UvA-DARE (Digital Academic Repository) Fats & Fakes ... · Artemisinin -based combination therapy (ACT) is currently recommended for the treatment of uncomplicated malaria caused

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Fats & FakesTowards improved control of malariaVisser, B.J.

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Citation for published version (APA):Visser, B. J. (2017). Fats & Fakes: Towards improved control of malaria.

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174

“The proportion of silt particles in the topsoil (i.e. mineral matter between 0.002 mm and 0.05 mm– USDA classification - or between 0.002 mm and 0.0625 mm - ISO and FAO classification). Silt istoo small to see with the naked eye. It is produced by the mechanical weathering of rock, as opposedto the chemical weathering that results in clays. This mechanical weathering can be due to aeolianabrasion (sandblasting by the wind) as well as water erosion of rocks on the beds of rivers andstreams. It is good agricultural soil due to high nutrient levels and good water retention in spacesbetween particles. Easy to cultivate but very prone to erosion.” Adapted from: Soil Atlas of Africa,2013. European Commission, Publications Office of the European Union, Luxembourg.1

175

Chapter 6

Health workers’ compliance to rapid diagnostic tests (RDTs) toguide malaria treatment: a systematic review and meta-analysis

Alinune N. Kabaghe

Benjamin J. Visser

Rene Spijker

Kamija S. Phiri

Martin P. Grobusch

Michèle van Vugt

Malaria Journal 2016 Mar 15;15(1):163

Appendices and supplementary material are available online at:https://malariajournal.biomedcentral.com/articles/10.1186/s12936-016-1218-5



174

“The proportion of silt particles in the topsoil (i.e. mineral matter between 0.002 mm and 0.05 mm– USDA classification - or between 0.002 mm and 0.0625 mm - ISO and FAO classification). Silt istoo small to see with the naked eye. It is produced by the mechanical weathering of rock, as opposedto the chemical weathering that results in clays. This mechanical weathering can be due to aeolianabrasion (sandblasting by the wind) as well as water erosion of rocks on the beds of rivers andstreams. It is good agricultural soil due to high nutrient levels and good water retention in spacesbetween particles. Easy to cultivate but very prone to erosion.” Adapted from: Soil Atlas of Africa,2013. European Commission, Publications Office of the European Union, Luxembourg.1

175

Chapter 6

Health workers’ compliance to rapid diagnostic tests (RDTs) toguide malaria treatment: a systematic review and meta-analysis

Alinune N. Kabaghe

Benjamin J. Visser

Rene Spijker

Kamija S. Phiri

Martin P. Grobusch

Michèle van Vugt

Malaria Journal 2016 Mar 15;15(1):163

Appendices and supplementary material are available online at:https://malariajournal.biomedcentral.com/articles/10.1186/s12936-016-1218-5



Chapter 6

176

Abstract

Background

The World Health Organization recommends malaria to be confirmed by either microscopy or a rapiddiagnostic test (RDT) before treatment. The correct use of RDTs in resource-limited settingsfacilitates basing treatment onto a confirmed diagnosis; contributes to speeding up considering acorrect alternative diagnosis, and prevents overprescription of anti-malarial drugs, reduces costs andavoids unnecessary exposure to adverse drug effects. This review aims to evaluate health workers’compliance to RDT results and factors contributing to compliance.

Methods

A PROSPERO-registered systematic review was conducted to evaluate health workers’ complianceto RDTs in sub-Saharan Africa, following Preferred Reporting Items for Systematic Reviews andMeta-Analyses (PRISMA) guidelines. Studies published up to November 2015 were searchedwithout language restrictions in Medline/Ovid, Embase, Cochrane Central Register of ControlledTrials, Web of Science, LILACS, Biosis Previews and the African Index Medicus. The primaryoutcome was health workers treating patients according to the RDT results obtained.

Results

The literature search identified 474 reports; 14 studies were eligible and included in the quantitativeanalysis. From the meta-analysis, health workers’ overall compliance in terms of initiating treatmentor not in accordance with the respective RDT results was 83 % (95 % CI 80–86 %). Compliance topositive and negative results was 97 % (95 % CI 94–99 %) and 78 % (95 % CI 66–89 %),respectively. Community health workers had higher compliance rates to negative test results thanclinicians. Patient expectations, work experience, scepticism of results, health workers’ cadres andperceived effectiveness of the test, influenced compliance.

Conclusions

With regard to published data, compliance to RDT appears to be generally fair in sub-Saharan Africa;compliance to negative results will need to improve to prevent mismanagement of patients andoverprescribing of anti-malarial drugs. Improving diagnostic capacity for other febrile illnesses anddeveloping local evidence-based guidelines may help improve compliance and management ofnegative RDT results.

