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INVITED ARTICLE HIV/AIDS Kenneth H. Mayer, Section Editor Preexposure Prophylaxis for Adolescents and Young Adults at Risk for HIV Infection: Is an Ounce of Prevention Worth a Pound of Cure?

Jill E. Pace, George K. Siberry, Rohan Hazra, and Bill G. Kapogiannis Pediatric, Adolescent and Maternal AIDS Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (See the Editorial Commentary by Mayer and Zanoni on pages 1156–8.) An alarming proportion of incident human immunodeﬁciency virus (HIV) infections worldwide occur in youth. In the United States, 69% of all new infections among youth occurred in young men who have sex with men (YMSM). Recent studies show the promise of preexposure prophylaxis (PrEP) for preventing HIV infection, but research efforts suffer from disproportionately low representation of the youth who are most at risk. Youth-focused research is critical and should include behavioral, community, and biomedical interven- tions to create a comprehensive HIV prevention package. The many ethical, legal, and regulatory consider- ations in conducting HIV research among, and in providing care services to, youth must be addressed so that those at high risk and most likely to beneﬁt can have unfettered access to safe and effective health-promoting interventions. YMSM and minority youth are at substantial HIV risk and urgently need effective HIV preven- tion tools for which the short and long-term beneﬁts and risks have been carefully considered.

Keywords.HIV prevention; adolescents and young adults; preexposure prophylaxis; PrEP.

An alarming proportion of incident HIV infections worldwide occur in adolescents and young adults. The United Nations Joint Programme on HIV/AIDS (UNAIDS) estimates that 5 million youths are living with HIV worldwide. In 2008, there were approxi- mately 920 000 new infections among youth, or 2500 new infections per day [1]. Although data show that young people now practice safer sex and experience a lower incidence of infection with human immunodeﬁ- ciency virus (HIV), UNAIDS reports a global resur- gence of the epidemic in men who have sex with men (MSM) [2].In the United States, the epidemic disproportionately impacts racial and ethnic minorities. The HIV inci- dence rate is nearly 8 times higher in blacks and 3 times higher in Hispanics compared to that in whites [3].

Even more disparate are the epidemic’s effects on vul- nerable youth and minority MSM populations. Youth aged 13–29 years accounted for 39% of incident HIV infections in 2009 [3]. More than two-thirds (69%) of all new youth infections occurred in young MSM (YMSM) [3]. Among young black MSM (BMSM), new HIV infections increased 48% during 2006–2009 [3].

Typical adolescent risk-taking behaviors do not explain the disproportionate rates of HIV infection among BMSM [4–6]. BMSM are less likely to be aware of their HIV serostatus or to get tested, suggesting that disparities in access to and quality of care may also play a role [4–6].

Recent studies have shown promise for prevent- ing HIV infections. Two studies in Africa, Partners PrEP and TDF2, enrolled HIV-serodiscordant couples and HIV-uninfected, sexually active women and men, Received 9 July 2012; accepted 26 October 2012; electronically published 7 December 2012.

Correspondence: Bill G. Kapogiannis, MD, FAAP, Center for Research for Mothers and Children, Pediatric, Adolescent and Maternal AIDS Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6100 Executive Blvd, Rm 4B11J, Bethesda, MD 20892-7510 ([email protected]).

Clinical Infectious Diseases 2013;56(8):1149–55 Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2012.

DOI: 10.1093/cid/cis1020 HIV/AIDS CID 2013:56 (15 April ) 1149 respectively [7,8]. Both studies demonstrated safety and efﬁcacy in reducing HIV risk in both women and men who received preexposure prophylaxis (PrEP) as tenofovir disoproxil fuma- rate (TDF) or as coformulated TDF and emtricitabine (FTC), known as FTC/TDF and commercially as Truvada [7,8].

