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research-article2014

AOPXXX10.1177/1060028014520880Annals of PharmacotherapyLi et al

Review Article

Systemic Preexposure Prophylaxis for HIV: Translating Clinical Data to Clinical Practice

Annals of Pharmacotherapy 2014, Vol. 48(4) 507­–518 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014520880 aop.sagepub.com

Julius Li, PharmD1, Staci L. Dufrene, PharmD, AAHIVP1, and Jason F. Okulicz, MD2

Abstract Objective: To assess the real-world implications of oral tenofovir–emtricitabine (TDF-FTC) for HIV preexposure prophylaxis (PrEP) in clinical practice and highlight important considerations for its implementation. Data Sources: A search of PubMed (January 1996 through June 2013) was conducted using the terms HIV preexposure prophylaxis, HIV prevention, tenofovir, and emtricitabine. Abstracts from 2012-2013 HIV/AIDS conferences were also reviewed. Study Selection and Data Extraction: All pertinent original studies and review articles published in English were evaluated for inclusion. Reference citations from identified articles were examined for additional content. Data Synthesis: Although antiretroviral therapy has been highly successful in reducing AIDS outcomes and death in HIV-infected patients worldwide, transmission of HIV remains a major global health problem. The recent approval of oral TDF-FTC for HIV PrEP represents the latest biomedical intervention to help control this epidemic. Four published randomized studies evaluated the efficacy and safety of this combination to prevent HIV transmission in several at-risk populations, including men who have sex with men, serodiscordant couples, and heterosexuals residing in endemic regions. Overall, these studies demonstrated significant risk reductions in the incidence of new HIV infections with good short-term tolerability. Despite promising results from clinical studies, several limitations may hinder the utility of PrEP in clinical practice. Most importantly, PrEP was studied in the context of a comprehensive prevention program, including intensive counseling on adherence, high-risk behaviors, and traditional preventative measures. If PrEP is implemented without these adjunct measures, concerns about failure and increased resistance may eventually be realized. Conclusion: The greatest impact of PrEP, both clinically and financially, will likely arise from judicious application in select high-risk populations. If used appropriately, PrEP has the potential to augment reductions in the current incidence of new HIV infections, and pharmacists will have an important role in the careful selection and counseling of these targeted populations. Keywords human immunodeficiency virus, HIV, preexposure prophylaxis, prevention, tenofovir, emtricitabine

Introduction The burden of HIV/AIDS is substantial, with more than 34 million people infected worldwide, including an estimated 1.2 million persons in the United States.1 Although significant efforts have been made to control the epidemic, HIV/ AIDS still results in more than 1 million deaths per year and more than 2.5 million new infections annually.2,3 Traditional methods, such as education, barrier contraception, and avoidance of high-risk sexual behaviors, remain the cornerstone of HIV prevention strategies. Along with expanded access to antiretroviral therapy (ART), these approaches have reduced the number of new infections in many countries. However, for every person starting ART, there are 2 more individuals newly infected with HIV.4 Additionally, no preventative vaccine has been realized to date, with

estimates projecting up to 60 million new infections before the widespread implementation of an effective vaccine.5-7 Without more effective prevention methods, resource burdens on healthcare systems will continue to rise due to increased life expectancies of individuals infected with HIV. Therefore, there has been increasing interest in HIV prevention strategies involving the use of antiretroviral (ARV) agents, and this review will focus on their use as 1

South Texas Veterans Health Care System, San Antonio, TX, USA San Antonio Military Medical Center, Fort Sam Houston, TX, USA

2

Corresponding Author: Jason F. Okulicz, MD, HIV Medical Education Unit Director, Infectious Disease Service, San Antonio Military Medical Center, 3551 Roger Brooke Drive, Fort Sam Houston, TX 78234-6200, USA. Email: [email protected]

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systemic preexposure prophylaxis (PrEP) to prevent the sexual transmission of HIV.

