Interventions to improve daily medication use among

adolescents and young adults: what can we learn for

youth pre-exposure prophylaxis services?
Jennifer Vellozaa, Bill Kapogiannisb, Linda-Gail Bekkerc,
Connie Celuma,d, Sybil Hoseke, Sinead Delany-Moretlwef,
Rachel Baggaleyg and Shona Dalalg

Objective: Oral pre-exposure prophylaxis (PrEP) is an important HIV prevention

method and studies have shown that young people ages 15–24 have difficulty adhering
to daily PrEP. The field of PrEP delivery for young people is relatively nascent and
lessons about potential PrEP adherence interventions could be learned from the larger
evidence base of adherence interventions for other daily medications among youth.
Design: Systematic review of adherence support interventions for adolescents.
Methods: We searched PubMed, CINAHL, EMBASE, and PsycINFO through January
2020 for oral contraceptive pill (OCP), antiretroviral therapy (ART), asthma, and
diabetes medication adherence interventions. We reviewed primary articles about
OCP adherence interventions and reviewed systematic reviews for ART, asthma, and
diabetes medication adherence interventions. Studies were retained if they included
participants’ ages 10–24 years; measured OCP, ART, asthma, or diabetes medication
adherence; and were systematic reviews, randomized trials, or quasi-experimental
studies.
Results: Fifteen OCP articles and 26 ART, diabetes, and asthma systematic reviews
were included. Interventions that improved medication adherence for OCPs, ART,
asthma, and diabetes treatment included reminder text messages, computer-based and
phone-based support, and enhanced counseling. Multi-month prescriptions and same-
day pill starts also were found to improve OCP adherence and continuation. Adoles-
cent-friendly clinics and peer-based counseling significantly improved ART adherence,
and telemedicine interventions improved diabetes medication adherence.
Conclusion: Interventions that improve medication adherence among youth include
enhanced counseling, extended pill supply, adolescent-friendly services, and text
message reminders. PrEP programs could incorporate and evaluate such interventions
for their impact on PrEP adherence and continuation among at-risk adolescents.
Copyright ß 2020 The Author(s). Published by Wolters Kluwer Health, Inc.

AIDS 2021, 35:463–475

Keywords: adherence, adolescents and young adults, antiretroviral therapy,

asthma, diabetes, oral contraceptives, pre-exposure prophylaxis

a
Department of Global Health, University of Washington, Seattle, Washington, bMaternal and Pediatric Infectious Disease
Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA, cThe
Desmond Tutu HIV Centre, University of Cape Town, Cape Town, South Africa, dDepartment of Medicine, University of
Washington, Seattle, Washington, eDepartment of Psychiatry, Stroger Hospital of Cook County, Chicago, Illinois, USA, fWits
Reproductive Health and HIV Institute (Wits RHI), Faculty of Health Sciences, University of the Witwatersrand, Johannesburg,
South Africa, and gGlobal HIV, Hepatitis and STIs Programmes, World Health Organization, Geneva, Switzerland.
Correspondence to Jennifer Velloza, PhD, MPH, International Clinical Research Center, University of Washington, Box 359927,
325 Ninth Avenue, Seattle, WA 98104, USA.
Tel: +1 917 392 3561; fax: +1 206 520 3831; e-mail: jvelloza@uw.edu
Received: 17 April 2020; revised: 30 October 2020; accepted: 9 November 2020.
DOI:10.1097/QAD.0000000000002777
ISSN 0269-9370 Copyright Q 2020 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under the
Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited. 463
464 AIDS 2021, Vol 35 No 3

