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Keywords:

  • antiretroviral therapy;
  • HIV;
  • medication adherence;
  • patient compliance;
  • systematic review

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Objectives

The objective of this systematic review was to evaluate the effectiveness of adherence-enhancing interventions for highly active antiretroviral therapy (HAART) in HIV-infected patients in developed countries.

Methods

A systematic literature search was performed (January 2001 to May 2012) in EMBASE, including MEDLINE records, CENTRAL and PsycInfo. Trials meeting the following predefined inclusion criteria were included: adult patients with an HIV infection treated with HAART, an intervention to enhance patient adherence, adherence as the outcome, clinical outcomes, randomized controlled trial (RCT), article written in English or German, patient enrolment after 2001, and trial conducted in World Health Organization (WHO) stratum A. Selection was performed by two reviewers independently. All relevant data on patient characteristics, interventions, adherence measures and results were extracted in standardized tables. The methodological trial quality was evaluated by two reviewers independently. All discrepancies were discussed until a consensus was reached. A meta-analysis could not be performed because of the heterogeneity of trials.

Results

In total, 21 trials fulfilled all inclusion criteria. Of 21 trials, only one that examined motivational interviewing for alcohol-dependent patients showed statistically significant results for adherence rates and viral load in favour of the intervention. One trial showed a statistically significant clinical effect of the intervention; however, inconsistent results were presented for adherence depending on the underlying adherence definition. The results of the remaining 19 trials were not statistically significant or were conflicting for adherence and/or clinical outcomes. However, the methodological trial quality was low.

Conclusions

It is not possible to definitively assess the effectiveness of adherence-enhancing interventions. However, it appears that most adherence interventions have no effect.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Adherence to highly active antiretroviral therapy (HAART) is an important factor to obtain viral suppression in HIV-infected patients [1]. Furthermore, it is relevant to avoid the evolution of resistant strains [2]. Currently, HIV infection can be regarded as a chronic condition. Thus, patients need to remain on lifetime HIV medication. However, their adherence to HAART may be insufficient, as persons infected with HIV often have difficult living conditions. Adherence rates vary widely depending on patient characteristics [3]. Overall, it is estimated that only 62% of adult patients taking HAART reach an intake rate of ≥ 90% of the prescribed amount [3], which is assumed to be needed to maintain sufficient viral suppression [4-6]. Viral suppression is a validated surrogate and is considered to be of clinical relevance [7]. Low patient adherence is one reason for the low estimated rate of no more than 28% of HIV-infected patients with adequate viral suppression in many developed countries [8].

To enhance patient adherence, different types of intervention can be applied that target one or several, simultaneously, of the five adherence-influencing dimensions: the indication, the treatment, the patient, the patient's socioeconomic status and the health care system [9].

The objective of this systematic review of RCTs was to assess the effectiveness of adherence-enhancing interventions for HAART in adult HIV-infected patients in developed countries [World Health Organization (WHO) mortality stratum A].

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The systematic literature search was performed in the following databases: EMBASE (via EMBASE, including MEDLINE records), CENTRAL (via the Cochrane Library) and PsycInfo (via EBSCO). A basic search strategy was developed and adapted for each database provider. The search strategy combined various synonyms, antonyms, acronyms and medical subject headings related to adherence, HIV and HAART. Furthermore, a modified version of the Cochrane search filter to identify RCTs was included [10] (the full search strategies are available in Appendix 1). The search was limited to a publication date after January 2001 (for an explanation of search period limitation, see inclusion criteria) and was conducted on 25 May 2012.

The inclusion criteria for the review were as follows.

  1. Patients: adult (at least 80% of trial population at least 18 years of age) patients with an HIV infection currently treated with HAART.
  2. Intervention/comparison: interventions including any type of adherence-enhancing component (no different dosages or different types of application of the same substance; intake without the presence of a health care professional).
  3. Primary outcome: adherence.
  4. Secondary outcomes: clinical parameters (CD4 cell count or viral load as an outcome).
  5. Study type: RCT or cluster RCT.
  6. Language: article in English or German.
  7. Patient enrolment: after 2001.
  8. Region: trial conducted in WHO mortality stratum A.

