Chaiyachati, Krisda H.a; Ogbuoji, Osondub; Price, Matthewb; Suthar, Amitabh B.c; Negussie, Eyerusalem K.c; Bärnighausen, Tillb,d
Antiretroviral treatment (ART) has converted a highly fatal HIV infection into a chronic condition that requires lifelong care . Within the past decade, worldwide access to ART has improved significantly, with almost 10 million people receiving ART by the end of 2012 . In addition to its life-prolonging effects, ART can also reduce HIV transmission to uninfected people [3,4]. In this new era of HIV treatment, the continued success of ART will depend on improving our understanding of when to initiate therapy, creating continuity of care, and ensuring high treatment adherence. Adherence is the extent to which a person uses a medication according to medical recommendations, inclusive of timing, dosing, and consistency. Arguably, adherence is the most critical factor in ensuring ART success, because without good adherence, treatment failure is likely, leading to avoidable HIV-related morbidity and mortality. Additionally, imperfect adherence increases the risk of developing resistant HIV strains and transmitting the virus to others [5–7]. Because adherence behaviours and patterns can profoundly affect an individual's treatment response and potentially narrow future therapeutic options, improving and sustaining ART adherence is a critical component and priority of public health efforts.
People living with HIV and their care providers often face challenges in ensuring good adherence. A 2011 meta-analysis, which pooled ART adherence of 33 199 adults in 84 observational studies, reports that only 62% of individuals took at least 90% of their prescribed ART doses . Given these adherence difficulties, effective, feasible and acceptable interventions to enhance ART adherence are urgently needed to ensure the continued success and clinical and financial sustainability of the global ART scale-up [9–11]. Multiple systematic reviews and meta-analysis of ART adherence-enhancing interventions have been conducted over the past few years, but these studies have often been limited to particular interventions, populations, or settings [12–16].
To inform the evidence base for the 2013 WHO consolidated guidelines on the Use Antiretroviral Drugs for Treating and Preventing HIV Infection , we conducted a rapid systematic review synthesizing the research results on ART adherence-enhancing interventions across intervention types, populations, and settings. Our review advances the existing literature in three ways: first, it is the most comprehensive compilation of the evidence on adherence-enhancing interventions to date; second, it allows evaluation of robustness of interventions across settings; and third, we indicate studies that focus on specific populations of particular interest because of comorbidities and other vulnerabilities that may interfere with their ability to adhere to ART. In addition to the contribution to the WHO 2013 consolidated guidelines, our review aims to provide a guide for ART programme managers, policy makers, and researchers to the portfolio of ART adherence-enhancing interventions for practice, policy and further study.
General methodology of rapid systematic reviews
We conducted a rapid systematic review of the global evidence on interventions to improve ART medication adherence. Rapid systematic reviews differ from traditional systematic reviews in that they utilize pre-existing systematic reviews to identify relevant research evidence in addition to screening databases for recent primary studies [18–21]. This practice is useful for making health policy decisions, because it allows examination of the evidence while ensuring that information is assimilated as fast as possible given prior work [18–24].
Using pre-existing systematic reviews to identify relevant primary articles reduces the time needed to identify the relevant body of evidence on a particular topic. However, given that the time required to conduct, complete, and publish a systematic review typically ranges from 1 to 2 years [20,22], synthesis solely based on pre-existing systematic reviews runs the danger of failing to incorporate evidence that has accrued over the most recent few years. We thus supplement our systematic review of systematic reviews, with a complete screening of databases of primary evidence, but – in order to maintain rapidity in the identification of primary studies – we constrained these searches to the past 2 years (2010–2012) and to randomized controlled trials (RCTs).
