INTRODUCTION
By the end of 2012, there were an estimated 2.1 million adolescents (aged 10–19 yrs) living with HIV; approximately two-thirds of new HIV infections in adolescents aged 15–19 years were among girls.1 interventions to prevent new HIV infections and also to treat people living with HIV to ensure that they survive and thrive. Yet, because of their age, adolescents face specific barriers in accessing interventions because of factors that include community and service provider attitudes about adolescent sexual activity and government laws and policies that may prevent the majority of adolescents from independently seeking services and support. As a result, new infections, and late diagnosis and poor outcomes among adolescents living with HIV, are common.2
To substantially reduce the scale and impact of the AIDS epidemic, national AIDS responses must strengthen the quality and impact of programming for HIV prevention , treatment, and care for adolescents . To do this, program responses for adolescents must be more strategic. They must focus on interventions that are known to be effective and also address the underlying factors driving incidence and lack of effective treatment and care in this age group.
This article presents the results of a systematic review of systematic reviews examining the evidence on the effectiveness of selected HIV prevention , treatment, and care interventions among adolescents . We primarily focused on addressing the question of “Which interventions should be included in HIV programs targeting adolescents ?” In addition, based on the available evidence, the review sought to answer the questions of how adolescents can be reached more effectively with impactful HIV interventions , how interventions can be delivered more successfully to adolescents , and how programs should be designed to ensure optimal HIV impact in adolescents ? For example, how can a condom promotion and access program best be designed to ensure that the particular needs of adolescents are addressed to ensure they will have access to condoms?
METHODS
The number of interventions among adolescents that might reduce HIV transmission risk, morbidity, and mortality is large. Intervention types included in this review were initially selected based on an a priori list of potential interventions . These were critically and iteratively reviewed, first by United Nations International Children's Emergency Fund (UNICEF) and then by panels of experts in adolescent research, programming, and policy at 2 technical meetings. The first meeting was held in April 2013 at the UNICEF Headquarters in New York. The second was a UNICEF meeting in London in July 2013. At each meeting, participants were asked to identify any known review articles of relevance, and these were also evaluated for inclusion in this review. Interventions have been divided into 2 categories as follows:
Interventions Primarily Designed for Adults
1. Voluntary medical male circumcision (VMMC),
2. Antiretrovirals (ARVs) for the prevention of mother-to-child transmission (PMTCT) of HIV,
3. HIV testing and counseling,
4. HIV treatment,
5. Condom use,
6. Provision of opioid substitution therapy to people who inject opioid drugs,
7. Provision of clean injecting equipment to people who inject drugs (PWID),
8. Oral preexposure prophylaxis (PrEP),
9. Topical PrEP (microbicides with antiviral activity against HIV) for the general population of women and for men who have sex with men (MSM),
10. Individual and group behavior change interventions among 3 key populations (MSM, PWID, and sex workers),
11. Sexually transmitted infection (STI) screening and treatment among 3 key populations (MSM, PWID, and sex workers), and
12. Mass media interventions .
The key questions in this category were whether these interventions can be effective, what characteristics make each intervention most effective, and what needs to be done differently to ensure that adolescents will also benefit from any prevention, treatment, care, and support interventions that were found to be effective among adults.
Interventions Specifically Designed for Adolescents and Young Adults
In-school HIV prevention education,
Delivery of services (eg, HIV testing, condoms) in youth centers,
Increasing adolescents ' use of HIV prevention interventions (eg, HIV testing, condoms) by making health services more adolescent friendly (eg, increased privacy, youth-friendly hours, staff trained to work with adolescents ),
School-based health services,
Community-wide interventions within geographically defined communities,
Conditional cash transfers (CCTs) to adolescents who stay in school,
CCTs to adolescents who remain STI free, and
Unconditional cash transfers (UCTs) to adolescents .
This category focused on specific interventions designed for adolescents and young adults aged 10–24 years. The key questions in this category were whether such interventions can be effective, and if so, how best to design and implement them for maximum effectiveness.