Chemoprophylaxis for HIV Antiretroviral chemoprophylaxis has been traditionally used for perinatal HIV exposure and for the prevention of HIV following occupational (eg, needlesticks) and nonoccupational (eg, sexual) exposures. Observational data suggest that postexposure prophylaxis is about 80% effective in averting HIV acquisition following high-risk exposures.8,9 Perinatal prophylaxis has reduced the number of infants born with HIV by roughly 40% worldwide and 90% in the United States over the past decade.1,2,10,11 Despite the successes of perinatal and postexposure prophylaxis, horizontal transmission of HIV, defined as transfer of virus between sexual partners or needle-sharing partners, still remains a major problem, with sexual transmission accounting for 75% of new infections in the United States and more than 90% in certain regions of the world.1-3 Combination ART in HIV-infected persons dramatically reduces the amount of HIV in plasma and genital secretions, and may reduce the risk of transmission to sexual partners.12-14 The HPTN 052 trial tested this hypothesis by comparing the incidence of new infections in serodiscordant couples, defined as a relationship between HIV-negative and HIV-positive partners.15 Couples were randomized to either early or delayed initiation of ART in the infected partners. In the early therapy group, ART was initiated in the HIVpositive partner at enrollment. In the delayed therapy group, ART was initiated when CD4 count was 250 cells/mm3 or less on 2 consecutive measurements or after the development of an AIDS-related illness. Early initiation of ART resulted in 1 linked transmission, compared with 27 linked transmissions in the delayedtherapy group, translating to a relative risk reduction of 96% (hazard ratio [HR] = 0.04; 95% confidence interval [CI] = 0.01-0.27; P < .001). Most of these couples were in stable, heterosexual relationships, with 95% of individuals reporting a single sex partner. Also, these couples received intense risk-reduction counseling on a regular basis, which presumably contributed to the low reported rates of both unprotected intercourse and multiple sex partners. The results of HPTN 052 provide further evidence supporting current recommendations to initiate ART in all HIVinfected individuals, regardless of CD4 count, to help prevent sexual transmission.16 Although these results have significant implications for the use of ART to prevent sexual transmission of HIV, there are limitations to this strategy. For example, it is estimated that 21% of the HIV-infected population remains undiagnosed in the United States, and only 19% of HIV-infected individuals have a suppressed viral load.17 An alternative chemoprophylaxis strategy that would potentially circumvent these limitations would be the use of PrEP in HIV-uninfected persons.

Preexposure Prophylaxis Preexposure prophylaxis, defined as the use of medications to prevent infection in uninfected individuals with high exposure or vulnerability to a given pathogen, is commonly used to prevent various infections, including malaria and opportunistic infections.18 Theoretically, ARVs blunt sexual transmission of HIV by limiting the founder viral population and blocking viral replication to allow host immune responses to eradicate this smaller invading inoculum.19 However, initial thoughts of PrEP for HIV were hindered by the significant toxicities and pill burdens of older ARVs. The principles of ART are based on using multiple agents to durably suppress viremia and prevent resistance, and PrEP is centered on a similar doctrine. Although the use of more than one ARV increases potential for toxicities, animal studies demonstrated more robust protection against transmission of HIV with combination therapy compared with monotherapy.20 Combination therapy may also reduce the development of resistant virus.21 Based on these data, human clinical trial regimens investigating the use of PrEP focused on combination therapy.

Topical PrEP Topical ARV products can provide higher drug concentrations to target tissue sites compared with oral formulations, which may translate to greater protection against HIV. Topical formulations would also minimize systemic drug exposures and the risk for toxicities. The CAPRISA 004 trial investigated the use of vaginal tenofovir 1% gel compared with placebo to prevent the acquisition of HIV in 889 uninfected South African women.22 Tenofovir gel was applied pericoitally up to 12 hours before and after intercourse. This study demonstrated a significant reduction in the incidence of new HIV infections after 30 months of follow-up from 9.1 to 5.6 per 100 women-years with placebo gel and tenofovir 1% gel, respectively (incidence ratio rate [IRR] = 0.61; 95% CI = 0.40-0.94; P = .017). Greater reduction (IRR = 0.46; 95% CI = 0.2-0.96; P = .025) was seen at higher levels (>80%) of adherence as determined by return of used study product. The results of CAPRISA 004 provide promising insight into the future of topical ARVs for HIV prevention. However, the topical arm of the VOICE (MTN-003) study investigating daily tenofovir gel use was discontinued early because of lack of efficacy (HR = 0.85, 95% CI = 0.6-1.2).23,24 Differences in dosing strategies (eg, pericoital vs daily administration) may have influenced disparate adherence rates between the 2 studies, which were shown to affect efficacy in the CAPRISA 004 trial. Ongoing studies are investigating additional tenofovir preparations, other ARVs, and novel delivery systems such as vaginal rings.25-28 However, topical ARV formulations are unlikely to be available in the near future because of conflicting

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Li et al Table 1.  Recommendations for Selection of HIV Preexposure Prophylaxis Agents.29 Safe for episodic and chronic use in diverse HIV-uninfected populations Penetrates target tissues Protects against HIV infection in target tissue Long lasting activity in the target tissue for convenient dosing Displays a unique resistance profile and/or a high genetic barrier to resistance No clinically significant interactions with other medications Ideally not included in current treatment regimens Affordable, easy to use and implement

clinical data and lack of a licensed commercial product. Thus, further PrEP trials focused on the development of oral agents.

