Adherence to antiretroviral medication is a critical component of HIV treatment and management. The probability of the progression to AIDS and death decreases with consistent and proper adherence to antiretroviral therapy (ART), and poor adherence can result in negative health outcomes and treatment-resistant strains of the virus.1–3 Among adolescents and young adults living with HIV, rates of suboptimal adherence produce poorer outcomes than their adult counterparts.4 In the US and globally, adolescents living with HIV face unique barriers to maintaining high adherence levels because they progress through major milestones in cognitive and social development and transition to adult HIV care.5 Compared with adults, adolescents and young adults in the United States have poorer retention in care, a larger delay in the initiation of ART, and lower rates of virological suppression.6,7
Of the 33.4 million people living with HIV, 4.9 million are youth.8 Youth in the US generally have noteworthy challenges in sexual health and self-care9 and poverty, discrimination, homophobia, and discrimination are well-recognized factors influencing both risk for HIV infection and utilization of HIV care. Despite the high prevalence and incidence of HIV in adolescent and young adult populations across the globe, this population is highly under-represented in evidence bases of effective intervention approaches to promote rapid and durable viral suppression. Adherence interventions, specifically, target viral suppression and have a long history and robust presence in the literature, with multiple meta-analyses and synthesis10–12 published to date and resources available to implement demonstrated interventions.13 In contrast, youth-focused interventions, particularly within key populations,5 have not been as comprehensively represented in the evidence base. A recent systematic review characterized service delivery interventions among individuals 10–19 years of age, finding 11 studies published through 2014 that suggested some promising approaches but ultimately provided limited evidence for effective linkage, retention, and adherence strategies specific to adolescent and young adult populations.14
Adolescents and young adults living with HIV, through behavioral or perinatal routes of infection, require specific focused attention. Youth have diverse needs that are unique from adults and to date the appropriateness of adapting adult interventions to youth remains suspect because of the dramatic differences between adults and youth in executive functioning, emotional development, and self-regulation.15 Adherence may also be challenging during adolescence because of reactivity to feeling different from peers.16 Intertwined in these processes are different levels of identification, including ethnic/racial, gender, sexuality, moral and religious identities17,18 that shape engagement in care and adherence. Strategies and messages to support adherence and well-being should arguably reflect shifts from concrete to abstract thinking and from an invulnerable to self-preserving mindset. It is important to note that the definition of adolescence can vary by culture, yet these developmental themes are persistent throughout and have implications for adherence. Given the ongoing disproportionate burden of HIV in youth worldwide, taking stock of the available evidence on efforts to fully engage adolescents and young adults in adhering to their medication regimens can identify areas of promise and areas that should be addressed in research agendas.
To identify the “front facing” evidence base specific to ART adherence interventions for adolescents and young adults, and gaps in evidence, we selected the most frequently used research database linking to peer reviewed publications among medical care providers,19 PubMed. This differs substantially from meta-analytic or research syntheses approaches that cull across a wide range of resources, including databases for peer-reviewed publications and conference presentations, cross-referencing, and efforts to contact authors when data are insufficiently detailed in a given publication that allow for characterization of the full research database in a given area. Our work focuses on what faces an individual, organization, or group searching a common access database (“front facing”) for interventions that were effective for potential adoption, thus representing the operations and dissemination intersection of consumer (service provider) and evidence (peer-reviewed publications cataloged in PubMed) rather than a full capture of emerging research available through more databases or conference and meeting venues. Also, distinct from work already available,14 our efforts focused on interventions evaluated within populations ranging from 13 to 24 years of age, the range that the Centers of Disease Control and Prevention (CDC) identifies as accounting for an estimated 26% of all new HIV infections in the US.9 Additionally, this population faces unique barriers to adequate adherence as they transition from pediatric to adult care settings20
Adolescent and young adult-focused intervention articles were identified using the PubMed database covering work published through September 14, 2015. Search terms evaluated for inclusion and resulting data are presented in Figure 1. Inclusion was based on the following criteria: (1) focus of intervention was on adolescents to young adults (average age range 13–24), (2) participants were HIV positive, (3) participants were on or beginning ART, (4) evaluated an intervention targeting ART adherence in full or in part, and (5) reported adherence, viral load (VL), and/or CD4 count outcomes.