Introduction adults to identify lessons learned about adherence support

approaches that could have relevance for PrEP programs
Adolescent girls and young women are at high risk of for youth. OCPs are likely most similar to PrEP because
HIV in high-burden countries, as are young key they are also recommended for daily use, only during
populations in all regions and may substantially benefit periods of need, in an otherwise healthy population, and
from pre-exposure prophylaxis (PrEP) [1–4]. However, we pay particular attention to primary articles from the
efficacy trials and demonstration projects have shown that OCP field. We also reviewed systematic reviews for ART,
youth have difficulty adhering to and persisting with daily asthma, and diabetes medication interventions as these
oral PrEP [5–10]. For example, in the Adolescent also require daily adherence over a long period of time.
Medicine Trials Network for HIV/AIDS Interventions
(ATN) 110 and 113 studies and the PrEP Brasil
demonstration study, young MSM had declining PrEP
adherence over time [10–12]. The PlusPills Study with Methods
adolescent girls in Cape Town found similar adherence
drops offs when clinic visits moved from monthly to We conducted a review of interventions (e.g. randomized
quarterly [6]. trials, quasiexperimental studies) that assessed OCP
uptake, adherence, and continuation; and a review of
PrEP programs are now focused on identifying PrEP systematic reviews focused on ART, diabetes, and asthma
adherence approaches to maximize its public health impact medication adherence among youth. We chose to
[13,14]. Behavior change theories postulate that adherence conduct a review of systematic reviews for the second
could be improved by influencing information about component, rather than a review of original research,
medication dosing and side effects, increasing motivation because a number of relevant reviews have already been
and social support around taking medication, improving done. This work was conducted in line with the Preferred
skills and self-efficacy to use medication, and increasing Reporting Items for Systematic Reviews and Meta-
availability and access [15,16]. Based on these models, PrEP Analyses guidelines [21].
projects have used a combination of adherence support
targeting information, motivation, support, skills, and self- Search strategy
efficacy, including counseling, two-way text message We searched PubMed, CINAHL, PsycINFO, and
communication with providers and text reminders, drug- EMBASE for primary articles on OCP interventions
level feedback, adherence support clubs, integrated PrEP and systematic reviews focused on ART, diabetes, and
delivery with sexual and reproductive health, and asthma medication among youth, published through 24
adolescent-friendly clinics [6,17–20]. While these January 2020 (refer to Fig. 1 footnote for search terms).
approaches have been designed to address PrEP adherence
challenges for young people, they are typically tested Study selection
together as a package, making it difficult to estimate the OCP use studies were included if they met the following
impact of each approach alone compared with standard-of- inclusion criteria: first, population included female
care services [13]. Gaps remain in understanding the adolescents or young adults (ages 10–24 years) and there
strengths, limitations, and effectiveness of various adher- was a separate effect measure for adolescents or young
ence support approaches currently under evaluation in adults; second, study was a randomized trial or quasi-
PrEP trials and identifying other support strategies to experimental study; third, contraceptive adherence or
address adolescent concerns around PrEP use. continuation were included as outcomes; and fourth,
interventions focused on daily OCP use and were
PrEP implementation is scaling up, but challenges remain intended to influence contraceptive use.
for adolescents. There is a larger evidence base from other
prevention and disease management interventions for ART, diabetes, and asthma medication reviews were
adherence among youth such as oral contraceptive pills included if they included at least one study with youth ages
(OCPs), antiretroviral therapy (ART), and daily medica- 10–24 years; were systematic reviews; and included
tions for chronic disease management (e.g. asthma, interventions for ART, diabetes, or asthma medication use.
diabetes). Interventions in these areas target theoretical
mediators of daily medication use that may be relevant for Two reviewers (J.V. and S.D.) assessed 10% of full-text
improving PrEP adherence and continuation. While articles for inclusion; discrepancies were resolved through
specific motivators of PrEP adherence among youth may discussion. One reviewer (J.V.) completed the full-text
differ from those driving prevention of pregnancy or review of the remaining articles.
chronic disease progression, consistencies across this
literature can provide insights on next directions for PrEP Data extraction and synthesis
interventions. We conducted a systematic review on Reviews on ART, diabetes, and asthma generally
intervention strategies for daily OCP, ART, asthma, and included a mix of adult-focused and adolescent
diabetes medication use among adolescents and young focused-articles. We included data from the studies that
 Adherence interventions among youth Velloza et al. 465

Fig. 1. Flowchart of reviewed and included studies. Search terms for oral contraceptive pill articles: our search included terms for
contraceptive use (e.g. ‘contraceptive agents’, ‘birth control’, ‘family planning’), adolescents and young adults (e.g. ‘adolescent’,
‘youth’, ‘girl’, ‘teen’), intervention studies (e.g. ‘randomized controlled trial’, ‘comparative study’, ‘follow-up study’), and
medication use (e.g. ‘medication adherence’, ‘medication compliance’, ‘continuation’, ‘adoption’, ‘contraceptive device
utilization’). Search terms for antiretroviral therapy, diabetes, and asthma articles: we searched databases with terms to identify
antiretroviral therapy use (e.g. ‘ART’, ‘antiretroviral’, ‘anti-HIV agents’), diabetes and asthma medication (e.g. ‘chronic disease
drug therapy’, ‘diabetes’, ‘diabetes mellitus drug therapy’, ‘oral hypoglycemic agents’, ‘asthma’, ‘anti-asthmatic agents’, ‘asthma
drug therapy’), adolescents and young adults (e.g. ‘adolescent’, ‘youth’, ‘teen’), review studies (e.g. ‘systematic review’, ‘meta-
analysis’), and medication use (e.g. ‘medication adherence’, ‘medication compliance’, ‘continuation’, ‘adoption’). The numbers
provided for antiretroviral therapy, diabetes, and asthma articles reflect the number of systematic reviews included/excluded
rather than the number of individual studies from these reviews. ART, antiretroviral therapy; OCP, oral contraceptive pills.

included adolescents 10–24 years old by extracting data between 1984 and 2019. Ten OCP studies were
from the systematic review text and tables on study details randomized trials, two were cluster randomized trials,
and by consulting the primary articles to obtain additional and three were quasi-experimental studies. Sample sizes
details. We extracted pooled effect measures where ranged from 33 to 10 600. Three studies included male
available for interventions targeting 10–24 years old but, participants who were asked about their partners’ OCP
given that few reviews included a meta-analysis with use. Primary studies on ART, asthma, and diabetes
adolescent trials, we primarily focused on extracting identified from systematic reviews were all randomized
effect measures from individual studies. trials or quasi-experimental studies. The majority of
OCP-focused studies were conducted in the United
States, and one study each was conducted in China,
Iceland, and Cameroon. ART, asthma, and diabetes
Results studies were predominantly conducted in the United
States, but several systematic reviews also included studies
Study characteristics conducted in Africa, Asia, and Europe.
We identified 3264 unique abstracts related to OCP
adherence and 1194 related to studies of ART, diabetes, Summary of interventions
and asthma medication use (Fig. 1). Forty-one articles Based on descriptions of the interventions provided in
met inclusion criteria. Included studies were conducted included articles, we grouped interventions into four
466 AIDS 2021, Vol 35 No 3

Table 1. Summary of medication adherence interventions and their efficacies among 10–24 years old, by condition.