We conducted a systematic review of systematic reviews of interventions within these categories to evaluate the evidence of impact of each of these types of interventions on the key outcomes: HIV risk, HIV transmission, and HIV morbidity and mortality.3 interventions specifically designed to target adolescents and young adults, a broader range of outcomes were included, as most evaluations of interventions targeting adolescents have not measured biological outcomes but have measured the impact on knowledge, self-reported sexual behavior, self-reported self-efficacy, and attitudes, or on uptake of health services. Furthermore, it is reasonable to expect that many of these interventions , on their own, would only improve these reported behavioral and knowledge outcomes, at least in the short term.
There are many types of HIV prevention interventions , which have not been evaluated in this report. We briefly present additional types of interventions and discuss the reasons for why they have not been reviewed in the Supplemental Digital Content (https://links.lww.com/QAI/A538
Search Strategy
For each intervention type, we conducted a search of the PubMed and Cochrane databases for systematic reviews of effectiveness published between January 2000 and April 30, 2013. The search was limited to English language review articles of studies in humans. Review articles which were based solely on mathematical modeling were excluded. Search terms used for each intervention type, the number of unique citations found, and the number of citations selected for inclusion in this article are found in the Supplemental Digital Content (https://links.lww.com/QAI/A538
The title and abstract of all citations identified were reviewed for relevance by 2 reviewers (E.L. and S.N.M.). Potentially relevant citations underwent full text review by 1 reviewer (S.N.M.) based on our predefined criteria for inclusion (Table 1 ). Any citation whose suitability for inclusion was unclear was reviewed by a second author (E.L.). A third reviewer (D.R.) was available in the event of a discrepant decision by the first 2 reviewers. We also conducted a hand search of references of all the selected citations identified through the electronic searches to identify any additional relevant citations. Relevant data were then extracted systematically. Articles identified by expert panels at the technical meetings were also evaluated for inclusion in this review. Finally, where available, we also included information from unpublished systematic reviews and current recommendations conducted by the World Health Organization.
TABLE 1: Criteria for Inclusion
For interventions designed primarily for adults, we reviewed the most recent evidence first and worked in reverse chronological order. We selected one or more of the most recent, high-quality systematic reviews for inclusion, until we had high-quality evidence demonstrating that a type of intervention could be effective (as per our strength of evidence criteria, below) and/or was representative of the available evidence on the effectiveness of the intervention type. For interventions designed specifically for adolescents and young adults, all review citations that met our eligibility criteria were included.
Strength of Evidence
We used the evidence on the effectiveness of the specific intervention types as the basis for proposing recommendations on the key priority interventions for adolescent HIV programming. We developed a set of criteria for assessing the strength of the available evidence and evaluated each intervention type against these criteria. The assessment took into account the quantity of available evidence and quality of that evidence in terms of study design. This was assessed on a 3-level scale, denoted as A, B, or C, defined as follows:
A. High-quality evidence, defined as 3 or more experimental trials and/or high-quality quasi-experimental studies, or at least one meta-analysis of such studies, coupled with evidence from observational studies.
B. Moderate-quality evidence, defined as 1–2 experimental trials and/or high-quality quasi-experimental studies, coupled with evidence from observational studies.
C. Low quality of evidence, defined as observational data only, or only one moderate- or low-quality quasi-experimental study, coupled with evidence from observational studies.
We then looked at whether available evidence was in support of the intervention's efficacy. This was assessed on a 4-point scale:
All, or virtually all, studies showed statistically significant effectiveness.
Studies largely, but not consistently, showed significant effectiveness.
Mixed beneficial and ineffective or harmful results.
Consistently ineffective or harmful results.
