Recent successes in HIV prevention have been predominately biomedical and include antiretroviral therapy (ART) for prevention, voluntary medical male circumcision (VMMC), and vaginal microbicides.14–19 Both treatment as prevention (ART taken by HIV-infected individuals to reduce HIV transmission) and preexposure prophylaxis (PrEP; ART taken by HIV negative individuals to prevent HIV acquisition) demonstrate effectiveness in preventing HIV acquisition or transmission. Although PrEP has been found to be effective in 1 randomized controlled trial (RCT) among men who have sex with men,18 results from 4 trials among heterosexual individuals have been mixed with 2 trials showing that PrEP was effective15,20 and 2 trials finding no effect.21,22
There are numerous reasons why the results of trials among heterosexual individuals may be conflicting, although adherence is likely one of the most important drivers of efficacy.23 In fact, in the VOICE trial, adherence, as measured by drug levels in blood, was particularly low (29%) despite the fact that self-reported adherence and pill count suggested good adherence (90%). Being over the age of 25 years was a significant predictor of drug detection in the blood.22 In contrast, data from the Partners PrEP trial found that daily oral tenofovir (TDF) and emtricitabine/TDF (FTC/TDF) were as efficacious in young women under the age of 30 years as among all women. Specifically, the efficacy of TDF among women <30 years of age was 77% [95% confidence interval (CI), 29 to 92] and the efficacy of FTC/TDF was 72% (95% CI, 25 to 90) compared with all women in whom the efficacy of TDF was 71% (95% CI, 37 to 87) and FTC/TDF was 66% (95% CI, 28 to 84).24 These discrepant findings in PrEP trials for young women highlight the need for well-designed PrEP pilot studies to better understand discrepancies between self-reported measures of adherence and actual use, best dosing for young women (e.g. daily vs. intermittent), motivations for young women to participate in trials, and appropriate messages and interventions to support adherence and methods that allow participants to accurately report usage and likes and dislikes of products in trial settings. Thus, while promising, questions remain about the scalability and generalizability of ART for prevention in general and in particular to adolescents.
Although adherence to ART is critical for treatment and prevention, taking medication in the long term is challenging. Adolescents with HIV are less likely than are adults to be adherent to ART.25–29 A literature review examining medication nonadherence among adolescents suggests that simple solutions remain elusive.30–34 For HIV-uninfected youth, low HIV risk perception may result in a lack of interest in or poor adherence to interventions such as PrEP or microbicides.35 Furthermore, adolescents are often not in long-term relationships; it is unclear how partnership characteristics affect adherence to prevention interventions. More research is needed among adolescents to understand testing, linkage to and retention in care, and understand factors affecting the uptake of biomedical prevention interventions.
Vaginal and rectal microbicides, applied topically before sex, may be appropriate for young women and men who have sex intermittently. Although 1 trial of coitally dependent vaginal TDF was found to show signs of efficacy among women in South Africa,19 the use of daily topical TDF was found not to be effective in a second trial in Africa.22 The explanation for differences in the studies has been attributed to women not using the product, again stressing the fact that adherence is critical to the efficacy of these interventions.23 Two safety and acceptability trials of a TDF gel-based microbicides in adolescent women are planned in the United States (Kapogianis B. National Institute of Health and Microbicides Trial Network plan safety and acceptability trial of tenofavir gel-based microbicide in adolescent women. 2012. Written personal communication) and in South Africa.36 A phase 2 trial of rectally applied TDF gel among men and transgendered women will begin enrollment soon and would benefit from bridging studies to adolescents following sufficient safety signals.37 Research evaluating how best to support uptake, delivery, and adherence will be required to facilitate widespread implementation.
Given the high levels of unplanned pregnancy and unmet need for contraception among many young women in high-prevalence settings, multipurpose technologies, methods that could prevent HIV, other sexually transmitted infections and pregnancy, are urgently needed.38 Some products are in development, but their acceptability and safety for adolescent girls are unknown. Interventions integrating the provision and uptake of sexual and reproductive health services with HIV prevention need to be evaluated.