The Iniciativa Proﬁlaxis Pre-Exposición (iPrEx) study found that daily FTC/TDF as PrEP was an effective and well- tolerated intervention to prevent HIV infection in MSM and transgender women [9]. This phase III clinical trial also high- lighted the importance of adherence: the protective efﬁcacy was 44% overall but increased to 92% in those with detectable drug levels [9]. There are several limitations of the iPrEx study. The study population was not fully representative of the epidemic in the United States. The majority of the participants were from South America, with only 10% from the United States, making it difﬁcult to determine the effects of the inter- vention at the US trial sites speciﬁcally [9]. The limited number of US minority participants, youth, and particularly minority youth participants in iPrEx did not proportionally reﬂect the epidemic in the United States (Figure 1A)[3,9].

Despite the promising results of studies of PrEP in several at-risk populations, including serodiscordant couples, HIV- uninfected and sexually active women and men, and MSM [7–9], none of these studies has included adequate representation of youth (Figure1A).

Relative to their contribution to new HIV infections, youth are underrepresented in prevention research, particularly for biomedical intervention studies. This disparity is especially pronounced for youth under 18 years of age (Figure1B). The Adolescent Medicine Trials Network for HIV/AIDS Interven- tions (ATN), sponsored by the Eunice Kennedy Shriver Na- tional Institute of Child Health and Human Development (NICHD), is addressing this gap through an ambitious domes- tic PrEP research and implementation agenda for youth at risk for HIV infection.

RESEARCH IN YOUTH POPULATIONS Behavioral Interventions for HIV Risk Reduction Are Important Components of a Comprehensive Prevention Package for Youth Combination HIV prevention is a blend of evidence-based be- havioral, structural, and biomedical prevention strategies adapted for speciﬁccontexts[10,11] and is recognized as one of the best hopes for reducing and eliminating HIV worldwide [12].

Behavioral HIV prevention interventions are effective in re- ducing risky behavior and decreasing acquisition of HIV and other sexually transmitted infections (STIs) among high-risk populations [13,14]. Such interventions address several domains, including mental health, medical adherence, and HIV risk. The Centers for Disease Control and Prevention’s (CDC) HIV/AIDS Prevention Research Synthesis project has Figure 1.HIV prevention research infrastructure vs needs.A, Partici- pant demographic characteristics in recent human immunodeﬁciency virus (HIV) preexposure prophylaxis (PrEP) studies. The purple bar shows the total participant sample for each study. The red bar shows the number of participants who were between 18 and 25 years of age. The green bar shows the number of participants who were younger than 18 years. The blue bar shows the number of US participants. In the iPrEX study, partici- pants included men who have sex with men or transgender females who have sex with men; among the 28 US participants younger than 25 years, 5 were black/African American; 9% of the total participants (n = 214) were black, including African Americans, Afro Peruvians, Afro Brazilians, and black South Africans; sites were located in South America, South Africa, Thailand, and the United States. In the TDF2 study, participants included males and females; sites were located in Botswana. In the Part- ners PrEP study, participants included males and females; sites were located in Uganda and Kenya; total participant sample (purple bar) in- cludes only the susceptible partner.B, HIV infections and HIV prevention research funding for youth. Age ranges for youth differ owing to different deﬁnitions of youth used by database sources (ie, Centers for Disease Control and Prevention [CDC], National Institutes of Health [NIH], World Health Organization, and Joint United Nations Programme on HIV/AIDS).

The blue bars show the proportion of HIV infections among youth in a given age stratum during the year for which the report was published.

The green bars show the proportion of HIV research funding from NIH during the year 2010, for HIV prevention research (includes biomedical ) or only HIV biomedical prevention research, among youth in a given age stratum. Based on available data and statistical methods, CDC incident estimates do not allow for a stable HIV incidence estimate of youth younger than 18 years (third bar from bottom); given the age of this group and of expected sexual debut, it is likely that HIV prevalence data are a reasonable approximation of HIV incidence. Abbreviations: CDC, Centers for Disease Control and Prevention; HIV, human immunodeﬁciency virus. 1150 CID 2013:56 (15 April) HIV/AIDS recommended behavioral interventions that range from inten- sive one-on-one counseling to group sessions to standard risk- reduction counseling [15]. The identiﬁed interventions are ranked by tiers of evidence, creating a framework for classifying HIV behavioral interventions, from those with the most robust evidence to unevaluated interventions [16]. For research on the implementation of HIV biomedical prevention interventions, particularly in vulnerable youth, it is essential to include at least 1 established behavioral intervention to determine the most effective strategy to support participants. Larger trials may have the capacity to compare 2 or more behavioral ap- proaches. Such research will identify psychosocially, develop- mentally, and culturally relevant behavioral interventions with demonstrated real-world feasibility among high-risk youth.