To identify systematic reviews, we conducted searches in the Cochrane Library, EMBASE, MEDLINE, Web of Science, and WHO Global Health Library (which includes both regional and global indices). The search algorithms are shown in Boxes A1 and A2 in the appendix ( http://links.lww.com/QAD/A499). Abstracts from conferences and meetings were excluded because they do not undergo the same level of peer review as published full-text articles and they do not provide the necessary references for extracting study-level data. Publications on adherence interventions were excluded if they were letters to the editor, editorials, commentaries, or opinion articles. We further excluded systematic reviews of interventions studying programme retention, efficacy of combination antiretrovirals (fixed or multiple medications), dosing strategies, or use of antiretrovirals for pre-existing or post-exposure prophylaxis. We did not limit our search to particular times, locations, or languages. Additionally, we searched ClinicalTrials.gov, Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, Web of Science, and WHO Global Health Library for RCTs published between 1 September 2010 and 31 August 2012 that investigated interventions targeted towards improving ART adherence. To be included in this review, RCTs could report an adherence intervention as the primary or secondary aim or simply report adherence measurements in the presence of an intervention. Studies comparing or validating adherence measurement approaches without reporting on an adherence-enhancing intervention were excluded. We followed the reporting standards described in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement .
Three investigators (K.C., M.P., and O.O.) worked independently, completing separate screenings of the literature. We screened titles and abstracts of studies that were identified in previous systematic reviews on the effectiveness of interventions aimed at increasing antiretroviral adherence; as well as titles and abstracts of records identified in the search of databases for RCTs investigating adherence interventions. All records were screened by two of the three reviewers; two reviewers have been found to be sufficient to carry out a high-quality systematic review . The same reviewers used the inclusion and exclusion criteria to independently assess the full eligibility of studies identified in the databases. Reviewers were not blinded to study authors, conclusions, or outcomes, because blinding is complicated to implement and has been shown to have little effect on the quality of systematic reviews . Once all potentially relevant full-text articles and abstracts were identified, the three reviewers achieved consensus regarding eligibility and extracted data onto a standardized extraction form. Where consensus was not possible, a fourth reviewer (T.B.) served as arbiter. After relevant systematic reviews were identified, we searched for the primary studies featured in these reviews and extracted the data from the studies. Data entry was compared, and discordant information was resolved by consensus through data checks and discussion between the data extractors. When necessary, the further reviewer (T.B.), who guided but was not directly involved in the primary data extraction process, was asked to mediate. Figures 1 and 2 show flowcharts of the study selection processes.
We organized the synthesis of results by adherence intervention type, that is, the actual intervention activity, such as directly observed therapy (DOT) or depression treatment. In addition to the intervention types, we extracted from the studies the following data: author and year of publication, study period, study design, country of study, population, source of information, and healthcare setting, in which the study took place; study duration, sample size, loss to follow-up, intervention, control group, adherence measure, and study results. Web Appendix, http://links.lww.com/QAD/A506 shows the study characteristics; Table 1 provides an overview of the different adherence-enhancing interventions that were tested in the studies and reports the results by outcome measure. We report on results for subjective adherence measures (self-report by patients), objective adherence measures (pill count, pharmacy refill, and electronic monitoring), and the biological correlates of adherence (viral load, CD4+ cell count, and change in body weight). A few studies report composite adherence indices incorporating information from several outcome measures. We do not include the results in terms of these outcome measures in our review, because the use of these indices is usually particular to one study, and all studies using indices also report results in terms of outcome based on individual measures.
A total of 124 studies met our selection criteria (Figures 1 and 2). These studies included 86 RCTs, 6 non-randomized controlled trials (NRCT), 19 before-after studies, 8 cohort studies, 4 case-control studies, and 1 cross-sectional study. Seventy-five studies were carried out in North America, 30 in Africa, 11 in Europe, 4 in Asia, 3 in Central and South America, and 2 in Australia. Publication intensity in studies testing ART adherence-enhancing interventions increased over time; each year before 2003 three or fewer articles were published, whereas in 2003 and thereafter, at least six articles were published each year and in many years more than 10 articles (Web Appendix, http://links.lww.com/QAD/A506).