Trial registration

CRD42015016151 (PROSPERO)

Health workers’ compliance to RDTs to guide malaria treatment: a meta-analysis

177

BackgroundPlasmodium falciparum malaria is estimated to have caused 528,000 deaths and 163 millionclinical episodes in sub-Saharan Africa in 2013.4 Early diagnosis and treatment withappropriate anti-malarial drugs can prevent severe illness and lethal outcome.38, 96

Artemisinin-based combination therapy (ACT) is currently recommended for the treatmentof uncomplicated malaria caused by P. falciparum10, 38 and is increasingly used for non-falciparum malaria.420 Effective case-management of malaria consists of an efficacioustreatment, prompt access to treatment and diagnosis, provider compliance to treatmentguidelines, and patient adherence to medication (Figure 1). 38, 462

Figure 1. Pathway of health systems effectiveness of malaria diagnosis and treatment. (Adaptedfrom MalERA consultative group)462

Presumptive diagnosis and treatment of malaria based on symptoms leads to over- diagnosisof malaria and missed diagnosis for patients without malaria.463, 464 The World HealthOrganization (WHO) recommends that any suspected malaria case in any epidemiologicalsetting should be parasitologically-confirmed by either microscopy or rapid diagnostic test(RDT) before treatment.38 Lack of trained personnel, equipment,465 and reagents formicroscopy in most remote rural areas in Africa466, 467 with high malaria burden makes theRDT the most practically suitable tool to confirm a malaria diagnosis.4, 468 RDTs areimmunochromatographic test kits which confirm the presence of malaria parasites insuspected patients by detecting one or a combination of the following three Plasmodiumantigens: Plasmodium falciparum histidine-rich protein-2 (PfHRP-2) for P. falciparum or a‘pan-specific’ aldolase to detect other species, such as P. vivax or Plasmodium lactate



6

Chapter 6

176

Abstract

Background

The World Health Organization recommends malaria to be confirmed by either microscopy or a rapiddiagnostic test (RDT) before treatment. The correct use of RDTs in resource-limited settingsfacilitates basing treatment onto a confirmed diagnosis; contributes to speeding up considering acorrect alternative diagnosis, and prevents overprescription of anti-malarial drugs, reduces costs andavoids unnecessary exposure to adverse drug effects. This review aims to evaluate health workers’compliance to RDT results and factors contributing to compliance.

Methods

A PROSPERO-registered systematic review was conducted to evaluate health workers’ complianceto RDTs in sub-Saharan Africa, following Preferred Reporting Items for Systematic Reviews andMeta-Analyses (PRISMA) guidelines. Studies published up to November 2015 were searchedwithout language restrictions in Medline/Ovid, Embase, Cochrane Central Register of ControlledTrials, Web of Science, LILACS, Biosis Previews and the African Index Medicus. The primaryoutcome was health workers treating patients according to the RDT results obtained.

Results

The literature search identified 474 reports; 14 studies were eligible and included in the quantitativeanalysis. From the meta-analysis, health workers’ overall compliance in terms of initiating treatmentor not in accordance with the respective RDT results was 83 % (95 % CI 80–86 %). Compliance topositive and negative results was 97 % (95 % CI 94–99 %) and 78 % (95 % CI 66–89 %),respectively. Community health workers had higher compliance rates to negative test results thanclinicians. Patient expectations, work experience, scepticism of results, health workers’ cadres andperceived effectiveness of the test, influenced compliance.

Conclusions

With regard to published data, compliance to RDT appears to be generally fair in sub-Saharan Africa;compliance to negative results will need to improve to prevent mismanagement of patients andoverprescribing of anti-malarial drugs. Improving diagnostic capacity for other febrile illnesses anddeveloping local evidence-based guidelines may help improve compliance and management ofnegative RDT results.

Trial registration

CRD42015016151 (PROSPERO)


177

BackgroundPlasmodium falciparum malaria is estimated to have caused 528,000 deaths and 163 millionclinical episodes in sub-Saharan Africa in 2013.4 Early diagnosis and treatment withappropriate anti-malarial drugs can prevent severe illness and lethal outcome.38, 96

Artemisinin-based combination therapy (ACT) is currently recommended for the treatmentof uncomplicated malaria caused by P. falciparum10, 38 and is increasingly used for non-falciparum malaria.420 Effective case-management of malaria consists of an efficacioustreatment, prompt access to treatment and diagnosis, provider compliance to treatmentguidelines, and patient adherence to medication (Figure 1). 38, 462

Figure 1. Pathway of health systems effectiveness of malaria diagnosis and treatment. (Adaptedfrom MalERA consultative group)462

Presumptive diagnosis and treatment of malaria based on symptoms leads to over- diagnosisof malaria and missed diagnosis for patients without malaria.463, 464 The World HealthOrganization (WHO) recommends that any suspected malaria case in any epidemiologicalsetting should be parasitologically-confirmed by either microscopy or rapid diagnostic test(RDT) before treatment.38 Lack of trained personnel, equipment,465 and reagents formicroscopy in most remote rural areas in Africa466, 467 with high malaria burden makes theRDT the most practically suitable tool to confirm a malaria diagnosis.4, 468 RDTs areimmunochromatographic test kits which confirm the presence of malaria parasites insuspected patients by detecting one or a combination of the following three Plasmodiumantigens: Plasmodium falciparum histidine-rich protein-2 (PfHRP-2) for P. falciparum or a‘pan-specific’ aldolase to detect other species, such as P. vivax or Plasmodium lactate