VMMC reduces HIV risk by approximately 65% and reduces the risk of sexually transmitted infection acquisition and transmission.16,17,39 An additional benefit of encouraging early VMMC is that it is almost invariably preceded by HIV testing and counseling (HTC). Given the low uptake of HTC in young men in some settings, there is a need to better link adolescent VMMC with interventions to encourage healthy behaviors including regular HIV testing.
Most of the research on biomedical interventions has been conducted in adults, partly due to the ethical complexities of research in minors. Although there is increasing recognition of the importance of engaging children and adolescents in research, there remain ethical, legal, and logistical challenges.40,41 Inclusion of minors in clinical research is governed by ethical principles that vary globally but generally consider need, risk, benefit, and consent.42,43 Who consents for adolescent involvement is typically governed by the age of the majority by state and/or country with some exceptions. There are also important considerations of the appropriate timing of adolescent involvement in the research of the clinical development of a product or intervention. Excluding adolescents from these studies may delay access to prevention interventions. It is essential that biomedical prevention interventions be implemented with a better understanding of behavioral and contextual factors that impede uptake and adherence. Clearer guidance around safety bridging studies, and when extrapolation to adolescents is acceptable versus when efficacy and/or effectiveness should be demonstrated, is vital for newly developed biomedical interventions.44
Behavioral interventions have been used with the aim of reducing the risk for HIV by delaying sexual debut, promoting condom use, and/or reducing concurrency, partner change, or substance use. Numerous behavioral interventions have been evaluated; however, few have HIV endpoints, and those that have, have not shown a reduction in HIV incidence.45–47 The US Centers for Disease Control and Prevention has identified interventions with good or best evidence for HIV risk reduction based on their impact on proximate determinants of incidence.48 However, there is the need for critical consideration of the role of these interventions in high-prevalence settings. Interventions offered in group settings, such as in schools, may be most feasible in resource-constrained environments.
Schools are often used to deliver behavioral interventions because they reach a large number of youth, often before sexual debut. Of the 3 published adolescent HIV prevention RCTs conducted with HIV incidence endpoints, 2 have been school based.49–51 None of the studies found an impact on HIV, and results were mixed for sexual behavior. Overall, those with greatest success were curriculum based, adult led, and followed specific guidelines (“Kirby characteristics”).52,53 Combining modalities to deliver biomedical interventions, such as HCT, in schools may lead to a greater program uptake.
Understanding the larger context of behavioral interventions is critical to their success.54 Many school-based interventions were implemented in settings where massive gender and power inequities may undermine programs' success.50 Further, issues related to proper intervention implementation and fidelity likely compromised efficacy.55
There is increasing emphasis on addressing prevention issues with HIV-infected individuals. Positive health dignity and prevention (PHDP) interventions help people living with HIV to lead complete and healthy lives and reduce HIV transmission. PHDP involves the systematic delivery of a range of combination, behavioral, and sociocultural services within local communities.56 Although the core components of PHDP have been defined, evidence is required to tailor these for use with adolescents in diverse settings and evaluate cost effectiveness.
At the structural and contextual levels, important drivers of adolescent risk are poverty, discrimination, gender and power inequities, stigma, and environments that are not youth friendly.47,57 Few interventions address these structural factors. Given the high prevalence of rape in sub-Saharan Africa,58 and that HIV transmission in the context of gender-based violence is common,59 we must examine approaches that tackle HIV prevention within the broader context of gender inequity.
Structural barriers to accessing care need to be addressed for adolescents. Youth-friendly reproductive health services can attract and retain youth in care.60 Health facilities that are successful in making services more adolescent friendly have consistently included provider training and community activities.53 Given the central role of HTC and biomedical interventions in the prevention landscape, we need to identify the successes of reproductive health services and adapt and/or integrate HIV prevention in these services. Models for youth-friendly services offering testing have been developed61–63; however, adolescents' uptake of HTC is not well understood. Research to explore how to increase HTC uptake, disclosure of serostatus, and linkages to prevention (eg, PrEP) and care (eg, treatment as prevention) is required.
