The authors have declared that no competing interests exist.
Conceived and designed the experiments: KB CG SPK DS. Performed the experiments: KB. Analyzed the data: KB. Contributed reagents/materials/analysis tools: KB CG SPK DS. Wrote the paper: KB CG SPK DS. Conceived and designed the review: KB CG SPK DS. Conducted the literature search: KB. Abstracted the data: KB. Analyzed results: KB. Wrote the first draft of the paper, with inputs from all authors: KB. Read and approved the final paper: KB CG SPK DS.
High levels of patient adherence to antimalarial treatment are important in ensuring drug effectiveness. To achieve this goal, it is important to understand levels of patient adherence, and the range of study designs and methodological challenges involved in measuring adherence and interpreting results. Since antimalarial adherence was reviewed in 2004, there has been a major expansion in the use of artemisinin-based combination therapies (ACTs) in the public sector, as well as initiatives to make them more widely accessible through community health workers and private retailers. These changes and the large number of recent adherence studies raise the need for an updated review on this topic.
We conducted a systematic review of studies reporting quantitative results on patient adherence to antimalarials obtained for treatment.
The 55 studies identified reported extensive variation in patient adherence to antimalarials, with many studies reporting very high adherence (90–100%) and others finding adherence of less than 50%. We identified five overarching approaches to assessing adherence based on the definition of adherence and the methods used to measure it. Overall, there was no clear pattern in adherence results by approach. However, adherence tended to be higher among studies where informed consent was collected at the time of obtaining the drug, where patient consultations were directly observed by research staff, and where a diagnostic test was obtained.
Variations in reported adherence may reflect factors related to patient characteristics and the nature of their consultation with the provider, as well as methodological variations such as interaction between the research team and patients before and during the treatment. Future studies can benefit from an awareness of the impact of study procedures on adherence outcomes, and the identification of improved measurement methods less dependent on self-report.
While considerable progress has been made in the last decade to reduce malaria morbidity and mortality, malaria continues to cause more than 200 million cases and more than 600,000 deaths per year
In order for antimalarial treatment to be effective, multiple steps must occur
To achieve this goal, it is important for policymakers to understand levels of patient adherence to antimalarials, how they vary by context, and how adherence can be improved. However, studies measuring patient adherence encounter substantial methodological challenges, such as selection of appropriate definitions of adherence and appropriate measurement methods. This results in a broad diversity of study designs which, along with the wide range of study contexts and different antimalarial drugs, can challenge interpretation of adherence results.
The use of antimalarial drugs was last reviewed by Yeung and White in 2004
Here, previously reviewed and recent studies providing quantitative results on adherence to antimalarials obtained for treatment are analysed. We examine how results vary by definition of adherence and key methodological characteristics, and we present the studies' own findings on factors associated with adherence. We emphasize challenges in measuring adherence, avoiding bias, and implications for future research.
Studies included in this review were identified by three methods. First, a systematic literature search was conducted on PubMed using MeSH and free text terms as follows: (Medication Adherence (MeSH) or Patient Compliance (MeSH) or compliance or adhere*) and (Antimalarials (MeSH) or antimalarial*). Secondly, reference lists from studies and reviews identified were searched manually for relevant studies. Finally, researchers known to be currently active in the field were contacted.
Studies that were clearly irrelevant were immediately discarded, and abstracts and manuscripts of the remaining studies were examined in detail to determine relevance. Published studies that provided quantitative data on patient adherence to antimalarials obtained for treatment of malaria were included in this review. Where papers employed both quantitative and qualitative methods, only the quantitative results are reported here. Studies were included from all parts of the world in any language utilizing various study designs, including household surveys and clinical trials examining the effectiveness of supervised versus unsupervised treatment that specifically reported data on adherence in the unsupervised arm. Studies assessing adherence to antimalarials obtained for prophylaxis, and effectiveness studies that did not report data on adherence were excluded. Manuscripts of studies meeting inclusion criteria were read in detail and data on study settings, objectives, study design, definitions of adherence, methods of assessing adherence and results were systematically reviewed and abstracted into a database.
