have been observed in HIV-infected persons treated with combination antiretroviral therapy (including TDF-containing regimes) 84,85 . However, it is unclear whether this 3%-4% decline would be seen in HIV-uninfected persons taking fewer antiretroviral medications for PrEP. The iPrEx trial (TDF/FTC) and the CDC PrEP safety trial in MSM (TDF) conducted serial dual-emission x-ray absorptiometry (DEXA) scans on a subset of MSM in the trials and determined that a small (~1%) decline in BMD that occurred during the first few months of PrEP either stabilized or returned to normal 20,86 . There was no increase in fragility (atraumatic) fractures over the 1-2 years of observation in these studies comparing those persons randomized to receive PrEP medication and those randomized to receive placebo.
Therefore, DEXA scans or other assessments of bone health are not recommended before the initiation of PrEP or for the monitoring of persons while taking PrEP. However, any person being considered for PrEP who has a history of pathologic or fragility bone fractures or who has significant risk factors for osteoporosis should be referred for appropriate consultation and management.

# THERAPEUTIC DRUG MONI TORING
Similar to the limited use of therapeutic drug monitoring (TDM) in the treatment of HIV infection 66 , several factors mitigate against the routine use of TDM during PrEP. These factors include (1) a lack of established concentrations in blood associated with robust efficacy of TDF or FTC for the prevention of HIV acquisition in adults after exposure during penile-rectal or penile-vaginal intercourse 87 and (2) the limited but growing availability of clinical laboratories that perform quantitation of antiretroviral medicine concentrations under rigorous quality assurance and quality control standards.
However, some clinicians may want to use TDM periodically to assess adherence to PrEP medication. If so, a key limitation should be recognized. The levels of medication in serum or plasma reflect only very recent doses, so they are not valid estimates of consistent adherence 88 . However, if medication is not detected or is detected at a very low level, support to reinforce medication adherence would be indicated.

# Persons with Documented HIV Infection
All persons with HIV-positive test results whether at screening or while taking TDF/FTC or TDF alone as PrEP should be provided the following services 66 .  Laboratory confirmation of HIV status (see Figure )  Determination of CD4 lymphocyte count and viral load to guide therapeutic decisions  Documentation of results of genotypic HIV viral resistance testing to guide future treatment decisions  Provision of, or referral to, an experienced provider for the ongoing medical management of HIV infection  Counseling about their HIV status and steps they should take to prevent HIV transmission to others and to improve their own health  Assistance with, or referral to, the local health department for the identification of sex partners who may have been recently exposed to HIV so that they can be tested for HIV infection, considered for nonoccupational postexposure prophylaxis (nPEP), and counseled about their risk-reduction practices 89 In addition, a confidential report of new HIV infection should be provided to the local health department.

# Discontinuing PrEP
Patients may discontinue PrEP medication for several reasons, including personal choice, changed life situations resulting in lowered risk of HIV acquisition, intolerable toxicities, chronic nonadherence to the prescribed dosing regimen despite efforts to improve daily pill-taking, or acquisition of HIV infection.
Upon discontinuation for any reason, the following should be documented in the health record:  HIV status at the time of discontinuation  Reason for PrEP discontinuation  Recent medication adherence and reported sexual risk behavior For persons with incident HIV infection, see Persons with Documented HIV Infection.
For persons with active hepatitis B infection, see Special Clinical Considerations.
Any person who wishes to resume taking PrEP medications after having stopped should undergo all the same pre-prescription evaluation as a person being newly prescribed PrEP. In addition, a frank discussion should clarify the changed circumstances since discontinuing medication that indicate the need to resume medication, and the commitment to, take it,

# Special Clinical Considerations
The patient with certain clinical conditions requires special attention and follow-up by the clinician.