Almost half (55) of the 124 studies investigated the effectiveness of combination interventions, that is, interventions that were composed of several clearly identifiable components. The most commonly tested interventions were cognitive-behavioural therapy (CBT) (60), followed by education (28), treatment supporters (26), DOT (20) and active reminder devices (20). The less commonly tested intervention types included structural interventions (such as changes in the person delivering ART, or in the location where ART were provided) (10), counselling (8), nutritional support (7), financial incentives (5), passive reminder devices (5), and drug use treatment (4). Active reminder devices included both telephone reminders and other technologies, such as pagers and pillboxes with in-built timers and alarms. Passive reminder devices included pillboxes and diary cards. Detailed information on intervention types and the interventions are shown in Table 1 . Commonly (in 29 studies), CBT, education or counselling were combined with other interventions. DOT, passive reminder devices, treatment supporters, nutritional support, and financial incentives were combined with other interventions in more than two-fifths of the studies, whereas the other interventions were less likely to be investigated in combination.
The synthetic picture that emerges becomes even more complex when the success of particular interventions is considered across different outcomes. Table 2 shows the distribution of outcome measures used across the 124 studies. Two-fifths of studies followed the general recommendation to use both outcomes that capture adherence (subjective measures-self-reported adherence levels, or objective measures – pill count, pharmacy refill, etc.), as well as those that capture the biological outcomes determined by adherence behaviour (viral load, CD4+ cell count, body weight). However, 16% of the studies measured adherence using only subjective outcomes. Overall, 72 of the 124 studies were found to generate significant positive effects as assessed by at least one outcome measure. But only 24 studies (or one-fifth) found significant positive effects in at least one biological and one (objective or subjective) ART-adherence measure. Combination interventions were not more or less likely to succeed in significantly improving outcomes than single interventions (P = 0.80 for having at least one positive effect across all outcomes; P = 0.55 for having at least one positive effect each for a biological and a subjective or objective adherence outcome).
Table 3 shows a synthesis of the study results by intervention type. In the case of combination interventions, each component intervention is counted separately. The table shows that for most interventions, at least three-fifths of the studies found a positive result for at least one outcome, but the proportion of studies finding positive results for both at least one biological and one subjective or objective adherence outcome is less than 50%.
Most studies (87) investigated adherence-enhancing interventions in the general population; the remainder focused on particular sub-populations. The most commonly researched sub-populations were persons who use drugs (PWUD), with 22 studies, followed by women (8 studies), children (4 studies), and persons with mental health disorders (2 studies). It is an important finding that despite overall small sample sizes, there were significant effects in 12 out of the 22 studies in PWUD. Syntheses of results by outcome measure are presented in Table 1 .
A large global evidence base on ART adherence-enhancing interventions – a total of 124 studies including 86 RCTs – provides important information for ART programming and planning. The field of ART adherence intervention research is developing rapidly and relatively more rapidly than research into ART access, linkage to care, and retention. The reason for this differential in research intensity within the overall field of HIV operations and health services research plausibly reflects the importance of ART adherence – we would prefer only to initiate patients on ART once we are able to ensure good ART adherence. It could also reflect the fact that ART adherence is more easily conducted than research into other aspects of ART services, because unlike studies of access, linkage, and retention, it only requires data collection in clinical cohorts and not in HIV-infected populations in communities. Whatever the reason for the intensity of the research on ART adherence-enhancing interventions, the speed of study implementation, analysis, and publication means that evidence syntheses will rapidly grow out of date. Our review provides an updated synthesis on the body of knowledge on the effectiveness of ART adherence-enhancing interventions.
Each of the following interventions has been tested in more than 20, mostly rigorous studies, either singly or in combination with other interventions: CBT, education, treatment supporters, DOT, and active adherence reminder devices (such as mobile phone text messages). Whereas there is strong evidence that all five of these interventions can significantly increase ART adherence in some settings, each intervention has also been found not to produce significant effects in several studies.
