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Interventions to improve antiretroviral therapy adherence among adolescents in low- and middle-income countries: A systematic review of the literature

  • Kathleen Ridgeway ,

    Roles Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Validation, Writing – original draft, Writing – review & editing

    kridgeway@fhi360.org

    Affiliation Global Health, Population, & Nutrition, Durham, NC, United States of America

  • Lisa S. Dulli,

    Roles Validation, Writing – review & editing

    Affiliation Global Health, Population, & Nutrition, Durham, NC, United States of America

  • Kate R. Murray,

    Roles Conceptualization, Formal analysis, Writing – review & editing

    Affiliation Global Health, Population, & Nutrition, Durham, NC, United States of America

  • Hannah Silverstein,

    Roles Formal analysis, Validation

    Affiliation Maternal and Child Health, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC, United States of America

  • Leila Dal Santo,

    Roles Formal analysis

    Affiliation Global Health, Population, & Nutrition, Washington, D.C., United States of America

  • Patrick Olsen,

    Roles Formal analysis

    Affiliation Global Health, Population, & Nutrition, Durham, NC, United States of America

  • Danielle Darrow de Mora,

    Roles Conceptualization

    Affiliation Global Health, Population, & Nutrition, Washington, D.C., United States of America

  • Donna R. McCarraher

    Roles Conceptualization, Validation, Writing – review & editing

    Affiliation Global Health, Population, & Nutrition, Durham, NC, United States of America

Interventions to improve antiretroviral therapy adherence among adolescents in low- and middle-income countries: A systematic review of the literature

  • Kathleen Ridgeway, 
  • Lisa S. Dulli, 
  • Kate R. Murray, 
  • Hannah Silverstein, 
  • Leila Dal Santo, 
  • Patrick Olsen, 
  • Danielle Darrow de Mora, 
  • Donna R. McCarraher
PLOS
x

Abstract

Introduction

Globally, an estimated 30% of new HIV infections occur among adolescents (15–24 years), most of whom reside in sub-Saharan Africa. Moreover, HIV-related mortality increased by 50% between 2005 and 2012 for adolescents 10–19 years while it decreased by 30% for all other age groups. Efforts to achieve and maintain optimal adherence to antiretroviral therapy are essential to ensuring viral suppression, good long-term health outcomes, and survival for young people. Evidence-based strategies to improve adherence among adolescents living with HIV are therefore a critical part of the response to the epidemic.

Methods

We conducted a systematic review of the peer-reviewed and grey literature published between 2010 and 2015 to identify interventions designed to improve antiretroviral adherence among adults and adolescents in low- and middle-income countries. We systematically searched PubMed, Web of Science, Popline, the AIDSFree Resource Library, and the USAID Development Experience Clearinghouse to identify relevant publications and used the NIH NHLBI Quality Assessment Tools to assess the quality and risk of bias of each study.

Results and discussion

We identified 52 peer-reviewed journal articles describing 51 distinct interventions out of a total of 13,429 potentially relevant publications. Forty-three interventions were conducted among adults, six included adults and adolescents, and two were conducted among adolescents only. All studies were conducted in low- and middle-income countries, most of these (n = 32) in sub-Saharan Africa. Individual or group adherence counseling (n = 12), mobile health (mHealth) interventions (n = 13), and community- and home-based care (n = 12) were the most common types of interventions reported. Methodological challenges plagued many studies, limiting the strength of the available evidence. However, task shifting, community-based adherence support, mHealth platforms, and group adherence counseling emerged as strategies used in adult populations that show promise for adaptation and testing among adolescents.

Conclusions

Despite the sizeable body of evidence for adults, few studies were high quality and no single intervention strategy stood out as definitively warranting adaptation for adolescents. Among adolescents, current evidence is both sparse and lacking in its quality. These findings highlight a pressing need to develop and test targeted intervention strategies to improve adherence among this high-priority population.