The judgment of effectiveness was based on the statistical significance rather than on the absolute size of effect. Assessment of the quantity/quality of evidence and support for effectiveness were combined to give each intervention type a strength of evidence rating, with A1 being the strongest level of evidence of likely benefit and C4 the weakest. This strength of evidence rating then corresponded to the authors' recommendations, which were based solely on the evidence of effectiveness (Table 2 ). It is important to note that this methodology for assessing strength of evidence does not take account of the fact that different interventions will need different strengths of evidence to justify their implementation based on their feasibility, cost, potential size of benefit, risk of harm, acceptability, and other social or health benefits.4
TABLE 2: Strength of Evidence
RESULTS
Results and recommendations for each intervention type within each category are shown in Table 3 and Table 4 . All citations that met our criteria for inclusion and any additional reviews or specific studies that informed our results are listed in the Supplemental Digital Content (https://links.lww.com/QAI/A538
TABLE 3-a: Summary of the Evidence on Effectiveness of Interventions Primarily Designed for Adults
TABLE 3-b: Summary of the Evidence on Effectiveness of Interventions Primarily Designed for Adults
TABLE 3-c: Summary of the Evidence on Effectiveness of Interventions Primarily Designed for Adults
TABLE 4: Summary of the Evidence on Effectiveness of Interventions Specifically Designed to Target Adolescents and Young Adults
Interventions Primarily Designed for AdultsFor many of the preselected interventions primarily designed for adults, there was strong evidence of a significant impact on HIV incidence. Based on the data from randomized controlled trials (RCTs) conducted in the general population of men living in high HIV-burden countries in sub-Saharan Africa, VMMC significantly decreased HIV incidence.5–9 5–9 10,11 15 18 15 systematic review was not conducted of the independent effects on HIV acquisition or onward transmission of HIV testing and counseling among adults as there is no other way for HIV-positive individuals to be identified. This intervention has therefore been recommended as the essential entry point to treatment, care, and support rather than as a potential HIV prevention intervention in its own right. Additionally, there was strong evidence that the provision of opioid substitution therapy to PWID had a significant impact on HIV incidence.20,21 24,25
For other intervention types within this category, the evidence supporting an impact on our key HIV outcomes was less strong. In terms of ARV for oral PrEP, although 3 early well-conducted RCTs among heterosexual couples and MSM demonstrated a significant reduction in incident HIV with both tenofovir disoproxil fumarate and tenofovir disoproxil fumarate plus emtricitabine oral PrEP, 2 recent trials of these interventions among women were either stopped for futility or showed no effect.26 28 29,30
Behavior change interventions among PWID have demonstrated effectiveness in reducing self-reported risk behaviors, with some evidence indicating the potential to affect HIV incidence.31 interventions among this population included HIV testing and result disclosure, individual-level behavioral interventions , behavior change interventions with HIV-discordant couples, network- or peer-based interventions , provision of injecting equipment, condom provision, opioid substitution therapy, STI treatment, and antiretroviral therapy. Similarly, there is evidence that behavior change interventions among MSM have the potential to effectively reduce self-reported unprotected anal intercourse, though there was no evidence of a significant impact on HIV incidence.32,33 interventions seemed to be more effective than individual-level interventions . There was a small amount of evidence, which indicated that individualized risk reduction counseling or community-level interventions may be effective in reducing reported risky behavior among adolescent MSM. In low-income countries, there was strong evidence that behavior change interventions among sex workers can effectively reduce incident STIs and promote reported behavior change, including increased self-reported condom use and a reduction in use of psychoactive drugs.40–42 interventions , the promotion and increased availability of condoms through outreach, peer promotion and risk counseling, and outreach by health workers. Structural interventions , such as microenterprise support for sex workers, also demonstrated success in increasing self-reported condom use.
There was evidence from high-income countries that interventions to increase HIV and STI screening and treatment for STIs among MSM could effectively increase uptake of HIV testing.45–47 interventions among MSM, other than the utilization of the now-standard point-of-care rapid testing (as opposed to remote testing in a laboratory) and opt-out, rather than opt-in, HIV testing strategies.