OCP ART Asthma Diabetes

Individual Education and counselingM Education and counselingM Education and counselingM Education and counselingM
level Phone reminders and supportM Computer-based counselingM Computer-based counselingM Computer-based counselingM
Phone reminders and supportM Phone reminders and supportM Phone reminders and supportM
Financial incentives DOT
DOT
Interpersonal Peer support Family-based counselingM Family-based counselingM Family-based counselingM
level Peer modeling Peer supportM Peer support Peer support
Peel modelingM Peer modeling Peer modeling
Health facility Youth-friendly clinics Youth-friendly clinicsM – Youth-friendly clinics
level Specially trained counselors Transition coordinators
Same-day pill startsM TelecareM
Multi-month dispensingM
Community School-based servicesM – School-based services School-based services
level Broad education and social multisystemic therapyM multisystemic therapyM
marketing campaigns Broad education campaigns
Decentralized OCP provisionM

ART, antiretroviral therapy; DOT, directly observed therapy; OCP, oral contraceptive pills.
M
Significant intervention effects, as defined by a P value for the main intervention effect of less than 0.05. For ART, asthma, and diabetes
interventions, this P value and determination of significance was made from the individual, primary articles rather than from the systematic review
or any meta-analysis.

categories: individual-level, interpersonal-level, health ‘OCP use’ was defined as current OCP use at a follow-up
facility-level, and community-level (Table 1). For OCP- visit (assessed via self-report), without incorporating
focused studies, individual-level interventions included metrics of OCP adherence, missed pills, or missed visits.
education about OCPs, side effects, and plans for pill ‘OCP continuation’ was defined as continuous OCP use
management; enhanced counseling using motivational throughout follow-up. Interventions with statistically
interviewing or problem-solving techniques to cover significant effects were those using daily text message
topics such as contraceptive goal-setting and safe sex reminders [odds ratio (OR): 1.4; 95% confidence interval
behaviors; and text message or phone call reminders (CI): 1.0–2.0 [22]], extended multi-month prescriptions
about clinic appointments and regular pill-taking. (OR: 7.6; 95% CI: 2.4–24.0 [23]), same-day pill starts
(OR: 1.8; 95% CI: 1.1–3.3 [21]; OR: 1.5; 95% CI: 1.0–
Interpersonal-level interventions included peer modeling 2.1 [25]), and enhanced counseling (relative risk: 3.25;
(e.g. interacting with peers to observe them take their 95% CI: 1.83–5.77 [26]; P value ¼ 0.05 [27]). The effect
medications) and support groups. Health-facility level sizes ranged from ORs of 1.1 to 7.6; the highest was from
interventions focused on same-day pill starts where a small study of 43 girls [23].
medications were dispensed at the visit with directly
observed pill taking, regardless of menstrual cycle; multi- Participants in one randomized controlled trial (RCT)
month pill dispensing; and youth-friendly OCP clinics and who received daily text messages about OCP use for 6
specially-trained counselors. Community-level interven- months and two-way text message communication with
tions included enhanced sexual and reproductive health providers to address their questions [22] had 44% greater
curriculums in schools, social marketing campaigns (e.g. odds (OR: 1.4; 95% CI: 1.0–2.0) of OCP continuation
OCP-related commercials and radio advertisements), and than those in the control.
decentralized OCP provision (e.g. delivery in schools).
In a study of multi-month pill dispensing with 85
Interventions for ART, asthma, and diabetes were similar adolescent girls and young women, participants in the
including counseling about adherence, phone reminders, intervention arm who received seven pill packs had
and directly observed therapy, but also included financial seven-fold higher odds of OCP continuation (OR: 7.6;
incentives for ART adherence, multisystemic therapy (a 95% CI: 2.4–24.0) than those receiving three pill packs
community-level intervention whereby therapists involve after 6 months [23].
patients and their family, teachers, and providers to
address determinants of medication adherence) and Two randomized trials examined the influence of same-
family-based counseling, and transition coordinators to day start of OCPs on continuation [24,25]. In these
support the change from pediatric to adult care (Table 1). studies, intervention participants took their first dose of
OCP while in the clinic regardless of menstrual cycle.
Effects of interventions on oral contraceptive pill Control participants were given pill packs and advised to
use start OCPs at the onset of their next menstrual cycle.
Fifteen studies measured either OCP use (N ¼ 7) or Although neither trial found statistically significant effects
continuation (N ¼ 6) following an intervention (Table 2). after 6 months, both showed significant effects of same-
Table 2. Studies on improving oral contraceptive pills medication adherence among adolescents and young adults, by intervention (N U 15).

Year Author Sample size, sex, ages Location Study design Intervention description Control description Primary outcome Effectsa