The initial literature search using PubMed identified 1340 studies (
Three main types of studies were identified: descriptive studies, interventions to improve adherence, and studies with clinical outcomes as a primary endpoint (
Study, (Country), Source(s) of drugs | Drug regimen(s) |
Method(s) of assessing adherence | Approach(es) to assessing adherence |
Day of follow-up visit (Day 1 = drug dispensed) | Level of adherence (N = denominator) |
Abuaku et al. 2004 |
SP, chloroquine (CQ), & amodiaquine (AQ) | Household survey questionnaire | Completed treatment | n/a | SP - 100% (N = 4); CQ - 11.1% site 1 (N = 171); CQ - 36.4% site 2 (N = 195); AQ - 12.9% site 1 (N = 9); AQ - 50% site 2 (N = 2) |
Ajayi et al. 2008 |
AL in Nigeria and Uganda & artesunate-amodiaquine in Ghana | Household survey questionnaire | Completed treatment | n/a | Ghana - 97% (N = 153); Nigeria - 93% (N = 60); Uganda - 81% (N = 31); Overall - 94% (N = 244) |
Amin et al. 2004 |
SP & amodiaquine | Household survey questionnaire | n/a | SP - 66.7% (N = 78); AQ - 13.8% (N = 94) | |
Barnes et al. 2005 |
AL | Household survey questionnaire | Completed treatment | n/a | 96% (N = 235) |
Beer et al. 2009 |
Artesunate-amodiaquine (3 days) | Self-report, pill count | Verified completed treatment & |
Day 4 | Verified completed treatment - 77% (N = 174); |
Chinbuah et al. 2006 |
AL (3 days) | Self report | Timely completion | Day 4 | 100% (N = 334) |
Cohen et al. 2012 |
AL (3 days) | Self-report, pill count | Verified completed treatment | Day 4 | 65.8% (N = 152) |
Deming et al. 1989 |
Chloroquine | Household survey questionnaire | Completed treatment | n/a | 29% (N = 370) |
Depoortere et al. 2004 |
SP + artesunate (3 days) | Self-report, pill count | Verified timely completion | Day 4 | 39.4% (N = 162) |
Depoortere et al. 2004 |
AL (3 days) | Self-report, pill count | Verified timely completion | Day 4 | 59.1% (N = 93) |
Fogg et al. 2004 |
AL (3 days) | Self-report, pill count, lumefantrine assay |
Verified timely completion | Day 4 | 90% (N = 210) |
Gerstl et al. 2010 |
Artesunate-amodiaquine (3 days) | Self-report, pill count | Verified timely completion | Day 4 | 48% (N = 118) |
Kabanywanyi et al. 2010 |
AL (3 days) | Self-report | Timely completion & Completed treatment | Randomized to follow-up visit close to time of one of the five doses to be taken at home | Timely completion - 90% (N = 552); Completed treatment - 98% (N = 552) |
Kachur et al. 2004 |
SP + artesunate (3 days) | Self-report, pill count | Timely completion & Verified timely completion | After 48 hours | Timely completion - 76.6% (N = 128); Verified timely completion - 75% (N = 128) |
Kalyango et al. 2013 |
AL (3 days) | Self-report, pill count | Verified completed treatment & |
Day 4 | Verified completed treatment - 86% (N = 667); |
Khantikul et al. 2009 |
Chloroquine + primaquine (14 days) | Self-report | Completed treatment | Up to one year | 24.8% (N = 206) |
Kolaczinski et al. 2006 |
Chloroquine + SP (3 days) | Self-report, pill count | Verified completed treatment | Day 4 | 96.3% (N = 241) |
Krause & Sauerborn 2000 |
Antimalarial drugs (mostly chloroquine & quinine) | Pill count | Middle of the treatment course | 68% (N = 47) | |
Lawford et al. 2011 |
AL (3 days) | Self-report, pill count | Verified completed treatment | Day 4 | 64.1% (N = 918) |
Lemma et al. 2011 |
AL (3 days) | Self-report, pill count | Verified timely completion & Completed treatment | Day 4 | Verified timely completion - 38.7% (N = 155); Completed treatment - 73.5% (N = 155) |
Mace et al. 2011 |
AL (3 days) | Self-report, pill count | Verified timely completion & Verified completed treatment | Day 4 | Verified timely completion - 65% (N = 386); Verified completed treatment - 75% (N = 386) |
Nshakira et al. 2002 |
Chloroquine (3 days) | Self-report | Completed treatment | Day 4 | 37.8% (N = 463) |
Nsungwa-Sabiiti et al. 2005 |
Chloroquine & chloroquine + SP | Household survey questionnaire | Completed treatment | n/a | 25% (N = 65) |
Onyango et al. 2012 |
AL | Household survey questionnaire | Completed treatment | n/a | 47% (N = 297) |
Peeters Grietens et al. 2010 |
Primaquine (7 days) | Self-report, triangulation with health centre records | Completed treatment & |
Up to one year | Completed treatment - 71.9% (N = 185); |
Pereira et al. 2011 |
Chloroquine + primaquine (7 days) | Self-report, pill count | Verified timely completion | Day 7 | 86.4% (N = 280) |
Reilley et al. 2002 |
Chloroquine + primaquine (5 days) | Self-report | Completed treatment | Day 6 | 74% (N = 132) |
Simba et al. 2012 |
AL (3 days) | Self-report, lumefantrine assay |
Timely completion | Day 7 | 88.3% (N = 444) |
Thera et al. 2000 |
Chloroquine | Household survey questionnaire | Completed treatment | n/a | 37.8% (N = 152) |
Twagirumukiza et al. 2010 |
Quinine tablets (7 days, last 4 unsupervised) | Self-report, pill count, electronic pill boxes | Verified timely completion & |