# WOMEN WHO BECOME PREGNANT OR BREASTFEED WHILE TAKING PREP MEDICATION
Women without HIV infection who have sex partners with documented HIV infection are at substantial risk of HIV acquisition during attempts to conceive (i.e., without a condom). In addition, pregnancy is associated with an increased risk of HIV acquisition 90 . PrEP use periconception and during pregnancy by the uninfected partner may offer an additional tool to reduce the risk of sexual HIV acquisition. Both the FDA labeling information 6 and the perinatal antiretroviral treatment guidelines 91 permit this use. However, data directly related to the safety of PrEP use for a developing fetus are limited. Providers should discuss available information about potential risks and benefits of beginning or continuing PrEP during pregnancy so that an informed decision can be made. (See Clinical Providers' Supplement, Section 5 at ).
In the PrEP trials with heterosexual women, medication was promptly discontinued for those who became pregnant, so the safety for exposed fetuses could not be adequately assessed. A single small study of periconception use of TDF in 46 uninfected women in HIV-discordant couples found no ill effects on the pregnancy and no HIV infections. 92 Additionally, because TDF and FTC are widely used for the treatment of HIV infection and continued during pregnancies that occur, 76,77,93 The data on pregnancy outcomes in the Antiretroviral Pregnancy Registry provide no evidence of adverse effects among fetuses exposed to these medications 94 .
Providers should educate HIV-discordant couples who wish to become pregnant about the potential risks and benefits of all available alternatives for safer conception 95 and if indicated make referrals for assisted reproduction therapies. Whether or not PrEP is elected, the HIVinfected partner should be prescribed effective antiretroviral therapy before conception attempts 96 : if the infected partner is male, to reduce the risk of transmission-related viral load in semen; and in both sexes, for the benefit of their own health 53 .
In addition, health care providers are strongly encouraged to prospectively and anonymously submit information about any pregnancies in which PrEP is used to the Antiretroviral Pregnancy Registry at /.
The safety of PrEP with TDF/FTC or TDF alone for infants exposed during lactation has not been adequately studied. However, data from studies of infants born to HIV-infected mothers and exposed to TDF or FTC through breast milk suggest limited drug exposure. 93,97 Additionally, the World Health Organization has recommended the use of TDF/FTC or 3TC/efavirenz for all pregnant and breastfeeding women for the prevention of perinatal and postpartum mother-tochild transmission of HIV 98 . Therefore, providers should discuss current evidence about the potential risks and benefits of beginning or continuing PrEP during breastfeeding so that an informed decision can be made.

# PATIENTS WITH CHRONIC ACTIVE HEPATITIS B VIRUS INFECTION
TDF and FTC are each active against both HIV infection and HBV infection and thus may prevent the development of significant liver disease by suppressing the replication of HBV. Only TDF, however, is currently FDA-approved for this use. Therefore, in persons with substantial risk of both HIV acquisition and active HBV infection, daily doses of TDF/FTC may be especially indicated.
All persons screened for PrEP who test positive for hepatitis B surface antigen (HBsAg) should be evaluated by a clinician experienced in the treatment of HBV infection. For clinicians without this experience, co-management with an infectious disease or a hepatic disease specialist should be considered. Patients should be tested for HBV DNA by the use of a quantitative assay to determine the level of HBV replication 99 before PrEP is prescribed and every 6-12 months while taking PrEP.
TDF presents a very high barrier to the development of HBV resistance. However, it is important to reinforce the need for consistent adherence to the daily doses of TDF/FTC to prevent reactivation of HBV infection with the attendant risk of hepatic injury, and to minimize the possible risk of developing TDF-resistant HBV infection 100 .
If PrEP is no longer needed to prevent HIV infection, a separate determination should be made to about whether to continue TDF/FTC as a means of providing TDF to treat HBV infection. Acute flares resulting from the reactivation of HBV infection have been seen in HIV-infected persons after the cessation of TDF and other medications used to treat HBV infection. Such flares have not yet been seen in HIV-uninfected persons with chronic active HBV infection who have stopped taking TDF-containing PrEP regimens. Nonetheless, when such patients discontinue PrEP, they should continue to receive care from a clinician experienced in the management of HBV infection so that if flares occur, they can be detected promptly and treated appropriately.