Enhanced clinic-based or school-based counseling

2015 Minguez [26] N ¼ 2076 high school students; 908 USA QS Enhanced school-based services and SOC health services Self-reported OCP use at 12 months 9th Graders: RR ¼ 0.15 (95% CI: 0.02–
women and 1168 men; 14–18 decentralized OCP dispensing 1.46)
years old 10–12th Graders: RR U 3.25 (95% CI:
1.83–5.77)
2012 Berenson [29] N ¼ 1155 women, 16–24 years old USA RCT Enhanced clinic-based counseling SOC counseling OCP continuation at 12 months, OR ¼ 0.80 (95% CI: 0.63–1.40)
Enhanced clinic-based counseling measured via self-report, pill OR ¼ 1.09 (95% CI: 0.86–1.53)
and weekly phone calls counts, and medical records
2005 Wang [33] N ¼ 2227 women, 15–24 years China QS Peer-based counseling sessions SOC counseling Self-reported OCP use at 20 months OR ¼ 0.75 (95% CI: 0.52–1.08)
2004 Gilliam [31] N ¼ 33 postpartum women, <25 USA RCT SOC counseling and post-delivery SOC counseling Self-reported OCP continuation at 12 OR ¼ 0.67 (95% CI: 0.11–3.99)
years old OCP counseling months
2004 Bender [93] N ¼ 160 women, <24 years Iceland RCT Enhanced OCP counseling SOC counseling Self-reported OCP use at 6 months OR ¼ 1.08 (95% CI: 0.54–2.14)
1997 Kirby [28] N ¼ 354 7th grade students, 12–13 USA CRCT Enhanced school-based OCP SOC curriculum Self-reported OCP use at last sex OR U 0.57 (95% CI: 0.36–0.91)
years old (sex breakdown not counseling
specified)
1997 Kirby [34] N ¼ 10 600 middle school students, USA CRCT Adult-led enhanced school-based SOC curriculum Self-reported OCP use at last sex RR ¼ 0.79 (95% CI: 0.46–1.35)
mean age 12.5 years old (sex OCP counseling RR ¼ 0.78 (95% CI: 0.47–1.28)
breakdown and age range not Peer-led enhanced school-based OCP
specified) counseling
1993 Hanna [27] N ¼ 51 women, 16–18 years old USA RCT Enhanced clinic-based counseling SOC counseling Self-reported mean OCP adherence 10.24 in intervention versus 8.95 in
score at 3 months control, ratio of 1.14, P U 0.05
1984 Jay [32] N ¼ 57 women, 15–19 years old USA RCT Peer-based counseling SOC nurse-led Mean OCP adherence score, 0.85 in intervention versus 1.06 in control;
counseling measured as noncompliance at 4 ratio of 0.80
months measured via urinary
marker for OCP use
Phone and web-based interventions
2012 Castaño [22] N ¼ 962 women, 13–25 years old USA RCT Daily one-way and two-way text SOC counseling Self-reported OCP continuation at 6 OR U 1.44 (95% CI: 1.03–2.00)
messages months
1999 Chewning [30] N ¼ 949 women, <20 years old, USA RCT Enhanced OCP counseling via web- SOC counseling Self-reported OCP use Chicago: 96.6% in intervention versus
mean age 17 (age range not based application 91.2% in control
specified) Madison: 98.8% in intervention versus
97.7% in control
Self-reported mean number of months Chicago: 8.2 months in intervention versus
with OCP use 8.6 months in control
Madison: 9.4 months in intervention
versus 9.5 months in control
Multi-month dispensing
2011 White [23] N ¼ 85 women, <18 years old (age USA RCT Increased number of pill packs (7 Standard Self-reported OCP continuation at 6 OR U 7.55 (95% CI: 2.38–23.95)
range not specified) packs) 3 pill packs months
Same-day pill starts
2008 Edwards [24] N ¼ 539 women, 12–17 years old USA RCT Same-day start of OCPs with DOT Standard Starting second pill pack OR U 1.80 (95% CI: 1.10–3.30)
OCP start
Self-reported OCP continuation at 6 OR ¼ 1.1 (95% CI: 0.70–1.80)
months
2007 Westhoff [25] N ¼ 1720 women, <25 years old USA RCT Same-day start of OCPs with DOT Standard Starting second pill pack OR U 1.5 (95% CI: 1.00–2.10)
OCP start
Self-reported OCP continuation at 6 OR ¼ 1.1 (95% CI: 0.80–1.30)
months
Social marketing campaigns
2000 Van Rossem [94] N ¼ 868 women, 12–22 years old Cameroon QS Social marketing and mass media SOC OCP Self-reported OCP use 15.0% Increase in OCP use in intervention
campaign, youth clubs provision preintervention and setting versus 9.4% increase in control
postintervention setting; x2 ¼ 0.96, P ¼ 0.33

95% CI, 95% confidence interval; CRCT, cluster randomized controlled trial; DOT, directly observed therapy; OCP, oral contraceptive pills; OR, odds ratio; QS, quasi-experimental; RCT, randomized
controlled trial; RR, relative risk; SOC, standard of care.
a
Bold text denotes a statistically significant intervention effect.
Adherence interventions among youth Velloza et al.
467
468 AIDS 2021, Vol 35 No 3

day OCP start on self-reported completion of one OCP intervention participants. Six studies reported data on
pack and continuation to a second pill pack by 3 months unintended pregnancies as a secondary outcome but the
(OR: 1.8; 95% CI: 1.1–3.3 [24]; OR: 1.5; 95% CI: 1.0– numbers of pregnancies were too small to compare
2.1 [25]), suggesting that same-day starts may have a between groups [24,25,29,30,34]. Finally, three studies
short-term effect. Both trials had 15–25% loss to follow- did not disaggregate between female participants who
up by the 6-month interview and only 25–40% of were asked directly about their own OCP use and male
participants reported OCP use after 6 months. participants who were asked about partners’ OCP use
[28,33,34], which affects their interpretability.
Three RCTs of counseling interventions showed
contrasting results. Two showed improved OCP adher- Effects of interventions on youth antiretroviral
ence through either clinic [27], or school-based therapy, diabetes and asthma medication
counseling with decentralized OCP dispensing [26]. adherence
However, the school-based intervention did not impact Across several systematic reviews, enhanced counseling
OCP use among younger students (9th graders), (whether in groups, families, or computer-delivered), and
potentially because the analysis was restricted to sexually phone-based support (e.g. one-way and two-way text
active students who were less prevalent in this younger messages), improved ART adherence [35–42], asthma
group [26]. Conversely, a third school-based cluster RCT symptom control [43–46], and HbA1c levels (a measure
with 7th graders found a significant negative effect of of better glycemic control) among people with diabetes
counseling whereby participants in the intervention arm [43,50–53]. Peer support interventions showed signifi-
had lower OCP use compared with the control cant effects for ART [36,42], but neither peer-based nor
(OR: 0.57; 95% CI: 0.36–0.91) [28]. The authors school-based interventions were efficacious for asthma
hypothesized that their findings could be explained by symptom control [44,47–49]. Adolescent-friendly ser-
their choice of pregnant teens as the peer counselors, who vices [36] were also effective for ART adherence, as was
may have had an unintended effect on OCP use [28]. The telemedicine for providers for diabetes [52,53]. Detailed
enhanced counseling interventions in these trials included results for each health condition are provided in Table 3
one-time clinic-based or school-based sessions on OCP and Supplementary Appendix 1, http://links.lww.com/
dosing, side effects, barriers and facilitators to OCP use, QAD/B919.
and contraceptive goal setting during the OCP
initiation visit.