Day 8 | Verified timely completion - 100% (N = 56); |
1 Duration of drug regimen in days not given for household surveys;
2 See
3 Not incorporated into approach to assessing adherence.
Study, (Country), Source(s) of drugs | Drug regimen(s) |
Intervention | Method(s) of assessing adherence | Approach(es) to assessing adherence |
Day of follow-up visit (Day 1 = drug dispensed) | Level of adherence without intervention (N = denominator) | Level of adherence with intervention (N = denominator) |
Agyepong et al. 2002 |
Chloroquine (3 days) | Drug labels & verbal instructions | Self-report | Timely completion & |
Day 4 | Timely completion |
Timely completion (control) - 27% (N = 78); Timely completion (intervention) - 39% (N = 121); |
Ansah et al. 2001 |
Chloroquine (3 days) | Introduction of tablets to replace syrup | Self-report, pill count or measurement of remaining syrup |
Timely completion | Day 4 | 42% (N = 144) | 91% (n = 155) |
Denis et al. 1998 |
Quinine + tetracycline (7 days) | Posters & video | Self-report, pill count |
Completed treatment | Day 7 (Day 4 if doses were purchased for only 3 days) | Group 1 - 1% (N = 95); Group 2 - 10% (N = 82) | Group 1 (posters and video) - 39% (N = 88); Group 2 (posters only) - 15% (N = 120) |
Kangwana et al. 2011 |
AL (3 days) | Subsidised AL, shopkeeper training, & community awareness activities | Self-report | Completed treatment | n/a | Group 1 - 40.5% (N = 26); Group 2 - 53.1% (N = 30) | Group 1 (control) - 24.8% (N = 89); Group 2 (intervention) - 67% (N = 221) |
Lauwo et al. 2006 |
Chloroquine + SP (3 days) | Packaging & counselling | Self-report | Timely completion | Day 4 | 76.5% (N = 119) | Counselling - 92.9% (N = 112); Counselling & packaging - 95.5% (N = 91) |
Marsh et al. 1999 |
Chloroquine | Shopkeeper training | Household survey questionnaire; laboratory assay in a subset of children given a full dose |
Completed treatment | Day 4 | 3.7% (N = 109) | 75% (N = 108) |
Marsh et al. 2004 |
Chloroquine & SP | Shopkeeper training | Household survey questionnaire | Completed treatment | n/a | Chloroquine - 8% (N = 160) | SP - 64% (N = 441) |
Okonkwo et al. 2001 |
Chloroquine | Pictorial insert & verbal instructions | Self-report, measurement of remaining syrup | Verified timely completion | 48 hours after start of treatment | 36.5% (N = 190) | Pictorial insert - 51.9% (N = 225); Pictorial insert & verbal instructions - 73.3% (N = 217) |
Qingjun et al. 1998 |
Chloroquine + primaquine (8 days) | Packaging | Self-report, laboratory assay | Timely completion & Biological assay (by phenobarbital markers) | Day 4 or Day 9 | Timely completion - 83% (N = 163); Biological assay - 80.5% (N = 134) | Timely completion - 97% (N = 161); Biological assay - 97% (N = 138) |
Shwe et al. 1998 |
Artesunate + mefloquine (3 days) | Packaging & training | Laboratory assay | Biological assay (by chloroquine & quinine markers) | Day 7 | n/a | 99.5% (N = 380) |
Sirima et al. 2003 |
Chloroquine | Packaging & availability through community health workers | Household survey questionnaire | Completed treatment | n/a | n/a | 52% (N = 1806) |
Winch et al. 2003 |
Chloroquine (3 days) | Community health worker training | Self-report, pill count or measurement of remaining syrup | Timely completion & |
Day 4 | Timely completion - 1.5% (N = 131); |
Timely completion - 42.1% (N = 151); |
Yeboah-Antwi et al. 2001 |
Chloroquine (3 days) | Age-based packaging of syrup & tablets | Self-report, pill count or measurement of remaining syrup |
Timely completion | Day 4 | Tablets - 60.5% (N = 152); Syrup - 32.6% (N = 95); Overall - 49.8% (N = 247) | Tablets - 82.0% (N = 167); Syrup - 54.7% (N = 95); Overall - 72.1% (N = 262) |