The 2013 WHO consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection describe the portfolio of adherence-enhancing interventions and recommends that ‘[M]obile phone text messages could be considered as a reminder tool for promoting adherence to ART as part of a package of adherence interventions’. This recommendation, as well as the descriptions of the evidence on other adherence-enhancing interventions in the guidelines, have been informed and are broadly supported by this systematic review. In addition – and with the caveats regarding context-specificity of findings discussed below – our review suggests that the other four interventions which have been widely tested in rigorous studies – CBT, education, treatment supporters, and DOT – warrant consideration by ART programme managers. Given the critical importance of adherence for the long-term individual and population-level success of ART, routine implementation of adherence-enhancing interventions should be considered.
Whereas the current evidence base provides a portfolio of interventions that have been shown to be effective in high-quality studies at least in some settings, adherence is a behaviour and as such is affected by culture and circumstance. The standard approaches to synthesizing evidence on effectiveness take on a different meaning when considering behavioural interventions as opposed to biological interventions. For behavioural interventions, consistency of causal effects across studies is an indicator of the degree of generalizability of an intervention effect to other settings rather than a measure of the degree to which an effect is ‘true’ as in the case of biological interventions.
We would expect that behavioural interventions that have been truly successful in one setting may not be effective in another one with different economic, social and behavioural barriers to adherence. Thus, health policy makers and programme planners need to carefully consider which adherence intervention to choose for routine implementation in a particular setting based on socio-cultural context, feasibility, acceptability, and health systems organization. The adherence-enhancing interventions identified in this review are likely to differ widely in implementation-relevant aspects, such as costs, human resources requirements, and scalability. Thus, other factors than the effectiveness evidence covered in this review will likely guide implementation decisions. For instance, DOT is labour-intensive and expensive, but it may be a good strategy for particular settings, for example, where patients can be easily reached, such as in hospitals or prisons. In contrast, some types of mobile phone text messaging interventions are comparatively inexpensive and do not require substantial human resources investment. As such, they may be a good option for general populations with high individual mobile phone coverage. Future meta-analyses of the contextual predictors of success of particular types of ART adherence interventions can further inform these choices. Additionally, it will be critical to monitor the performance of an adherence-enhancing intervention as it is introduced into routine ART services. Quasi-experimental designs, such as stepped wedge scale-up of adherence interventions across HIV clinics, might offer ‘natural’ opportunities for rigorous confirmation of effectiveness of the five interventions that the currently available body of evidence can increase adherence.
Whereas the global evidence on effectiveness of adherence-enhancing interventions is rich, our review has identified several important knowledge gaps that will be relevant for implementation decisions and should increasingly be filled with evidence from implementation science research. First, more evidence is needed to examine interventions that have shown promise in a few studies, but have only been tested in a limited range of settings. Our review finds that these interventions include the following: alternative health system structures for ART delivery, nutrition support, financial incentives, passive reminder devices (such as diary cards and compartmentalized pill boxes), drug use treatment, and anti-depressive treatment.
Second, comparative information on costs and cost-effectiveness of different effective adherence interventions is largely lacking, and when it is available, it is unclear in how far the costs assessed in a research setting are transferable to routine implementation situations. More cost-benefit studies as part of routine care are needed to provide this critical component for deciding between alternative effective adherence-enhancing interventions. Whereas several studies investigated combination interventions (see Table 1 ), differential effectiveness of alternative combination portfolios and interaction effects between different intervention components were rarely examined. It would seem plausible that combination adherence interventions will be particularly successful in increasing ART adherence because they commonly work through different pathways. However, our synthesis shows that combination interventions tend to be similarly likely to succeed in increasing ART adherence as single interventions. One reason for this finding could be that there is usually one dominant intervention within the combination, and the other interventions merely moderately enhance the effectiveness of the dominant intervention. Another reason could be that combination interventions are more difficult to implement than single interventions, and the achieved effects reflect these implementation difficulties. Future experimental research should increasingly use factorial designs that allow precise determinations of component intervention and interaction effects.