Several studies incorporated mHealth approaches to Discussion

support enhanced counseling which did not demonstrate
an effect on OCP use. These included one RCT of The current article provides the first synthesis of
regular counseling phone calls [29] and another testing a adherence support interventions for daily medication
menu-driven computer program for one-time tailored use across a range of health conditions among adolescents
patient counseling [30]. and young adults, with the goal of informing future PrEP
delivery for this priority population. Overall, interven-
Summary of key limitations from oral tions which resulted in improved adherence included text
contraceptive pill use interventions message reminders and two-way texting communication
Many studies in this review had limitations which are with providers, enhanced counseling, same-day pill starts
summarized here given their potential impact on the and multi-month dispensing, peer support, and youth-
conclusions of this review. Six studies had loss to follow- friendly clinics. There was no evidence of effectiveness
up rates between 20 and 50%, which hampered the for financial incentives, directly observed therapy, broad
measurement of the intended outcome [23– social marketing campaigns, or transition care coordina-
25,27,31,32]. Two studies with enhanced peer-based tors (Table 4).
counseling reported differential loss to follow-up and/or
a lack of exchangeability between arms (the groups OCP use is perhaps the closest corollary to PrEP use
receiving enhanced counseling differed from the control because it is also a daily medication used for prevention of
in baseline characteristics which may also influence a health condition in an otherwise healthy population and
intervention engagement and OCP use) making the is only necessary while a woman perceives a need. In
interpretations of the effects of peer-based counseling addition, young women using OCPs and/or PrEP often
difficult [32,33]. Neither found a statistically significant report stigma related to their sexuality and perceived
effect [32,33]. With the exception of two studies that used promiscuity as barriers to both medications [61–63].
pill counts and medical records [29] and urine samples OCP interventions generally targeted mediators of daily
[32] to assess OCP use, all studies relied on self-reported pill use (e.g., information, motivations, support, avail-
OCP use as their primary outcome, which could bias ability) that have been described as barriers to PrEP
intervention effects if control participants felt less adherence and continuation among adolescents [5–
comfortable disclosing true OCP use compared with 7,15,16]. One OCP study found that daily one-way and
Table 3. Summary of systematic reviews focused on interventions to improve antiretroviral therapy, asthma, and diabetes medication adherence among adolescents and young adults (N U 26).a

Year Author Locationb N studiesb Intervention(s)b Control(s)b Primary outcomeb Key findingsb

ART medication adherence

2018 Ridgeway [35] South Africa, 2 Enhanced group and SOC counseling Self-reported ART adherence; pill counts; Group counseling intervention: x2 U 14.7, df U 1, P
Thailand family-based pharmacy refills at 2–8 weeks post value < 0.001
counseling interventions Family-based counseling intervention: P value U 0.05
2018 Henny [37] USA 1 Computer-delivered counseling Active nutrition and Self-reported 7-day and weekend ART 7-Day outcome: Cohen’s d U 0.49, P < 0.05
physical activity control adherence at 6 months Weekend outcome: Cohen’s d U 0.66, P < 0.01
2017 Navarra [38] USA 2 Phone-based counseling; web- SOC counseling Self-reported 7-day, weekend, and 30-day 7-Day outcome: Cohen’s d U 0.49, P < 0.05
based counseling ART adherence at 6–12 months Weekend outcome: Cohen’s d U 0.66, P < 0.01
30-Day outcome: P U 0.007b
2017 Schaefer [43] USA 1 Enhanced counseling SOC counseling HIV viral load at 6 and 9 months 6 Months: P U 0.03
9 Months: P > 0.05
2016 Shaw [40] USA 1 Phone-based counseling SOC counseling 30-Day ART adherence at 6–12 months P U 0.007c
2015 Claborn [39] USA 1 Computer-delivered counseling Active nutrition and Self-reported 7-day and weekend ART 7-Day outcome: Cohen’s d U 0.49, P < 0.05
physical activity control adherence at 6 months Weekend outcome: Cohen’s d U 0.66, P < 0.01
2015 MacPherson [36] USA, South 4 Adolescent-friendly clinic; SOC ART provision, clinic Gaps in ART coverage in last 12 months Adolescent friendly-clinic intervention and gaps in
Africa, France, longer clinic hours; family- services, and counseling and cumulative incidence of ART coverage outcome: RR U 5.56 (95% CI: 1.20–25.0)
Kenya, Mozambique, Tanzania, based therapy; peer support initiation; missed last dose in past 3 Longer clinic longer hours intervention and ART
Rwanda months; proportion with undetectable initiation: HR ¼ 1.06 (95% CI: 0.89–1.27)
viral load at 24 months Family-based therapy intervention and missed last dose
outcome: P ¼ 0.05
Peer support intervention and undetectable viral load
outcome: P ¼ 0.06c
2013 Arrivillaga [41] USA 1 Phone-based counseling SOC counseling 30-Day ART adherence at 6–12 months P U 0.007c
2011 Bain-Brickley [42] France 1 Peer support SOC counseling Undetectable viral load at 24 months P ¼ 0.06c
Asthma medication adherence
2019 Ramsey [45] USA 1 Web-based counseling Generic asthma websites Symptom days, symptom nights, Symptom days: aRR U 0.50 (95% CI: 0.40–0.80);
hospitalizations at 12 months symptom nights: aRR U 0.40 (95% CI: 0.20–0.80);
hospitalizations: aRR U 0.20 (95% CI: 0.20–0.90)
2018 Lancaster [46] USA 1 Web-based counseling SOC counseling Symptom days at 12 months aOR U 0.49 (95% CI: 0.24–0.79)
2018 Ng [49] USA 1 School-based care SOC counseling Symptom days at 12 months aRR ¼ 0.88 (95% CI: 0.74–1.04)
2017 Kew [47] USA 1 Peer support SOC counseling Self-reported adherence, electronically P ¼ 0.929c
measured adherence at 10 weeks
2017 Schaefer [43] USA 1 Enhanced counseling with phone SOC counseling Asthma symptoms at 3 months Difference: 10.94 (95% CI: 1.63–20.25); Cohen’s
support d U 0.96
2016 Mosnaim [44] USA; United Kingdom 4 School-based care; web-based SOC counseling Asthma symptom control and symptom School-based care intervention and asthma control
counseling; MST; enhanced days at 12 months; phone diary outcome: RR ¼ 0.97 (95% CI: 0.91–1.04)
counseling medication adherence at 7 months; Web counseling intervention and symptom days
self-reported adherence at 8 weeks outcome: RR U 0.80 (95% CI: 0.60–1.00)
MST intervention and adherence outcome: b U 0.18
(95% CI: 0.02–0.34)
Enhanced counseling intervention and mean adherence
outcome: 4.4 versus 4.3, ratio of 1.02
2011 Salema [48] The Netherlands; United Kingdom 2 Enhanced counseling; school- SOC counseling Self-reported adherence and Enhanced counseling intervention and self-reported
based care asthma symptom control adherence outcome: 7.7 intervention versus 6.7
control; ratio of 1.15, P ¼ 0.05
School-based care intervention and asthma control
outcome: RR ¼ 0.97 (95% CI: 0.91–1.04)
Diabetes medication adherence
2019 Virella Perez [55] Canada, Denmark 2 Phone and tablet-based support SOC counseling Percent changes in HbA1c All P > 0.05
levels at 12 months
2018 Ng [49] United States 2 Enhanced counseling; web- SOC counseling Percent change in HbA1c levels between 6 Enhanced counseling: P > 0.05
based counseling and 12 months Web-based counseling: P > 0.05
2018 Feldman [50] USA, Denmark, United Kingdom 11 Enhanced counseling (N ¼ 9); SOC counseling; waitlist Mean change in HbA1c levels between 3 Enhanced counseling intervention: Cohen’s d ranged
MST (N ¼ 2) control; nutritional and 12 months from S1.57 to 0.38, all P < 0.05
counseling MST intervention: Cohen’s d ranged from 0.24 to 0.64,
all P < 0.05
Adherence interventions among youth Velloza et al.
469
 470