Ideal Characteristics for Oral PrEP Agents There are several optimal properties for ARV agents used as PrEP (Table 1).29 Since PrEP necessitates ongoing drug exposure in healthy individuals, the most important consideration is safety. Other important properties include adequate penetration and protection against HIV in target tissues and long-lasting activity with convenient dosing. Hypothetically, these agents should have activity before integration of the viral genetic material into the host genome and in both active and resting T-cells to prevent establishment of latent infection.30-32 Selected agents should also possess high barriers to resistance that would both prevent the rapid development of resistance and protect against transmission of resistant viral strains. ARVs with no or limited cross-resistance would also be optimal in the setting of PrEP. Ideally, PrEP agents should not be a component of current HIV treatment regimens in the event that resistance precludes their use for treatment of individuals failing PrEP. Several clinical characteristics of both non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) preclude their use for PrEP, including significant drug interactions and adverse effects.30-33 Agents from both of these classes of ARVs generally achieve lower drug concentrations in the genital tracts of both men and women compared with blood plasma.34 NNRTIs have a low barrier to resistance and significant cross-resistance within the class.35 Although PIs have a higher barrier to resistance, their toxicity profile includes long-term metabolic effects and a mechanism of action involving postintegration phases of the HIV life cycle. Both maraviroc and raltegravir exhibit several ideal characteristics for PrEP, including good tolerability and penetration into genital tissues.36 Maraviroc and raltegravir have demonstrated robust protection against HIV in animal

models, but only maraviroc was further pursued in human studies due to concerns about low barrier to resistance and the need for twice-daily dosing with raltegravir.36,37 Since preclinical studies demonstrated protective efficacy with once-daily dosing of maraviroc, it is currently being studied at 300 mg daily in combination with tenofovir or emtricitabine in the NEXT-PrEP study (HPTN 069).38 Investigational, long-acting parenteral drugs, such as rilpivirine, S/GSK1265744 (an integrase inhibitor), and ibalizumab (an anti-CD4 monoclonal antibody), are also in early phase development as potential PrEP candidates.37 Most of the nucleoside reverse transcriptase inhibitors (NRTIs) achieve adequate concentrations in genital tissues with resistance profiles intermediate to NNRTIs and PIs. Toxicities and increased pill burdens of older NRTIs make them less desirable for prophylaxis in uninfected persons. Of the NRTIs, tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) emerged as the most promising agents for PrEP.31,39 Concentrations of both drugs are detected in cervicovaginal fluid within 2 hours of systemic administration and remain above plasma levels for most of the dosing interval.34 The active phosphate analogues of TDF and FTC reach similar intracellular concentrations in seminal cells, compared with peripheral blood mononuclear cells, with long plasma half-lives (40-150 hours).40,41 TDF and FTC are available as a fixed-dose, once-daily combination tablet (TDF-FTC; Truvada). Both ARVs have minimal potential for drug interactions, as they are not substrates, inhibitors, or inducers of the cytochrome P450 system. For these reasons, TDF-FTC has been further investigated in clinical studies of PrEP in humans.

Clinical Trials for Systemic PrEP Agents Four randomized, placebo-controlled clinical trials evaluating the safety and efficacy of oral daily PrEP have been published (Table 2).42-45 These trials included young healthy subjects from broad patient populations at high risk of acquiring HIV infection. Most subjects enrolled in these trials were from sub-Saharan Africa, with only one study enrolling patients in the United States. All 4 study protocols mandated intensive clinical and counseling procedures. This included monthly HIV testing for early identification of breakthrough infections, regular laboratory testing, and individualized medication adherence counseling (Table 3). PrEP was administered in conjunction with comprehensive HIV prevention services, including counseling on the reduction of high-risk behaviors, screening and treatment of sexually transmitted infections, and continuation of traditional prevention methods (eg, condom use). The iPrEx study enrolled 2499 HIV-negative men who have sex with men (MSM) across 6 countries, with the majority of participants from South American sites and

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Table 2.  Study Design and Results From Published Trials of Preexposure Prophylaxis for HIV. Study

Design

Location

Thigpen et al (2012)44 Baeten et al (2012)45

Phase III, safety and South Africa efficacy (R, PC, DB) Phase III, safety and Brazil, Ecuador, Peru, efficacy (R, PC, DB) South Africa, Thailand, United States Phase III, safety and Kenya, Tanzania, South Africa effectiveness (R, PC, DB) Phase III, safety and Botswana efficacy (R, PC, DB) Phase III, safety and Kenya, Uganda efficacy (R, PC, DB)

Marazzo et al (2013)24,46

Phase III, safety and South Africa, Uganda, efficacy (R, PC, DB) Zimbabwe

Karim et al (2010)22 Grant et al (2010)42 Van Damme et al (2012)43

Population

Intervention Arms

Median Follow-up (Years) b

RR (95% CI); P Value

889 heterosexual women 2499 MSM

Pericoital tenofovir 1% vaginal gela Daily oral TDF-FTC

1.5

39% (6, 60); P = .017

1.2

44% (15, 63); P = .005

2120 heterosexual women

Daily oral TDF-FTC

NRc

6% (−52, 41); P = .81

1219 heterosexual men and women 4758 serodiscordant heterosexual couples 5029 heterosexual females

Daily oral TDF-FTC

1.1

63% (22, 83); P = .01

Daily oral TDF Daily oral TDF-FTC

1.9

75% (55, 87); P < .001d

Daily tenofovir 1% vaginal gel Daily TDF Daily TDF-FTCe

NR

4% (−51, 27); P = NRd

Abbreviations: R, randomized; PC, placebo-controlled; DB, double blind; RR, relative risk; CI, confidence interval; MSM, men who have sex with men; TDF, tenofovir disoproxil fumarate; TDF-FTC, tenofovir–emtricitabine; NR, not reported. a Given as 1 dose 12 hours before sex and second dose after sex and no more than 2 doses in a 24-hour period (BAT24). b Reported as mean years of follow-up. c Recruitment period about 2 years. d TDF-FTC compared with placebo. e Daily tenofovir 1% gel was compared with a placebo gel and daily oral TDF and TDF-FTC was compared with a placebo pill.