Chapter 6

178

dehydrogenase (LDH) variants (pLDH) (with clonality specific to the various Plasmodiumspecies infecting humans).37, 469

The use of malaria RDT can reduce over-prescribing of anti-malarial drugs (AMD). Studieshave shown that in most endemic countries in sub-Saharan Africa, health workers ofdifferent cadres do not comply with malaria RDTs; they prescribe AMDs to patients withRDT negative results.468, 470-472 This has implications on resources for patient, familymembers and health system since some drug combinations are relatively expensive.473, 474

Non-compliance to malaria negative results by prescribing AMDs neglects underlying causeof fever and expose patients unnecessarily to adverse effects; underlying infections, such assepsis, pneumonia and meningitis,475-478 present as malaria clinically but are not routinelyinvestigated479 and may not be treated.466, 480

To treat malaria effectively, to reduce costs and avoid unnecessary exposure to drug adverseeffects, there is a need to correctly diagnose and comply with malaria treatment guidelinesor clinical decision algorithms. Health workers (HWs) need to use the correct treatmentbased on the RDT results.

This systematic review examines data available on HWs compliance to RDT results in sub-Saharan Africa, and investigates factors associated with compliance to results (HW treatingpatients according to the RDT result). The primary outcome is the percentage of HWscompliant to overall, positive or negative, test results.

MethodsThis systematic review was registered in advance in the International prospective register ofsystematic reviews (PROSPERO; registration number CRD42015016151) which includedpre-specified the objectives and inclusion criteria.481

An experienced information specialist (RS) conducted a search without language or timerestrictions in the online electronic databases Ovid Medline, Ovid Embase, Cochrane CentralRegister of Controlled Trials, CINAHL Plus with Full Text, African Index Medicus, andAfrican Journals Online (AJOL). The search used both free text words and medical subjectheadings for ‘malaria’, ‘RDT’, ‘health worker’ and ‘compliance’. The search was conductedon 3 March 2015 and updated on 12 November 2015. Studies reporting on malaria suspectedpatients of any age presenting to HWs of any cadre in sub-Saharan Africa were searched.The intervention was the use of a WHO recommended RDT kit for parasitologicalconfirmation of a malaria diagnosis (a list of WHO recommended RDTs is availableonline482).

Bibliographies of relevant studies retrieved from the studies were checked for additionalpublications. The search strategy is described in Additional file 1. EndNote X7.4 (Thomson


179

Reuters) was used to manage, de-duplicate and screen the references for eligibility. Theinclusion criteria were: studies were conducted in sub-Saharan Africa; RDTs were used todiagnose malaria in symptomatic patients; the RDTs used were WHO-recommended;absolute numbers of RDT result adherence as primary or secondary outcome were reported.Exclusion criteria were: studies using RDT for active case finding and population screening;conference abstracts; no absolute numbers were reported; studies outside sub-SaharanAfrica. Eligibility assessment of studies was performed independently in a blinded,standardized way by two reviewers (ANK and BJV). Titles and abstracts were screened first,and the two reviewers screened and selected relevant full-text articles. ANK extractedquantitative data based on the pre-specified criteria into an excel sheet (Additional file 2);factors associated with compliance were also extracted into the same sheet. All thequantitative data was independently checked by BJV. Data extracted included author name,year of publication, place of study, transmission setting, type of RDT, cadre and number ofHW, age of patients, number of test results, RDT positives treated and RDT negatives nottreated. Both qualitative and quantitative factors were also extracted from included studieswhich reported them. The risk of bias of studies was not assessed because of the diversity ofthe study designs included.

The primary outcome measure was proportions in percentage of RDT results withappropriate AMD prescription disaggregated to positive and negative results adherence.Appropriate treatment was defined as AMDs prescribed to RDT positive and AMD notprescribed to RDT negative patients (Figure 2). Formulae for these calculations are includedin Additional file 3. STATA version 13 (StataCorp, College Station, TX, USA) was used tocalculate the pooled estimate of proportions appropriately treated overall and negative andpositive compliance using random effects. Random effects analysis was used after an initialfixed effect analysis had I2 above 50 %, suggesting heterogeneity. Pooled estimates werealso stratified by health personnel cadre, age of patients and malaria transmission setting. Aqualitative synthesis of factors contributing to compliance was also reported for the includedstudies.



6

Chapter 6

178

dehydrogenase (LDH) variants (pLDH) (with clonality specific to the various Plasmodiumspecies infecting humans).37, 469

The use of malaria RDT can reduce over-prescribing of anti-malarial drugs (AMD). Studieshave shown that in most endemic countries in sub-Saharan Africa, health workers ofdifferent cadres do not comply with malaria RDTs; they prescribe AMDs to patients withRDT negative results.468, 470-472 This has implications on resources for patient, familymembers and health system since some drug combinations are relatively expensive.473, 474

Non-compliance to malaria negative results by prescribing AMDs neglects underlying causeof fever and expose patients unnecessarily to adverse effects; underlying infections, such assepsis, pneumonia and meningitis,475-478 present as malaria clinically but are not routinelyinvestigated479 and may not be treated.466, 480

To treat malaria effectively, to reduce costs and avoid unnecessary exposure to drug adverseeffects, there is a need to correctly diagnose and comply with malaria treatment guidelinesor clinical decision algorithms. Health workers (HWs) need to use the correct treatmentbased on the RDT results.

