The Impact of Introducing Malaria Rapid Diagnostic Tests on Fever Case Management: A Synthesis of Ten Studies from the ACT Consortium.

Since 2010, the World Health Organization has been recommending that all suspected cases of malaria be confirmed with parasite-based diagnosis before treatment. These guidelines represent a paradigm shift away from presumptive antimalarial treatment of fever. Malaria rapid diagnostic tests (mRDTs) are central to implementing this policy, intended to target artemisinin-based combination therapies (ACT) to patients with confirmed malaria and to improve management of patients with nonmalarial fevers. The ACT Consortium conducted ten linked studies, eight in sub-Saharan Africa and two in Afghanistan, to evaluate the impact of mRDT introduction on case management across settings that vary in malaria endemicity and healthcare provider type. This synthesis includes 562,368 outpatient encounters (study size range 2,400-432,513). mRDTs were associated with significantly lower ACT prescription (range 8-69% versus 20-100%). Prescribing did not always adhere to malaria test results; in several settings, ACTs were prescribed to more than 30% of test-negative patients or to fewer than 80% of test-positive patients. Either an antimalarial or an antibiotic was prescribed for more than 75% of patients across most settings; lower antimalarial prescription for malaria test-negative patients was partly offset by higher antibiotic prescription. Symptomatic management with antipyretics alone was prescribed for fewer than 25% of patients across all scenarios. In community health worker and private retailer settings, mRDTs increased referral of patients to other providers. This synthesis provides an overview of shifts in case management that may be expected with mRDT introduction and highlights areas of focus to improve design and implementation of future case management programs.

Use of malaria rapid diagnostic tests by community health workers in Afghanistan: cluster randomised trial.

BACKGROUND: The World Health Organisation (WHO) recommends parasitological diagnosis of malaria before treatment, but use of malaria rapid diagnostic tests (mRDTs) by community health workers (CHWs) has not been fully tested within health services in south and central Asia. mRDTs could allow CHWs to diagnose malaria accurately, improving treatment of febrile illness. METHODS: A cluster randomised trial in community health services was undertaken in Afghanistan. The primary outcome was the proportion of suspected malaria cases correctly treated for polymerase chain reaction (PCR)-confirmed malaria and PCR negative cases receiving no antimalarial drugs measured at the level of the patient. CHWs from 22 clusters (clinics) received standard training on clinical diagnosis and treatment of malaria; 11 clusters randomised to the intervention arm received additional training and were provided with mRDTs. CHWs enrolled cases of suspected malaria, and the mRDT results and treatments were compared to blind-read PCR diagnosis. RESULTS: In total, 256 CHWs enrolled 2400 patients with 2154 (89.8%) evaluated. In the intervention arm, 75.3% (828/1099) were treated appropriately vs. 17.5% (185/1055) in the control arm (cluster adjusted risk ratio: 3.72, 95% confidence interval 2.40-5.77; p < 0.001). In the control arm, 85.9% (164/191) with confirmed Plasmodium vivax received chloroquine compared to 45.1% (70/155) in the intervention arm (p < 0.001). Overuse of chloroquine in the control arm resulted in 87.6% (813/928) of those with no malaria (PCR negative) being treated vs. 10.0% (95/947) in the intervention arm, p < 0.001. In the intervention arm, 71.4% (30/42) of patients with P. falciparum did not receive artemisinin-based combination therapy, partly because operational sensitivity of the RDTs was low (53.2%, 38.1-67.9). There was high concordance between recorded RDT result and CHW prescription decisions: 826/950 (87.0%) with a negative test were not prescribed an antimalarial. Co-trimoxazole was prescribed to 62.7% of malaria negative patients in the intervention arm and 15.0% in the control arm. CONCLUSIONS: While introducing mRDT reduced overuse of antimalarials, this action came with risks that need to be considered before use at scale: an appreciable proportion of malaria cases will be missed by those using current mRDTs. Higher sensitivity tests could be used to detect all cases. Overtreatment with antimalarial drugs in the control arm was replaced with increased antibiotic prescription in the intervention arm, resulting in a probable overuse of antibiotics. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01403350 . Prospectively registered.

Impact of introduction of rapid diagnostic tests for malaria on antibiotic prescribing: analysis of observational and randomised studies in public and private healthcare settings.