Selection of Articles for Review
As presented in Figure 1, 151 articles were identified by the applied search terms. Title and abstract review excluded 87 articles; complete text review eliminated another 54. In full, only 10 articles met all criteria and were used in the current research synthesis. The main reason for elimination was not having evaluated an adherence intervention followed by exclusion due to average age being outside the range of 13–24 years.
Each article that met selection criteria was reviewed for characteristics of the cohort or population included in the research (eg, sample size, sex distribution, race, and ethnicity), design features (eg, randomization, study arms/conditions, and sampling strategy), intervention characteristics/adherence strategies in treatment condition (eg, duration, dosage, and targets), adherence support offered or available to control or comparison group if applicable, outcomes measured, methodology for and frequency of measurement, overall outcome of evaluation as reported in article. For articles providing such information, the details were extracted and recorded in an excel worksheet database. All content was extracted by (S.S.) with discussion of all authors to adjudicate or clarify any content that could not be clearly interpreted.
Meta-analytic procedures synthesizing effect sizes across the evidence base were not used because of the small set of studies included and diversity in their research, evaluation and inferential statistics strategies, and reporting. Rather, we conducted an iterative review of the 10 included studies to identify commonalities in main results and conclusions, intervention approaches, and outcomes that characterize the current “state of the science” for ART adherence support interventions for adolescent and young adult populations. Data extracted from each article were summarized and iteratively reviewed by both authors to identify common themes and limitations in the current evidence base.
In full, 10 articles met inclusion (Table 1) and represented a total of 346 youth. The average enrolled sample size was about 35 participants per study, ranging from 4 to 108. The average evaluated sample size was about 23, ranging from 4 to 91. Most studies presented findings from small pilot interventions (only 2 studies had over 60 participants,21,24 1 of which included over 100 participants21). Only 2 studies were conducted outside the US: 1 at the Thai Red Cross AIDS Research Centre clinics in Bangkok, Thailand21 and the other in the United Kingdom.27 Samples were largely drawn from pediatric clinics and 2 studies recruited participants from sites in the Adolescent Trials Network for HIV/AIDS.22,24 The study populations in all 8 of the US interventions consisted of primarily African American and Hispanic/Latino/a youth. Only 1 study included or reported transgender identity23 and sexual identity was reported by only 2 studies.21,24 Mode of HIV infection was commonly reported, with the evidence better representative of cohorts with mixed routes of infection (3 of the 9 studies reporting infection route represented almost exclusively perinatally infected youth25–27). The average age of intervention participants ranged from 15 to 23 years of age. A total of 8 out the 10 articles reported an average or median age greater than 18 years of age, whereas only 225,26 looked at an average below 18 years of age (15 and 15.5 years).