# PATIENTS WITH CHRONIC RENAL FAILURE
HIV-uninfected patients with chronic renal failure, as evidenced by an eCrCl of <60 ml/min, should not take PrEP because the safety of TDF/FTC for such persons was not evaluated in the clinical trials. TDF is associated with modestly reduced renal function when used as part of an antiretroviral treatment regimen in persons with HIV infection (which itself can affect renal function). Because other HIV prevention options are available, the only PrEP regimen proven effective to date (TDF/FTC) and approved by FDA for PrEP is not indicated for persons with chronic renal failure. 6 ADOLESCENT MINORS 101 As a part of primary health care, HIV screening should be discussed with all adolescents who are sexually active or have a history of injection drug use. Parental/guardian involvement in an adolescent's health care is often desirable but is sometimes contraindicated for the safety of the adolescent. However, laws and regulations that may be relevant for PrEP-related services (including HIV testing), such as those concerning consent, confidentiality, parental disclosure, and circumstances requiring reporting to local agencies, differ by jurisdiction 5 . Clinicians considering providing PrEP to a person under the age of legal adulthood (a minor) should be aware of local laws, regulations, and policies that may apply 102 .
Although the FDA labeling information specifies PrEP indications for "adults," an age above which an adolescent is considered an adult is not provided. 6 None of the completed PrEP trials have included persons under the age of 18. Therefore, clinicians should consider carefully the lack of data on safety and effectiveness of PrEP taken by persons under 18 years of age, the possibility of bone or other toxicities among youth who are still growing, and the safety evidence available when TDF/FTC is used in treatment regimens for HIV-infected youth 103 . These factors should be weighed against the potential benefit of providing PrEP for an individual adolescent at substantial risk of HIV acquisition.

# NONOCCUPATIONAL POSTEXPOSURE PROPHYLAXIS
Persons not receiving PrEP who seek care within 72 hours after an isolated sexual or injectionrelated HIV exposure should be evaluated for the potential need for nPEP 104 . If such exposures are not isolated, and the person is determined not to have HIV infection, clinicians should consider beginning PrEP immediately because PrEP during the first 28 days is consistent with a recommended nPEP regimen 104 . If the exposure is isolated (e.g., sexual assault, infrequent condom failure), nPEP should be prescribed, but continued antiretroviral medication is not indicated after completion of the 28-day PEP course.
Persons who repeatedly seek nPEP should be evaluated for possible PrEP use after confirming they have not acquired HIV infection 105 . Because HIV infection has been reported in association with exposures soon after an nPEP course 98 , daily PrEP may be more protective than repeated episodes of nPEP.