It is critical to address limited education and poverty that increase the risk for HIV infection.64–67 A recent trial among young women in Malawi showed that cash transfers lowered HIV and HSV-2 prevalence and demonstrated positive changes in the age of the sex partner and frequency of sex acts.68 Providing cash to young women may have allowed them to change partnership characteristics, reducing their risk of contracting HIV infection; however, the mechanism through which such programs work is still unclear. Several large RCTs examining cash transfers with HIV incidence endpoints are currently underway and may help identify the mechanism of action of such interventions.69,70 There is a need to explore a range of interventions to reduce poverty and improve the financial independence of young people.
Other structural approaches that change social norms through media campaigns or community mobilization can reach out to a large number of adolescents. Messages that target larger audiences and work to reinforce HIV prevention and care messages play a key role in normalizing HIV testing and in the uptake of newer prevention technologies.71 The role of community mobilization to increase the uptake of HTC or VMMC is promising, yet it is understudied. Ultimately, interventions combining multiple strategies with sufficient community coverage are likely to have the greatest impact.
Despite the high risk of HIV transmission among young people, few rigorously designed prevention interventions with HIV endpoints have been evaluated. Many interventions focus on changing individual-level behaviors rather than on addressing the larger contextual and structural landscape within which young people live. Further, few studies have explored the use of biomedical interventions among young people. Although biomedical prevention offers considerable promise, further research is needed to determine the applicability, safety, and efficacy of these approaches among the youth. The factors affecting HIV risk are complex and will require a combination approach incorporating a supportive behavioral, structural, and/or biomedical intervention. Developing a prevention menu where adolescents, depending on their phase of transition and sexual activity, may tailor their individual prevention package would represent a major advance in preventing HIV among youth.
1. Nugent R. Youth in a Global World. Washington, DC: Population Reference Bureau; 2006.
2. UNAIDS. UNAIDS Report on the Global AIDS Epidemic. UN Joint Programme on HIV/AIDS: Geneva, Switzerland. 2010.
3. Gouws E, Stanecki KA, Lyerla R, et al.. The epidemiology of HIV infection among young people aged 15–24 years in southern Africa. AIDS. 2008;22(suppl 4):S5–S16.
4. Pettifor AE, Rees HV, Kleinschmidt I, et al.. Young people's sexual health in South Africa: HIV prevalence and sexual behaviors from a nationally representative household survey. AIDS. 2005;19:1525–1534.
5. The Panel on Transitions to Adulthood. Growing up Global: The Changing Transitions to Adulthood in Developing Countries: a Review of Published Data. National Academies Press: Washington, DC. 2005.
6. Schmithorst VJ, Yuan W. White matter development during adolescence as shown by diffusion MRI. Brain Cogn. 2010;72:16–25.
7. Casey BJ, Jones RM, Hare TA. The adolescent brain. Ann N Y Acad Sci. 2008;1124:111–126.
8. Erikson EH. Childhood and Society. New York, NY: W. W. Norton & Company; 1950.
9. Erikson EH. Identity: Youth and Crisis. New York, NY: W. W. Norton & Company; 1968.
10. Brooks-Gunn J, Graber J. What’s sex got to do with it? The development of sexual identities during adolescence. In: Contrada RJ, Ashmore RD, eds. Self, Social Identity and Physical Health. 1st ed. Oxford, United Kingdom: Oxford University Press; 1999; 155–184.
11. Flisher AJ, Chalton DO. Adolescent contraceptive non-use and covariation among risk behaviors. J Adolesc Health. 2001;28:235–241.
12. Swartz L, Kagee A, Kafaar Z, et al.. Social and behavioral aspects of child and adolescent participation in HIV vaccine trials. J Int Assoc Physicians AIDS Care (Chic). 2005;4:89–92.
13. Coates TJ, Richter L, Caceres C. Behavioural strategies to reduce HIV transmission: how to make them work better. Lancet. 2008;372:669–684.
14. Cohen MS, Chen YQ, McCauley M, et al.. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365:493–505.
15. Baeten JM, Donnell D, Ndase P, et al.. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367:399–410.
16. Bailey RC, Moses S, Parker CB, et al.. Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial. Lancet. 2007;369:643–656.