Objectives To examine the impact of use of rapid diagnostic tests for malaria on prescribing of antimicrobials, specifically antibiotics, for acute febrile illness in Africa and Asia.Design Analysisof nine preselected linked and codesigned observational and randomised studies (eight cluster or individually randomised trials and one observational study).Setting Public and private healthcare settings, 2007-13, in Afghanistan, Cameroon, Ghana, Nigeria, Tanzania, and Uganda.Participants 522 480 children and adults with acute febrile illness.Interventions Rapid diagnostic tests for malaria.Main outcome measures Proportions of patients for whom an antibiotic was prescribed in trial groups who had undergone rapid diagnostic testing compared with controls and in patients with negative test results compared with patients with positive results. A secondary aim compared classes of antibiotics prescribed in different settings.Results Antibiotics were prescribed to 127 052/238 797 (53%) patients in control groups and 167 714/283 683 (59%) patients in intervention groups. Antibiotics were prescribed to 40% (35 505/89 719) of patients with a positive test result for malaria and to 69% (39 400/57 080) of those with a negative result. All but one study showed a trend toward more antibiotic prescribing in groups who underwent rapid diagnostic tests. Random effects meta-analysis of the trials showed that the overall risk of antibiotic prescription was 21% higher (95% confidence interval 7% to 36%) in intervention settings. In most intervention settings, patients with negative test results received more antibiotic prescriptions than patients with positive results for all the most commonly used classes: penicillins, trimethoprim-sulfamethoxazole (one exception), tetracyclines, and metronidazole.Conclusions Introduction of rapid diagnostic tests for malaria to reduce unnecessary use of antimalarials-a beneficial public health outcome-could drive up untargeted use of antibiotics. That 69% of patients were prescribed antibiotics when test results were negative probably represents overprescription.This included antibiotics from several classes, including those like metronidazole that are seldom appropriate for febrile illness, across varied clinical, health system, and epidemiological settings. It is often assumed that better disease specific diagnostics will reduce antimicrobial overuse, but they might simply shift it from one antimicrobial class to another. Current global implementation of malaria testing might increase untargeted antibiotic use and must be examined.

Towards a strategy for malaria in pregnancy in Afghanistan: analysis of clinical realities and women's perceptions of malaria and anaemia.

BACKGROUND: Afghanistan has some of the worst maternal and infant mortality indicators in the world and malaria is a significant public health concern. Study objectives were to assess prevalence of malaria and anaemia, related knowledge and practices, and malaria prevention barriers among pregnant women in eastern Afghanistan. METHODS: Three studies were conducted: (1) a clinical survey of maternal malaria, maternal anaemia, and neonatal birthweight in a rural district hospital delivery-ward; (2) a case-control study of malaria risk among reproductive-age women attending primary-level clinics; and (3) community surveys of malaria and anaemia prevalence, socioeconomic status, malaria knowledge and reported behaviour among pregnant women. RESULTS: Among 517 delivery-ward participants (1), one malaria case (prevalence 1.9/1000), 179 anaemia cases (prevalence 346/1000), and 59 low-birthweight deliveries (prevalence 107/1000) were detected. Anaemia was not associated with age, gravidity, intestinal parasite prevalence, or low-birthweight at delivery. Among 141 malaria cases and 1010 controls (2), no association was found between malaria infection and pregnancy (AOR 0.89; 95 % CI 0.57-1.39), parity (AOR 0.95; 95 % CI 0.85-1.05), age (AOR 1.02; 95 % CI 1.00-1.04), or anaemia (AOR 1.00; 95 % CI 0.65-1.54). Those reporting insecticide-treated net usage had 40 % reduced odds of malaria infection (AOR 0.60; 95 % CI 0.40-0.91). Among 530 community survey participants (3), malaria and anaemia prevalence were 3.9/1000 and 277/1000 respectively, with 34/1000 experiencing severe anaemia. Despite most women having no formal education, malaria knowledge was high. Most expressed reluctance to take malaria preventive medication during pregnancy, deeming it potentially unsafe. CONCLUSIONS: Given the low malaria risk and reported avoidance of medication during pregnancy, intermittent preventive treatment is hard to justify or implement. Preventive strategy should instead focus on long-lasting insecticidal nets for all pregnant women.