Introduction

Recent years have seen great improvements in access to antiretroviral therapy (ART) for people living with HIV, as global ART coverage has more than doubled from 2010 to 2015 [1]. These efforts, however, are insufficient to ensure positive health outcomes; patients must be highly adherent to ART regimens in order to achieve viral suppression [2, 3] and experience reduced likelihood of HIV-related mortality [4, 5], drug resistance [68], and secondary HIV transmission [9]. Taking at least 95% of all ART doses is widely regarded as a standard benchmark for adequate adherence [3].

Global stakeholders and decision-makers have recently prioritized targeted programming and differentiated care for adolescents with HIV in response to a growing burden among young people [1013]. Thirty percent of new HIV infections occurred among adolescents (15–24 years) in 2014, and HIV is the second leading cause of death among adolescents globally [1416]. The burden of the epidemic lies largely in sub-Saharan Africa, where the prevalence is estimated to be 2.2% among young women (15–25 years) and 1.1% among young men compared to global estimates of 0.4% and 0.3%, respectively [17].

Estimates of ART adherence among adolescents living with HIV (ALHIV) in low- and middle-income countries (LMIC) vary substantially. A 2014 systematic review found estimates of adherence ranging from 16% to 99% among adolescent populations globally [18]; a meta-analysis of data for adolescents and young adults (12–24 years) in 53 countries, also from 2014, found adherence based on either self-report or viral load measures was 84% in both Africa and Asia [19]. Virologic data for ALHIV are limited but indicate that rates of viral suppression (<400 copies/mL) range from 27% to 89% in Africa, from 52% to 87% in Asia, and from 37.5% to 49% in Central and South America [20]. Expanding HIV testing efforts and new “Test and Treat” or “Test and Start” programming in many LMIC will see a larger number of patients diagnosed with HIV and immediately eligible for treatment, challenging providers to ensure high adherence among a larger, likely healthier patient population [21].

Given the limited body of evidence on adherence interventions for ALHIV [2224], this systematic review included interventions designed to increase ART adherence among both HIV-infected adults and adolescents in LMIC. The specific objectives of this review were to 1) identify interventions available in the peer-reviewed and grey literature designed to increase ART adherence among adults and adolescents, 2) describe the body of literature in both populations, and 3) identify evidence-based intervention strategies that have potential to be scaled-up or adapted for ALHIV in LMIC. Although numerous systematic reviews have evaluated the effectiveness of adherence interventions for the general population [2534], few have focused specifically on ALHIV in LMIC and none to date have included literature from adult populations to propose ALHIV-specific recommendations.

Methods

We used a systematic search strategy to search PubMed, Web of Science, Popline, the USAID Development Experience Clearinghouse [35], and USAID’s AIDSFree Project website [36] (see supporting information). Teams of reviewers (among KR, KM, LD, DM, PO, DD, and LCD) conducted title, abstract, and full text review and evaluated the methodological quality of each publication with the aid of the NIH National Heart, Lung, and Blood Institute (NHLBI) quality assessment tools [37]. Additional methodological details are available in a companion article, which reviews interventions designed to increase retention of adults and adolescents in HIV care [38].

A study was eligible to be included if it met all of the following criteria: 1) evaluated the effects of or examined the associations between an intervention or program and ART adherence or retention in HIV care; 2) reported quantitative measures of ART adherence or retention in care; 3) conducted among adults (age ≥18) or adolescents (mean age 10–19); and 4) published within the five-year search period (20 November 2010 to 20 November 2015). Letters, editorials, conference abstracts, and presentations were not eligible for inclusion. We excluded studies that were not available in English or were conducted in World Bank high-income countries [39]. Pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) interventions, interventions to increase HIV testing rates or increase engagement in pre-ART care, and pharmaceutical interventions to change drug combinations were excluded. We also excluded interventions tailored to the specific needs of sub-populations (e.g. prisoners, people who inject drugs). This article focuses on interventions to improve ART adherence; a companion article describes interventions to improve retention in HIV care [38].