17. Gray RH, Kigozi G, Serwadda D, et al.. Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet. 2007;369:657–666.
18. Grant RM, Lama JR, Anderson PL, et al.. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363:2587–2599.
19. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al.. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2010;329:1168–1174.
20. Thigpen MC, Kebaabetswe PM, Paxton LA, et al.. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012;367:423–434.
21. Van Damme L, Corneli A, Ahmed K, et al.. Preexposure prophylaxis for HIV infection among African women. New Engl J Med. 2012;367:411–422.
22. Marrazzo J, Ramjee G, Nair G, et al.. Pre-Exposure Prophylaxis for HIV in Women: Daily Oral Tenofovir, Oral Tenofovir/Emtricitabine, or Vaginal Tenofovir Gel in the VOICE Study (MTN 003). Conference on Retroviruses and Opportunistic Infections. Atlanta, GA: 2013.
23. Amico KR, Mansoor LE, Corneli A, et al.. Adherence support approaches in biomedical HIV prevention trials: experiences, insights and future directions from four multisite prevention trials. AIDS Behav. 2013 Feb 23 [Epub ahead of print].
24. Murnane PM, Celum C, Kahle EM, et al.. Daily Oral Pre-Exposure Prophylaxis in Highly Effective Among Subsets of Highest-risk Participants: Partners PrEP Study. Conference of Retroviruses and Opportunistic Infections (CROI). Atlanta, GA: 2013.
25. Belzer ME, Fuchs DN, Luftman GS, et al.. Antiretroviral adherence issues among HIV-positive adolescents and young adults. J Adolesc Health Official Publ Soc Adolesc Med. 1999;25:316–319.
26. Fetzer BC, Mupenda B, Lusiama J, et al.. Barriers to and facilitators of adherence to pediatric antiretroviral therapy in a sub-Saharan setting: insights from a qualitative study. AIDS Patient Care STDS. 2011;25:611–621.
27. Murphy DA, Wilson CM, Durako SJ, et al.. Antiretroviral medication adherence among the REACH HIV-infected adolescent cohort in the USA. AIDS Care. 2001;13:27–40.
28. Barclay TR, Hinkin CH, Castellon SA, et al.. Age-associated predictors of medication adherence in HIV-positive adults: health beliefs, self-efficacy, and neurocognitive status. Health Psychol. 2007;26:40–49.
29. Rudy BJ, Murphy DA, Harris DR, et al.. Patient-related risks for nonadherence to antiretroviral therapy among HIV-infected youth in the United States: a study of prevalence and interactions. AIDS Patient Care STDS. 2009;23:185–194.
30. Bain-Brickley D, Butler LM, Kennedy GE, et al.. Interventions to improve adherence to antiretroviral therapy in children with HIV infection. Cochrane Database Syst Rev. 2011;12:CD009513.
31. Fernandez MI, Hosek S, Warren JC, et al.. Development of an easy to use tool to assess HIV treatment readiness in adolescent clinical care settings. AIDS care. 2011;23:1492–1499.
32. Garvie PA, Flynn PM, Belzer M, et al.. Psychological factors, beliefs about medication, and adherence of youth with human immunodeficiency virus in a multisite directly observed therapy pilot study. J Adolesc Health. 2011;48:637–640.
33. Gray WN, Janicke DM, Fennell EB, et al.. Piloting behavioral family systems therapy to improve adherence among adolescents with HIV: a case series intervention study. J Health Psychol. 2011;16:828–842.
34. Wohl AR, Garland WH, Wu J, et al.. A youth-focused case management intervention to engage and retain young gay men of color in HIV care. AIDS care. 2011;23:988–997.
35. Pugatch D, Bennett L, Patterson D. HIV medication adherence in adolescents. J HIV/AIDS Prevention & Education for Adolescents & Children. 2002;5:9–29.
37. Microbicide Trials Network 017: a phase 2 randomized sequence open label expanded safety and acceptability study of oral emtricitabine/tenofovir disoproxil fumarate tablet and rectally-applied tenofovir reduced-glycerin 1% gel. Available at: http://www.mtnstopshiv.org/news/studies/mtn017
. Accessed March 7, 2013.
