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.
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.
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
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
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.
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