Community Prevention Infrastructure Is Critical to the Successful Conduct of HIV Prevention Interventions in Youth There is a growing awareness among researchers that commu- nities in large urban settings with access to minority at-risk youth provide an invaluable opportunity for HIV prevention interventions, such as those at the structural level [17–21].

NICHD has sponsored, through the ATN, a novel and prom- ising community-level approach to studying HIV risk reduc- tion interventions [17,22]. Forming community coalitions, expanding existing community advisory structures, and edu- cating parents and adolescents at a community level provide an infrastructure to implement HIV prevention interventions and to create positive structural change within communities to lower rates of HIV infection [17,22]. Engaging communities in HIV prevention research can help scientists prioritize and tailor research and interventions to speciﬁc community needs and can increase effectiveness and dissemination of new HIV prevention strategies.

Communities may also pose barriers to prevention imple- mentation, such as mistrust of research, a lack of perceived advantages to participating in clinical trials, and perceived stigma associated with participation [23]. On the other hand, communities also can help remove barriers to less accessible populations and can generate support for research and inter- ventions [17,23]. They should be educated on the importance, need, and limitations of current HIV prevention, care, and re- search services, particularly for adolescents and young adults, in advance of implementing interventions [17]. Relevant edu- cational materials should focus on topics and concepts that are key to HIV research (eg, clinical research and ethics) and should be effective in communicating the intended messages readily to the target audience.

Interim CDC Guidance for Preexposure Prophylaxis in MSM A comprehensive review of PrEP implementation guidelines is beyond the scope of this review. Based on the results of iPrEXstudy, the CDC released interim guidance on PrEP for the prevention of HIV infection in MSM [24].

This interim guidance does not address age, but theﬁnal implementation recommendations are likely to be limited to populations who have attained the age of majority and are to be consistent with the Food and Drug Administration (FDA) labeling of Truvada, approved by the FDA for an HIV preven- tion indication. In the future, as guidance for PrEP in YMSM and other youth is formulated, agencies should consider ad- dressing relevant issues such as the ethical considerations around PrEP in youth and the unique struggles that YMSM and minority youth experience around identiﬁcation, testing, linkage to care, and adherence. The prevention research com- munity, including members with youth expertise, must work closely with healthcare implementation programs and regula- tors to develop guidance for use of PrEP in minors.

ETHICAL CONSIDERATIONS IN RESEARCH WITH YOUTH Regulations Protect Vulnerable Populations but Can Prevent Their Access to and Participation in Important Prevention and Treatment Research Human subjects research ethical guidelines and regulations provide special protections for research participants who have not reached the age of majority, a concept that is well accept- ed [25]. An extension of this concept is the principle that en- suring access of minors to appropriate research is necessary to protect this group from widespread use of therapies that have never been adequately tested in them. It is likely that PrEP will be used widely in minors at high risk of HIV acquisition.

Maximizing the safety and effectiveness of this intervention in minors will require ethically sound, scientiﬁcally rigorous studies in this group. Extrapolation from studies of PrEP in white, adult MSM may not be appropriate for predicting PrEP effectiveness in YMSM and BMSM. Sociocultural, hormonal, and many other differences require studies speciﬁcally in this population.

An average 17-year-old BMSM is clearly different from a middle-aged, white MSM but differs little from an average 19- year-old BMSM; however, under US human subjects research regulations, there is a great distinction between these 2 teenag- ers. A competent 19-year-old is allowed to consent for partici- pation in research, whereas a 17-year-old routinely requires parental permission to do so [26]. There are 2 exceptions: (1) waiver of parental permission and (2) local laws that allow a minor to consent for certain protected conditions (eg, STI treatment) without parental permission [26]. One drawback of the waiver of parental permission approach is that different IRBs (in a multicenter trial ) may reach discordant conclusions about whether requirements for the waiver are met. Another HIV/AIDS CID 2013:56 (15 April ) 1151 important consideration is that the FDA regulations do not allow waiver of parental permission, and therefore, FDA- monitored studies (Investigational New Drug studies) cannot include parental waiver of permission [27].