Project Design/Study Type
Most of the interventions (60%) conducted repeated measures of within-group comparisons, generally including 6 to 9 assessments of outcomes over 24–96 weeks (average 37 weeks). All but 228,29 of the studies evaluated outcomes postcompletion of the intervention. Experimental and quasi-experimental designs were used in 4 studies21,22,24,25 which implemented diverse strategies for allocation and comparison condition. Use of attention control or active intervention comparison arms was common in trials which adopted randomized controlled trial (RCT) designs (3 of the 4 studies using random assignment).21,24,25
The most frequently evaluated intervention strategy was individual sessions (90%)21,22,24–30 followed using technology in some capacity (80%).22,23–26,28–30 Cell phones were evaluated in 3 studies,22,28,30 pagers in 2,23,29 and Skype,25 telephones,26 computers,24 and wrist-watches23 were included in interventions in single studies. Of the included articles, 40% incorporated reminder strategies,22,28–30 30% included parents sessions,23,25,26 30% employed motivational interviewing,21,24,27 20% involved families or family members other than parents,23,25 and 10% used group sessions.23 Length of intervention varied from brief (2 sessions a month apart)24 to a 12-month intervention that consisted of 2 motivational interviewing sessions and financial incentives based on scheduled VL assessments.27 Most of the interventions were 12 or 24 weeks in length (70%).21–23,25,28–30
The articles included in the review applied varying modalities to conduct the interventions. Three interventions21,23,27 were delivered in-person whether at health clinics or a children's hospital with strategies including motivational interviewing and educational sessions. Four of the interventions21,24,28,30 were delivered through technology. One article described daily personalized text messages,28 whereas another delivered a computer-based brief intervention.24 The other 2 were phone-based interventions in which daily calls served as medication reminders and monitors.21,30 The remaining 3 interventions were delivered both in-person and through technology.25,26,29
Delivery of the interventions involved a diverse set of professionals with various educational and career backgrounds: 20% of interventions were delivered by or partially delivered by a case manager,22,23 20% by a research assistant,21,22 30% by a clinical psychologist, clinical nurse or physician,21,23,27 and 70% by other professional or academic personnel,23–26,28–30 including masters level therapists,25 study coordinators or interventionists hired by the study,28–30 graduate students,26 and mental health professionals.23 One study used computer software to deliver the intervention.24 Only 1 article stated a focus on using lower-cost staff as the facilitators could not be licensed clinicians such as nurses, psychologists, or master's level social workers.22
Type of Adherence-Related Outcome
Reporting on VL or CD4 t-cell counts and/or some measure of adherence was required for inclusion in the review. Thus, all studies report on one or more of these outcomes. All 10 articles included VL as an outcome, 5 included CD4 count,23,25,27–29 and 9 included a measure of adherence.21–26,28–30 Of these 9 studies that included an adherence outcome, most were derived from self-report,21–25,28,29 1 a combination of directly observed therapy (DOT)29 and self-report, and 1 used Medication Event Monitoring System (MEMS) data.26 Measurement strategies included: (1) Visual Analog Scale, (2) AIDS Clinical Trials Group adherence questionnaire, (3) Medication Event Monitoring System (MEMS), (4) TrackCaps, (5) pill counts, (6) paper-based monitoring log, (7) NIH Adherence to Medication Questionnaire, and (8) Visual Analog Scale through audio computer-assisted self-interviewing. The most common operationalizations of self-reported adherence were percent of doses taken over doses prescribed and a count of missed doses. Time periods for these measures ranged from the previous day23 to past 3 months.21 A recall interval of 4 weeks was used by half of the studies21,22,25,29,30 and 40% of studies dichotomized adherence, 2 with a 90% cutoff,22,25 1 with whether or not any doses were skipped and the final study used >93%.29 One study in this review used a MEMS supplemented by pill counts and self-report when MEMS data were missing.26 MEMS was used to monitor weekly adherence for one of the medications the participations were taking. In this study, adherence data were gathered from MEMS whenever possible but pill count and self-report were also used to measure this variable in 17 incidences (23.8%).
“Graded” Evidence Base
All articles were evaluated in the context of their potential strength of evidence, prioritizing studies of highest methodological rigor and confidence in findings. This resulted in the organization of studies (Table 1) into the following categories: (1) RCT with significance testing on outcomes21,22,25; (2) within-group studies with statistical testing on outcomes28; (3) RCTs with descriptive results24; (4) within-group studies with descriptive results.23,26,27,29,30
Evidence Level 1
Three studies contributed the strongest evidence through use of RCT designs and statistical evaluation of outcomes.21,22,25 The 2 focused on improving ART adherence demonstrated significant positive outcomes on self-reported medication adherence and viral suppression at 622 and 9 months.25 Each targeted nonadherent youth and used some aspect of problem solving, with Belzer et al22 using cell phone outreach by monitors to work with youth on problem solving around dose times, and Letourneau et al25 using weekly in-person or internet-facilitated family and patient counseling to target training and skills building. Despite relatively small samples, effects were significant on adherence and biological outcomes and seemed robust over time. Alternatively, the final RCT included in this category21 was focused in part on adherence but predominantly on reduction of risk behaviors and did not select participants on the basis of known history with nonadherence. In this study of youth in Thailand, the implementation of an evidence-based risk reduction intervention (12-week 4-session Healthy Choices intervention), in comparison to a health education comparison condition, did not impact adherence or VL.