Finally, there was evidence that mass media interventions were a promising approach to increasing uptake of HIV testing in adults.48–50
Overall, evidence from systematic reviews for how adolescents can best access the most promising of interventions primarily designed for adults was modest, at best. Few systematic reviews of evidence of this nature were identified, with limited additional evidence available from other reviews that did not meet our criteria for inclusion for several other intervention types. For adolescents ' access to HIV testing and counseling, there was evidence that they face unique barriers to access, at least in some contexts.13 Interventions may therefore require tailored support, such as targeted out-of-facility services (eg, mobile clinics, street- and youth center–based services, home-based testing), opt-out provider-initiated testing and counseling, the use of rapid testing, and provision of testing within a setting providing adolescent-friendly health services.13,14 interventions to increase HIV treatment access among adolescents , there were data indicating that, when compared with North Americans and Europeans, African children and adolescents starting treatment tended to be older and at more advanced levels of immunosuppression.16,17 75 adolescents , and combination of specific condom promotion interventions with other interventions , such as education and training related to communication and decision-making skills, also showed potential for increasing condom use among adolescents .14,19 adolescents who inject drugs, the strongest evidence of effectiveness for this reducing HIV incidence is for methadone replacement therapy, and there were clear legal obstacles to adolescents in the United States accessing methadone replacement therapy.23 interventions showed potential to be effective for improving several outcomes among adolescents , including HIV prevalence, through the use of interventions combining television and radio with supporting material.51 interventions , including using cellular communication, social media, and mobile health products to reach participants. They represent innovative new platforms for delivering interventions .
Interventions Specifically Designed to Target Adolescents and Young AdultsThe interventions in this second category, by their very nature, were designed specifically for an adolescent population. With the exception of in-school interventions , there were few reviews of the interventions in this category that met our criteria for inclusion. In-school interventions remain an efficient means of targeting school-going adolescents , and several such interventions have been demonstrated to be effective in improving knowledge, reported attitudes, and skills.52–69 interventions by trained adult facilitators, having multiple session programs, curricula that include skills and knowledge-building activities, and programs that are specifically designed or adapted for the local context were key characteristics of the more successful interventions .57,61,62,65,69 interventions were not effective.
We did not find evidence that youth centers, ie, youth-specific venues where young people can access information and services which address their needs and wants, were an effective or cost-effective method of increasing use of clinical sexual and reproductive health services. Although they were primarily accessed by males for recreational services, females were the primary users of the sexual and reproductive health services they provided, and overall, the number of unique clinic users was usually so low that the services were not cost-effective.70
Making health services more adolescent friendly by rigorous implementation of interventions , including training of service providers, outreach activities, and out-of-facility services tailored to context and target population, demonstrated some impact on uptake of health services.14,53,62,66,76,77 adolescents remained underserved by school-based health services, and therefore, they should be used to complement, not replace, health-care services for adolescents located outside schools.71,72
There was some evidence that community-level interventions have the potential to affect HIV prevalence and herpes simplex virus type-2 (HSV-2) incidence.57,78,79 interventions included those that specifically target adolescents and create their own system or structure for intervention delivery.
Overall, data on the impact of cash transfers on HIV-related outcomes were limited but promising. Trials of CCTs to stay in school showed some evidence of an impact on biological outcomes, including HIV incidence and HSV-2 prevalence.73 73,74 young people , however. Whereas 1 trial in Tanzania reported a significant impact on STI incidence, a Malawi trial found no significant impact on HIV incidence and mixed effects on self-reported sexual risk behaviors. There was also a small amount of evidence suggesting that UCTs can decrease school dropout rates, by addressing structural barriers which increase adolescent risk of HIV.73
DISCUSSION
A summary of the recommendations from this review is found in Table 5 , and the intervention types are presented by strength of evidence rating in Table 6 . Importantly, recommendations from this review are based solely on the available evidence on effectiveness and do not take into consideration other important factors, such as feasibility, cost, potential size of benefit, risk of harm, acceptability, and other social or health benefits.80 interventions to prioritize among adolescents . First, for interventions that are designed primarily to target adults, the current uptake of each intervention among adolescents and how this compares with coverage among adults will be important for prioritizing specific interventions to ensure adolescents ' access to interventions that are of known effectiveness among adults. Second, we did not review intervention costs, where they have been reported. Estimates of the costs of each of the interventions will be important for the allocation of available funding.
TABLE 5: Summary of Recommendations
TABLE 6: Interventions by Strength of Evidence Rating
Adolescence is a period of major transitions, particularly in terms of sexual and reproductive health needs. Interventions that are appropriate for older adolescents may not be relevant or appropriate for younger adolescents . In addition to sexual orientation and gender, interventions should be tailored to the specific populations targeted, taking into account, for example, whether youth are attending school, whether they are married, and other variables. Although we set out to disaggregate the results based on criteria, such as age, marital status, and whether the adolescent was still in formal education, the data were not usually reported by such subgroups in the review articles included in this report.