38. Thurman A, Clark M, Doncel G. Multipurpose prevention technologies: biomedical tools to prevent HIV-1, HSV-2, and unintended pregnancies. Infect Dis Obstet Gynecol. 2011;2011:1–10.
39. Auvert B, Taljaard D, Lagarde E, et al.. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial. PLoS Med. 2005;2:e298.
40. Jaspan H, Tucker T, Wright P, et al.. Inclusion of adolescents in preventative HIV vaccine trials: public health policy and research design at a crossroads. J Acquir Immune Defic Syndr. 2008;47:86–92.
41. DiClemente RJ, Ruiz MS, Sales JM. Barriers to adolescents' participation in HIV biomedical prevention research. J Acquir Immune Defic Syndr. 2010;54(suppl 1):S12–S7.
42. Nelson RM, Lewis LL, Struble K, et al.. Ethical and regulatory considerations for the inclusion of adolescents in HIV biomedical prevention research. J Acquir Immune Defic Syndr. 2010;54(suppl 1):S18–S24.
43. Jaspan HB, Soka NF, Strode AE, et al.. Community perspectives on the ethical issues surrounding adolescent HIV vaccine trials in South Africa. Vaccine. 2008;26:5679–5683.
44. Pettifor A, Bekker LG. Adolescent enrolment in HIV prevention trials. Lancet. 2012;380:646.
45. Kamali A, Quigley M, Nakiyingi J, et al.. Syndromic management of sexually-transmitted infections and behaviour change interventions on transmission of HIV-1 in rural Uganda: a community randomised trial. Lancet. 2003;361:645–652.
46. Koblin B, Chesney M, Coates T. Effects of a behavioural intervention to reduce acquisition of HIV infection among men who have sex with men: the EXPLORE randomised controlled study. Lancet. 2004;364:41–50.
47. Padian NS, McCoy SI, Karim SS, et al.. HIV prevention transformed: the new prevention research agenda. Lancet. 2011;378:269–278.
49. Cowan FM, Pascoe SJ, Langhaug LF, et al.. The Regai Dzive Shiri project: results of a randomized trial of an HIV prevention intervention for youth. AIDS. 2010;24:2541–2552.
50. Ross DA, Changalucha J, Obasi AI, et al.. Biological and behavioural impact of an adolescent sexual health intervention in Tanzania: a community-randomized trial. AIDS. 2007;21:1943–1955.
51. Doyle AM, Ross DA, Maganja K, et al.. Long-term biological and behavioural impact of an adolescent sexual health intervention in Tanzania: follow-up survey of the community-based MEMA kwa Vijana Trial. PLoS Med. 2010;7:.
52. Ross D. Preventing HIV/AIDS in Young People: A Systematic Review of the Evidence From Developing Countries: UNAIDS Interagency Task Team on HIV and Young People. Geneva, Switzerland: WHO Press; 2006.
53. Napierala-Mavedzenge S, Doyle A, Ross D. HIV prevention among young people in subSaharan Africa: a systematic review. In: Ross D, ed. London, United Kingdom: Department of Epidemiology and Population Health, LSHTM; 2010;49:568–586.
54. Mathews C, Aarø LE, Grimsrud A, et al.. Effects of the SATZ teacher-led school HIV prevention programmes on adolescent sexual behaviour: cluster randomised controlled trials in three sub-Saharan African sites. Int Health. 2012;4:111–122.
55. Michielsen K, Chersich MF, Luchters S, et al.. Effectiveness of HIV prevention for youth in sub-Saharan Africa: systematic review and meta-analysis of randomized and nonrandomized trials. AIDS. 2010;24:1193–1202.
56. Sharer MF, Fullem A. Transitioning of Care and Other Services for Adolescents Living with HIV in Sub-Saharan Africa. Arlington, VA: AIDSTAR-One; 2012.
57. McCoy SI, Watts CH, Padian NS. Preventing HIV infection: turning the tide for young women. Lancet. 2010;376:1281–1282.
58. Dartnall E, Jewkes R. Sexual violence against women: the scope of the problem. Best Pract Res Clin Obstet Gynaecol. 2013;27:3–13.