A more consistent approach to establishing the right of ad- olescents to consent to their participation in HIV prevention research should be considered. Efforts would be needed to work with local authorities at each clinical site to establish a more regular determination for criteria for adolescents to consent to participate in research within the parameters of local laws. In jurisdictions where local law precludes the right of adolescents to consent for participation, there is a need for policy level discussions within the local community.

In the US, local jurisdictions determine the criteria under which minors can consent to receivetreatmentfor certain conditions. With the exception of contraception and some STI prevention, the ability of minors to consent for themselves to receive care for thepreventionof a condition like HIV infec- tion, whether for research or clinical practice, has been less well established. Implementation guidelines, based on the evi- dence of efﬁcacy for PrEP among MSM, are not expected to include in their scope a policy focused on prevention for minors—a major group that would stand to beneﬁt from such intervention. To ensure timely and safe access to PrEP for minors, it is essential that policy makers, providers, communi- ty members, and other opinion leaders and stakeholders begin addressing this tremendous gap in HIV prevention efforts.

Similar engagement will be necessary with international policy makers, taking into consideration their regional regulatory landscape and perhaps an even greater epidemiologic burden of HIV infections among youth.

IMPLICATIONS FOR PrEP IN YOUTH YMSM and Minority Youth Are at Substantial HIV Risk The interim CDC guidance recommends that PrEP be consid- ered in populations that are at substantial, ongoing, and high risk of HIV infection [24]. In the United States, the overwhelm- ing majority of new adolescent HIV infections are due to sexual activity [3,28]. Despite the recommendation for routine HIV testing, most youth, particularly YMSM and minority youth, who report risky behaviors do not get tested and many experience a multitude of social, behavioral, and economic challenges that impede their identiﬁcation for services and re- search [29]. Even if at-risk youth can successfully be identiﬁed for services or research, adherence to medication may be difﬁ- cult [30]. PrEP studies have illustrated the impact of adherence on effectiveness and shown that adherence to antiretrovirals (ARVs) for prevention or treatment is suboptimal among many populations, including MSM and youth [31,32]. Given adolescent risk behaviors and domestic HIV epidemiology,researchers, policy makers, and community leaders should con- sider deﬁning sexually active adolescents, including minors, as a population at substantial, ongoing, and high risk of HIV in- fection and should develop HIV prevention efforts that focus on youth, particularly among those most vulnerable racial and ethnic minorities and YMSM. Toxicity Potential of ARVs in Youth May Have Implications for Feasibility The potential immediate and longer-term complications of ARVs must be deliberated when considering PrEP interven- tion. The immediate adverse effects of TDF-FTC, such as nausea, vomiting, and headaches, have been better character- ized in adults than in adolescents but are expected to be rela- tively mild, reversible, and not to lead to discontinuation [7–9].

Renal toxicity, related to the TDF component of TDF-FTC, though uncommon, can be detected through routine monitor- ing of serum creatinine and urinalysis, and is generally revers- ible upon discontinuation in adults receiving treatment for HIV infection or PrEP [33]; data are more limited about renal safety of TDF in youth, especially in those youth using TDF as part of PrEP.

An area of special concern for use of TDF-FTC as PrEP in youth is the potential for adverse effects on bone. Bone mineral density (BMD) loss and potential increased fracture risk have been associated with antiretroviral therapy (ART; es- pecially TDF) use in HIV-infected adults in some, but not all, studies [34–36]. More limited data raise concerns that TDF may have greater adverse effects on still-developing bones of HIV-infected children and adolescents [37,38]. The contribu- tions of HIV infection itself, and other factors, make it difﬁ- cult to extrapolateﬁndings in HIV-infected populations to potential TDF effects on bones of HIV-uninfected PrEP recip- ients. Studies show that adult MSM participating in PrEP trials have exhibited a small but statistically signiﬁcant decline in BMD [39]. Youth may be more vulnerable to greater adverse bone effects of TDF-containing PrEP because BMD normally continues to increase into the third decade of life.