Certain types of interventions in this review have considerable amounts of evidence and/or evidence of high quality, whereas other interventions have very little evidence in terms of their effectiveness on HIV-related outcomes and/or only have evidence of relatively low quality. In some cases, this may be because of the limited effectiveness having been found within the initial intervention studies and thus little impetus to conduct additional and higher quality research. However, in other instances, this may not be a reflection of the potential of the intervention but rather the barriers to conducting high-quality interventions , in terms of logistics and/or resources. Such studies are particularly problematic among adolescents , for several reasons. First, the incidence of HIV among young adolescents is generally relatively low so population-based studies need to be very large. Studies of adolescents below the age of 18 years (or even older in some countries) are also complicated by additional parental informed consent requirements, especially if they include collection of biological specimens. Finally, if an intervention type is relatively new, sufficient studies may not have yet been conducted to have resulted in the publication of a systematic review . This review was not able to distinguish between these various possibilities but rather was designed to present the current state of the published evidence.
A major constraint on this review was that, with the exception of a few intervention types, there was a dearth of systematic review data on how best to enable adolescents to access the intervention types that were identified as having proven effective among adults. There is a clear need for more rigorous research in this area.
Strengths and Limitations
This review provides an important summary of the existing evidence on the effectiveness of a wide range of different types of interventions . We employed a systematic review of systematic reviews methodology24,33,81 interventions , and to explore the evidence from systematic reviews of how adolescents can best access those interventions with proven effectiveness. This approach allowed us to rigorously and systematically review a large number of intervention types in 1 document using a standard transparent methodology. We developed criteria for assessing the strength of the available evidence on effectiveness, which was systematically applied to each intervention type and used to develop author recommendations for what intervention types are most promising to consider for adolescent HIV programming in terms of their evidence of effectiveness. Methodological limitations are inherent in this strategy. In using only review articles rather than primary data, we relied on the data and focus presented by the review authors. There is likely to have been heterogeneity of interventions , outcomes, and study designs. Furthermore, the reports of the studies had already been summarized; so, the information will have been less detailed than in the primary study reports, resulting in the potential for exclusion of more nuanced descriptions of characteristics of interventions important to their effectiveness or lack thereof. In addition, by only searching for review articles, we may have missed effective interventions that have been evaluated but have not yet been included in a published systematic review . Nonetheless, systematic review of systematic reviews is a useful strategy that has been proposed by the UK Health Development Agency81 24,33 interventions , and a systematic review of systematic reviews was employed for practical reasons and also because, for most intervention types, high-quality reviews could be identified that adequately summarized the available data. Our review did highlight an absence of systematic reviews of some intervention types, which is likely to reflect the lack of published primary data, at least up to the recent past.
Another methodological limitation is that we limited our search to just 2 databases, PubMed and Cochrane; therefore, there is the possibility that we did not identify all high-quality systematic reviews. However, with the large volume of citations included in these databases, we feel it is unlikely that we overlooked any high-quality reviews that would have substantively altered the results presented here. We also did not systematically search the gray literature. After reviewing our results, expert consultants in adolescent HIV research and programming were asked to inform us of any other review articles of relevance, and these were included when they met the inclusion criteria. We also summarized unpublished systematic reviews conducted for the World Health Organization related to recent global or regional HIV guidelines and referred to these guidelines where available. For interventions specifically designed to target adolescents and young adults, we systematically reviewed all review articles that met our criteria for inclusion, but for the interventions primarily designed for adults, we selected the most recent, high-quality systematic reviews for inclusion that adequately summarized the available data from all the citations identified. In doing so, we may have overlooked important reviews that were published less recently.
We limited the review to the impact of interventions on biological HIV-related outcomes. Where such evidence was not available, or did not strongly support the intervention type, we looked beyond our 3 key outcomes to capture data on reported behavior change. For interventions that target adolescents , we also incorporated data on the impact on knowledge and reported attitudes. Some interventions may have effects on other outcomes, which are not directly HIV related but may be potential structural or other indirect determinants of HIV acquisition risk, such as poverty or employment, which we will not have captured yet may be extremely important. For example, cash transfers conditioned on adolescent girls remaining in, or returning to, school may have important effects on educational attainment, earning potential, desirability as a potential spouse, subsequent mothering skills, other health outcomes for themselves and their future families, and so on.