59. Jewkes R, Sikweyiya Y, Morrell R, et al.. The relationship between intimate partner violence, rape and HIV amongst South African men: a cross-sectional study. PLoS One. 2011;6:e24256.
60. Ross D, Dick B, Ferguson J. Preventing HIV/AIDS in Young People: A Systematic Review of the Evidence From Developing Countries: UNAIDS Interagency Task Team on HIV and Young People. Geneva, Switzerland: World Health Organization; 2006.
61. MietAfrica. Literature Review: Youth-Friendly Health Services. Miet Africa: Durban: South Africa. 2011.
62. WHO, FCH, CAH. Adolescent Friendly Health Services—An Agenda for Change. Geneva, Switzerland: World Health Organization; 2002.
64. Barnighausen T, Hosegood V, Timaeus IM, et al.. The socioeconomic determinants of HIV incidence: evidence from a longitudinal, population-based study in rural South Africa. AIDS. 2007;21(suppl 7):S29–38–S–38.
65. Hargreaves JR, Bonell CP, Morison LA, et al.. Explaining continued high HIV prevalence in South Africa: socioeconomic factors, HIV incidence and sexual behaviour change among a rural cohort, 2001–2004. AIDS. 2007;21(suppl 7):S39–48–S–48.
66. Madise N, Zulu E, Ciera J. Is poverty a driver for risky sexual behaviour? Evidence from national surveys of adolescents in four African countries. Afr J Reprod Health. 2007;11:83–98.
67. Msisha WM, Kapiga SH, Earls F, et al.. Socioeconomic status and HIV seroprevalence in Tanzania: a counterintuitive relationship. Int J Epidemiol. 2008;37:1297–1303.
68. Baird SJ, Garfein RS, McIntosh CT, et al.. Effect of a cash transfer programme for schooling on prevalence of HIV and herpes simplex type 2 in Malawi: a cluster randomised trial. Lancet. 2012;379:1320–1329.
71. Bharath-Kumar U, Becker-Benton A, Lettenmaier C, et al.. Communication and the antiretroviral treatment rollout: beyond the medical model. AIDS Educ Prev. 2009;21:447–459.
75. Kreutzer T. Assessing cell phone usage in a South African township school. Int J Educ Devel. 2009;5:43–57.
76. Bull SS. Technology Based Health Promotion. 1st ed. Thousand Oaks, CA: Sage; 2010.
77. Albarracin D, Gillette JC, Earl AN, et al.. A test of major assumptions about behavior change: a comprehensive look at the effects of passive and active HIV-prevention interventions since the beginning of the epidemic. Psychol Bull. 2005;131:856–897.
78. Albarracin D, Kumkale GT, Johnson BT. Influences of social power and normative support on condom use decisions: a research synthesis. AIDS Care. 2004;16:700–723.
79. Jemmott JB III, Jemmott LS. HIV risk reduction behavioral interventions with heterosexual adolescents. AIDS. 2000;14(suppl 2):S40–52–S–52.
80. Moreno MA, Vanderstoep A, Parks MR, et al.. Reducing at-risk adolescents' display of risk behavior on a social networking web site: a randomized controlled pilot intervention trial. Arch Pediatr Adolesc Med. 2009;163:35–41.
81. Bull SS, Breslin LT, Wright EE, et al.. Case study: an ethics case study of HIV prevention research on Facebook: the Just/Us study. J Pediatr Psychol. 2011;36:1082–1092.
82. Levine D, Madsen A, Wright E, et al.. Formative research on MySpace: online methods to engage hard-to-reach populations. J Health Commun. 2011;16:448–454.
83. Juzang I, Fortune T, Black S, et al.. A pilot programme using mobile phones for HIV prevention. J Telemed Telecare. 2011;17:150–153.
84. Levine D, McCright J, Dobkin L, et al.. SEXINFO: a sexual health text messaging service for San Francisco youth. Am J Public Health. 2008;98:393–395.
85. Lester RT, Ritvo P, Mills EJ, et al.. Effects of a mobile phone short message service on antiretroviral treatment adherence in Kenya (WelTel Kenya1): a randomised trial. Lancet. 2010;376:1838–1845.