For this review, we included studies that reported any quantitative measure of ART adherence including viral load, measures of drug concentrations, CD4 cell counts, self-reported adherence using either novel or validated measures, pill counts, and data from electronic adherence monitoring devices (EAMDs).

Results and discussion

We identified 13,429 potentially relevant publications, of which fifty-two were eligible for inclusion in this review (Fig 1). Forty-five studies were conducted among adults, five were conducted among both adults and adolescents, and two were conducted among adolescents only. Fourteen of the adult studies were of good methodological quality, 15 of fair quality, and 16 of poor quality. Among the five studies that included both adults and adolescents, one was rated good, one was rated fair, and three were rated poor quality. Both of the studies that involved adolescents exclusively were fair quality.

All 52 studies were published in peer-reviewed journals. We found 33 single-country studies from sub-Saharan Africa (10 countries), 11 from Asia (four countries), five from Central and South America (three countries), one from Haiti, and one from Pakistan. There was one multi-country study that was conducted in five sub-Saharan African countries, Brazil, Haiti, and Peru.

The 52 publications described 51 unique interventions. Among studies targeting adults exclusively, mHealth-based interventions (n = 12), community- or home-based care (n = 10), and individual or group adherence counseling (n = 8) were most common (Table 1). Other interventions among adults included instrumental support (n = 5), task shifting or decentralization (n = 4), multi-component facility-based interventions (n = 3), pharmacist counseling (n = 1), and depression treatment (n = 1). Interventions for combined adult and adolescent study populations included adherence counseling (n = 2), community-based adherence support (n = 2), and short message service (SMS) reminders (n = 1). Both studies conducted with adolescents evaluated group adherence counseling interventions.

Adherence was measured using varied methods. Biological measures included CD4 counts, ART concentrations in hair samples, and viral load. Viral load measures included viral suppression using cut-offs of <50, <100, <200, or <400 copies/mL; and virologic failure with cut-offs of >40, >400 or >5,000 copies/mL. Pill counts were conducted by clinic staff or lay health workers and measured the number of pills remaining compared to the number of doses that should have been taken over a specified time period. Similarly, EAMDs such as MEMSCapTM or WisepillTM measured whether and when patients opened pill bottles for each medication. Self-reported measures included the Adult AIDS Clinical Trial Group (AACTG) self-report measure [42], the Antiretroviral General Adherence Scale (AGAS) [43], the Pediatric AIDS Clinical Trials Group (PACTG) self-report measure [44, 45], and Visual Analog Scales (VAS) [46].

The 52 studies presented in this review included randomized controlled trials (RCTs) (n = 29), quasi-experimental studies (n = 5), single-group pre-test/post-test studies (n = 5), prospective cohort studies (n = 6), and retrospective cohort studies (n = 4). Studies are grouped by type and discussed below, with detailed information in Table 2.

Counseling interventions

12 studies described counseling interventions that were delivered to individuals, groups, or combined individual and group sessions [4752, 54, 5658, 60, 61]. Two studies were conducted among adolescents only [58, 60], two among both adults and adolescents [50, 61], and eight among adults only [4749, 51, 52, 54, 56, 57]. Three additional studies that combined individual counseling with SMS reminders are described in the following section.

Individual adherence counseling

We identified four studies (two RCTs, one single-group pre-test/post-test study, and one retrospective cohort study) that evaluated individual adherence counseling interventions; three of these were conducted among adults only [4749] and one among both adults and adolescents [50]. Counseling sessions were held by lay health workers, trained health professionals, or multidisciplinary teams, and aimed to increase HIV knowledge and address adherence barriers. None of the studies found statistically significant effects on adherence. All studies were fair to poor quality, and faced methodological issues such as high refusal rates (>20%) [47], inconsistent intervention implementation [49], and large amounts of missing data [50]. Two publications failed to report sample size calculations or power analyses [49, 50].

Group adherence counseling

Group counseling interventions were described in seven studies, five of which were conducted among adults [51, 52, 54, 56, 57] and two among adolescents [58, 60].