1 Duration of drug regimen in days not given for household surveys;
2 See
3 Not incorporated into adherence definition;
4 Weighted results for three control and three intervention clinics.
Study, (Country), Source(s) of drugs | Drug regimen(s) |
Approach(es) to assessing adherence |
Approach(es) to assessing adherence |
Day of follow-up visit (Day 1 = drug dispensed) | Level of adherence with intervention (N = denominator) |
Achan et al. 2009 |
AL (3 days) & quinine (7 days) | Self-report, pill count | Day 4 | AL - 94.5% (N = 85); Quinine - 85.4% (N = 75) | |
Bell et al. 2009 |
AL (3 days) & chloroproguanil-dapsone (CPD, 3 days) | Self-report, electronic pill boxes, laboratory assays |
Completed treatment & |
Day 8 | Completed treatment (AL) - 100% (N = 185); Completed treatment (CPD) - 99.2% (N = 371); |
Congpuong et al. 2010 |
Artesunate + mefloquine + primaquine (3 days) | Self-report, drug assays | Completed treatment & Biological assay | Day 4 | Completed treatment - 100% (N = 240); Biological assay (mefloquine marker) - 96.3% (N = 215); Biological assay (quinine marker) - 98.5% (N = 214) |
Duarte et al. 2003 |
Quinine + doxycycline (7 days) & primaquine + chloroquine (14 days) | Self-report | Completed treatment | Up to 4 months | 83.8% (N = 488) |
Dunyo et al. 2010 |
AL (3 days) & chloroproguanil-dapsone (CPD, 3 days) | Self-report (pill count for some |
Completed treatment | Day 4 | AL - 67% (N = 600); CPD - 94% (N = 599) |
Faucher et al. 2009 |
AL (3 days) & artesunate-amodiaquine (ASAQ) (3 days) | Self-report, pill count | Verified completed treatment | Day 4 | AL - 83% (N = 96); ASAQ - 91% (N = 96) |
Fungladda et al. 1998 |
Artesunate (4 days) & quinine + tetracycline (7 days) | Self-report, pill count | Verified completed treatment | Day 5 or Day 8 | Artesunate - 98.4% (N = 61); Quinine + tetracycline - 71.7% (N = 53) |
Na-Bangchang et al. 1997 |
Artemether + mefloquine (2 days) | Laboratory assays | Biological assay | Day 3 | 86.8% (N = 106) |
Rahman et al. 2008 |
AL (3 days) | Self-report, pill count, lumefantrine assay |
Verified timely completion | Day 4 | 93% (N = 160) |
Souares et al. 2008 |
SP + amodiaquine (3 days) | Self-report, laboratory assays |
Timely completion & |
Day 4 | Timely completion - 37.7% (N = 289); |
Takeuchi et al. 2010 |
Chloroquine + primaquine (14 days) | Self-report | Completed treatment | Day 8 & Day 15 | 85% (N = 101) |
Yepez et al. 2000 |
Chloroquine + primaquine (3 days for |
Self-report | Timely completion | Day 4 or Day 8 |
1 Duration of drug regimen in days not given for household surveys;
2 See
3 Not incorporated into adherence definition
More than half of the 55 studies were descriptive (30 studies)
Thirteen studies evaluated interventions to improve adherence
The third type of studies, those assessing clinical outcomes as a primary endpoint in addition to reporting patient adherence, included seven RCTs comparing effectiveness and adherence of different drug regimens
Of the 55 studies, 40 took place in Africa, 11 in Asia, and four in Latin America. Subjects included all age groups in 25 studies, only children under five in 19 studies, both children under five and older children in an additional seven studies, and only adults in four studies. Most studies assessed adherence to antimalarials taken to treat infection with
Patient adherence to more than one drug regimen was assessed in 12 studies, while 43 studies reported adherence to a single drug (
The 55 studies reviewed here employed a wide range of definitions and methodologies. Adherence was measured by questionnaires containing varying detail about how and when drugs were taken (self-report); physical counts of tablets remaining in packaging or dispensing envelopes (pill counts) and volumetric measurement of syrups; pill containers with electronic caps that record the date and time of each opening (electronic pill boxes); assays for drug levels in biological samples; and composites of these methods.