This systematic review examines data available on HWs compliance to RDT results in sub-Saharan Africa, and investigates factors associated with compliance to results (HW treatingpatients according to the RDT result). The primary outcome is the percentage of HWscompliant to overall, positive or negative, test results.

MethodsThis systematic review was registered in advance in the International prospective register ofsystematic reviews (PROSPERO; registration number CRD42015016151) which includedpre-specified the objectives and inclusion criteria.481

An experienced information specialist (RS) conducted a search without language or timerestrictions in the online electronic databases Ovid Medline, Ovid Embase, Cochrane CentralRegister of Controlled Trials, CINAHL Plus with Full Text, African Index Medicus, andAfrican Journals Online (AJOL). The search used both free text words and medical subjectheadings for ‘malaria’, ‘RDT’, ‘health worker’ and ‘compliance’. The search was conductedon 3 March 2015 and updated on 12 November 2015. Studies reporting on malaria suspectedpatients of any age presenting to HWs of any cadre in sub-Saharan Africa were searched.The intervention was the use of a WHO recommended RDT kit for parasitologicalconfirmation of a malaria diagnosis (a list of WHO recommended RDTs is availableonline482).

Bibliographies of relevant studies retrieved from the studies were checked for additionalpublications. The search strategy is described in Additional file 1. EndNote X7.4 (Thomson


179

Reuters) was used to manage, de-duplicate and screen the references for eligibility. Theinclusion criteria were: studies were conducted in sub-Saharan Africa; RDTs were used todiagnose malaria in symptomatic patients; the RDTs used were WHO-recommended;absolute numbers of RDT result adherence as primary or secondary outcome were reported.Exclusion criteria were: studies using RDT for active case finding and population screening;conference abstracts; no absolute numbers were reported; studies outside sub-SaharanAfrica. Eligibility assessment of studies was performed independently in a blinded,standardized way by two reviewers (ANK and BJV). Titles and abstracts were screened first,and the two reviewers screened and selected relevant full-text articles. ANK extractedquantitative data based on the pre-specified criteria into an excel sheet (Additional file 2);factors associated with compliance were also extracted into the same sheet. All thequantitative data was independently checked by BJV. Data extracted included author name,year of publication, place of study, transmission setting, type of RDT, cadre and number ofHW, age of patients, number of test results, RDT positives treated and RDT negatives nottreated. Both qualitative and quantitative factors were also extracted from included studieswhich reported them. The risk of bias of studies was not assessed because of the diversity ofthe study designs included.

The primary outcome measure was proportions in percentage of RDT results withappropriate AMD prescription disaggregated to positive and negative results adherence.Appropriate treatment was defined as AMDs prescribed to RDT positive and AMD notprescribed to RDT negative patients (Figure 2). Formulae for these calculations are includedin Additional file 3. STATA version 13 (StataCorp, College Station, TX, USA) was used tocalculate the pooled estimate of proportions appropriately treated overall and negative andpositive compliance using random effects. Random effects analysis was used after an initialfixed effect analysis had I2 above 50 %, suggesting heterogeneity. Pooled estimates werealso stratified by health personnel cadre, age of patients and malaria transmission setting. Aqualitative synthesis of factors contributing to compliance was also reported for the includedstudies.



Chapter 6

180

Figure 2. Patient pathway for malaria diagnosis and treatment. The shaded areas representappropriate management (RDT rapid diagnostic test, AMD anti-malarial drug)

Results

Study selection

The total number of articles after removing duplicates was 474 (Figure 3). After screeningtitle and abstracts for eligibility, 75 full-text articles were examined for eligibility; 14 studieswere included in the quantitative analysis.463, 470-472, 483-492 Five of the studies reported onfactors associated with compliance to RDT results and were included in the summary ofassociated factors.463, 471, 483, 484, 489


181

Figure 3. Study selection flow (PRISMA)111

There were five study designs (Table 1): one randomized control trial,484 fourobservational,485-487, 491 four cross-sectional,471, 472, 489, 490 four cluster randomized trials463,

470, 483, 488 and pre-post intervention study.492 RDT adherence was a secondary outcome infive out of the 14 studies.471, 484, 488, 490, 492



6

Chapter 6

180

Figure 2. Patient pathway for malaria diagnosis and treatment. The shaded areas representappropriate management (RDT rapid diagnostic test, AMD anti-malarial drug)

Results

Study selection

The total number of articles after removing duplicates was 474 (Figure 3). After screeningtitle and abstracts for eligibility, 75 full-text articles were examined for eligibility; 14 studieswere included in the quantitative analysis.463, 470-472, 483-492 Five of the studies reported onfactors associated with compliance to RDT results and were included in the summary ofassociated factors.463, 471, 483, 484, 489


181

Figure 3. Study selection flow (PRISMA)111

There were five study designs (Table 1): one randomized control trial,484 fourobservational,485-487, 491 four cross-sectional,471, 472, 489, 490 four cluster randomized trials463,