Cost-effectiveness of malaria diagnosis using rapid diagnostic tests compared to microscopy or clinical symptoms alone in Afghanistan.

BACKGROUND: Improving access to parasitological diagnosis of malaria is a central strategy for control and elimination of the disease. Malaria rapid diagnostic tests (RDTs) are relatively easy to perform and could be used in primary level clinics to increase coverage of diagnostics and improve treatment of malaria. METHODS: A cost-effectiveness analysis was undertaken of RDT-based diagnosis in public health sector facilities in Afghanistan comparing the societal and health sector costs of RDTs versus microscopy and RDTs versus clinical diagnosis in low and moderate transmission areas. The effect measure was 'appropriate treatment for malaria' defined using a reference diagnosis. Effects were obtained from a recent trial of RDTs in 22 public health centres with cost data collected directly from health centres and from patients enrolled in the trial. Decision models were used to compare the cost of RDT diagnosis versus the current diagnostic method in use at the clinic per appropriately treated case (incremental cost-effectiveness ratio, ICER). RESULTS: RDT diagnosis of Plasmodium vivax and Plasmodium falciparum malaria in patients with uncomplicated febrile illness had higher effectiveness and lower cost compared to microscopy and was cost-effective across the moderate and low transmission settings. RDTs remained cost-effective when microscopy was used for other clinical purposes. In the low transmission setting, RDTs were much more effective than clinical diagnosis (65.2% (212/325) vs 12.5% (40/321)) but at an additional cost (ICER) of US$4.5 per appropriately treated patient including a health sector cost (ICER) of US$2.5 and household cost of US$2.0. Sensitivity analysis, which varied drug costs, indicated that RDTs would remain cost-effective if artemisinin combination therapy was used for treating both P. vivax and P. falciparum. Cost-effectiveness of microscopy relative to RDT is further reduced if the former is used exclusively for malaria diagnosis. In the health service setting of Afghanistan, RDTs are a cost-effective intervention compared to microscopy. CONCLUSIONS: RDTs remain cost-effective across a range of drug costs and if microscopy is used for a range of diagnostic services. RDTs have significant advantages over clinical diagnosis with minor increases in the cost of service provision. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov under identifier NCT00935688.

Rapid diagnostic tests to improve treatment of malaria and other febrile illnesses: patient randomised effectiveness trial in primary care clinics in Afghanistan.

OBJECTIVE: To assess the impact of rapid diagnostic tests on the diagnostic accuracy and treatment of malaria and non-severe fever in an Asian setting. DESIGN: Patient randomised trial in primary level clinics. SETTING: Two areas of Afghanistan where Plasmodium vivax and Plasmodium falciparum are endemic; one area with moderate transmission (eastern region) and one with low transmission (northern region). PARTICIPANTS: 5794 patients of all ages with suspected malaria enrolled by 80 clinicians in 22 clinics. INTERVENTIONS: Malaria rapid diagnostic tests were compared with clinical diagnosis where no parasite diagnostic test was available, longer established field microscopy, and recently introduced microscopy. MAIN OUTCOME MEASURES: Proportion of patients appropriately treated with an antimalarial, defined as patients with P vivax who received chloroquine, patients with P falciparum who received artemisinin based combination therapy, and patients with no malaria parasites who did not receive an antimalarial. Secondary outcomes included diagnostic test accuracy and the proportion of patients negative for malaria who received antibiotics and antimalarials. RESULTS: In the low transmission area, comparing rapid diagnostic tests with clinical diagnosis, 65% (212/325) versus 12% (40/321) of febrile patients were appropriately treated for malaria (adjusted odds ratio 92.7, 95% confidence interval 12.4 to 694.1, P<0.001). The proportion of patients who were negative for malaria and received an antibiotic was 57% (185/325) in the rapid diagnostic test arm compared with 14% (46/321) in the clinical diagnosis arm (16.9, 3.8 to 75.4, P<0.001). In the comparison of rapid diagnostic test with microscopy in the moderate transmission area, 83.6% (1696/2028) versus 76.3% (1512/1983) of patients were appropriately treated for malaria (1.70, 1.30 to 2.23, P<0.001). A higher proportion of P falciparum cases received appropriate treatment with artemisinin based combination therapy when malaria was diagnosed by rapid diagnostic test (82%, 58/71 v 32%, 24/76; 9.2, 3.88 to 21.66, P<0.001). CONCLUSIONS: In South and central Asian regions of low to moderate malaria transmission where clinics lack capacity for diagnosis with rapid diagnostic tests or microscopy, the introduction of the tests should be considered to improve clinical care, reduce the overuse of antimalarials, and improve disease surveillance.