At least one approach used in 52 of the 55 studies could be classified under one of five overarching approaches defined for the purpose of this review, based on both the nature of adherence required and the method used to measure adherence (
Approach | Definition | Method | Number of studies |
Completed treatment | Patient completed treatment | Self-report | 28 |
Verified completed treatment | Patient completed treatment | Self-report and pill count | 10 |
Timely completion | Patient exactly followed instructions in terms of dose, frequency and duration | Self-report | 12 |
Verified timely completion | Patient exactly followed instructions in terms of dose, frequency and duration | Self-report and pill count | 11 |
Biological assays | Sufficient levels of drug(s) in biological samples | Biological assays | 4 |
Unique approaches | Various | Various | 11 |
1 All studies are included if adherence is reported by at least one of these five approaches (n = 52 studies) and are included more than once if multiple approaches were used.
Correct timing of doses, involving the correct dose, frequency, and duration, was required in 22 studies (“timely completion” and “verified timely completion”), 11 of which were studies of ACTs. However, there was considerable variation in which intervals were considered “correct”, “recommended” or “prescribed”. Several studies calculated the expected time of each dose per the manufacturer's instructions and allowed an interval of several hours on either side
The studies reported a very wide range of results for the percentage of patients adherent, ranging from 1.5% to 100% across different studies and settings. Below we explore how the results varied firstly by the approach to assessing adherence and data collection, secondly by antimalarial and outlet type, and thirdly by the nature of the interaction between patients and dispensers or researchers during the study. Scatter plots are used to facilitate the identification of general patterns in these results. Finally we present the studies' own findings on factors found to be associated with adherence in multivariate models.
i. Variation by approach and data collection method
Overall, it does not appear that using stricter approaches involving correct dose timing (“timely completion” and “verified timely completion”) or requiring pill counts in addition to self-reported histories (“verified completed treatment” and “verified timely completion”) are associated with lower adherence, but this does not account for differences in contexts and methodologies. However, among studies of AL, adherence by “verified timely completion” (38.7%–65%)
Household surveys, which all used the “completed treatment” approach and assessed adherence from both public and private community sources, tended to have lower adherence results than studies with other designs, particularly studies with primary clinical outcomes (
Among studies using unique approaches, two studies used electronic pill boxes (Medication Events Monitoring Systems – MEMS™) to measure adherence
Results using biological assays to assess adherence were high (above 90%), but this accounted for only a few studies
ii. Variation by antimalarial type and outlet type
The pattern of adherence results between antimalarials was not clear. Across all approaches and by “completed treatment” adherence to AL (47%–100%)
Although most studies evaluated adherence to antimalarials obtained in the public sector, the two descriptive private sector follow-up studies had low adherence, with Nshakira
iii. Variation by nature of interaction of patients with dispensers and research personnel
We explored how adherence results varied depending on the nature of the interaction reported between patients and their dispensers, and between patients and research personnel.