Different dosages and application types were excluded because they have different pharmacodynamics and pharmacokinetics, which could be associated with adverse events that might have an impact on adherence. The patient recruitment period (criterion 7) was restricted because the first protease inhibitor (lopinavir/Kaletra®, AbbVie Inc., North Chicago, Illinois, USA) was approved by the U.S. Food and Drug Administration in September 2000 and the European Medical Association in April 2001. This was the beginning of a new era for HAART regimes, and it involved a change in clinical outcomes as well as intake regimes, side effects and, consequently, adherence. Adherence is difficult to measure, and several definitions of adherence were used, making it difficult to compare different interventions only on the basis of adherence rates. Furthermore, adherence has no direct patient benefit. Therefore, it is necessary to focus on clinical outcomes when comparing interventions (criterion 4). Clinical endpoints were chosen because it was not expected that patient-relevant outcomes (e.g. AIDS, death and quality of life) would be analysed in the trials and, moreover, viral load and CD4 cell count are validated surrogates [7]. As adherence interventions are specific in their settings and patient profiles, a comparison between developed and less/least developed countries did not seem reasonable. Thus, RCTs conducted exclusively in regions of WHO mortality stratum A were considered.

Titles and abstracts were screened by two reviewers independently according to a priori defined inclusion criteria. The full texts of potentially eligible articles were then obtained. Two reviewers assessed the eligibility of the full texts according to the review inclusion criteria. Differences between reviewers were discussed until a consensus was reached. The references of the included publications were checked for further potentially relevant publications. If the fulfilment of the inclusion criteria could not be assessed because of a lack of information in the publication, the corresponding authors were contacted. If the authors did not reply within 4 weeks, the respective inclusion criterion was considered as not fulfilled, and the trial was excluded.

The data were extracted in standardized tables. Information on the region and setting of the trial, special inclusion criteria regarding gender and mental disorders, patient characteristics (see Appendix 3), intervention(s) and control, the duration of intervention and follow-up, the definition and measurement of adherence and the results were summarized in these tables. Gender and mental disorders were extracted because both were expected to have a strong influence on adherence [11, 12]. If outcomes were measured at multiple time-points, only the last assessment of the intervention and follow-up period was extracted. For different measures of the same clinical outcome (e.g. undetectable viral load and mean viral load), the measure assessed at baseline and follow-up was presented. The results were considered statistically significant if the P-value was < 0.05 or the authors declared the results in their publication to be statistically significant without stating a level of significance. In the latter case, a note was made. All data were extracted by one reviewer and checked by a second for quality assurance.

The Cochrane risk of bias tool was used for methodological quality assessment of the included trials [10].

Because of the obvious nature of adherence-enhancing interventions, the blinding of patients and personnel was not applicable. The respective quality criteria were therefore unnecessary and not assessed. Therefore, the following six evaluation criteria were used to assess the risk of bias.

  • Was the random sequence generated adequately?
  • Was the allocation concealment adequate?
  • Was the outcome assessment/analysis blinded?
  • Was the analysis performed according to intention-to-treat?
  • Were the results not reported selectively?
  • Were there no other sources of bias?

The criteria were rated as ‘fulfilled’, ‘not fulfilled’ or ‘not applicable’. The original Cochrane risk of bias tool also allows the category of ‘unclear’. In the assessment presented here, the category ‘unclear’ was judged as ‘not fulfilled’. The quality assessment was performed by two reviewers independently, and discrepancies were resolved in a discussion or by involving an unbiased third person.

High heterogeneity was expected as a consequence of the diversity of existing adherence-enhancing interventions and different target populations. Therefore, a quantitative data synthesis using a meta-analysis was not conducted.

There was no study protocol for this review.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

After removing the duplicates (EndNote X4, software tool for publishing and managing bibliographies), 1552 potentially relevant articles were identified with the search strategy. Through title and abstract screening, 1441 publications were excluded. The full texts of the remaining 111 publications were screened. In this step, 89 publications were rated as nonrelevant (see Appendix 2); thus, 22 publications remained [4, 5, 13-32], although for one trial, two publications were identified [13, 31]. Consequently, 21 RCTs (22 publications) were included in this systematic review. A manual search of references of the included publications revealed no further relevant trials. Figure 1 illustrates the selection process.

figure

Figure 1. Flow chart for study selection.

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The overall methodological quality of the included trials was deficient. All of the trials had methodological flaws. In particular, the criteria related to allocation concealment, blinding of outcome assessment and analysis according to intention-to-treat were not fulfilled. Four trials lacked only one quality criterion [4, 14, 25, 28]. Five trials fulfilled only the criterion related to selective reporting [15, 17, 23, 24, 26]. Table 1 provides an overview of the methodological quality of the included trials.

Table 1. Quality of included studies
StudyGeneration of allocation sequenceAllocation concealmentBlinding of outcome assessmentAnalysed according to intention-to-treatSelective reportingOther sources of bias
  1. +, fulfilled; −, not fulfilled.