Among adults, statistically significant results were found in only one of the five studies, which were overall of fair quality. A quasi-experimental pilot study in Nigeria found significant differences in mean adherence (Z = -3.581, p<0.001) and three other adherence outcomes between adult women receiving a group motivational interviewing intervention and women that did not [51]; however, this evidence is limited because baseline measures were not presented. An RCT in Zambia found significant improvements in adherence among adults receiving a group counseling intervention compared to individual counseling; however, these differences were no longer detectable once the groups were crossed over, and adherence decreased in both groups [52]. Based on these studies, evidence supporting group counseling as a strategy to improve adherence among adults is currently lacking.

Among the two studies that evaluated group counseling for ALHIV (Figs 2 and 3), one found statistically significant intervention effects [58] and the other did not [60]. A pilot RCT in Thailand delivered group counseling to adolescents (15–24 years) and found significant differences in the proportions of patients >95% adherent to ART at endline (χ2 = 14.723, p<0.001) [58]. A second pilot RCT in South Africa evaluated a group counseling intervention delivered to young ALHIV (10–13 years) and their family members and did not find a significant treatment effect (β = 1.527, p = 0.05) [60]. It is difficult to draw conclusions based on two studies with small sample sizes; however, the presence of some significant findings for the effect of group counseling on adolescent adherence shows that further investigation is warranted.

Individual plus group adherence counseling

An RCT in Indonesia used a psychiatrist to deliver both individual and group counseling sessions to adult women and found no statistically significant effects on self-reported adherence or viral load [61]. The validity of these findings are uncertain given the authors’ failure to describe the control group or report p-values for outcome analyses, and reporting of point estimates outside of reported confidence intervals.

mHealth interventions

Thirteen studies described interventions that included the use of mobile phones as a platform to improve adherence [6375]; 12 of these studies were conducted among adults [6367, 6975] and one was conducted among adults and adolescents combined [68]. Interventions included SMS reminder messages sent at regular intervals or triggered by EAMDs, interactive voice response (IVR) phone calls, and multi-faceted interventions using SMS reminders combined with adherence counseling.

SMS reminders

Four RCTs conducted among adults tested interventions that reminded participants to take their medications by sending SMS messages at regular intervals [6366]. A multi-site RCT in Kenya found that receiving weekly SMS that solicited responses from participants decreased rates of non-adherence (RR = 0.81 [0.69, 0.94]) and virologic failure (RR = 0.85 [0.72, 0.99]) among intervention participants compared to a standard-of-care control [63]. Another RCT in Kenya compared each of four study arms–short daily messages, short weekly messages, long daily messages, and long weekly messages–to a control of no SMS reminders and found no statistically significant effects [64]. Additional analyses revealed that weekly delivery of SMS (whether short or long) was associated with improved adherence compared to the control (p = 0.03), but no effect was observed for other combined groups of daily, short, or long reminders [64]. The remaining two studies found no effect on adherence [65, 66]. The mixed results of these four studies—which were overall fair quality—provides no clear support for the effectiveness of SMS reminders to improve adherence. Statistically significant results from the study that asked participants to respond to the SMS rather than sending “one-way” messages indicate that further investigation into the effectiveness of this strategy is warranted.

EAMD-triggered SMS reminders

Two good-quality RCTs evaluated interventions that delivered triggered SMS reminders when EAMDs were not opened during scheduled dosing periods [67, 68]. An RCT conducted among adults initiating ART in China found statistically significant differences between intervention and control groups in the likelihood of achieving ≥95% adherence (RR = 1.69 [1.29, 2.21]) and mean adherence (p = 0.003) post-intervention [67]. The study did not find significant differences in virologic outcomes, which may be attributable to the relatively short follow-up time (6 months) or to high rates of viral suppression in the control group (98%) at baseline. Another RCT conducted with adults and adolescents in South Africa found no significant effects on adherence or virologic failure after 6 months on the intervention [68]. Given the mixed findings of these two studies, more research is needed to better explore the potential of EAMD-triggered SMS reminders.