Table 3 (continued )
AIDS

Year Author Locationb N studiesb Intervention(s)b Control(s)b Primary outcomeb Key findingsb

2017 Charalampopoulos [51] United Kingdom 5 Phone support (N ¼ 1); enhanced SOC counseling Mean change in HbA1c levels between 5 Pooled risk difference from meta-analysis with five
counseling days and 12 months adolescent-focused studies: 0.06 (0.21 to 0.09);
relative risk estimates ranged from 0.38 to 0.58 and
one P < 0.05
2017 O’Hara [58] Italy, Germany, United States 4 Transition coordinators; SOC counseling Percent change in HbA1c levels between 3 Transition coordinator intervention: mean difference of
adolescent friendly clinic; and medication and 12 months 0.01, P > 0.05
enhanced education; services Adolescent friendly clinic intervention: P > 0.05c
computer management Enhanced education intervention: mean difference of
system 0.64% (95% CI: 0.79 to 0.50%)
Computer management intervention: P > 0.05c
2021, Vol 35 No 3

2017 Schaefer [43] United Kingdom, United States 3 Enhanced counseling SOC counseling Mean change in HbA1c levels between 3 P < 0.05c
and 12 months
2017 Schultz [59] Italy, Australia, Spain, Denmark, 18 Transition coordinators SOC counseling and Mean change in HbA1c levels between 3 Pooled risk difference from meta-analysis with 18
United Kingdom, United States, medication services and 12 months adolescent-focused studies: 0.11 (0.31 to 0.08)
Israel, Canada
2016 Viana [52] United States, Israel, Canada 6 Enhanced counseling, telecare, SOC counseling Mean change in HbA1c levels between 3 Enhanced counseling intervention: mean
or educational intervention and 12 months difference U 0.31 (95% CI: S0.60 to S0.02)
Telecare intervention: mean difference ¼ 0.12 (95% CI:
0.27 to 0.02)
Educational intervention: mean difference ¼ 0.01 (95%
CI: 0.20 to 0.20)
2015 Deacon [54] United States 1 Text message adherence support SOC counseling Mean change in HbA1c Mean change of 0.06 in control versus 0.20 in
levels at 1 month intervention, P > 0.05
2014 Edwards [60] United States 1 School-based care SOC services Mean change in HbA1c Mean change of 11.5 (95% CI: 9.3–14.0) in control
levels at 3 months versus 9.2 (95% CI: 7.4–11.0) in intervention
2013 Herbert [53] United States, Norway, Austria 3 Phone and text message SOC counseling Mean change in HbA1c Mobile app intervention: P > 0.05b
adherence support levels at 3–6 months Web-based app: 8.8% in intervention (no change in
HbA1c levels from baseline) versus 9.9% in control
(elevated HbA1c levels from baseline) (P for group
and time interaction U 0.006)
Telemedicine support: HbA1c improvement from 9.0%
at enrollment to 9.2% at month 6 for the
telemedicine period versus continued HbA1c levels
of 8.9% at enrollment and at month 6 for the
conventional support period, P < 0.05
2011 Salema [48] United States, Canada 4 Enhanced counseling SOC counseling Mean change in HbA1c Cohen’s d estimates ranged from 0.20 to 0.48, all
levels at 3–12 months P > 0.05
2010 Hood [56] United States, 9 Enhanced counseling SOC counseling Mean change in HbA1c Cohen’s d estimates ranged from 0.55 to 0.59; pooled
United Kingdom, India levels at 3–12 months mean difference from meta-analysis with 9
adolescent-focused studies: 0.11 (95% CI: 0.01 to
0.23); all P > 0.05
2000 Hampson [57] United States 7 Enhanced counseling SOC Mean change in HbA1c Cohen’s d estimates ranged from 0.48 to 2.03; pooled
levels at 3–6 months mean difference from meta-analysis with 7
adolescent-focused studies: 0.33 (SD ¼ 0.67)