Evidence Level 2
As depicted in Table 1, only 1 study was ranked at the second level of evidence (within groups design using statistical test of effects). Dowshen et al28 delivered a 24-week intervention among youth with adherence problems which consisted of daily text reminders at dose time, followed by a texted inquiry about whether or not the dose was taken an hour later. Self-reported adherence improved significantly from baseline (75%) to the final assessment at week 24 (93%). Although VL and CD4 patterned in a promising direction (dropping from a VL of over 2700 to 28 from baseline to 24 weeks, and increasing CD4 counts from 501 at baseline to 545 at 24 weeks), significance was not reached. Of note, the text intervention seemed to have been implemented throughout the project period, thus no assessment after removal of texts was provided.
Evidence Level 3
Only 1 study was included in this level.24 Although the trial was a high methodological rigor RCT and did include some subanalyses with significance testing, we position it in level 3 given the overall approach of description of effect sizes. This study evaluating a 2-session computer-delivered Motivational Enhancement System for Adherence (MESA) for treatment-naïve youth used an active comparison condition (a nutritional and physical activity program: Medication Subject Healths [MeSH]). Evaluation of self-reported adherence at 6 months, proportion of participants suppressed, and change in log VL favored the intervention condition as suggested by small to large effect size estimates. Contrasts of effect sizes on 2 of the adherence measures were significant. Given that the intervention and comparison condition were typically implemented within the first 3 months of enrollment into the study, the final endpoint did reflect a durability of gains, largely evident by month 3.
Evidence Level 4
Most of the intervention studies with youth targeting ART adherence in the literature fall in the lowest level for strength of evidence where within-group designs are used and outcomes are largely descriptive. The 5 studies included in this level23,26,27,29,30 (Table 1) have final observation sample sizes ranging from 4 to 21 and did not include a comparison group. These studies vary in intervention approach, applying strategies including educational and psychotherapy sessions,23 phone calls aligned with medication dose,30 DOT,29 adapted behavioral family systems therapy with an HIV/HAART education session,26 and motivational interviewing.27 Two studies intervened at both the individual and family group level.23,26 Two studies had notably small samples sizes.26,30 One involved use of cell phone reminders with a final sample of 5 participants and presented mixed- and short-lived improvements.30 The other evaluated behavioral family systems therapy with 4 case reports and presented enhanced adherence overall and mixed support for decreased VL.26 Foster et al27 implemented a motivational interviewing session at initiation of ART, followed by a financial incentive program, with a final sample of 10 participants at 24 months. The study reported improved a CD4 count and VL at final assessment. The use of DOT within a tapered individual approach was evaluated by Gaur et al29 with a final sample of 14 youth. Higher self-reported adherence and viral suppression was observed around 12 weeks on DOT, however, improvements were diminished at final assessment (week 24) when participants had stopped or tapered from DOT. Lyon et al23 implemented an educational curriculum which alternated between family and youth sessions and youth-only sessions with 21 participants at final assessment (month 6). Improvements across self-reported measures of adherence were noted; however, only 20% of the sample had improvements in VL or CD4 counts.