Table 3.  Concomitant Preventative Interventions to Tenofovir–Emtricitabine in Published Preexposure Prophylaxis Trials.42-45 Structural interventions   •  Counseling on appropriate and consistent condom use   •  Provision of condom supply at each visit anticipated to last until next visit with counseling to return between scheduled visits if more condoms needed   •  Initial screening for sexually transmitted infections and treatment if indicated   •  Scheduled assessments every 24 weeks for sexually transmitted infections with additional testing as needed Behavioral interventions   •  Monthly adherence counseling and assessments through pill counts and self-reporting   •  Monthly risk reduction counseling and assessments through interviews and structured behavioral questionnaires Laboratory assessments   •  Quarterly plasma samples for drug concentration analysis   •  Monthly HIV testing with rapid antibody test and confirmatory tests if positive in addition to pretest, reduction, and posttest counseling   •  Discontinuation of medication upon positive HIV test with referral and establishment of HIV care, including access to treatment

9% from the United States.42 This trial demonstrated a significant relative risk reduction of 44% (HR = 0.56; 95% CI = 0.34-0.85; P = .005) with daily oral TDF-FTC compared with placebo. Subgroup analyses demonstrated higher rates of efficacy at higher levels of adherence to study medication, determined by counts of unused pills (pill use greater than 90%, HR = 0.27; 95% CI = 0.120.59; P < .001). Analysis of serum drug concentrations showed a similar link with efficacy. Less than 10% of infected individuals had detectable plasma drug concentrations compared with more than 50% of matched subjects who remained HIV-negative. Having detectable serum drug concentrations was also strongly associated

with a lower risk of infection (HR = 0.08; 95% CI = 0.010.6; P < .001). The FEM-PrEP study compared the use of TDF-FTC to placebo in 2120 high-risk, uninfected heterosexual females from Kenya, South Africa, and Tanzania to prevent HIV infection but was terminated early due to futility (HR = 0.94; 95% CI = 0.59-1.52; P = .81).43 Almost all women (99%) reported a primary partner, but 27% also reported sexual encounters with other partners. Although both self-reporting and pill count data suggested high rates of adherence, serum drug analysis revealed consistently detectable concentrations in only 15% and 24% of HIV-positive subjects and HIV-negative controls, respectively. The investigators

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Li et al concluded an inability to accurately assess the efficacy of TDF-FTC on HIV acquisition due to low adherence. The TDF2 study enrolled 1219 high-risk, uninfected heterosexual men and women in Botswana.44 Results from this study demonstrated that TDF-FTC reduced the relative risk of HIV acquisition by 62% (HR = 0.38; 95% CI = 22% to 83%; P = .01). Most subjects (81%) reported one sexual partner in the past month, with about half of subjects reporting more than 5 lifetime partners. Rates of unprotected sex at baseline were low at approximately 20%. Plasma drug concentration analysis revealed significantly lower concentrations in subjects failing PrEP compared with subjects who remained uninfected (TDF, 0.3 vs 30.6 ng/mL, P = .007; FTC, 0.5 vs 103.3 ng/mL, P = .009). There were no differences in efficacy observed between male and female subjects, but the subgroup analyses lacked statistical power for definitive conclusions. The Partners-PrEP study enrolled 4758 predominantly heterosexual serodiscordant couples from Kenya and Uganda and compared TDF-FTC as well as TDF alone with placebo.45 Efficacy analysis revealed relative risk reductions of 67% with TDF (HR = 0.33; 95% CI = 0.19-0.56; P < .001) and 75% with TDF-FTC (HR = 0.25; 95% CI = 0.13-0.45; P < .001), with no difference between the 2 active arms (P = .23). Degree of protection was also similar between genders, with significant reductions for both males (TDF-FTC, HR = 0.16; 95% CI = 0.06-0.46; P < .001) and females (TDF-FTC, HR = 0.34; 95% CI = 0.16-0.72; P = .005). Similar to the other PrEP trials, serum drug analysis revealed higher rates of detection in those remaining HIV-negative (82%) compared to HIV-positive subjects (31%). Detection of tenofovir was associated with substantial protection against HIV (TDF, HR = 0.14, P < .001; TDF-FTC, HR = 0.1, P = .002). Preliminary results from the VOICE trial reported no differences in risk reduction in acquiring HIV among the treatment groups.24 This trial enrolled 5029 heterosexual females from South Africa, Uganda, and Zimbabwe and assessed the safety and efficacy of 1% vaginal tenofovir gel, oral TDF, and oral TDF-FTC. Both the topical and TDF alone arms were discontinued early due to futility (relative risk reduction = −48.8%; HR = 1.49; 95% CI = 0.97-2.29; P = .07). The TDF-FTC arm was continued but also demonstrated no efficacy in protection against HIV infection (relative risk reduction = −4.2%; HR = 1.04; 95% CI = 0.73-1.49; P > .2). In a subgroup analysis, serum or vaginal drug concentrations were detected in 28% of participants randomized to TDF, 29% to TDF-FTC, and 22% to tenofovir gel. Predictors of detectable concentrations were being married and age >25 years. Incidence of HIV in young, unmarried women was 8.8% compared to 0.8% in older, married women.46 Detectable drug concentrations were present in 21% and 54% of women in these groups, respectively. Definitive conclusions from VOICE are pending the final publication of study results.