To better inform guidance on implementation of PrEP among younger populations, studies should be grounded on an ac- ceptable level of risk vs beneﬁt by taking into careful consider- ation toxicities of ARVs, and should evaluate appropriate immediate and longer-term safety signals in carefully designed licensure bridging studies that ideally also determine the ap- propriate indications for initiation and duration of PrEP among youth.

Additional Considerations: Postexposure Prophylaxis vs PrEP The CDC interim guidance does not address the use of post- exposure prophylaxis (PEP) in coordination with a PrEP regimen. In practice, ARVs prescribed as PrEP may be taken 1152 CID 2013:56 (15 April) HIV/AIDS by users only after a high-risk exposure (similar to PEP), par- ticularly by youth who may least recognize the difference between these prevention strategies. More data are required to understand the need for and implications of PEP in someone who is already prescribed PrEP. Accordingly, for adolescents who may be participating in PrEP trials, the ethics and scien- tiﬁc implications of adolescents using PrEP ARVs for PEP should also be carefully considered in protocol design. The extent of risk compensation (behavioral disinhibition) that may emerge among youth who will be receiving PrEP remains to be determined in ongoing research by iPrEx investigators.

Real-world demonstration projects will likely offer the most reliable estimates of this phenomenon. Researchers need to examine the current PrEP platform and identify areas of concern for participants to best understand how individuals will take these agents in the real world so that only the most promising research strategies are advanced into these clinical trials [40].

Priorities for PrEP Studies in YMSM and Minority Youth There are several priorities for upcoming PrEP studies in YMSM and minority youth. First, bridging studies that explore tolerability and longer-term safety related to potential side effects and long-term consequences of PrEP should be conducted. Second, demonstration projects in urban centers with large YMSM and minority youth populations will be in- tegral in determining how best to identify and recruit this hard-to-reach group, and how to optimally implement PrEP.

This includes feasibility studies that look at the most effective models and places to implement PrEP for youth. Third, studies on supporting adherence in youth, with a focus on the potential for risk compensation, should be prioritized.

Cost-effectiveness Varies by Geographic HIV Incidence Density Studies of cost-effectiveness of PrEP using mathematical models and various assumptions [41–44] have shown that PrEP is most cost-effective when it is targeted to populations with a higher baseline incidence, where there are more infec- tions to avert, and where ART coverage is low [42–44]. In South Africa, PrEP was the most cost-effective when targeted to 25- to 35-year-old women. The study assumed a baseline incidence of 0.8% per year with a low ART coverage rate [44].

In this particular population, the cost per infection averted using PrEP was estimated to be as low as US$12 000 [44].

Importantly, as ART coverage expands throughout the pop- ulation, the cost per infection averted with PrEP dramati- cally increases and its cost-effectiveness as an intervention decreases [44]. Modeling shows that PrEP appears to have a window of opportunity to be most cost-effective during the time when the incidence is high and the ART coverage remains low, making PrEP ideal for low-resource settings [44].In the United States, a recent cost-effectiveness study of daily PrEP among the MSM population predicted a cost of US $298 000 per year of life gained [42,43]. This estimate was based on the current treatment cost of Truvada and estimates of PrEP efﬁcacy [42,43], with a background HIV incidence of 1.6 events per 100 person-years. The estimate also assumes the cost of treating incident HIV to be between US$1139 and $3338 per month, depending on the ARV regimen [43]. The study concludes that the high cost per year of life gained would make PrEP a less cost-effective intervention option for the United States [42,43]; however, should drug costs di- minish or if the targeted population were at higher risk, the intervention would be made more cost-effective [42]. Epidemi- ological data suggest that MSM, YMSM, and BMSM popula- tions are at an increasing risk for infection [3,4,6], making them an appropriate population for targeted PrEP. In this group, the most cost-effective strategy is to initiate PrEP among the highest-risk MSM [41,42]. Provision of PrEP for all high-risk MSM (average of 5 partners per year) would cost approximately US$50 000 per quality-adjusted life-years (QALYs) gained, compared to US$172 091 per QALY gained if only 20% of all MSM (any risk) receive PrEP and US $216 480 per QALY if all MSM receive PrEP [41]. Using PrEP as an intervention in the populations highest at risk is the most cost-effective and is more appropriate for resource- sufﬁcient settings. Given the expense of PrEP and the high- risk youth populations most likely to beneﬁt, youth will need to rely on access via both public and private insurance pro- grams; however, careful coordination with insurance compa- nies at the local level will be important to ensure that conﬁdentiality is managed in accordance to the patient’s wishes [45].