Berger et al. (2008) [14]+++++
Collier et al. (2005) [15]++
DeBruin et al. (2010) [16]+++
Dilorio et al. (2008) [17]++
Feaster et al. (2010) [4]+++++
Fisher et al. (2011) [18]+++
Golin et al. (2006) [19]+++
Holstad et al. (2011) [20]++
Ingersoll et al. (2011) [21]+++
Kalichman et al. (2011) [22]+++
Levin et al. (2006) [23]++
Parsons et al. (2007) [24]++
Rathburn et al. (2005) [25]+++++
Reynolds et al. (2008) [26]++
Rosen et al. (2007) [27]++++
Ruiz et al. (2010) [28]+++++
Safren et al. (2012) [29]++++
Simoni et al. (2009) [30]+++

Sorensen et al. (2007) [31]

Barnett et al. (2009) [13]

++++
Wagner et al. (2006) [5]+++
Webel et al. (2010) [5]+++

The mean age of the study population ranged from 36 to 49 years. The vast majority of study participants were male, except for one trial with almost the same proportion of both sexes [21] and two trials focused on women [4, 20]. In most trials, a considerable proportion of the trial population were affected by a mental disorder, especially mood disorders and drug dependences. Except for two studies [14, 16, 28], all trials were located in the USA, most of them in agglomeration areas.

The investigated study interventions varied widely regarding type, arrangement and extent. Educational or behavioural interventions or combinations of these were primarily applied. The study interventions were compared with usual care, which sometimes included adherence-enhancing activities, such as reading material, other types of intervention or other intensities of the same intervention. Only one study compared an adherence intervention with no intervention [2]. The patient characteristics and interventions are outlined in Table 2 (for further information, see Appendix 3).

Table 2. Characteristics of included studies
StudyNumber of randomized patients (IG/CG)Region/settingSpecific inclusion criteriaInterventionControlStudy period
  1. ART, antiretroviral therapy; CB, cognitive behavioural; CG, control group; EM, electronic monitoring; HAART, highly active antiretroviral therapy; IG, intervention group; MI, motivational interviewing; NR, not reported.

Berger et al. (2009) [14]53/51Switzerland/HIV out-patient clinicsCB stress management (weekly group sessions of 2 h during a 12-week period in groups of four to 10 persons)No intervention12 months
Collier et al. (2005) [15]140/142Puerto Rico; USA; Italy/NR

Usual adherence support

Scripted telephone calls (1–3 days after initiation of the study regimen and at weeks 1, 2, 3, 6 and 12 and every 8 weeks thereafter)

Usual adherence support96 weeks
deBruin et al. (2010) [16]66/67HIV outpatient clinic, Amsterdam, the NetherlandsTailored information on the basis of EM data, identification of causes for nonadherence, active self-monitoring of medication intake, feedback on adherence each day, and examination of MEMS reports with nurse after 3 monthsInformation about treatment and nonadherence, tailored schedules, promotion of use of helpful devices (e.g. alarms), discussion of adherence problems (every 3–4 months), and feedback on viral load and CD4 count9 months
Dilorio et al. (2008) [17]125/122Atlanta, USA/HIV AIDS clinicFive individual MI counselling sessions with a study nurse counsellor over a 3-month periodTailored adherence education12 months
Feaster et al. (2010) [4]59/67USA/NRFemale (inclusion criterion); drug abuse (inclusion criterion)Strengthen family support for adherence, draw clear boundaries between the woman and any substance-using social contacts, and develop a plan to address potential relapse (weekly for 50 min for up to 4 months)Psycho-educational intervention (biweekly for a total of eight 90-min sessions)12 months
Fisher et al. (2011) [18]290/304Connecticut, USA/HIV care clinicEnhanced interactive computer intervention (14 sessions of 26 min for 18 months)Basic interactive computer intervention18 months
Golin et al. (2006) [19]77/78North Carolina, USA/infectious diseases clinic

A 20-min audiotape and booklet, and two one-on-one sessions with a health educator (at weeks 4 and 8 of follow-up, with a mailing 2 weeks after each individual session)

Two MI sessions at 4-week intervals (each session 15–20 min), and letters reviewing issues raised in the MI session (2 weeks after each session)