Translating to Clinical Practice The subjects in these studies represented individuals at substantial risk for acquiring HIV. Most of the MSM in iPrEx engaged in regular unprotected intercourse, with an average of 18 sexual partners over a span of 3 months.42 The HIVnegative partners of serodiscordant couples in PartnersPrEP are at ongoing risk for acquiring HIV, especially if engaging in consistent intercourse with their untreated HIVpositive partners.45 Both TDF2 and FEM-PrEP were conducted in heterosexual populations living in sub-Saharan Africa, where the prevalence of HIV is as high as 20% in some countries.44,45 In high-risk MSM with multiple sexual partners, the prevention of one infection may also avert many more infections downstream in their sexual partners. The benefits of PrEP are likely amplified in serodiscordant couples when the HIV-positive partner remains untreated due to the HIVnegative partner’s inherent risk for acquiring HIV from ongoing exposure. Conversely, the results from the TDF2 study in Botswana are less applicable to countries like the United States where the overall prevalence of HIV is as low as 0.5% to 1%.2 Given the high prevalence rates in many sub-Saharan countries, the probability of encountering an HIV-infected individual is substantial. Additionally, the importance of adjunctive prevention measures should not go unrecognized. Concomitant interventions resulted in an annualized incidence of HIV infection of 2% in the placebo group in Partners-PrEP compared with more than 10% among HIV-serodiscordant couples in sub-Saharan African community settings.13 PrEP with FTCTDF further reduced the incidence to 0.5%. However, the effectiveness of PrEP in the absence of these interventions is uncertain. Despite the promising results from the published PrEP trials, they need to be evaluated in the context of the subjects’ baseline characteristics, risk factors, and the study environment.

Safety of Tenofovir–Emtricitabine Both TDF and FTC have a strong track record of safety in HIV-infected individuals, with rare reports of serious toxicities.47 FTC is relatively well tolerated, with gastrointestinal side effects as the most commonly reported adverse events. Although TDF is also relatively well tolerated, it has been associated with nephrotoxicity that can present as proximal tubular dysfunction with either preserved or decreased renal function.48 Decreased bone mineral density and osteomalacia may result from phosphate wasting and vitamin D deficiency secondary to renal dysfunction.49 Early postmarketing surveillance data from the first 4 years of TDF use in clinical practice have reported an increase in serum creatinine ≥0.5 mg/dL in 2.2% of patients and rates of severe adverse events (eg, acute kidney injury, Fanconi

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syndrome, bone fractures) at less than 0.1%.50 Although 2 more recent studies reported higher rates of nephrotoxicity at 17% to 22%, a meta-analysis estimated the risk difference for acute kidney injury to be 0.7%, with a statistically significant but clinically modest decrease in creatinine clearance of 3.92 mL/min (95% CI = 2.13-5.70 mL/min).5153 Predictors of nephrotoxicity associated with TDF include advanced age, low body weight, preexisting renal dysfunction, concomitant use of nephrotoxic drugs, comorbidities (eg, hypertension, diabetes), and advanced HIV infection.48,49 Longer term drug exposures over a patient’s lifetime may increase their risk of adverse effects, and patients started on TDF should be regularly evaluated for signs of renal dysfunction. Two initial phase II safety studies of PrEP with MSM in the United States and female sex workers in sub-Saharan Africa revealed no short-term differences in the rates of adverse events over a span of 1 year in subjects taking oral TDF and placebo.54,55 Safety data from the 4 published PrEP trials demonstrated a similar safety profile in other uninfected populations. Across all 4 trials, no differences were seen in serious adverse events or laboratory abnormalities defined as grade 3 or higher in subjects receiving TDF-FTC compared with placebo. No additional safety concerns were seen in VOICE.24 However, in iPrEx, there was a small but statistically significant decrease in creatinine clearance associated with TDF-FTC compared with placebo (−2.4 versus −1.1 mL/min; P = .02).56 Also, in TDF2, bone mineral density scores were significantly lower in the TDF-FTC arm, but these differences were small and of unknown clinical significance.44 Fractures after initiation of study treatment occurred in 7 and 6 patients in the TDFFTC and placebo groups, respectively (P = .74). Since adherence was not optimal in all subjects, the low incidence of adverse events may have resulted from low drug exposures. Long-term safety data with drug exposures greater than 2 years are needed.