CONCLUSIONS Although the HIV/AIDS epidemic is stabilizing for many groups, adolescents, YMSM, blacks, and other minority popu- lations continue to be at high risk. PrEP studies, despite their limited generalizability to US minority youth, have shown ex- citing promise in the prevention of new HIV infections among MSM. PrEP should continue to be explored in combi- nation biomedical and behavioral clinical trials that focus on vulnerable populations. Such trials should account for appro- priate psychosocial and developmental factors that affect the levels of adherence necessary for effectiveness. A prevention platform grounded in community education and engagement will best enable research interventions on PrEP for adolescents and young adults. Ethical issues of informed consent for ado- lescents under the age of 18 and the ability for adolescents to make informed decisions should be explored and a dialogue begun with regulators to address policy-level changes needed HIV/AIDS CID 2013:56 (15 April ) 1153 to ensure that these most vulnerable youths have access to ef- fective HIV prevention research and care as they emerge.

PrEP has important implications for YMSM and minority youth in the United States because of their high risk of HIV acquisition. These implications include the much-needed beneﬁt of preventing new infections, weighed carefully against the potential for harm from issues such as risk of ARV toxici- ty among healthy individuals, downstream disinhibition of risk behaviors, surreptitious and/or inappropriate use of PrEP, and barriers to proper access of what may likely become a popular HIV prevention method. These considerations and the need for newer, less expensive, safer, and more efﬁcacious PrEP regimens notwithstanding, an ounce of combination prevention is quite deﬁnitely worth a pound of cure. The current alternative possibility of acquiring lifelong HIV infec- tion is unacceptable.

Notes Acknowledgments.We thank Dr Lynne Mofenson for her thoughtful review and valuable guidance in helping produce this manuscript.

Disclaimer.The comments and views of the authors do not necessar- ily represent the views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Financial support.This work was completed as part of ofﬁcial federal government duties of all authors.

Potential conﬂicts of interest.All authors: No reported conﬂicts.

All authors have submitted the ICMJE Form for Disclosure of Potential Conﬂicts of Interest. Conﬂicts that the editors consider relevant to the content of the manuscript have been disclosed.

References 1. Joint United Nations Programme on HIV/AIDS. UNAIDS annual report 2009: uniting the world against AIDS, 2009. Geneva, Switzer- land: UNAIDS;2009.

2. Joint United Nations Programme on HIV/AIDS. Global report:

UNAIDS report on the global AIDS epidemic, 2010. Geneva, Switzer- land: UNAIDS;2010.

3. Prejean J, Song R, Hernandez A, et al. Estimated HIV incidence in the United States, 2006-2009. PLoS One2011; 6:e17502.

4. Flores SA, Bakeman R, Millett GA, Peterson JL. HIV risk among bi- sexually and homosexually active racially diverse young men. Sex Transm Dis2009; 36:325–9.

5. Millett GA, Flores SA, Peterson JL, Bakeman R. Explaining disparities in HIV infection among black and white men who have sex with men: a meta-analysis of HIV risk behaviors. AIDS2007; 21:2083–91.

6. Millett GA, Peterson JL, Wolitski RJ, Stall R. Greater risk for HIV infection of black men who have sex with men: a critical literature review. Am J Public Health2006; 96:1007–19.