Malaria "diagnosis" and diagnostics in Afghanistan.

In many malaria-endemic areas, including Afghanistan, overdiagnosis of malaria is common. Even when using parasite-based diagnostic tests prior to treatment, clinicians commonly prescribe antimalarial treatment following negative test results. This practice neglects alternative causes of fever, uses drugs unnecessarily, and might contribute to antimalarial drug resistance. We undertook a qualitative study among health workers using different malaria diagnostic methods in Afghanistan to explore perceptions of malaria diagnosis. Health workers valued diagnostic tests for their ability to confirm clinical suspicions of malaria via a positive result, but a negative result was commonly interpreted as an absence of diagnosis, legitimizing clinical diagnosis of malaria and prescription of antimalarial drugs. Prescribing decisions reflected uncertainty around tests and diagnosis, and were influenced by social- and health-system factors. Study findings emphasize the need for nuanced and context-specific guidance to change prescriber behavior and improve treatment of malarial and nonmalarial febrile illnesses.

Overdiagnosis and mistreatment of malaria among febrile patients at primary healthcare level in Afghanistan: observational study.

OBJECTIVE: To assess the accuracy of malaria diagnosis and treatment at primary level clinics in Afghanistan. DESIGN: Prospective observational study. SETTING: 22 clinics in two Afghan provinces, one in the north (adjoining Tajikistan) and one in the east (adjoining Pakistan); areas with seasonal transmission of Plasmodium vivax and Plasmodium falciparum. PARTICIPANTS: 2357 patients of all ages enrolled if clinicians suspected malaria. INTERVENTIONS: Established (>5 years) microscopy (12 clinics in east Afghanistan), newly established microscopy (five clinics in north Afghanistan), and no laboratory (five clinics in north Afghanistan). All clinics used the national malaria treatment guidelines. MAIN OUTCOME MEASURES: Proportion of patients positive and negative for malaria who received a malaria drug; sensitivity and specificity of clinic based diagnosis; prescriber's response to the result of the clinic slide; and proportion of patients positive and negative for malaria who were prescribed antibiotics. Outcomes were measured against a double read reference blood slide. RESULTS: In health centres using clinical diagnosis, although 413 of 414 patients were negative by the reference slide, 412 (99%) received a malaria drug and 47 (11%) received an antibiotic. In clinics using new microscopy, 37% (75/202) of patients who were negative by the reference slide received a malaria drug and 60% (103/202) received an antibiotic. In clinics using established microscopy, 50.8% (645/1269) of patients who were negative by the reference slide received a malaria drug and 27.0% (342/1269) received an antibiotic. Among the patients who tested positive for malaria, 94% (443/472) correctly received a malaria drug but only 1 of 6 cases of falciparum malaria was detected and appropriately treated. The specificity of established and new microscopy was 72.9% and 79.9%, respectively. In response to negative clinic slide results, malaria drugs were prescribed to 270/905 (28.8%) and 32/154 (21%) and antibiotics to 347/930 (37.3%) and 99/154 (64%) patients in established and new microscopy arms, respectively. Nurses were less likely to misprescribe than doctors. CONCLUSIONS: Despite a much lower incidence of malaria in Afghanistan than in Africa, fever was substantially misdiagnosed as malaria in this south Asian setting. Inaccuracy was attributable to false positive laboratory diagnoses of malaria and the clinicians' disregard of negative slide results. Rare but potentially fatal cases of falciparum malaria were not detected, emphasising the potential role of rapid diagnostic tests. Microscopy increased the proportion of patients treated with antibiotics producing a trade-off between overtreatment with malaria drugs and probable overtreatment with antibiotics.

The impact of phenotypic and genotypic G6PD deficiency on risk of plasmodium vivax infection: a case-control study amongst Afghan refugees in Pakistan.