Adherence Across the 4 published oral PrEP trials, higher levels of adherence translated to greater protection against HIV. Current adherence measures lack a standardized, objective approach, forcing clinicians to rely on subjective measures, such as self-reporting. In FEM-PrEP, subjects reported about 95% adherence to study regimens, but serum drug concentrations were detectable in less than 40% of subjects sampled.43 Subjects in VOICE also reported high rates of adherence but had low levels of detectable drug concentrations.46 Less than 40% of women had detectable plasma TDF at the first study visit, and more than half of subjects did not have TDF detected in any sample. The iPrEx study demonstrated differential effectiveness based on adherence thresholds, with reported pill use greater than 50% and 90%

resulting in relative risk reductions of 50% and 73%, respectively.42 Detectable drug concentrations were strongly correlated with greater prophylactic effects. Both iPrEx and Partners-PrEP demonstrated risk reductions of more than 90% associated with detectable drug concentrations.42,45 In the TDF2 subgroup analysis, drug concentrations were substantially lower in subjects failing PrEP compared with subjects who remained uninfected.44 Similar to the approach in HIV-infected individuals, providers will need to identify barriers to adherence in order to maximize the impact of PrEP. The importance of adherence counseling is highlighted by the results of FEM-PrEP. Most of the female subjects (70%) perceived themselves to be at little to no risk for HIV infection, which may have contributed to low adherence rates.43 These subjects may have also had difficulty with daily pill regimens as suggested by the high pregnancy rate among women prescribed oral contraceptives. Initial data from the VOICE trial suggested that younger, unmarried women were less likely to adhere to product use compared with older, married women, which may reflect differences in beliefs and attitudes about risk for acquiring HIV.24,46 Qualitative studies have demonstrated that persons most willing to start PrEP have the highest risk of acquiring HIV.57,58 However, these individuals also exhibited the lowest self-perceived risk, which may compromise their adherence as observed in FEM-PrEP. Among serodiscordant couples, qualitative data indicate trust and commitment between partners as critical factors influencing adherence.59 These data further emphasize the need to implement PrEP in the setting of strict, ongoing adherence counseling as well as general education about HIV and its transmission. Additional information from 2 qualitative behavioral studies of subjects in VOICE, VOICE-C and VOICE-D, will hopefully provide more insight into community-based factors, beliefs, and attitudes that may have had an impact on young women’s adherence to product use.46 Ongoing demonstration projects, such as the open-label extension of the iPrEx study (iPrEx-OLE), aim to address behavioral characteristics that affect adherence rates in other populations of PrEP candidates.

Risk Compensation Risk compensation has often confounded the introduction of preventative innovations by altering risk perception.60 Advances in technological approaches may diminish a person’s perceived risk, making it more difficult to embrace and continue with fundamental protective measures. For example, the use of seatbelts has been shown to protect participants of motor vehicle collisions, but these benefits may be negated in drivers who presume seatbelts will protect them from more risky driving.61 Individuals taking PrEP may perceive themselves to be at lower risk for acquiring

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Li et al HIV, and consequently become more lax about regular condom use while engaging in more high-risk behaviors. Evidence from other HIV settings has revealed variable risk compensation that is dependent upon not only the perceived magnitude of protection, but also associated drug toxicities and cost of therapy.62,63 Surveys during gay-pride events found that a small percentage of participants had already tried TDF as PrEP in the past.64,65 These practices raise concern about potential for abuse and misuse of TDF-FTC, particularly if widely prescribed for PrEP. In clinical trial settings, there was no evidence of increased high-risk sexual behaviors. Some studies even reported increases in safer sex practices, including significant reductions in unprotected intercourse and the number of sexual partners.42-45 However, these decreases in risk-taking behavior were noted in the setting of intensive monthly risk-reduction counseling as an adjunct to PrEP. The incidence of risk compensation in PrEP users not receiving concurrent risk-reduction counseling is unknown. Similar to issues with adherence measures, there may also be a disconnect between self-reporting and actual sexual practices. The high rate of pregnancy in FEM-PrEP suggests a common occurrence of unprotected intercourse. Qualitative studies of potential PrEP candidates revealed significant differences between their actual and perceived risks for acquiring HIV. These differences were associated with decreased predicted condom use and decreased likelihood to use multiple prevention methods.57,58 These findings again underscore the significance of risk-reduction counseling, in addition to PrEP, as part of a comprehensive prevention program.