A 20-min audiotape and booklet, and two one-on-one sessions with a health educator (at weeks 4 and 8 of follow-up, with a mailing 2 weeks after each individual session)12 weeks
Holstad et al. (2011) [20]104/103Southeast USA/HIV clinicFemale (inclusion criterion)MI (eight weekly group sessions of 1.5−2 h)Tailored health education (weekly group sessions of 1.5−2 h)9 months
Ingersoll et al. (2011) [21]28/28USA/university hospitalCrack or cocaine abuse (inclusion criterion)MI plus feedback (four weekly sessions; two sessions scheduled biweekly; each session lasted 45–60 min)Video information about adherence and crack cocaine use (four weekly intervention sessions; two sessions were scheduled biweekly), video (of 30–45 min), debriefing discussion (of 10 min) and reading materials5–6 months
Kalichman et al. (2011) [22]217/219Georgia, USA/AIDS service providerCounselling on the basis of conflict theory of decision making: one-on-one orientation and goal-setting session (45 min), five group sessions (120 min) and a post-group one-on-one counselling session (60 min)Education: one-on-one orientation and goal-setting session (45 min), five group sessions (120 min) and a post-group one-on-one counselling session (60 min)10 months
Levin et al. (2006) [23]26/23 (baseline analysis)NR/out-patient HIV clinicPrinted card for each antiretroviral medication with a colour picture, dosing schedule, pill box, and bimonthly postal mailings containing motivational messages and remindersUsual care24 weeks
Parsons et al. (2007) [24]65/78New York City, USA/research centreScore ≥ 8 alcohol use disorder identification test (inclusion criterion)MI plus CB skills training (eight weekly sessions)Information: structured discussions about videotapes pertaining to HIV, HAART adherence and alcohol6 months
Rathburn et al. (2005) [25]16/17 (baseline analysis)Oklahoma, USA/HIV clinic

Education visit at the initiation of HAART (of 1.5 h)

Education follow-up visit after 2 weeks (of 30 min)

Telephone follow-up to identify early problems

Education provided during the patients' office visits28 weeks
Reynolds et al. (2008) [26]54/55USA/NR

Education (baseline)

Telephone calls (weeks 1 to 12, 14 and 16)

Education (baseline)

Scheduled face-to-face visits

64 weeks
Rosen et al. (2007) [27]28 (IG1 + IG2)/28Connecticut, USA/HIV clinic

Contingency management (weekly sessions for 16 weeks)

Monthly letters with EM data (32 weeks)

In the case of adherence, participation in a lottery (maximum earnings $800)

Supportive counselling (weekly sessions for 16 weeks)

Providers were sent monthly letters stating the participant's self-reported adherence

32 weeks
Ruiz et al. (2010) [28]120/120Spain/hospitalsPsycho-education by a health care professional (first visit 1 h; three additional visits of 30 min)Psycho-education by a peer (first visit 1 h; three additional visits of 30 min)6 months
Safren et al. (2012) [29]44/45Boston, USA/methadone clinics, HIV clinicsCurrently in opioid treatment (inclusion criterion); subsyndromal depressive mood disorder (inclusion criterion)

One session on 11 informational problem-solving and CB steps

CB therapy for adherence and depression (eight weekly sessions of 50 min)

One session on 11 informational problem-solving and CB steps12 months
Simoni et al. (2009) [30]

57 (IG1)/

56 (IG2)/

56 (IG3)/

57 (CG)

Washington, USA/HIV primary care out-patient clinic

IG1

Usual care (education by health care professionals)

Group sessions (six biweekly of 1 h each) with peers (clinic patients who were currently on HAART)

Phone calls from peers to participants (weekly); feedback on adherence

IG2

Usual care (education by health care professionals)

Pager text messages (3 months)

IG3 (IG1 + IG2)

Usual care (CG)

Group sessions with peer; phone calls from peer (see IG1)

Pager messages

CG

Usual care (education by health care professionals)

9 months

Sorensen et al. (2007) [31]

Barnett et al. (2009) [13]

34/32San Francisco, USA/methadone maintenance clinics

Medication coaching: feedback on EM data; personalized schedules (4 weeks)

Vouchers exchangeable for goods and services in the community for opening the EM bottles as scheduled (12 weeks)

Medication coaching: feedback on EM data; personalized schedules (4 weeks)20 weeks
Wagner et al. (2006) [5]

66 (IG1)/

66 (IG2)/

67 (CG)

California, USA/HIV primary care clinicsActive substance abuse (inclusion criterion)

IG1

Education, tailoring the regimen to daily routine, and pill box

CB components (three sessions of 30−45 min before the patient started ART; sessions 4 and 5 were during the first 2 weeks of treatment)

A 2-week practice trial: adherence data were used to facilitate the adherence training

IG2

Education, tailoring the regimen to daily routine, and pill box

CB components (three sessions of 30–45 min before the patient started ART; sessions 4 and 5 were during the first 2 weeks of treatment)

CG

Education, tailoring the regimen to daily routine, and pill box

48 weeks
Webel et al. (2010) [5]43/46 (only 73% of population on HAART)San Francisco, USA/HIV out-patient clinicsWomen (inclusion criterion)Self-management programme: (trained HIV-infected) peer-based HIV symptom management (seven weekly group sessions with 10 persons of 2 h each)Copy of HIV symptom management manual14 weeks

Five trials defined adherence as the proportion of patients with a certain level of drug intake [14, 15, 18, 19, 28]. In six trials, adherence was defined as the mean proportion of doses taken or missed [21-23, 26, 27, 32]. One trial used the mean proportion of doses taken on schedule [29]. Nine trials used more than one of these three definitions [4, 5, 16, 17, 20, 24, 25, 30, 31].