iv. Factors associated with adherence in multivariate models
Understanding the characteristics and behaviours associated with patient adherence to antimalarials is vital to designing interventions to improve appropriate use of ACTs. Twenty-four studies used multivariate analysis to examine factors associated with adherence: of these, 13 studies reported 30 factors significantly associated with adherence in multivariate models, nine studies found 12 factors associated with non-adherence, and five studies reported not finding any factors significantly associated with adherence or non-adherence
Factors | Studies |
- Caretaker education at least 7 years | Beer et al. 2009 |
- Attending some secondary school or beyond | Cohen et al. 2012 |
- Higher education | Onyango et al. 2012 |
Residence in one of two areas in study location | Duarte et al. 2003 |
- Respondent age 25-50 years versus less than 25 years | Lawford et al. 2011 |
- Patient age 15 years or more versus less than 15 years | Lawford et al. 2011 |
- Patient age less than 13 years | Onyango et al. 2012 |
Ownership of radio | Lemma et al. 2011 |
Higher household income | Onyango et al. 2012 |
Simba et al. 2012 |
|
Not having sought treatment at a public health facility | Cohen et al. 2012 |
Respondent sought treatment within 24 hrs of symptom onset versus waiting longer | Lawford et al. 2011 |
Delay of more than 1 day in seeking treatment after the onset of fever | Lemma et al. 2011 |
Previous care sought | Souares et al. 2008 |
Having received exact number of pills to complete treatment | Beer et al. 2009 |
Reporting having been given instructions at the shop | Cohen et al. 2012 |
Reporting that instructions given were clear | Cohen et al. 2012 |
Attended Migowi HC (one of three study outlets) | Mace et al. 2011 |
Package used as visual aid by dispenser to explain how to take the drug | Mace et al. 2011 |
Received written instructions | Pereira et al. 2011 |
Quality of history taking (i.e. nurses at the consultation asked questions about history, symptoms, and previous care) | Souares et al. 2008 |
Took first AL dose at HC | Mace et al. 2011 |
Taking AL with food or oil | Simba et al. 2012 |
Knowledge that only mosquitoes cause malaria | Gerstl et al. 2010 |
Knowledge of malaria aetiology | Khantikul et al. 2009 |
Respondent had seen the drug before | Lawford et al. 2011 |
Being able to cite at least one correct instruction on how to take AL | Lawford et al. 2011 |
Belief that malaria cannot be treated traditionally | Lemma et al. 2011 |
Access to information about antimalarials | Khantikul et al. 2009 |
Knowledge of the seriousness of the infection/knowing the species in mixed transmission areas | Yepez et al. 2000 |
Having an improved condition at follow-up | Cohen et al. 2012 |
Lower expectation of getting malaria in the next 30 days | Cohen et al. 2012 |
Did not report dislikes/side-effects to medication | Lawford et al. 2011 |
Preference for AL | Mace et al. 2011 |
Satisfaction with received information | Souares et al. 2008 |
Factors | Studies |
Being male | Achan et al. 2009 |
Pereira et al. 2011 |
|
Caretaker having different mother tongue to pharmacist | Depoortere et al. 2004 |
- Caretaker education (none versus some) | Depoortere et al. 2004 |
- Lack of formal education | Fogg et al.2004 |
- Being a child under 5 | Mace et al. 2011 |
- Being a child age 8–10 years versus 2–4 years | Souares et al. 2008 |
Head of household profession (retailer/employee vs. farmer) | Souares et al. 2008 |
No fever reported | Kalyango et al. 2013 |
Seeking care after 2 or more days | Kalyango et al. 2013 |
Takeuchi et al. 2009 |
|
Treatment with oral quinine versus AL | Achan et al. 2009 |
Being counselled about what to do in case of vomiting | Kachur et al. 2004 |
Not understanding instructions | Kalyango et al. 2013 |
Caregiver's perception that illness is not severe | Kalyango et al. 2013 |
Vomiting | Achan et al. 2009 |
Kalyango et al. 2013 |
1 Includes patients receiving Al only and AL plus antibiotics (treatment group not significant in multivariate analysis);
2 Associated with non-adherence in the second week of primaquine treatment for
Extensive variation was observed in patient adherence to antimalarials, with many studies reporting very high adherence (90–100%) and others finding clearly suboptimal adherence, sometimes of less than 50%. This may be an important problem, both in terms of clinical outcomes and also in the context of the development of resistance to artemisinin in South-East Asia
We identified five overarching approaches to assessing adherence based on recall (“completed treatment” and “timely completion”), recall and pill counts (“verified completed treatment” and “verified timely completion”) and on biological assays. By “completed treatment” and “verified completed treatment”, adherent patients were defined as completing the full course of treatment though not necessarily following a specific schedule. Whether these are appropriate approaches to assess adherence should be considered in light of the pharmacology of the specific drug: if the safety or efficacy of the drug is critically dependent on the timing of the doses then it will be important to assess this when evaluating adherence. As these approaches do not include the spacing of the doses, it is possible for patients to have taken some doses too close together or even to have taken all doses at one time and still be considered “adherent”, though such practices could be of concern for drug safety and efficacy. Furthermore, there is potential variation within each approach in what was considered correct treatment, with some studies taking into account national guidelines on the correct dose-for-weight that the patient should have consumed and other studies assuming the correct amount was obtained.