IVR or phone call reminders

Four studies conducted among adults tested the use of IVR calls or phone calls as reminders to improve adherence [6972]; three of these found statistically significant results [6971]. A single-group pre-test/post-test study in India that provided twice-daily IVR calls as well as SMS appointment reminders found significant increases in time elapsed since participants missed a dose (p = 0.015) from baseline to post-intervention [69]. Another single-group pre-test/post-test study in India that examined the effect of weekly IVR calls combined with picture SMS found a significant increase from baseline to post-intervention in the proportion of participants with ≥95% adherence (85% to 94%, p = 0.016) [70]; however, the study had a substantial (36%) refusal rate. An RCT in Pakistan combined a patient-designed ART dosing schedule with weekly reminder phone calls and found significant differences in proportions of patients reaching optimal adherence (reported as p = 0.000) and viral suppression (p = 0.012) between intervention and control groups [71]. The fourth study examined the effect of IVR calls on adherence and did not find significant intervention effects [72]. Despite significant results from three out of the four studies, the strength of the evidence is limited by nonexperimental study designs [69, 70] and methodological issues such as high refusal rates [70] and short intervention and follow-up times [69].

SMS or alarm reminders plus individual adherence counseling

Three studies found mixed results on the effect of SMS or alarm device reminders combined with individual adherence counseling for adults [7375]. An RCT in Nigeria examined the effects of individual adherence counseling and twice-weekly SMS reminders for non-adherent adults and found significant differences in the number of participants who achieved ≥95% self-reported adherence (χ2 = 5.211, p = 0.022) and in mean CD4 cell count (Mann-Whitney U-test, U = 2.44, p = 0.007) between intervention and control groups at endline [73]. However, the proportion of participants achieving adequate adherence was still sub-optimal (76.9% intervention, 55.8% control). A four-arm RCT in Kenya compared adherence improvements and rates of virologic failure between participants receiving individual adherence counseling, alarm reminders, or both counseling and reminders and patients receiving standard of care; the study only found statistically significant differences in virologic failure rates (p = 0.008) between participants who received adherence counseling and those who did not regardless of receiving reminders [74]. A third RCT in China allowed participants to self-select into one of three intervention conditions (alarm device, adherence counseling, or alarm device plus counseling) and compared all intervention participants to a control group receiving adherence education; the study found positive results on self-reported adherence (OR = 2.23 [1.05, 4.72]) and did not find any effect on clinical adherence measures [75]. Given the mixed results and methodological quality issues of these studies, better-designed and -implemented studies should be conducted before this strategy's effectiveness can be determined.

Community- and home-based interventions

Thirteen studies described 12 interventions implemented in participants’ communities or homes [40, 41, 7686]. These interventions included adherence support provided by lay health workers or volunteers, community- and facility-based adherence activities, home-based directly observed therapy (DOT) or adherence support by lay treatment supporters, and community-based social support. Two studies were conducted among both adults and adolescents [82, 83]; the remaining 11 were conducted among adults [40, 41, 7681, 8486].

Community-based adherence support

Eight studies (three RCTs, two quasi-experimental studies, and one prospective and two retrospective cohort studies) tested or examined associations between adherence outcomes and community-based adherence support (CBAS) interventions [7683]. Six studies were conducted among adults [7681] and two included adults and adolescents [82, 83]. CBAS interventions included adherence support through home visits by a community-based health worker or volunteer and included activities such as DOT, basic clinical assessments, referrals, pill counts, and home ART delivery.