BACKGROUND: The most common form of malaria outside Africa, Plasmodium vivax, is more difficult to control than P. falciparum because of the latent liver hypnozoite stage, which causes multiple relapses and provides an infectious reservoir. The African (A-) G6PD (glucose-6-phosphate dehydrogenase) deficiency confers partial protection against severe P. falciparum. Recent evidence suggests that the deficiency also confers protection against P. vivax, which could explain its wide geographical distribution in human populations. The deficiency has a potentially serious interaction with antirelapse therapies (8-aminoquinolines such as primaquine). If the level of protection was sufficient, antirelapse therapy could become more widely available. We therefore tested the hypothesis that G6PD deficiency is protective against vivax malaria infection. METHODS AND FINDINGS: A case-control study design was used amongst Afghan refugees in Pakistan. The frequency of phenotypic and genotypic G6PD deficiency in individuals with vivax malaria was compared against controls who had not had malaria in the previous two years. Phenotypic G6PD deficiency was less common amongst cases than controls (cases: 4/372 [1.1%] versus controls 42/743 [5.7%]; adjusted odds ratio [AOR] 0.18 [95% confidence interval (CI) 0.06-0.52], p = 0.001). Genetic analysis demonstrated that the G6PD deficiency allele identified (Mediterranean type) was associated with protection in hemizygous deficient males (AOR = 0.12 [95% CI 0.02-0.92], p = 0.041). The deficiency was also protective in females carrying the deficiency gene as heterozygotes or homozygotes (pooled AOR = 0.37 [95% CI 0.15-0.94], p = 0.037). CONCLUSIONS: G6PD deficiency (Mediterranean type) conferred significant protection against vivax malaria infection in this population whether measured by phenotype or genotype, indicating a possible evolutionary role for vivax malaria in the selective retention of the G6PD deficiency trait in human populations. Further work is required on the genotypic protection associated with other types of G6PD deficiency and on developing simple point-of-care technologies to detect it before administering antirelapse therapy.

A randomised trial of an eight-week, once weekly primaquine regimen to prevent relapse of plasmodium vivax in Northwest Frontier Province, Pakistan.

BACKGROUND: Vivax malaria remains a major cause of morbidity in the subtropics. To undermine the stability of the disease, drugs are required that prevent relapse and provide reservoir reduction. A 14-day course of primaquine (PQ) is effective but cannot safely be used in routine practice because of its interaction with glucose-6-phosphate dehydrogenase (G6PD) deficiency for which testing is seldom available. Safe and effective use of PQ without the need for G6PD testing would be ideal. The efficacy and safety of an 8-week, once weekly PQ regimen was compared with current standard treatment (chloroquine alone) and a 14-day PQ regimen. METHODS AND PRINCIPAL FINDINGS: 200 microscopically confirmed Plasmodium vivax patients were randomly assigned to either once weekly 8-week PQ (0.75 mg/kg/week), once weekly 8-week placebo, or 14-day PQ (0.5mg/kg/day) in North West Frontier Province, Pakistan. All patients were treated with a standard chloroquine dose and tested for G6PD deficiency. Deficient patients were assigned to the 8-week PQ group. Failure was defined as any subsequent episode of vivax malaria over 11 months of observation. There were 22/71 (31.0%) failures in the placebo group and 1/55 (1.8%) and 4/75 (5.1%) failures in the 14-day and 8-week PQ groups, respectively. Adjusted odds ratios were: for 8-week PQ vs. placebo-0.05 (95%CI: 0.01-0.2, p<0.001) and for 14-day PQ vs. placebo-0.01 (95%CI: 0.002-0.1, p<0.001). Restricted analysis allowing for a post-treatment prophylactic effect confirmed that the 8-week regimen was superior to current treatment. Only one G6PD deficient patient presented. There were no serious adverse events. CONCLUSIONS: A practical radical treatment for vivax malaria is essential for control and elimination of the disease. The 8-week PQ course is more effective at preventing relapse than current treatment with chloroquine alone. Widespread use of the 8-week regimen could make an important contribution to reservoir reduction or regional elimination where G6PD testing is not available. TRIAL REGISTRATION: ClinicalTrials.gov NCT00158587.