7. Baeten J, Celum C. Antiretroviral pre-exposure prophylaxis for HIV-1 prevention among heterosexual African men and women in Botswana:

the Partners PrEP study. Rome, Italy: IAS,2011.

8. Thigpen MC, Kebaabetswe PM, Smith DK, et al. Daily oral antiretro- viral use for the prevention of HIV infection in heterosexually active young adults in Botswana: results from the TDF2 study. Rome, Italy:

IAS,2011.

9. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophy- laxis for HIV prevention in men who have sex with men. N Engl J Med2010; 363:2587–99.10. Coates TJ, Richter L, Caceres C. Behavioural strategies to reduce HIV transmission: how to make them work better. Lancet2008; 372:

669–84.

11. Metzger DS, Navaline H. HIV prevention among injection drug users:

the need for integrated models. J Urban Health2003; 80(4 suppl 3):

iii59–66.

12. Marshall B, Evan W. Toward a comprehensive approach to HIV pre- vention for people who use drugs. J Acquir Immune Deﬁc Syndr 2010; 55:S23–6.

13. Crepaz N, Lyles CM, Wolitski RJ, et al. Do prevention interventions reduce HIV risk behaviours among people living with HIV? A meta- analytic review of controlled trials. AIDS2006; 20:143–57.

14. Semaan S, Kay L, Strouse D, et al. A proﬁle of U.S.-based trials of behavioral and social interventions for HIV risk reduction. J Acquir Immune Deﬁc Syndr2002; 30(suppl 1):S30–50.

15. Centers for Disease Control and Prevention. Diffusion of evidence based interventions. Available at:http://www.effectiveinterventions.

org/en/interventions.aspx. Accessed 12 December 2012.

16. Centers for Disease Control and Prevention. Tiers of evidence: a framework for classifying HIV behavioral interventions. Available at:

http://www.cdc.gov/hiv/topics/research/prs/tiers-of-evidence.htm. Ac- cessed 12 December 2012. 17. Ellen JM, Wallace M, Sawe FK, Fisher K. Community engagement and investment in biomedical HIV prevention research for youth: ra- tionale, challenges, and approaches. J Acquir Immune Deﬁc Syndr 2010; 54(suppl 1):S7–11.

18. Jaspan HB, Cunningham CK, Tucker TJ, et al. Inclusion of adolescents in preventive HIV vaccine trials: public health policy and research design at a crossroads. J Acquir Immune Deﬁc Syndr2008; 47:86–92.

19. Kapogiannis BG, Handelsman E, Ruiz MS, Lee S. Introduction: paving the way for biomedical HIV prevention interventions in youth. J Acquir Immune Deﬁc Syndr2010; 54(suppl 1):S1–4.

20. MacQueen KM, Karim QA. Practice brief: adolescents and HIV clini- cal trials: ethics, culture, and context. J Assoc Nurses AIDS Care2007; 18:78–82.

21. McClure CA, Gray G, Rybczyk GK, Wright PF. Challenges to con- ducting HIV preventative vaccine trials with adolescents. J Acquir Immune Deﬁc Syndr2004; 36:726–33.

22. Ziff MA, Willard N, Harper GW, Bangi AK, Johnson J, Ellen JM.

Connect to protect researcher-community partnerships: assessing change in successful collaboration factors over time. Glob J Communi- ty Psychol Pract2010; 1:32–9.

23. DiClemente RJ, Ruiz MS, Sales JM. Barriers to adolescents’participa- tion in HIV biomedical prevention research. J Acquir Immune Deﬁc Syndr2010; 54(suppl 1):S12–7.

24. Centers for Disease Control and Prevention. Interim guidance: preex- posure prophylaxis for the prevention of HIV infection in men who have sex with men. MMWR Morb Mortal Wkly Rep2011; 60:65–8.

25. 45 CFR 46. Human subjects protection. Washington, D.C.: Depart- ment of Health and Human Services;2009.

26. 45 CFR 46 Subpart D. Additional protections for children involved as subjects in research. Washington, D.C.: Department of Health and Human Services;2009.

27. 21 CFR 50. Protection of human subjects. Washington, D.C.: Food and Drug Administration;2012.