Ten trials used various self-reports (visual analogue scale, AIDS Clinical Trial Group (ACTG) questionnaire, timeline follow-back, and short medication adherence questionnaire) for adherence measurement [4, 14, 15, 18, 21, 23, 24, 26, 28, 30, 32]. Six trials used electronic monitoring [5, 16, 17, 19, 20, 25, 29]. One trial used pill count [22] as the adherence definition. The remaining trials used different methods at the same time [26, 27]. The level of detail regarding the definition and the measurement of adherence varied widely. In several trials, the period for adherence rate determination (recall period) was not given. Other trials described the type of measurement (e.g. self-report) but did not specify the measurement tool (e.g. questionnaire or visual analogue scale) (see Table 3 results).

Table 3. Adherence measurement and definition and results of included studies
StudyAdherence definitionAdherence measurementMean adherenceb [IG/CG (P)]Therapeutic outcomesMeanb [IG/CG (P)]
Post intervention periodLast follow-upPost intervention periodLast follow-up
Whole study periodWhole study period
  1. ACTG, AIDS Clinical Trial Group questionnaire; CG, control group; EM, electronic monitoring; HR, hazard ratio; IG, intervention group; NA, not applicable; NR, not reported; ns, not significant; OR, odds ratio; SMAQ, simplified medication adherence questionnaire; VAS, visual analogue scale.

  2. a

    P-values for comparisons of treatment by time interaction.

  3. b

    Unless otherwise stated, all values are means.