470, 483, 488 and pre-post intervention study.492 RDT adherence was a secondary outcome infive out of the 14 studies.471, 484, 488, 490, 492



Tab

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Cha

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486

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490

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2011

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6

Tab

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Cha

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92

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490

2010

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Chapter 6

184

Health workers’ compliance to malaria results

A pooled meta-analysis using random effects (Fig. 4) for the 14 studies463, 470-472, 483, 484, 486-

493 shows an overall compliance of 83 % (95 % CI 80–86 %); I2 = 99.9 %, Z = 54.35, p <0.001. Appropriate malaria treatment based on RDT results (Table 2) was as low as 39.7 %in a Zambian study491 to as high as 99.9 % in Zanzibar.472 The pooled meta-analysis resultusing random effects for RDT positives prescribed AMDs (Fig. 5) was 97 % (95 % CI 94–99 %); I2 = 99.2 %, Z = 37.31, p < 0.001. The proportion of positive RDT results prescribedAMDs ranged from 72.1 to 100 %. 12 studies reported appropriate prescription of AMDs toRDT positive patients above 93 %; six of these studies had 100 % RDT positive compliance(Table 2).

Figure 4. Pooled meta-analysis of overall compliance to RDT resultsT

able

2:A

ppro

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88.5

%10

0.0%

76.6

%



6

Chapter 6

184

Health workers’ compliance to malaria results

A pooled meta-analysis using random effects (Fig. 4) for the 14 studies463, 470-472, 483, 484, 486-

493 shows an overall compliance of 83 % (95 % CI 80–86 %); I2 = 99.9 %, Z = 54.35, p <0.001. Appropriate malaria treatment based on RDT results (Table 2) was as low as 39.7 %in a Zambian study491 to as high as 99.9 % in Zanzibar.472 The pooled meta-analysis resultusing random effects for RDT positives prescribed AMDs (Fig. 5) was 97 % (95 % CI 94–99 %); I2 = 99.2 %, Z = 37.31, p < 0.001. The proportion of positive RDT results prescribedAMDs ranged from 72.1 to 100 %. 12 studies reported appropriate prescription of AMDs toRDT positive patients above 93 %; six of these studies had 100 % RDT positive compliance(Table 2).

Figure 4. Pooled meta-analysis of overall compliance to RDT results

Tab

le2:

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d R

DT

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pers

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ives

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60.7

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19.0

%

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asan

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ians

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96.0

%

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ians

93.4

%95

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92.8

%

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CH

W97

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98.6

%95

.2%

Man

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oZa

mbi

aC

linic

ians

39.7

%93

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31.4

%

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ss se

ctio

nal

Chi

nkhu

mba

Mal

awi

Clin

icia

ns a

ndnu

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86.9

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.0%

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%

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eria

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icia

ns, n

urse

san

d C

HW

60.0

%10

0.0%

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%

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linic

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and

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100.

0%86

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ely

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ibar

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%

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TB

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ala

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ical

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icer

san

d nu

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88.5

%10

0.0%

76.6

%



Stud

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sign

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100.

0%96

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HW

99.0

%99

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92.4

%

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amer

oon

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icia

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.1%

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icia

ns70

.8%

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.4

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nye

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98.5

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ore

and

afte

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astia

ens

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ania

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ical

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s90

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100.

0%90

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W =

Com

mun

ity h

ealth

wor

ker;

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= D

rug

shop

ven

dors

; * e

xclu

des

mis

sing

dat

a; *

* ex

clud

es B

urki

na F

aso

resu

lts.a

= ba

sic

train

ing;

b=

enha

nced

train

ing


187



6

Stud

y de

sign

Aut

hor

Cou

ntry

Hea

lth

pers

onne

lca

dre

App

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trea

tmen

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sitiv

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hana

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100.

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99.0

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92.4

%

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cham

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amer

oon

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icia

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72.1

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nye

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98.5

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ania

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ical

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100.

0%90

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W =

Com

mun

ity h

ealth

wor

ker;

DSV

= D

rug

shop

ven

dors

; * e

xclu

des

mis

sing

dat

a; *

* ex

clud

es B

urki

na F

aso

resu

lts.a

= ba

sic

train

ing;

b=

enha

nced

train

ing


187



Chapter 6

188

Figure 5. (previous page) Pooled meta-analysis of RDT positive results appropriately prescribedAMDs stratified by HW cadre

Pooled meta-analysis using random effects for RDT negative patients not prescribed AMDs(Fig. 6) was 78 % (95 % CI 66–89 %); I2 = 99.8 %, Z = 14.60, p < 0.001. The proportion ofRDT negative patients appropriately not prescribed and AMD was between 19.0–99.9 %(Table 2). Five studies reported less than 60 % compliance to RDT negative results.470, 484,

489-491

Figure 6. (next page) RDT negative results not prescribed AMD stratified by HW

Community health workers (CHWs) had the highest adherence to negative results (Fig. 6)with a random effects pooled proportion of 95 % (95 % CI 92–98 %); I2 = 86.4 %, Z = 23.26,p < 0.001 than clinicians with a pooled proportion of 75 % (95 % CI 58–89 %); I2 = 99.8 %,Z = 11.30, p < 0.001. There were no differences in compliance when stratified by patient ageor transmission setting in pooled meta-analyses.