Resistance Resistance may impact the effectiveness of PrEP in 2 different ways: decreased efficacy against transmitted resistant virus and development of resistance in PrEP failures. PrEP may only confer partial or limited protection against drugresistant virus, but these concerns may be partially abated by data from animal studies demonstrating protection against TDF- or FTC-resistant virus in mice receiving TDFFTC.66,67 Protection against these variants may be explained by reduced mucosal transmission and viral replicative capacity. The clinical significance of these findings in humans is uncertain and needs to be elucidated. Current prevalence of TDF-resistant virus is unlikely to significantly compromise the efficacy of PrEP but depends on local prevalence of resistance, sexual behaviors, and viral characteristics.68,69 Since TDF-FTC form the NRTI backbone for preferred ART regimens in current treatment guidelines, the emergence of resistance in persons who develop HIV while on PrEP has important implications for treatment of HIV in these individuals. Resistance to TDF, FTC, or both would constrain therapeutic options to

alternative regimens, with the potential for greater toxicities and pill burdens, which may compromise treatment adherence and efficacy. Evidence from the published PrEP trials demonstrated the absence of resistance in individuals that became infected with HIV after enrollment, but this may be a result of low adherence rates.42-45 Since subjects failing PrEP were less likely to be adherent to study regimens, their viral inoculations had minimal drug exposure and thus, limited potential for the emergence of resistance. The impact of intermediate levels of adherence on resistance in persons who become HIV-positive while on PrEP is unknown. Data from the 4 published oral PrEP trials did identify resistance mutations in all 6 subjects who were HIV-positive at baseline and were inadvertently started on PrEP.42-45 The development of resistance in these subjects illustrates the importance of establishing the HIV status of potential PrEP candidates. Resistance mutations will likely emerge in individuals with undetected HIV infections who use PrEP because TDF-FTC alone represents a suboptimal treatment regimen for HIV-infected individuals.

Cost-Effectiveness The combination of TDF-FTC is currently only available as branded Truvada with the average monthly cost ranging from $700 to $900 in the United States.18,70-72 The financial investment may limit the widespread implementation of PrEP but should be weighed against the savings of preventing a lifetime of therapy and care after HIV acquisition. Three evaluations of cost-effectiveness on the implementation of PrEP in MSM populations in the United States demonstrated varying costs per quality-adjusted life years. The most optimistic predictions were seen if PrEP was only implemented in the highest risk MSM (ie, an average of 5 annual partners).70-72 Gilead Sciences, the manufacturer of both TDF and FTC, is partnering with the World Health Organization to provide TDF-FTC (Truvada) at discounted prices of US$26 per month to developing countries.18 The availability of generic formulations of both drugs in the near future may also help reduce medication costs. Despite these decreased drug costs, implementation of PrEP will still require significant fixed costs because of initial training of providers for adequate screening and monitoring, and provision of ongoing counseling. Therefore, the cost-effectiveness of PrEP may ultimately vary depending on drug costs as well as degree and setting of implementation. Preexposure prophylaxis will likely entail significant out-of-pocket expenses for patients. It is unclear at this time if insurance companies will provide coverage for TDF-FTC to HIV uninfected persons due to cost and concerns about real-world effectiveness. If covered by insurance companies, PrEP may require complex approval procedures, such as prior authorization, and significant copays. These factors

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Table 4.  Summary of Recommendations From the Interim CDC Guidance on the Use of PrEP in MSM and Heterosexual Adults.74,75 Screening procedures for eligibility   •  Document negative antibody test immediately before starting PrEP   •  Test for acute HIV in persons with symptoms or recent unprotected sex with an HIV-positive person   •  Confirm substantial, ongoing, very high risk for acquiring HIV infection   •  Confirm adequate renal function (CrCl >60 mL/min)   •  Determine pregnancy and breastfeeding status of women and disclose that safety in infants exposed not fully assessed but no harm has been reported   •  Screen for HBV infection and vaccinate if susceptible or treat if active infection exists   •  Screen and treat for STIs Initiating PrEP   •  Prescribe no more than 90-day supply of TDF-FTC 300-200 mg daily renewable only after HIV testing confirms patient remains HIV-uninfected and pregnancy testing confirms patient is not pregnant   •  Consider using TDF-FTC as treatment for HBV infection as well as prevention of HIV if diagnosed with active infection   •  Provide risk-reduction and medication adherence counseling as well as condoms Follow-up (every 2-3 months unless otherwise noted)   •  Perform HIV antibody test and document negative result   •  Perform pregnancy test and document results as well as discussing continued use of PrEP with patient and prenatal care provider if pregnant   •  Evaluate and support medication adherence (more often than 2-3 months if needed)   •  Assess risk behaviors and provide risk-reduction counseling as well as condoms   •  Assess for STI symptoms and test and treat as needed, if present   •  Test for STIs even if asymptomatic every 6 months and treat as needed   •  Assess renal function by CrCl 3 months after initiation and every 6 months thereafter Discontinuing PrEP (at patient request, for safety concerns, or if patient becomes HIV positive)   •  Perform HIV tests to confirm whether HIV infection has occurred   •  If HIV positive, test and document resistance and establish linkage to HIV care   •  If HIV negative, establish linkage to risk-reduction support services as indicated   •  If active hepatitis B diagnosed at initiation, consider appropriate medication for continued treatment of HBV   •  If pregnant, inform prenatal-care provider of use of TDF-FTC early in pregnancy and coordinate care to maintain HIV prevention measures during pregnancy and breast-feeding Abbreviations: PrEP, preexposure prophylaxis; MSM, men who have sex with men; CDC, Centers for Disease Control and Prevention; CrCl, creatinine clearance; HBV, hepatitis B virus; STI, sexually transmitted infection; TDF-FTC, tenofovir–emtricitabine.

may diminish the uptake of PrEP among potential candidates at high risk for acquiring HIV.