By “timely completion” and “verified timely completion”, adherent patients were defined as exactly following instructions in terms of dose, frequency and duration according to their responses to interview questions. As noted above, there was considerable variation in definitions of “correct” timing, which may have affected comparability within these approaches. More information is needed on how precise time intervals between doses must be in order for drugs to be efficacious. For example, the packaging of various brands of AL states that the second dose should be taken eight hours after the first dose, which would fall in the middle of the night if the drug is obtained in the evening. In this situation it is unclear whether a patient should still be considered adherent if they take the drugs first thing the next morning instead.
The majority of the adherence studies used one or more of these approaches relying primarily on self-reported drug histories, which may be susceptible to recall and social desirability bias. Studies in Tanzania and Cambodia found high levels of antimalarials circulating in the blood among patients stating they had not taken any drugs in the previous 28 days
To avoid being seen as ignorant or negligent, patients who are aware of the expected behaviour may say they were adherent even if they actually were not. A study by Peeters Grietens
In order to reduce recall and social desirability bias, some studies incorporated manual examination of drug packaging into their definitions of adherence (“verified completed treatment” and “verified timely completion”). For studies of AL, these approaches yielded lower adherence results than the equivalent approaches without the pill counts (“completed treatment” and “timely completion”). However, even results including pill counts may over-estimate true adherence as removing pills from blister packs does not guarantee that the pills were consumed. Similarly, opening electronic pill boxes does not guarantee a dose was consumed. Patients may have “played” with their pill boxes, opening them without removing pills, or alternatively, they may also have removed multiple doses at one opening, either to discard, consume, or save until the appropriate time.
Despite the limitations of self-reported and pill count approaches, Souares
Regardless of the approach used for assessing adherence, Hawthorne bias may occur if a patient's awareness of being studied positively influences medication-taking behaviour. Similarly, if researchers observe patient consultations with the dispenser, this may positively influence the care and advice provided by the dispenser and/or patients' attentiveness and adherence to the treatment. In the studies reviewed here, adherence was higher when informed consent was collected at the time of obtaining the drug and to some degree when patient consultations were directly observed (
Some specific patient-dispenser interactions might also be expected to improve adherence. For example, confirmation of diagnosis of malaria by an RDT or blood smear might increase adherence if patients are more aware that they are suffering from malaria, and if patients with confirmed malaria see a better response to treatment than those who have other conditions. Observing the first dose of treatment is another commonly recommended practice and was found to be significantly associated with adherence to AL in one study
In addition to the approach to measurement and the nature of the patients' consultations, other factors often hypothesised to influence adherence include patient characteristics, antimalarial type and outlet type. However, it was not possible to discern clear patterns across the studies reviewed. There was some evidence from multivariate studies that patients who had higher socio-economic status and were better educated or informed had higher adherence. While there is some concern that the greater number of tablets required for treatment with ACTs (i.e. 24 for an adult) contributes to lower adherence compared to antimalarials requiring fewer tablets, this was not clear in the studies reviewed here. One potential explanation for this is that ACTs often come in co-formulated or co-packaged blister packs, with different coloured packages for each age or weight group. This is in contrast to loose tablets dispensed into paper envelopes, which was often the case for older antimalarials. Not only can the dispenser give the patient the incorrect number of tablets, but the tablets may need to be cut in half to achieve the appropriate doses, and it may be more difficult for the patient to remember how many to take. Secondly, more effective antimalarials such as ACTs may encourage higher patient adherence; if drugs are perceived to be ineffective, patients may use a drug briefly or not at all before looking for a more effective alternative
It was hard to assess variation across outlet types as of the 55 studies included, only five specifically evaluated adherence to antimalarials from private drug shops
The literature reports extensive variation in patient adherence to antimalarials. The unsatisfactory patient adherence sometimes reported to ACTs obtained in the public sector, and the current dearth of data from the private sector, represent significant challenges for maximising the impact of ACTs. Variations in adherence may reflect factors related to patient characteristics and knowledge, their treatment seeking behaviour, and the nature of their consultation with the provider. However, methodological variations between studies are also likely to be an important source of variability in results, including the methods used for collecting data, and any interaction between the research team and patients before and during the treatment course. Future studies could be strengthened by a greater awareness of the impact of study procedures on adherence outcomes, and the identification of improved measurement methods that are less dependent on self-report.
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