# Improving Medication Adherence
Data from the published studies of daily oral PrEP indicate that medication adherence is critical to achieving the maximum prevention benefit (see Table 4) and reducing the risk of selecting for a drug-resistant virus if non-adherence leads to HIV acquisition 106,107 . Three additional studies reinforce the need to prescribe, and support adherence to uninterrupted daily doses of TDF/FTC.
A study of the pharmacokinetics of directly observed TDF dosing in MSM in the STRAND trial found that the intracellular levels of the active form of TDF (tenofovir diphosphate), when applied to the drug detection-efficacy statistical model with iPrEx participants, corresponded to an HIV risk reduction efficacy of 99% for 7 doses per week, 96% for 4 doses per week, and 76% for 2 doses per week 87 . This finding adds to the evidence that despite some "forgiveness" for occasional missed doses, a high level of prevention efficacy requires a high level of adherence to daily medication.
A pilot study of daily TDF/FTC as PrEP with young MSM was stopped when the iPrEx trial results were reported. 108 Among the 68 men enrolled (mean age, 20 years; 53% African American; 40% Hispanic/Latino) plasma specimens were tested to objectively measure medication adherence. At week 4, 63% had detectable levels of tenofovir, but at week 24, only 20% had detectable levels of tenofovir.
In addition, a study with MSM and commercial sex workers in Kenya evaluated adherence to daily, fixed-interval (Mondays and Fridays), and coitally-timed (single post-coital) TDF/FTC dosing schedules by the use of pill bottles with caps monitored by an electronic medication event monitoring system (MEMS) and monthly interviews about sexual behavior 12 . Among the 67 men and 5 women in this study, 83% adhered to daily dosing, 55% to fixed-interval dosing, and 26% to post-coital dosing regimens. These findings suggest that adherence is better with daily dosing, as currently recommended, than with non-daily regimens (not yet proven effective as PrEP). These data confirm that medication education and adherence counseling (also called medication self-management) will need to be provided to support daily PrEP use.
A recent review of the antiretroviral treatment adherence studies over the past 15 years and adherence data from the completed PrEP trials suggests various approaches to effectively support medication adherence 109 . These approaches include educating patients about their medications; helping them anticipate and manage side effects; helping them establish dosing routines that mesh with their work and social schedules; providing reminder systems and tools; addressing financial, substance abuse, or mental health needs that may impede adherence; and facilitating social support.
Although many published articles address antiretroviral medication adherence among persons being treated for HIV infection, these findings may be only partially applicable to PrEP users. HIV treatment regimens include more than 2 drugs (commonly including more than 1 pill per day), resulting in an increased pill burden, and the possibility of side effects and toxicities with 3 or more drugs may occur that would not occur with TDF/FTC alone. The motivations of persons being treated for HIV infection and persons trying to prevent HIV infection may differ. Because PrEP will be used in otherwise healthy adults, studies of the use of medications in asymptomatic adults for the prevention of potential serious future health outcomes may also be informative for enhancing adherence to PrEP medications. The most cost-effective interventions for improving adherence to antihypertensive and lipid-lowering medications were initiated soon after the patients started taking medication and involved personalized, regularly scheduled education and symptom management (patients were aware that adherence was being monitored) 110 . Patients with chronic diseases reported that the most important factors in adherence to medications were incorporating medication into their daily routines, knowing that the medications work, believing that the benefits outweigh the risks, knowing how to manage side effects, and low out-of pocket costs. 111,112 When initiating a PrEP regimen, clinicians must educate patients so that they understand clearly how to take their medications (i.e., when to take them, how many pills to take at each dose) and what to do if they experience problems (e.g., what constitutes a missed dose , what to do if they miss a dose). Patients should be told to take a single missed dose as soon as they remember it, unless it is almost time for the next dose. If it is almost time for the next dose, patients should skip the missed dose and continue with the regular dosing schedule.
Side effects can lead to non-adherence, so clinicians need a plan for addressing them. Clinicians should tell patients about the most common side effects and should work with patients to develop a specific plan for handling them, including the use of specific over-the-counter medications that can mitigate symptoms 113 . The importance of using condoms during sex, especially for patients who decide to stop taking their medications, should be reinforced.

# Box D: Key Components of Medication Adherence Counseling
Using a broad array of a health care professionals (e.g., physicians, nurses, case-managers, physician assistants, clinic-based and community pharmacists) that work together on a health care team to influence and reinforce adherence instructions 114 significantly improves medication adherence and may alleviate the time constraints of individual providers. 115,116 This broad-team approach may also provide a larger number of providers to counsel patients about selfmanagement of behavioral risks.
For additional information on adherence counseling, see the Clinical Providers' Supplement, Section 6 at .

# Reducing HIV Risk Behaviors
The adoption and the maintenance of safer behaviors (sexual, injection, and other substance abuse) are critical for the lifelong prevention of HIV infection and are important for the clinical management of persons prescribed PrEP.  117 have reduced STI incidence in a general clinic population. However, they take a general approach, so they do not allow tailoring to the sexual risk-reduction needs of individual patients (e.g., as partners change, PrEP is initiated or discontinued).