95% CI, 95% confidence interval; ART, antiretroviral therapy; MST, multisystemic therapy; RR, relative risk; SOC, standard of care.
a
The table has 30 rows but 26 studies, because Schaefer et al. is listed three times, Salema et al. is listed twice, and Ng et al. is listed twice.
b
Data are shown only for the studies reported in the systematic reviews that included a comparison group (e.g. randomized controlled trials, quasiexperimental studies) and those that were conducted
with 10–24 years old. Bold text indicates a significant effect. Measures of effect differ based on what was reported in the systematic review and/or included primary study (e.g. Cohen’s d, relative risk,
hazard ratio, F statistic). Pooled effect sizes from meta-analyses are reported and noted for those systematic reviews that included a meta-analysis restricted to ART, asthma, and diabetes intervention
studies with 10–24 years old.
c
Parent study only reported P value without a corresponding measure of effect.
 Adherence interventions among youth Velloza et al. 471

Table 4. Summary of key takeaways from this systematic review of store a large number of PrEP pill bottles and find it
adherence support interventions.
reassuring to check in with providers and peers at the
 Interventions which resulted in improved adherence included: text clinic [7,72,73]. Moreover, guidelines for PrEP delivery
message reminders and two-way text message communication with stipulate that individuals should come back to the clinic
providers, enhanced counseling, same-day pill starts and multi-
month dispensing, peer support, and youth-friendly clinics
every 3 months for HIV testing and do not advise
 mHealth and enhanced counseling interventions were effective providing more than 3 months of PrEP at a time [74].
across OCP, ART, diabetes, and asthma medication use. Evidence Rather than significantly extending the timing between
of effectiveness was more mixed for same-day pill starts, multi- pill pick-ups, PrEP programs could consider implement-
month dispensing, peer support, and youth-friendly clinics, where
intervention effectiveness varied by medication type ing decentralized provision (e.g. PrEP in schools or
 We did not find evidence of effectiveness for financial incentives, mobile sites). Telemedicine was effective at improving
directly observed therapy, broad educational or social marketing diabetes medication management [53] and may be
campaigns, or transition care coordinators
 OCP use interventions may be the closest corollary to PrEP
another approach to improve PrEP delivery in contexts
adherence given their focus on improving daily medication use and with busy clinics or in rural or remote regions where
preventing a health condition in an otherwise healthy population. participants may have difficulty getting to a clinic. This is
Investigators may want to weight evidence from OCP studies more particularly salient in the context of restrictions due to
strongly than ART, diabetes, and asthma interventions included in
this review. However, the effective interventions we identified COVID-19, where PrEP programs have had to rapidly
across all four types of medication use have the potential to target adapt to telemedicine to continue services [75]. These
commonly reported barriers to PrEP adherence for adolescent approaches could potentially improve PrEP adherence for
populations and hypothesized mediators of medication use based adolescents and young adults by reducing PrEP stigma
on the information–motivation–behavioral skills model, including
low social support and stigma, low risk perceptions, difficulties from providers and the burden of clinic visits [76].
with dosing regimens, side effects, and logistical challenges of
visiting the clinic and taking PrEP in daily life In at least one study for each health condition, enhanced
 Most included studies were conducted in the United States and
counseling (e.g. motivational interviewing [77], prob-
Europe, and PrEP delivery programs in resource-limited settings
should consider these findings in light of their context and target lem-solving therapy [78,79], multisystemic therapy [80–
population needs 82]) was effective at improving adherence. The counsel-
ing interventions varied in session number (e.g., one-
ART, antiretroviral therapy; OCP, oral contraceptive pill; PrEP, pre-
exposure prophylaxis. time, 8–12 weekly sessions), length, and facilitator (e.g.
lay counselor, peer). Family-based counseling signifi-
cantly improved ART, diabetes, and asthma medication
two-way text messaging with providers significantly management, although it was not tested as an OCP
increased OCP continuation [22], and similar text-based intervention [35,44,50]. Family support is likely an
interventions for HIV testing, ART use, and sexual and important facilitator of PrEP use among young people
reproductive health services found that two-way text who are still living with and financially dependent on
messaging with a provider improved adherence by parents or guardians [83–85], and may be feasibly
increasing knowledge about a medication, motivation, integrated into PrEP delivery for youth who have strong
and perceived support [64–68]. Two pilot studies and one relationships with family members and are willing to
PrEP demonstration project have already incorporated disclose their PrEP use. Interventions that did not show a
text message reminders and two-way text message significant effect on medication adherence were generally
provider communication in PrEP delivery in Kenya those that had fewer counseling sessions and/or measured
and Brazil and found that messages were an acceptable the outcome further from the last counseling session.
way for participants to report on PrEP adherence and
communicate issues with their provider [12,69,70]. In We observed mixed findings on the impact of peer
addition, a PrEP adherence intervention in South Africa counseling; peer interventions were effective for ART
and Zimbabwe found that one-way and two-way text adherence but not OCP, asthma, or diabetes medication
messages were feasible for scalable delivery to check in use. Youth living with HIV likely face greater stigma than
with participants and triage concerns for providers [71], those using OCPs, asthma, or diabetes medication and it
showing promise for future widespread use of text is possible that peer interventions for ART are efficacious
reminders and two-way support services in PrEP by increasing support and motivations to adhere where
programs with youth. HIV is highly stigmatized [86,87]. PrEP programs
incorporating group counseling have already been shown
Multi-month OCP prescriptions significantly improved to be acceptable among youth [71], and may lead to
OCP continuation in one small study [23]. However, this improved PrEP adherence particularly among those who
approach may not work for PrEP adherence among experience stigma related to HIV and sexual behavior
adolescents given data from prior trials showing [63,88,89]. However, group counseling may not be
consistent drop-offs in PrEP adherence and continuation appropriate for all youth, as some may not be able to
when clinic visits were switched from monthly to attend group sessions or may be concerned about
quarterly [5,6,8,9]. Adolescents and young adults have participating in a group where identity is based on a
reported concerns about not having a place to discreetly stigmatized behavior like sexual activity [71,90]. PrEP
472 AIDS 2021, Vol 35 No 3