28. Eaton DK, Kann L, Kinchen S, et al. Youth risk behavior surveillance— United States, 2009. MMWR Surveill Summ2010; 59:1–142.

29. Wilcox RD. Identiﬁcation of HIV-infected youth and linkage to care can be major challenges. HIV Clin2012; 24:1–2.

30. Woods JL, Shew ML, Tu W, Ofner S, Ott MA, Fortenberry JD. Pat- terns of oral contraceptive pill-taking and condom use among adoles- cent contraceptive pill users. J Adolesc Health2006; 39:381– 7.

31. Kahana SY, Rohan J, Allison S, Frazier TW, Drotar D. A meta-analysis of adherence to antiretroviral therapy and virologic responses in HIV- infected children, adolescents, and young adults. AIDS Behav2012 [Epub ahead of print]. 1154 CID 2013:56 (15 April) HIV/AIDS 32. Mayer KH. Antiretrovirals and HIV prevention: new insights, chal- lenges, and new directions. Curr Opin HIV AIDS2012; 7:495–7.

33. Hammer SM, Eron JJ Jr., Reiss P, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society–USA panel. JAMA2008; 300:555–70.

34. Brown TT, McComsey GA, King MS, Qaqish RB, Bernstein BM, da Silva BA. Loss of bone mineral density after antiretroviral therapy ini- tiation, independent of antiretroviral regimen. J Acquir Immune Deﬁc Syndr2009; 51:554–61.

35. McComsey GA, Tebas P, Shane E, et al. Bone disease in HIV infec- tion: a practical review and recommendations for HIV care providers.

Clin Infect Dis2010; 51:937–46.

36. Stellbrink HJ, Orkin C, Arribas JR, et al. Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir- emtricitabine in HIV-infected adults: 48-week results from the ASSERT study. Clin Infect Dis2010; 51:963–72.

37. Hazra R, Siberry GK, Mofenson LM. Growing up with HIV: children, adolescents, and young adults with perinatally acquired HIV infection.

Annu Rev Med2010; 61:169–85.

38. Jacobson DL, Lindsey JC, Gordon CM, et al. Total body and spinal bone mineral density across Tanner stage in perinatally HIV-infected and uninfected children and youth in PACTG 1045. AIDS2010; 24:687–96.39. Mulligan K, Glidden D, Gonzales P, et al. Effects of FTC/TDF on bone mineral density in seronegative men from 4 continents: DEXA results of the global iPrEx study. Conference on Retroviruses and Op- portunistic Infections; 27 February–2 March2011; Boston, MA.

40. Galea JT, Kinsler JJ, Salazar X, et al. Acceptability of pre-exposure pro- phylaxis as an HIV prevention strategy: barriers and facilitators to pre-exposure prophylaxis uptake among at-risk Peruvian populations.

Int J STD AIDS2011; 22:256–62.

41. Juusola JL, Brandeau ML, Owens DK, Bendavid E. The cost-effectiveness of preexposure prophylaxis for HIV prevention in the United States in men who have sex with men. Ann Intern Med2012; 156:541–50.

42. Matthews LT, Baeten JM, Celum C, Bangsberg DR. Periconception pre-exposure prophylaxis to prevent HIV transmission: beneﬁts, risks, and challenges to implementation. AIDS2010; 24:1975–82.

43. Paltiel AD, Freedberg KA, Scott CA, et al. HIV preexposure prophy- laxis in the United States: impact on lifetime infection risk, clinical outcomes, and cost-effectiveness. Clin Infect Dis2009; 48:806–15.

44. Pretorius C, Stover J, Bollinger L, Bacaer N, Williams B. Evaluating the cost-effectiveness of pre-exposure prophylaxis (PrEP) and its impact on HIV-1 transmission in South Africa. PLoS One2010;5:

e13646.

45. Cruz H. Dear colleague letter. Albany, NY: New York Department of Health;2012 . HIV/AIDS CID 2013:56 (15 April ) 1155 Copyright of Clinical Infectious Diseases is the property of Infectious Diseases Society of America and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.