Third, the majority of studies establishing the effectiveness of adherence-enhancing interventions have lasted 2 years or less. Antiretroviral therapy, however, requires life-long adherence, spanning several decades for many patients. Long-term studies of ART adherence are urgently needed, and several teams are currently conducting follow-up studies, which will generate these important results [171–174]. Fourth, many studies are internally inconsistent in their findings, establishing significant effects on some outcomes (e.g. self-reported adherence), but not on other, related outcomes (e.g. immunological recovery). Technological improvements in capturing ART adherence could substantially improve the strength of the evidence regarding adherence behaviours, which tend to be unreliably reported  and may also not be accurately measureable with objective approaches, such medication event monitoring systems (MEMS), pill counts, or observation of pharmacy refill. Finally, as ART initiation is moving into earlier disease stages, average effects of ART adherence-enhancing interventions may change, because the population composition of people on ART changes. For instance, people initiating in earlier stages of HIV infection are less likely to have experienced recovery from advanced HIV-related disease and may thus require different cognitive and behavioural strategies and different technological support to ensure good adherence than people who initiated in late stages of the infection .
Our study has several limitations. Although it was a systematic review, it was ‘rapid’ in the methodological sense that it utilized existing systematic reviews to identify studies on adherence-enhancing interventions. Some of these systematic reviews may have missed relevant studies related to their objective and timeframe, and these studies could have also been missed in our review. In particular, the reliance on previous systematic reviews and our focused search of recent published results from RCTs imply that our synthesis is largely based on experimental studies, and that an additional review of quasi-experimental and non-experimental evidence may provide important additional insights. Additionally, our selection of reviews to identify primary studies under the rapid review methodology we employed excluded reviews that were not systematic, for example, narrative reviews; and our identification of records reporting primary RCT-based results was limited to studies whose primary aim was to enhance ART adherence. These selection criteria may have led to the exclusion of some interventions that can be of use in enhancing ART adherence, in particular, approaches to optimize ART regimens . One example of such an intervention is single-tablet ART regimens, which have not been included in our review. Recently published reviews concluded that single-tablet regimens improve adherence and quality of life among ART patients in comparison to multi-tablet regimens [178,179].
Another unavoidable limitation of a systematic review based on formally published studies in a fast moving research field is that evidence that is emerging informally but has not yet been formally published will likely have been ignored, because academic writing, review and publication times in global health can last several years. These delays would have been particularly limiting if they led to the exclusion of completely novel interventions, for example, based on new technologies.
Although some studies were identified related to PWUD, data on other key populations were scarce. Given that these populations are disproportionately affected by the HIV epidemic and commonly face multiple challenges in ART adherence, future research focused on ART adherence-enhancing interventions tailored to key populations will be important, in particular, in sub-Saharan Africa, where such focused studies have been especially scarce.
In conclusion, we find a large and overall strong evidence base to support the claim that five interventions – CBT, education, treatment supporters, DOT, and active reminder devices – can improve ART adherence at least in some settings. These tested and effective adherence-enhancing interventions should increasingly be considered for routine implementation in ART programmes and health systems. However, rigorous on-going evaluation of the impact and performance of these interventions will be critical, because all interventions that proved effective in at least one setting were also found not to significantly increase adherence in at least one other setting. Significant evidence gaps on adherence-enhancing interventions need to be closed, including on cost-effectiveness, long-term effectiveness, and effectiveness in specific key populations.
Conflicts of interest
There are no conflicts of interest.
TB and KC were the lead authors, designing the study in close collaboration with EN and AS. KC, OO and MP scrutinized identified studies for eligibility and extracted data. TB and KC wrote the first draft of the manuscript; all authors contributed to the interpretation of the extracted data and critically reviewed the manuscript before submission.
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