Compliance factors

Six out of the 14 studies included463, 471, 483, 484, 489, 491 reported quantitative or qualitativeassessment of factors associated with compliance to RDT. Uzochokwu et al.489 reported thatHWs adhered to RDT positive results, as they believed they were more reliable in confirminga malaria diagnosis than presumptive diagnosis or microscopy. Bisoffi et al.484 comparedprescribing behaviour of HWs in the dry compared to rainy seasons and reported improvedRDT negative results compliance during the dry season; alternative diagnoses were alsomade in the dry than the rainy season.

Manyando et al.491 reported no association between prescribing of AMD to negative RDTsin children under five, and fever in a Zambian study. There was also no association betweencommunity health worker (CHW) or socio-demographic characteristics and classification ofmalaria based on RDT in a bivariate analysis in Uganda.487 In one study though, 70 % (14/20)of the respondents (HW) believed that RDTs gave inaccurate/false negative results formalaria.471 Persistence of symptoms and patient pressure and demand were other factorsreported to contribute to inappropriate AMD prescription in RDT negative cases.463, 471, 494

HWs would end up prescribing AMDs in these cases to satisfy patients and maintain theirreputation. Some HW reported that RDT negative patients improved when they wereprescribed AMDs.


189



6

Chapter 6

188

Figure 5. (previous page) Pooled meta-analysis of RDT positive results appropriately prescribedAMDs stratified by HW cadre

Pooled meta-analysis using random effects for RDT negative patients not prescribed AMDs(Fig. 6) was 78 % (95 % CI 66–89 %); I2 = 99.8 %, Z = 14.60, p < 0.001. The proportion ofRDT negative patients appropriately not prescribed and AMD was between 19.0–99.9 %(Table 2). Five studies reported less than 60 % compliance to RDT negative results.470, 484,

489-491

Figure 6. (next page) RDT negative results not prescribed AMD stratified by HW

Community health workers (CHWs) had the highest adherence to negative results (Fig. 6)with a random effects pooled proportion of 95 % (95 % CI 92–98 %); I2 = 86.4 %, Z = 23.26,p < 0.001 than clinicians with a pooled proportion of 75 % (95 % CI 58–89 %); I2 = 99.8 %,Z = 11.30, p < 0.001. There were no differences in compliance when stratified by patient ageor transmission setting in pooled meta-analyses.

Compliance factors

Six out of the 14 studies included463, 471, 483, 484, 489, 491 reported quantitative or qualitativeassessment of factors associated with compliance to RDT. Uzochokwu et al.489 reported thatHWs adhered to RDT positive results, as they believed they were more reliable in confirminga malaria diagnosis than presumptive diagnosis or microscopy. Bisoffi et al.484 comparedprescribing behaviour of HWs in the dry compared to rainy seasons and reported improvedRDT negative results compliance during the dry season; alternative diagnoses were alsomade in the dry than the rainy season.

Manyando et al.491 reported no association between prescribing of AMD to negative RDTsin children under five, and fever in a Zambian study. There was also no association betweencommunity health worker (CHW) or socio-demographic characteristics and classification ofmalaria based on RDT in a bivariate analysis in Uganda.487 In one study though, 70 % (14/20)of the respondents (HW) believed that RDTs gave inaccurate/false negative results formalaria.471 Persistence of symptoms and patient pressure and demand were other factorsreported to contribute to inappropriate AMD prescription in RDT negative cases.463, 471, 494

HWs would end up prescribing AMDs in these cases to satisfy patients and maintain theirreputation. Some HW reported that RDT negative patients improved when they wereprescribed AMDs.


189



Chapter 6

190

DiscussionThis is the first systematic review and meta-analysis evaluating the proportion of healthworkers’ compliance with RDT results. Overall the compliance is fair. However, it alsoconfirms that compliance to RDT negative results compared to positive results was generallylow among HWs.

Diagnostic accuracy of RDT for both falciparum and non-falciparum malaria is high;37, 469

sensitivity of up to 99.5 % and specificity of up to 90.6 % compared to microscopy for P.falciparum.37 Community health workers can appropriately diagnose and treat malaria usingRDT in resource limited settings.468 The use of RDT to guide treatment reduces AMDprescription especially where health workers adhere to results.36

The results show a high proportion of HWs prescribe appropriate treatment based on RDTresults. A proportion of patients still remain over- or under-treated, despite policy change ofadministering ACT to parasitological confirmed cases only. Approximately 17 % of RDTnegative patients are inappropriately prescribed AMDs. This estimate, extrapolated to sub-Saharan Africa means hundreds of thousands of patients are inappropriately diagnosed formalaria and prescribed AMD drugs unnecessarily; unnecessary (=incorrect) AMDprescription leads to drug wastage, unnecessary exposure to drug adverse effects and anincreased risk of drug resistance development for current AMDs.495 Where underlyinginfection is not treated, the patient’s illness prolongs and worsens; the patient or guardianmakes multiple visits to seek health services, lose productivity time or income and leads toschool absenteeism for school-going children474 leading to a vicious cycle of poverty andmalaria.52