Among the six overall fair-quality CBAS intervention studies conducted among adults [7681], five had statistically significant results [7680]. An RCT in China provided home visits by nurses and peer educators to non-adherent adults and found that greater proportions of patients achieved ≥90% adherence over the intervention period compared to the control (84% intervention, 53% control, p = 0.009) in adjusted analyses [76]; however, this study was limited by high loss to follow-up in the control group. A quasi-experimental study in Uganda provided weekly home visits by volunteer community members to perform pill counts, deliver ARTs, and assess clinical problems and provide referrals; compared clinic-based patients, participants had significantly higher odds of achieving virologic suppression (OR = 2.47 [1.01, 6.04]) [77]. A prospective observational cohort study compared patients receiving weekly home visits by patient advocates to patients receiving clinic-based care and found that patients receiving home visits were significantly more likely to be retained in care with a suppressed viral load after one year (aRR = 1.15 [1.03, 1.27]) [78]. Two additional studies found positive results [79, 80]; but were limited by selection bias [80] and differential attrition [79]. Despite some methodological limitations, current evidence suggests this intervention strategy warrants exploration.

Two retrospective cohort studies conducted among adults and adolescents found statistically significant associations between exposure to CBAS and adherence [82, 83]. A study in South Africa examined exposure to Patient Advocates (PA) as part of a CBAS project and observed higher odds of achieving viral suppression among patients who had PAs assigned to them compared to those who did not (aOR = 1.22 [1.14, 1.30] at 6 months; aOR = 2.66 [1.61, 4.4] at 5 years) [82]; however, these findings were limited by incomplete data and no measurement of the exposure or frequency of interactions with PAs. A second study in South Africa also compared adherence rates by exposure to PAs among patients and observed significantly higher rates of adequate adherence (X2 = 6.131; p = 0.021) among those with PAs compared to those who did not [83]; however, the evidence is weakened by selection bias as study sites were selected based on the completeness of data available. These two observational studies provide initial evidence that assignment to PAs may improve adherence, but methodological problems limit confidence in their results.

Multi-component facility- and community-based program

Two publications described one observational study that evaluated associations between program uptake and treatment outcomes among adults in Kenya [40, 41]. Program components included home visits by CHWs, treatment supporters, support groups, clinician pill counts, and pharmacist counseling. One publication reported significantly higher adherence among those who had participated in more than three support group meetings (p<0.05) and those who had four or more unannounced clinician pill counts (p = 0.001) compared to those who did not [40]. The second publication found a positive linear relationship between adherence and the number of unannounced pill counts performed (r = 0.21, p<0.01) [41].

Peer treatment supporters

Two RCTs evaluated peer treatment supporters that provided adherence reminders or DOT to adult patients [84, 85]. An RCT in Uganda found a significantly higher proportion of participants receiving adherence reminders from treatment supporters were ≥95% adherent compared to the control at endline (OR = 4.51 [1.22, 16.62], p = 0.027), but found no significant differences in mean adherence [84]. The second RCT, conducted among adults across sites in eight countries, tested the effect of DOT provided by peer treatment supporters but found no significant effects on adherence or virologic failure among adults on second-line ART [85]. Although both studies had randomized designs and were of good quality, the lack of consistent results and the small number of studies indicate the need for more research to determine the effectiveness of this strategy.

Community-based social network support

A quasi-experimental study in Kenya examined impacts on ART adherence of a community-based social network support intervention that provided education and social support to groups consisting of one HIV-infected individual and his or her close friends or family members [86]; no significant differences in hair ART concentrations were observed between the intervention and comparison groups. However, it should be noted that there were markedly higher refusal rates among the intervention group than in the comparison group, and that results may have been influenced by contamination between study groups.

Pharmacist counseling

One RCT tested a structured counseling intervention delivered by pharmacists to adult ART patients in Brazil that had no effects on self-reported adherence or viral load [87]. The authors attributed the lack of significant findings to high baseline adherence among study participants.

Depression treatment

An RCT in South Africa randomized HIV-infected adult patients with clinically diagnosed depression to receive either pharmacological treatment for depression or interpersonal psychotherapy and compared changes in patients’ adherence to patients without depression receiving standard of care [89]. There were no significant differences between either treatment arm and the control group, or between the two treatment arms. This study is limited by differences in baseline characteristics of individuals in the intervention and control groups as well as by a small sample size (n = 30 control group, 32 intervention group).