Berger et al. (2008) [14]Percentage of adherent patientsSMAQNR63/55 (0.47)HIV-1 RNA < 50 copies/mLNR81.1/74.5 (0.34)
Change in CD4 count (cells/μL)NR53.0/15.5 (0.29)
Collier et al. (2005) [15]Percentage of patients not missing a dose during the study periodSelf-reportOR = 0.86 (P = 0.46)Percentage with virological failureNR32/37 (NR)
deBruin et al. (2010) [17]Percentage of doses taken on scheduleEMNR/NR (nsa)Percentage with undetectable viral loadOR = 2.96 (P < 0.05)NR
Percentage of doses takenEMNR/NR (nsa)
Dilorio et al. (2008) [17]Percentage of doses takenEM70/65 (0.111a)64/55 (0.111a)Viral load (log copies/mL)3.13/3.15 (0.172a)At month 6: 3.05/3.39 (0.172a)
Percentage of doses taken on scheduleEM47/38 (0.006a)41/24 (0.006a)CD4 cell count240/242 (0.937a)At month 6: 227/262 (0.937a)
Feaster et al. (2010) [4]Percentage taking ≥ 90% of dosesACTGNR88/88 (ns)Viral loadIG>CG (P < 0.05)
Percentage of doses takenACTGIG>CG (P < 0.05a)CD4 cell countIG>CG (P < 0.05)
Fisher et al. (2011) [18]Percentage of patients with 100% adherenceACTGIG>CG (0.12*)Percentage with HIV-1 RNA ≤ 400 copies/mL79/74 (ns*)NR
Percentage of patients with 100% adherenceVASIG>CG (0.12*)
Golin et al. (2006) [19]Percentage taking ≥ 95 of dosesEMNR29/17 (0.13)Viral load (log10 copies/mL)NR52/44 (ns)
Holstad et al. (2011) [20]Percentage of doses takenEMNR/NR (ns*)Percentage with undetectable viral loadIG>CG (ns)
Percentage of doses taken on scheduleEMNR/NR (ns*)CD4 percentageIG>CG (ns)
Ingersoll et al. (2011) [21]Percentage of dosesTimeline follow-backIG>CG (ns*)Viral load (log copies/mL)No difference
Kalichman et al. (2011) [22]Percentage of doses takenPill countIG>CG (P < 0.05)Percentage with undetectable viral loadNR/NR (ns)
Percentage of doses takenPill countNRIG/CG (ns*)
Levin et al. (2006) [23]Percentage of doses takenVAS (30-day recall) plus question: how many doses were missed? (3- and 7-day recall)97; 2–100 (median; range)/97; 42–100 (median, range) (ns)NA (no follow-up)Viral load reduction (log copies/mL) (median)0.89/1.48 (0.88)NA (no follow-up)
Increase in CD4 count (cells/μL) (median)72/29 (0.52)NA (no follow-up)
Parsons et al. (2007) [24]Percentage of doses takenTimeline follow-back (2-week recall)NR91/88 (0.01)Viral load (log copies/mL)NR3.4/3.6 (0.01)
 Days with perfect adherence (not specified) in the past 2 weeksTimeline follow-back (2-week recall)NR89/83 (0.02)CD4 cell countNR463.5/424.0 (0.01)
Rathburn et al. (2005) [25]Percentage of doses takenEM86/73 (0.233)74/51 (0.080)HIV-1 RNA < 400 copies/mL63/29 (ns)94/65 (ns)
Percentage of doses taken on scheduleEM69/42 (0.025)53/31(0.046)Increase in CD4 count (cells/μL) (median)142/97 (ns)
Reynolds et al. (2008) [26]Percentage of doses takenACTG (one item, 4-day recall)IG>CG (ns)100/97 (0.032)Time to virological failureHR = 0.68 (P = 0.21)
Rosen et al. (2007) [27]Percentage of doses takenEMIG>CG (ns)Viral load (log10 copies/mL) (adjusted for baseline viral load)2.9/3.3 (0.02)3.1/3.0 (0.89)
Percentage of doses takenVAS81/70 (0.07*)72/74 (0.07*)
Percentage of doses missedACTG1/2 (0.66*)2/1 (0.66*)
Ruiz et al. (2010) [28]Percentage of adherent patients (definition nonadherence: ‘ “two or more forgotten doses in the last week, or two or more days without taking medication in the last three months” ’)SMAQNR57/60 (ns)Percentage with undetectable viral loadNR78.2/82.4 (ns)
Safren et al. (2012) [29]Percentage of doses taken on scheduleEM79/74 (NR)65/62 (0.22*)Viral load (log copies/mL) (adjusted for baseline viral load, CD4 count and resistances)2.349/2.044 (NR)2.203/2.177 (0.87*)
CD4 count (adjusted for baseline CD4 count and resistances)380.97/539.29 (NR)452.94/502.33 (0.03*)
Simoni et al. (2009) [30]100% adherence (no doses missed)SMAQ (one item, 1-week recall)56/57/70/47 (ns*)44/59/50/44 (ns*)Viral load (log copies/mL)3.3/3.1/2.8/3.2 (ns*)3.5/3.2/3.1/3.5 (ns*)
Percentage of doses taken (in last week)EM (last week data)47/42/50/39 (ns*)32/37/32/29 (ns*)CD4 count (cells/μL)246.6/256.2/250.3/232.5 (ns*)280.0/254.6/257.7/243.5 (ns*)

Sorensen et al. (2007) [31]

Barnett et al. (2009) [13]

Percentage of doses taken on scheduleEM78/56 (0.0069)66/53 (0.07)Viral load (copies/mL)6880.4/5549.6 (ns)15 932.6/2908.0 (ns)
Longest days continuous of doses taken on scheduleEM21/9 (0.0001)7/5 (ns)CD4 count (cells/μL)302.4/314.0 (ns)323.6/360.5 (ns)
Percentage of doses takenPill count86/75 (0.0187)81/78 (ns)
Percentage adherentACTG87/69 (0.0345)81/72 (ns)
Wagner et al. (2006) [5]Percentage taking ≥ 90% of dosesEM82/65 (0.01)57/65 (0.52)Change in viral load (log10 copies/mL)-1.83 [IG1]/-1.81 [IG2]/-1.82 [CG] (ns)-2.28 [IG1]/-2.15 [IG2]/-2.15 [CG] (ns)
Percentage of doses takenEM93.5/89.9 (0.10)83.5/86.4 (0.57)Change in CD4 count (cells/μL)56 [IG1]/70 [IG2]/-49 [CG] (ns)139 [IG1]/113 [IG2]/112 [CG] (ns)
Percentage of doses taken on scheduleEM56/40 (P < 0.05)IG/CG (no differences)
Percentage taking ≥ 90% of dosesEMNR [IG1]/NR [IG2] (ns)NR [IG1]/NR [IG2] (ns)
Percentage of doses takenEMNR [IG1]/NR [IG2] (ns)NR [IG1]/NR [IG2] (ns)
Webel et al. (2010) [32]Percentage of doses missedACTGNR/NR (0.20*)Viral loadNR/NR (ns*)
CD4 countNR/NR (ns*)