Centers for Disease Control and Prevention Guidance and Providers’ Roles for PrEP In July of 2012, the Food and Drug Administration approved the use of TDF-FTC (Truvada) 300-200 mg daily for the prevention of HIV, in combination with safer sex practices, in sexually active adults at high risk for acquiring HIV through sexual transmission.73 The updated package insert further emphasizes the need for adjunct prevention methods, strict adherence counseling, and documentation of negative HIV status prior to beginning PrEP. The Centers for Disease Control and Prevention (CDC) interim guidance provides recommendations on the appropriate and effective implementation of PrEP in high-risk individuals at risk for sexual acquisition of HIV (Table 4).74,75 The interim guidelines also include suggestions for baseline evaluations as well as monitoring parameters and counseling throughout therapy.

Although the interim guidance from the CDC recommends the use of PrEP in high-risk persons, these guidelines do not clearly delineate high-risk characteristics. Individuals most likely to benefit from PrEP include candidates similar to the subjects in the current studies. These populations may include MSM with multiple sexual partners engaging in unprotected intercourse and serodiscordant couples planning to conceive or in which the HIV-positive partner remains untreated. Current recommendations for safer conception in serodiscordant couples include non-intercourse insemination, sperm washing, and initiation of ART in the HIV-positive partner.76 Periconception PrEP represents an additional modality to reduce the risk of HIV transmission in couples wanting to conceive that may not have access to these methods. Additional benefits of combining PrEP with treatment of the HIV-positive partner are currently unclear. For heterosexuals, the use of PrEP will likely have the greatest impact in regions with a high prevalence of HIV (eg, sub-Saharan Africa) compared with countries with low prevalence (eg, the United States). Data from the FEMPrEP and VOICE trials raise significant concerns about the

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Li et al use of PrEP in females, but these studies were conducted in women from sub-Saharan Africa with suboptimal adherence. Whether similar concerns about effectiveness translate to high-risk females in the United States remains uncertain and may be clarified by ongoing demonstration projects. Some of the primary functions of pharmacists include adherence counseling, identification of drug–drug interactions, monitoring for adverse drug events, provision of patient education, and simplification of medication regimens. Although regimens may not be as complex in individuals receiving PrEP compared with HIV-infected persons on ART, the need for intensive counseling and monitoring of adherence remains critical to the appropriate use of PrEP. Pharmacists are well equipped to help realize successful implementation of this strategy.77 To effectively promote adherence, methods should be individualized based on specific patient barriers. Direct patient interactions with clinical pharmacists can significantly affect a patient’s knowledge, medication adherence, and quality of life.78 Adherence-enhancing instruments at a pharmacist’s disposal traditionally include pill boxes, refill reminders, medication schedules, alarms and beepers, and medication diaries. Newer technologically based tools include smartphone applications and text message reminders. Additional clinical activities include individualized patient counseling and education, and incorporating medication regimens into a patient’s daily routine to more effectively promote adherence. Since the efficacy of PrEP is strongly correlated with adherence rates, pharmacists will likely play a major role in the successful implementation of PrEP. After careful selection of candidates for PrEP, pharmacists should appropriately counsel and educate these patients.

Conclusion Preexposure prophylaxis represents the newest biomedical intervention used to combat the HIV/AIDS epidemic, but it should not be considered a panacea to prevent HIV transmission. The success of current PrEP methods will be constrained by rates of adherence, degree of risk compensation, emergence of resistance, and resource limitations. PrEP should likely be reserved for high-risk individuals with ongoing exposure to HIV, such as serodiscordant couples in which the HIV-positive partner is either unwilling or unable to start ART, high-risk MSM, or serodiscordant couples planning pregnancy. PrEP functions as part of a comprehensive package and should be initiated in conjunction with other preventative measures. Other components should include regular monitoring for HIV status, and screening and treatment of sexually transmitted diseases. Additional studies are investigating the use of alternative dosing schedules (eg, intermittent or pericoital

dosing), other agents for PrEP, and its use in other populations, including intravenous drug users. Demonstration projects will also provide further insight into several important issues surrounding the widespread use of PrEP and hopefully address some of the concerns regarding real-world effectiveness of PrEP. If used appropriately, PrEP has the potential to augment reductions in the current incidence of new HIV infections, and pharmacists will have an important role in the careful selection and counseling of these targeted populations. Acknowledgments We would like to thank James S. Lewis II, PharmD, FIDSA, for his critical review of this article.

Authors’ Note The content of this publication is the sole responsibility of the authors and does not necessarily reflect the views or policies of the Department of Veteran Affairs, Department of Defense, or the Departments of the Army, Navy, or Air Force.

Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

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