Facility-based interventions

Three studies examined the impact of facility-based interventions to increase adult patients’ ART adherence through strengthened patient services, support services such as adherence reminders, and changes to staff training and clinic workflow [90, 92, 93]; two of these studies reported statistically significant effects [90, 92]. A single-group, pre-test/post-test study in Uganda tested an enhanced adherence package that provided improved counseling, health education, adherence diaries, mobile reminders, treatment supporters, tracing, and strengthened adherence monitoring [90]. The study found that participants experienced a significant increase in mean adherence (97.4% to 99.1%, p<0.001) and that the proportion of participants with ≥95% adherence increased over time (7.0% [4.6, 9.4] p = 0.001). Another single-group, pre-test/post-test study in Uganda introduced a new appointment system, provided appointment reminders, encouraged providers to give longer prescriptions to reduce refill frequency, and “fast tracked” stable patients needing ART refills [92]. The study found a significant decrease in the odds having a gap in taking medication over the past 3 days comparing pre- to post-intervention (aOR = 0.69 [0.60, 0.79]). A third, quasi-experimental study that examined increased adherence monitoring and targeted adherence counseling for non-adherent patients did not find significant intervention effects; however, baseline adherence was high (>90%) in both study groups [93]. Although two studies found statistically significant results, their non-experimental study designs limit the strength of these findings.

Instrumental support interventions

Five interventions tested the effect of instrumental (tangible) support on ART adherence among adults [9498]. Four of these examined nutrition support through monthly food rations [9497], and one evaluated the provision of disability grants to people living with HIV [98].

Nutrition support

Four studies (two RCTs, one quasi-experimental study, and one retrospective cohort study) evaluated nutrition-support interventions [9497]; three found statistically significant effects on adherence [9496]. A quasi-experimental study in Zambia found significantly different estimates of mean adherence at endline between intervention and comparison groups (t = 4.06, p<0.01) [94]. Significant positive results were also found in a retrospective cohort study in Niger that examined associations between exposure to a monthly food ration and mean adherence (p<0.005) and mean CD4 counts (aRR = 43.0 [4.5, 81.5]) [95]. These findings are limited by their observational nature and the fact that no baseline adherence or clinical measures were reported for the exposure groups. The provision of a monthly household food basket was also examined in an RCT in Honduras [96] that found that participants receiving nutritional education plus the food basket had fewer delayed pharmacy refills than those receiving education only (β = -0.196, p<0.01) but did not have any effect on self-reported adherence or missed appointments. The fourth study, an RCT in Haiti, compared a standard ready-to-use supplementary food to a less expensive corn-soy blend on a variety of clinical outcomes including adherence [97]; over the 12-month intervention, adherence did not change significantly in either group nor were there significant differences between the two groups’ adherence at any time point (0, 6, and 12 months). Positive effects from the three studies that examined adding nutrition support to ART care provide preliminary evidence for the use of this strategy to improve adherence among adult patients.

Disability grants

One prospective cohort study examined the relationship between adherence and receiving disability grants among adult patients initiating ART in South Africa [98]. The authors compared self-reported adherence between patients continuing to receive a disability grant and those that had received a grant and later lost their eligibility status and found no statistically significant association, likely due to the fact that over 90% of study participants maintained >95% adherence while receiving and after losing the grants.

Task-shifting and decentralization interventions

Four studies tested ART service delivery interventions for adult patients [99102]; three of these evaluated task-shifting of services from physicians to lay health workers, nurses, or peer counsellors [99101], and one evaluated providing decentralized services at semi-mobile clinics [102].