# Establish trust and bidirectional communication
Interactive, client-centered counseling (in which content is tailored to a patient's sexual risk behaviors and the situations in which risks occur), in conjunction with goal-setting strategies is effective in HIV prevention 105, . An example of this method is Project Respect: although this counseling protocol alone did not reduce HIV incidence significantly 20-minute clinical counseling sessions to develop and review patient-specific, incremental risk-reduction plans led to reduced incidence of STIs in a heterosexual population, 121 . Project Aware included MSM and heterosexuals attending STD clinics and provided a single brief counseling session (using the Respect-2 protocol) while conducting rapid HIV testing. There was no reduction in the incidence of STIs attributed to counseling 122 . However, in the context of PrEP delivery, brief, repeated counseling sessions can take advantage of multiple visits for follow-up care 123 while addressing the limited time available for individual visits 124 and the multiple prevention 115,116 and treatment topics that busy practitioners need to address.
Reducing or eliminating injection risk practices can be achieved by providing access to drug treatment and relapse prevention services (e.g., methadone, buprenorphine for opiate users) for persons who are willing to participate 125 . For persons not able (e.g., on a waiting list or lacking insurance) or not motivated to engage in drug treatment, providing access to unused injection equipment through syringe service programs (where available), prescriptions for syringes or purchase from pharmacies without a prescription (where legal) can reduce HIV exposure. In addition, providing or referring for cognitive or behavioral counseling and any indicated mental health or social services may help reduce risky injection practices. See the Substance Abuse Treatment and Mental Health Treatment Locators at /.
For additional information on risk reduction interventions, see Clinical Providers' Supplement, Section 7 at .

# Box E: Key Components of Behavioral Risk-Reduction Counseling

# Financial Case-Management Issues for PrEP
One critical component in providing PrEP medications and related clinical and counseling services is identifying insurance and other reimbursement sources. Although some commercial insurance and employee benefits programs have defined policies for the coverage of PrEP, others have not yet done so. Similarly, public insurance sources vary in their coverage policy.
For patients who do not have health insurance, whose insurance does not cover PrEP medication, and whose personal resources are inadequate to pay out-of-pocket, Gilead Sciences has established a PrEP medication assistance program. In addition to providing Truvada to providers for eligible patients and access to free HIV testing, the program provides co-pay assistance for medical care visits and free condoms to patients on request 126 . Providers may obtain applications for their patients at /.

# Decision Support, Training and Technical Assistance
Decision support systems (electronic and paper), flow sheets, checklists (see Clinical Providers' Supplement, Section 1 for a PrEP provider/patient checklist at ), feedback reminders, and involvement of nurse clinicians and pharmacists will be helpful in managing the many steps indicated for the safe use of PrEP and to increase the likelihood that patients will follow them. Often these systems are locally developed but may become available from various sources including training centers and Web sites funded by government agencies; professional associations, or interested private companies. Examples include downloadable applications (widgets) to support the delivery of nPEP or locate nearby sites for confidential HIV tests (); and confidential commercial services to electronically monitor

# Related DHHS Guidelines
This document is consistent with several other guidelines from several DHHS agencies related to sexual health, HIV prevention, and the use of antiretroviral medications. Clinicians should refer to these other documents for detailed guidance in their respective areas of care.

# III. Expert opinion
The quality of scientific evidence ratings in Table 2 are based on the GRADE rating system. 28

# Appendices

# APPENDIX 1 HIV TEST TABLES
The working groups and expert panels listed here were convened by teleconference before trial results were available (2009-2010) and some were reconvened after each trial results for each population group was published. As technical experts, prevention partners, and key stakeholders, they were asked to assist us to identify relevant scientific/medical literature and share thoughts on topics that would inform the development of possible future guidelines for PrEP use in the US. They did not participate in the writing of these guidelines. No financial disclosures were sought. See Providers' Supplement section 10 for a description of the criteria use for constitution of the working groups. Institutional associations listed for participants are those at the time of the group discussions and may have changed since.