Lower cadres of HW showed more compliance to RDT results than trained HWs. The highadherence is likely due to trust in RDT result for confirming malaria diagnosis. Trained HWson the other hand may trust clinical symptoms and past experience more than RDT result.471,

496

Factors associated with HW compliance from qualitative studies include knowledge ofalternative diagnosis, fever during the dry season and a trust in RDT result.483, 484, 497 Trustmay be increased by improving diagnostic capacity for other common febrile illnesses, andby developing evidence informed guidelines for treatment of symptomatic RDT negativepatients. Such guidelines may not apply in non-endemic areas and therefore should bespecific to particular settings.

Knowledge of alternative diagnosis is related to the level of training and experience ofHW.498 HWs reported they likely made alternative diagnosis during the dry season whenmalaria transmission is perceived lower in febrile children with negative RDT resultcompared to the wet season when transmission peaks. For febrile patients, alternative


191

diagnoses were made during the dry season while more patients were treated for malariaduring the wet season in one study.484

Qualitative studies report pressure on prescribers to satisfy patient expectations as one factor,which contributes to non-compliance of RDT negative results.52, 499 Chandler et al.500

reported patient psychology and prescriber reputation as other factors influencing non-compliance to of HWs to negative RDT.

Interventions to improve compliance have not been successful, although they led to adecrease in ACT prescriptions in particular. Some HWs prescribed a non-recommendedAMD in malaria negative patients.470, 501

In cases of patients demanding AMDs, community sensitisation on RDTs was reported toimprove patient satisfaction.463 At facility level, involvement of patient in discussing malariaresults also improved patient satisfaction and reduced patient demand for AMDs.502

Notably, few studies were available which quantified HW’s compliance to malaria RDTresults, and even less studies investigated the factors contributing to compliance.Understanding these factors can help design effective strategies to improve compliance ofanti-malarial drugs. Chandler et al.500 describe a systematic method of designing anintervention in Tanzania; formative research would be key in designing such an intervention.However, interventions are context-specific and may not be applicable to all settings, andfor all HWs. It is essential to investigate factors contributing to non-compliance in specificcadres and settings, exploring impact in a context specific manner before designing andimplementing interventions.

Although ideal for rural areas in Africa, RDT kits inherently are not 100 % sensitive andspecific.36, 37 Clinically diagnosed malaria and positive malaria test may be due to otherunderlying causes of the fever.480 Crump et al.503 reported only 1.6 % of 820 patients withfever or history of fever actually had malaria infection in a Tanzanian prospective cohortstudy; bacterial and fungal bloodstream infections were responsible for 9.8 and 2.9 % of thefever, respectively. Resource limited settings lack diagnostic equipment and capacity forsome diseases. Diagnostic accuracy of RDTs can be affected further by low and extremelyhigh parasite densities,504, 505 patient-intrinsic factors such as rheumatoid factor positivity,506

user factors such as result interpretation and performance of the test, and environmentalstorage conditions including high temperatures. It is, therefore, possible, though infrequent,for malaria-infected patients to have a false positive (leading to not-indicated treatment) ormore importantly, false negative result, and hence miss malaria treatment if WHO malariatreatment guidelines are followed. A more robust and highly specific test may be useful torule out malaria. False positives, where malaria parasitaemia is not the cause of the illness(in endemic areas) lead to neglecting of other febrile illnesses.

Multidisciplinary research to explore, measure and design interventions for increasingcompliance to RDT results in different settings in Africa need to be conducted. More



6

Chapter 6

190

DiscussionThis is the first systematic review and meta-analysis evaluating the proportion of healthworkers’ compliance with RDT results. Overall the compliance is fair. However, it alsoconfirms that compliance to RDT negative results compared to positive results was generallylow among HWs.

Diagnostic accuracy of RDT for both falciparum and non-falciparum malaria is high;37, 469

sensitivity of up to 99.5 % and specificity of up to 90.6 % compared to microscopy for P.falciparum.37 Community health workers can appropriately diagnose and treat malaria usingRDT in resource limited settings.468 The use of RDT to guide treatment reduces AMDprescription especially where health workers adhere to results.36

The results show a high proportion of HWs prescribe appropriate treatment based on RDTresults. A proportion of patients still remain over- or under-treated, despite policy change ofadministering ACT to parasitological confirmed cases only. Approximately 17 % of RDTnegative patients are inappropriately prescribed AMDs. This estimate, extrapolated to sub-Saharan Africa means hundreds of thousands of patients are inappropriately diagnosed formalaria and prescribed AMD drugs unnecessarily; unnecessary (=incorrect) AMDprescription leads to drug wastage, unnecessary exposure to drug adverse effects and anincreased risk of drug resistance development for current AMDs.495 Where underlyinginfection is not treated, the patient’s illness prolongs and worsens; the patient or guardianmakes multiple visits to seek health services, lose productivity time or income and leads toschool absenteeism for school-going children474 leading to a vicious cycle of poverty andmalaria.52

Lower cadres of HW showed more compliance to RDT results than trained HWs. The highadherence is likely due to trust in RDT result for confirming malaria diagnosis. Trained HWson the other hand may trust clinical symptoms and past experience more than RDT result.471,

496

Factors associated with HW compliance from qualitative studies include knowledge ofalternative diagnosis, fever during the dry season and a trust in RDT result.483, 484, 497 Trustmay be increased by improving diagnostic capacity for other common febrile illnesses, andby developing evidence informed guidelines for treatment of symptomatic RDT negativepatients. Such guidelines may not apply in non-endemic areas and therefore should bespecific to particular settings.