One trial (Parsons et al.) investigating motivational interviewing vs. an educational intervention in alcohol-dependent individuals showed a statistically significant effect on the proportion of doses taken and the days with perfect adherence as well as the viral load in the follow-up period. However, the effect difference for all outcomes was low [24]. Strengthening family support vs. psychoeducation for drug-dependent women had a statistically significant effect on the viral load and CD4 cell count, but the effect on adherence rate varied depending on the measure used. The proportion of doses taken was statistically significantly higher in the intervention group, but the proportion of patients with a ≥ 90% intake was not [4]. With respect to the remaining 19 trials, the results at the end of the observation period or whole study period were not statistically significant for either endpoint type and/or conflicting for adherence and clinical outcome type. Additionally, as results were examined based on different definitions of adherence (proportion of patients taking a certain percentage of doses, or proportion of doses taken on schedule), different adherence measurements (self-reports or pill count/electronic monitoring) and different study populations (inclusion criterion of e.g. substance abuse disorders vs. no inclusion restriction), a clear tendency in favour of adherence interventions could not be found, and the results were partly contradictory. When each type of intervention was considered separately (educational, behavioural, psychosocial or mixed), the results did not show any tendency in favour of a certain adherence intervention type. The RCT comparing adherence intervention against no intervention showed no statistically significant effect [2].

Table 3 shows the results of individual trials (all values are means unless otherwise indicated).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Only one of the 21 included trials showed a statistically significant effect on the adherence rate and viral load in favour of the adherence intervention. This trial compared motivational interviewing vs. an informational intervention in alcohol-dependent patients. However, this trial had a low methodological study quality, as only two out of six quality criteria were fulfilled. Another trial examined an intervention aimed at strengthening family support vs. psychoeducation for drug-dependent women. Statistically significant superiority for CD4 cell count and viral load was observed, but only the adherence rate measure ‘proportion of doses taken’ favoured the intervention, while, in contrast, the difference in the proportion of patients with a ≥ 90% intake did not reach statistical significance. Moreover, the relevance of this result was limited, as the comparison referred to the entire trial period (not to the follow-up period). The sustainability of the intervention is therefore not assessable. For all other evaluated interventions and for those involving motivational interviewing for patient groups other than alcohol-dependent patients, no clear effect was found for adherence or clinical outcomes. When interpreting the results, it should be considered that, at an alpha level of 5%, one statistically significant trial out of 21 trials approximately corresponds with the expectancy value. Additionally, the results for quality of life were not statistically significant in three trials that are included in this review [13, 31, 32]. Furthermore, no statistically significant difference was found in resistance [29], adverse events [27] or the intensity of symptoms [32]. None of the trials analysed AIDS or mortality as an outcome.

In conclusion, it could be deduced that adherence-enhancing interventions are not promising.

Our results are in accordance with a previously published high-quality systematic review that only found a statistically significant effect of adherence-enhancing interventions for HIV-infected patients on the adherence rate and clinical outcomes in one out of 11 included trials [33]. In systematic reviews for other indications, the results were similarly heterogeneous [34, 35, 33]. A meta-analysis of directly observed therapy (drug intake in the presence of a health care professional) vs. standard of care for HAART showed statistically significant superiority [36].

When a certain patient group or type of intervention was considered individually, the results for adherence-enhancing interventions also showed no superiority. This finding is in accordance with a previous systematic review [37]. Quantitatively accounting for subpopulations was not possible because most trials did not perform a quantitative subgroup analysis. In addition, the numerous methodological flaws of almost all included trials reduced the strength of evidence. Several quality criteria were predominately not satisfactory and suggested a high risk of bias with respect to adherence interventions. First, the sample size calculation to detect statistically significant differences was completely missing in many trials or only performed on the basis of expected adherence differences. Therefore, most trials may have been underpowered to reveal differences in adherence and more so those in clinical outcomes. Secondly, in most of the trials the data were not analysed according to intention-to-treat principles. This criterion especially is a source of bias in analyses of adherence interventions because it could be assumed that patient groups that are at risk of being nonadherent are also more likely to be lost to follow-up [38]. Contamination is a well-known problem in educational interventions [39] and might also therefore be applicable to many adherence interventions. Methods to adjust for treatment contamination in RCTs have already been explored [40], but they were not applied in our included trials. Regardless of the nature of adherence interventions, where blinding is generally more difficult, it might still be a meaningful source of bias.