Task shifting

Three RCTs evaluated task-shifting of ART care and found equivalent or improved adherence outcomes for adult patients who received ART services from lay health workers, nurses, or peer counsellors compared to those who remained in standard care delivered by a physician or clinical officer [99101]. A study in South Africa found comparable rates of viral suppression and significantly higher mean CD4 counts at follow-up for participants who visited trained nurses for ART re-prescription compared to doctors (β = 24.2 [7.2, 41.3], p = 0.007) [99]. The other two studies, one which shifted services from doctors and certified counsellors to nurses and peer counsellors, and the other which provided care by trained lay health workers, demonstrated that services provided by lower cadre or lay health providers were not inferior to standard of care services [100, 101]. Two of the interventions required patients to be stable on ART for a defined period before they were eligible for task-shifted services [99, 101], which may limit the utility of this intervention for individuals initiating ART or experiencing clinical or adherence issues. Although limited in number, the three task-shifting studies provide promising indications that stable patients who are down-referred for ART care experience equivalent, if not improved, adherence compared to standard care.

Decentralization

One retrospective cohort study in Kenya examined the association between receiving care at a decentralized, semi-mobile clinic or a district hospital and adherence and CD4 cell counts [102]. This study found no statistically significant associations between where patients received care and their mean CD4 count or pill-count adherence; high proportions of patients reported taking all of their medication (81% of hospital-based patients, 86% of semi-mobile clinic patients).

Limitations of the reviewed studies

The quality of the studies included in this review varied; fewer than one-third of all studies achieved a “good” quality rating, and nearly all of these were RCTs. Our assessment of a study’s quality was often limited due to a failure to report critical information such as sample size or power calculations or participant inclusion criteria, or to adequately describe analyses or measures. Moreover, a substantial number of studies were affected by large, and often differential, attrition of study participants. Some studies, particularly several that did not find statistically significant intervention effects, were presented as pilot studies and were inadequately powered to detect modest effect sizes. A lack of methodologically rigorous, adequately powered studies, particularly among adolescents, makes it difficult to draw conclusions with regard to their potential for future implementation. More rigorous research in this field is critical, as is replication of studies with positive findings in other settings. Furthermore, many of the studies described in this review were multifaceted, with some delivering multiple intervention components and others providing adherence support as a part of a broader package of services; this makes it impossible to discern the relative effect of each intervention component or identify which aspects are most impactful on adherence.

Another limitation of these studies, and of adherence research as a whole, lies in the challenge of accurately measuring medication adherence and in the variety of methodologies utilized. Beyond issues of validity and precision of each measure used, it is difficult to compare the effectiveness of studies reporting different measures or different definitions of adequate adherence.

Recommendations

Interventions that involved task shifting and community-based adherence support had the most promising evidence for adult populations, and should be tested among ALHIV. Additionally, research should examine the acceptability and cost-effectiveness of adapting community-based adherence support interventions for ALHIV.

Interventions that used mHealth platforms were numerous, but largely focused on simple adherence reminders; new strategies for using mHealth platforms to improve adherence should be developed and evaluated with a special focus on soliciting participant engagement as well as targeting the specific barriers to adherence experienced by ALHIV.

Nutrition support found favorable results among adults, but future implementation may be hindered by high cost and an increasingly difficult funding environment. Adaptation and testing of nutrition support interventions for ALHIV may only be warranted in settings that are amenable to long-term support for this strategy.

The two studies that evaluated the effect of group adherence counseling interventions for adolescents provided preliminary evidence as to its utility. Further research should be conducted on this topic, particularly focusing on providing targeted counseling for ALHIV with suboptimal adherence.

Conclusions

We found a relatively large body of evidence on interventions to improve adherence among adults living with HIV in LMIC; however, many of these studies’ methodological quality are limited. Moreover, there is a striking lack of evidence on adherence interventions specifically for adolescents. Future research and programming should seek to answer critical questions as to whether or not existing approaches can be successfully adapted for ALHIV to address this population’s particular needs.

Acknowledgments

This manuscript was made possible by the support of the American People through the support of the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) through the U.S. Agency for International Development (USAID) under task order contract number AID- OAA-TO-15-00003, YouthPower Action under IDIQ contract number AID-OAA-I-15-00009, YouthPower: Implementation. The contents of this publication are the sole responsibility of FHI 360 and do not necessarily reflect the views of USAID or the United States Government. We would like to thank Carol Manion for assisting with the design of the search strategy and Michael Szpir for editing this manuscript.

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