programs may consider hosting digital peer groups to commonly reported barriers to PrEP adherence and
reduce some of these barriers. mediators of PrEP use for adolescent populations
[15,16,92]. However, the intervention choice will
The current review has a number of limitations. We did depend on context and population needs. Long-acting
not exclude studies for issues related to methodological HIV prevention and coformulated contraceptives and
rigor to be inclusive; however, a number of studies had HIV prevention products may become available in the
limitations in outcome measurement (e.g. used self- next few years, which will provide method choice for
reported adherence only), small sample sizes, and loss to young people but still requires adherence support.
follow-up. Excluding studies on the basis of quality such Similarly, the shorter, four-pill event-driven PrEP dosing
as those with imbalance across groups and high loss to regimen for young MSM requires only short-term
follow-up, would have excluded interventions on peer- adherence [95,96]. Future PrEP programs could focus on
based counseling, enhanced counseling with motiva- evaluating adherence support interventions outlined in
tional interviewing, and same-day OCP starts, but this review, paying particular attention to those that target
would not have substantially change our conclusions as theoretical mediators of medication adherence and
we did not otherwise find strong evidence in support of address empirically identified barriers to PrEP adherence,
peer-based counseling and motivational interviewing with the ultimate goal of developing effective interven-
for OCP use, and same-day pill starts did not appear to tions to achieve substantial reduction in new HIV
have an impact on long-term OCP continuation. In infections among adolescents and young adults world-
addition, we base our conclusions about promising wide.
interventions on the magnitude of effect sizes and
statistical significance. Despite these limitations, when
taken together, the results provide useful indications of
which interventions may be successful among youth. A
majority of studies were conducted in the United States Acknowledgements
and Europe (particularly OCP, asthma, and diabetes
We are grateful for the dedication of the thousands of
studies), making it difficult to extrapolate results to
young people who have participated in oral contra-
resource-limited settings. While information from
ceptives, ART, diabetes, and asthma clinical trials and
effective OCP, ART, diabetes, and asthma interventions
adherence studies around the world.
may be useful to inform PrEP interventions for young
people, there are key differences in populations, settings,
Author contributions: S.D. and R.B. conceived the study.
provider competencies, stigma, and motivations that
S.D., R.B., B.K., L.-G.B., C.C., S.H., S.D.-M., and J.V.
may influence whether these are successful with PrEP.
developed the systematic review protocol. J.V. conducted
Interventions for OCP, ART, diabetes, and asthma
the systematic review with support from S.D. B.K., L.-
medication adherence largely target similar theoretical
G.B., C.C., S.H., S.D.-M., R.B., and S.D. provided
mediators of medication use, which have also been
oversight of the methods and contributed to the
described as barriers to PrEP use, but some theoretical
interpretation of results. J.V. prepared the first draft of
constructs of behavior change may be more relevant
the article and all authors edited, reviewed, and approved
for PrEP adherence than these medications. For
the final article. All authors have made substantial
example, motivations to use PrEP may differ from
contributions to the work, drafted or revised it, and
motivations to use diabetes medication if consequences
agree to be accountable for all aspects of the work.
of nonadherence are seen to be more severe for one
health condition versus another or normative beliefs
Support for this work was provided by the WHO through
about medication differ by condition. Moreover,
Unitaid. J.V. was supported by the National Institute of
‘effective’ PrEP adherence is complex and PrEP needs
Mental Health of the US National Institutes of Health
may change as HIV risk and sexual behavior change.
(grant F31 MH113420) and the National Institute of
Interventions that improve ART, diabetes, and asthma
Allergy and Infectious Diseases (grant T32 AI007140).
medication management therefore may not be as
The results and interpretation presented here do not
appropriate for PrEP, compared with OCPs which also
necessarily reflect the views of the study funders. The
do not need to be taken with sustained, lifelong high
funder of the study had no role in data collection, analysis,
adherence [91].
interpretation, or writing of the report. The correspond-
ing author had full access to all the data in the study and
In conclusion, we identified a number of effective
had final responsibility for the decision to submit
interventions to support daily medication adherence
for publication.
among youth that may be relevant for PrEP, including
enhanced counseling, text messages and phone-based
counseling, same-day pill starts and multi-month
dispensing, peer support, and youth-friendly clinics. Conflicts of interest
These interventions have the potential to target The authors report no potential conflicts of interest.
 Adherence interventions among youth Velloza et al. 473

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