The study interventions were mainly compared with a control adherence intervention or usual care that included adherence-enhancing components. On one hand, this increases adherence rates and the viral load in the comparison group and reduces the chance of statistically significant effects between the study arms. On the other hand, the possibility of an increase in adherence caused simply by its measurement or as a result of participation in the trial (Hawthorne effect) in control arms without any interventions is reduced. The likelihood of finding only slight differences between groups is increased by a high baseline adherence, which introduces a type of ‘ceiling effect’, allowing only minor changes in adherence as a result of the intervention. It results in a high overall adherence level such that adherence differences become marginal. This makes it difficult to answer the question of whether adherence interventions in general are not effective and whether a larger sample size is needed to achieve statistically significant results in such populations.

Finally, the findings of the systematic review are limited because of the different definitions and measures of adherence used. For a substantial effect on the CD4 count increase or viral load reduction, patients have to reach a certain adherence level in terms of the amount and timing of medication intake. Taking this into account, the proportion of patients reaching this adherence level should be chosen as the definition of adherence instead of the mean of the entire trial population, as the overall mean does not allow for a conclusion to be drawn regarding how many patients could benefit from the intervention, because the variance is not accounted for. In future, such thresholds should be clinically ascertained because the thresholds used to date were verified for older HAARTs. Again, a lower bound of required adherence for an adequate suppression of HIV replication in newer HAARTs has not been determined [42, 41], and will depend on the type of regimen and patient characteristics. Furthermore, whether mean adherence could be used as a proxy for the threshold should be evaluated. Additionally, the time-frame in which antiretroviral therapy has to be taken to achieve optimal therapy success has not been specified. Adherence was measured with various instruments. All instruments seemed to have a tendency to overestimate adherence. For self-reporting instruments in particular, a higher estimation of intake than the true adherence has been shown [44, 43]. Electronic monitoring data and pill counts are more objective adherence measures, in contrast to questionnaires. Additionally, pill counts might overestimate the amount taken [44, 43]. Electronic monitoring is currently regarded as the gold standard for measuring adherence [45]. However, if timing is also considered, electronic monitoring could also have limitations. For example, double intakes could go unnoticed [46] because only bottle openings are recognized by the system. Furthermore, the caps could be opened without taking medication. Capturing unbiased, true adherence rates appears to be almost impossible. Consequently, the adherence measurement is likely to introduce bias in adherence-enhancing intervention trials.

The findings are limited by the possibility of language bias, because we searched for only articles written in English and German [47]. Although a systematic review [33] that included RCTs with patient enrolment before 2001 gave similar results to those presented here, a further limitation is that some relevant RCTs could have been missed because we only included publications with later patient enrolment. The risk of bias because unpublished work was not included seems low, as the majority of unpublished studies lack statistical significance; however, some relevant studies may not have been identified because, except for the reference check, no efforts were made to identify unpublished material.

Effective adherence-enhancing interventions should primarily be designed for patients at high risk for nonadherence, for example, substance abusers [48] or patients who do not reach the required adherence rates for viral suppression. These patients are most likely to benefit from an intervention. This assumption is supported by the fact that two of our included trials that showed an effect of the intervention on clinical outcomes were in patients at a high risk for low adherence, which was measured as a low baseline adherence [4, 24].

Screening for nonadherence with a validated measurement tool could be used to identify patients with low adherence. Another possibility could be to identify patients at high risk for nonadherence on the basis of risk factors, especially for patients starting HAART. Similar instruments that are more precise for evaluating readiness to receive psychological therapy and also for predicting HAART adherence have been developed [49]. Use of these instruments could help to increase the effects of adherence-enhancing interventions. Simultaneously, it could help to avoid unnecessary costs for health care systems and unethical inconvenience for patients who are already adequately adherent and are not in need of further adherence-enhancing interventions. Such approaches could also help to tailor the intervention to the specific challenges of different populations at risk. Therefore, extensive applicable interventions for the general HIV-infected population are necessary as well as specific models for patient groups with difficult living conditions. Additionally, educational material should be available on demand to ensure equity and maintain adherence. Further research should take this into account. More high-quality trials, with adequate sample size calculations, that satisfactorily tackle the issue of drop-outs and use valid surrogates or patient-relevant outcomes are needed to evaluate the effectiveness of adherence-enhancing interventions.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Conflicts of interest: The funder had no influence on any aspect of the systematic review. The authors declare no other conflicts of interest.

Financial disclosure: The systematic review was funded by Janssen-Cilag Germany.

Author contributions: TM contributed to research question development, search strategy development, study selection, data analysis, interpretation of results and preparation of the manuscript. DP contributed to research question development, search strategy development, study selection, data analysis, interpretation of results and review of the manuscript. S-LA contributed to research question development, search strategy development, study selection, data analysis, interpretation of results and linguistic revision of the manuscript. ME contributed to research question development, search strategy development and review of the manuscript.

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  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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