Our systematic review of ART adherence interventions for youth ages 13–24 identified 10 articles from the current evidence base. Overall, several of the studies reported results supportive of improvements in adherence outcomes. However, the progress in this area of research seems to continue to lag behind increasingly vast evidence base for adherence support in adults, despite previous calls for investigation of interventions specifically tailored to adolescent and young adult populations.14 The studies identified in our review were not only few, but were heterogeneous in intervention approach, duration and methodology, creating a scattered picture for what might work best for promoting ART adherence in youth.
Although slightly over half of the studies reviewed joined the evidence base relatively recently (in or after 2012), there is a nascent quality to this area that belies the long-recognized issues with nonadherence encountered by numerous youth living with HIV. Almost all studies were framed as pilots, used within-group designs, and most positioned outcomes as descriptive explorations. Few evaluated the impact of interventions, between or within groups, with sufficient power to detect even moderate effects and many opted for descriptive exploration because of these small-sample limitations. Despite this, our review did identify a number of strong evidence results, including strategies leveraged with nonadherent youth that incorporated texted outreach and multisystem therapy, and good evidence for interactive text-based outreach around dose times. Moreover, promising potential for positive impact through very brief computer-delivered in-clinic support may offer viable low implementation cost opportunities to assist youth.
Because of the diversity in rigor and overall approach, we separated findings relative to strength of evidence, in part to assist in the interpretation of a sometimes mixed profile of evidence. For example, 1 study provided strong evidence in support of interactive outreach phone call approach,21 whereas a very similar approach evaluated in a very small pilot did not seem to improve outcomes.30 Results do suggest support for a number of intervention packages, however, as noted within these studies, replication is needed as the evidence base is lacking in this process. Where results were supportive, the cohorts tended to include youth already known to have adherence problems, which is consistent with our earlier evaluations of the adherence literature with adults.31
The current state of the evidence for adherence support in youth is limited by a number of shortcomings. These include a paucity of research targeted to specific key populations within youth (eg, interventions specifically targeting sexual and gender minority youth), small sample size and pilots dominating the evidence base, relatedly low power, interventions that require interventionists with advanced degrees, most interventions conducted in the US, and diversity in follow-up periods. Results of this study regarding limitations in methodological rigor in the current evidence base and diversity in intervention strategies and results are aligned with the conclusions of a recently published synthesis of youth focused service delivery interventions to improve linkage, adherence, and retention in HIV care.14 Our review adds to the characterization of this evidence base as emerging, at best, with potential promise that will require considerable attention to move forward. Aggressive efforts to engage youth in adherence-related trials are needed, which depend in part on better strategies to reduce and manage regulatory challenges in research with minors. Innovative strategies to afford youth added privacy, confidentiality and autonomy in the context of behavioral trials are needed to facilitate a robust and representative evidence base.32–34
Limitations in the current review include reliance only on PubMed for identification of the evidence base for adherence interventions targeting youth living with HIV. Although PubMed catalogs peer reviewed research across most medical and social journals, we do not characterize all available research. Interventions presented in conference venues and scientific journals not indexed in PubMed are not included. We recognize that there are often substantial delays between presentation of effective interventions in conference venues and peer-reviewed publication; however, the focus on peer-reviewed publications affords access to the specific data needed for synthesis and offers added confidence in integrity of findings through the peer-review process, which is not available in conference abstracts, presentations, or other “grey literature.”
Almost 20 years have passed since the introduction of ART and near immediate realization that adherence is a major driver of successful treatment outcomes yet the evidence base remains small and dominated by pilots. Nearly half of all new HIV infections are occurring among those aged 13–24, and recommendations are increasingly adopting the rapid initiation of lifelong ART after diagnosis. Improved ART adherence leading to sustained viral suppression within this population is crucial to decreasing onward transmission.35,36 ART adherence remains an essential component in both individual and public health. The current pace of intervention research remains grossly disproportionate to needs of adolescents and young adults living with HIV. Prioritizing youth in research agendas and calling for innovative, rigorous designs to identify effective interventions are overdue and necessary for world-wide implementation of “90-90-90.”
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