Knowledge of alternative diagnosis is related to the level of training and experience ofHW.498 HWs reported they likely made alternative diagnosis during the dry season whenmalaria transmission is perceived lower in febrile children with negative RDT resultcompared to the wet season when transmission peaks. For febrile patients, alternative


191

diagnoses were made during the dry season while more patients were treated for malariaduring the wet season in one study.484

Qualitative studies report pressure on prescribers to satisfy patient expectations as one factor,which contributes to non-compliance of RDT negative results.52, 499 Chandler et al.500

reported patient psychology and prescriber reputation as other factors influencing non-compliance to of HWs to negative RDT.

Interventions to improve compliance have not been successful, although they led to adecrease in ACT prescriptions in particular. Some HWs prescribed a non-recommendedAMD in malaria negative patients.470, 501

In cases of patients demanding AMDs, community sensitisation on RDTs was reported toimprove patient satisfaction.463 At facility level, involvement of patient in discussing malariaresults also improved patient satisfaction and reduced patient demand for AMDs.502

Notably, few studies were available which quantified HW’s compliance to malaria RDTresults, and even less studies investigated the factors contributing to compliance.Understanding these factors can help design effective strategies to improve compliance ofanti-malarial drugs. Chandler et al.500 describe a systematic method of designing anintervention in Tanzania; formative research would be key in designing such an intervention.However, interventions are context-specific and may not be applicable to all settings, andfor all HWs. It is essential to investigate factors contributing to non-compliance in specificcadres and settings, exploring impact in a context specific manner before designing andimplementing interventions.

Although ideal for rural areas in Africa, RDT kits inherently are not 100 % sensitive andspecific.36, 37 Clinically diagnosed malaria and positive malaria test may be due to otherunderlying causes of the fever.480 Crump et al.503 reported only 1.6 % of 820 patients withfever or history of fever actually had malaria infection in a Tanzanian prospective cohortstudy; bacterial and fungal bloodstream infections were responsible for 9.8 and 2.9 % of thefever, respectively. Resource limited settings lack diagnostic equipment and capacity forsome diseases. Diagnostic accuracy of RDTs can be affected further by low and extremelyhigh parasite densities,504, 505 patient-intrinsic factors such as rheumatoid factor positivity,506

user factors such as result interpretation and performance of the test, and environmentalstorage conditions including high temperatures. It is, therefore, possible, though infrequent,for malaria-infected patients to have a false positive (leading to not-indicated treatment) ormore importantly, false negative result, and hence miss malaria treatment if WHO malariatreatment guidelines are followed. A more robust and highly specific test may be useful torule out malaria. False positives, where malaria parasitaemia is not the cause of the illness(in endemic areas) lead to neglecting of other febrile illnesses.

Multidisciplinary research to explore, measure and design interventions for increasingcompliance to RDT results in different settings in Africa need to be conducted. More



Chapter 6

192

innovation in diagnosis of common febrile illnesses in malaria endemic regions needs to beavailable. There is sparse data on prevalence of other non-malaria febrile illnesses in mostmalaria endemic regions of Africa.

The meta-analysis may have overestimated compliance: studies evaluating diagnostic testsgenerally report higher compliance when assessed in the study setting compared to a non-study setting. Most studies reported higher compliance to positive results compared tonegative results.

A limitation for the results in the review is that risk of bias and publication bias were notassessed for the studies included; the quality of evidence therefore cannot be reported.

ConclusionHWs compliance to RDT is fair; compliance to positive RDT results is generally highercompared to negative RDT results. Over-treatment of malaria is still a major problem in sub-Saharan Africa. Both HW and patient factors contribute to inappropriate prescribing ofAMDs to RDT negative patients; interventions to improve compliance should target bothpatients and HWs. Treatment guidelines should be developed for other causes of feverinformed by local context and research. Multidisciplinary research will improve complianceof HWs to RDT results.

Acknowledgements

This study was supported by the Dioraphte Foundation, The Netherlands. We thank thereviewer for his/her thorough and excellent review.

Electronic supplementary material

Additional file 1. Search strategy.

Additional file 2. Data extraction form.

Additional file 3. Formulae for appropriate treatment.

193

Part II:

The quality of anti-malarial drugs

Documents

UvA-DARE (Digital Academic Repository) Fats & Fakes ... · Artemisinin -based combination therapy (ACT) is currently recommended for the treatment of uncomplicated malaria caused