We developed a methodology to assess the strength of evidence available for each intervention type and to generate recommendations. It is relatively simple to use, can be applied across multiple intervention types, and indicates the weights assigned to the evidence on each intervention type. However, this methodology has limitations. First, although an experimental study is considered the strongest form of evidence, for ethical or other reasons, the comparison arm in an experimental study may not always have been the complete absence of any intervention but rather the current standard of care. In such cases, the measured effectiveness would likely be less than if the intervention had been evaluated against no intervention. Second, this methodology does not explicitly take account of geographical representativeness of the existing studies or their likely generalizability. Lastly, the methodology does not take account of the fact that different interventions will need different strengths of evidence to justify implementation based on their feasibility, cost, potential size of benefit, risk of harm, acceptability, and other social or health benefits.4
Also worth noting is that this review attempted to examine individual intervention types but did not look at combinations of interventions . Integrated programs with multiple, linked synergistic interventions may be more effective than any single intervention. Programs such as MEMA kwa Vijana in Tanzania82–84 85,86 interventions targeting adolescents , and several large rigorous evaluations of combination HIV interventions are currently in progress, such as the Population Effects of Antiretroviral Therapy to Reduce HIV Transmission (PopART) trial in Zambia and South Africa, which includes young adults, but not adolescents .87
CONCLUSIONS
From our systematic review of systematic reviews, we identified a number of interventions that showed strong promise of effectiveness (Tables 5 and 6 ). Of the interventions designed specifically for adolescents , there was high-quality evidence which indicated that, if they include identified key characteristics, in-school interventions and interventions in geographically defined communities can have a positive impact on a number of important HIV outcomes. Based on these results, it is recommended that these interventions should be considered for wide-scale implementation. Additionally, there is promising evidence that some cash transfer interventions can positively affect HIV outcomes in adolescents , though additional results from a number of ongoing trials and careful consideration of cost-effectiveness and sustainability are required before these can be recommended for scale-up. As health services are a gateway to a number of other effective interventions , including antiretroviral therapy, PMTCT, treatment as prevention strategies, STI treatment, and provision of condoms, resources should be allocated toward the development and implementation of interventions to increase health service use among adolescents and young people , including making them more adolescent friendly. Few other interventions in this category can be recommended for scale-up, due to weak evidence of effectiveness, evidence for an impact on self-reported behavior only, or there having been too few rigorous intervention studies.2,12,22,27,34–39,43,44,79
A number of interventions designed primarily for adults have high-quality evidence of potential efficacy: VMMC, ARVs for PMTCT, HIV testing and counseling, HIV treatment, condom use, and provision of sterile injecting equipment to PWID. There was also evidence of potential efficacy for oral PrEP among heterosexual couples and MSM and behavior change interventions among PWID and MSM. These should be priority interventions , which should be included in all HIV prevention programming for adolescents . A key public health question is “What does it take to reach adolescents more effectively with these high-impact interventions ?” However, with only a few notable exceptions, there was a dearth of rigorous reviews of their current uptake by adolescents relative to older age groups and of what should be done differently to enable adolescents to access these interventions at least as much as adults. While there may have been primary studies addressing this question, the lack of systematic reviews indicates that inadequate attention has been paid to adolescent access to effective HIV prevention , treatment, and care strategies. We recommend that the generation of such evidence through operations research, and age and sex disaggregation of programmatic and research study coverage and utilization data, be an urgent research priority, with rigorous studies focusing on those interventions of proven efficacy identified here.
ACKNOWLEDGMENTS
The authors thank Susan Kasedde, Ken Legins, Craig McClure, Rachel Yates, Chewe Luo, and Upjeet Chandan of UNICEF for advice and critical review of an earlier draft of this report. The authors also thank participants of the April 2013 meeting at UNICEF Headquarters in New York and of the July 2013 UNICEF meeting in London for their comments and suggestions. The authors thank Harriet Hallas and Claudia DaSilva of the Infectious Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, for administrative support.
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