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Background: Studies evaluating mass drug administration (MDA) in malarious areas have shown reductions in malaria immediately following the intervention. However, these effects vary by endemicity and are not sustained. Since the 2013 version of this Cochrane Review on this topic, additional studies have been published., Objectives: Primary objectives To assess the sustained effect of MDA with antimalarial drugs on: - the reduction in malaria transmission in moderate- to high-transmission settings; - the interruption of transmission in very low- to low-transmission settings. Secondary objective To summarize the risk of drug-associated adverse effects following MDA., Search Methods: We searched several trial registries, citation databases, conference proceedings, and reference lists for relevant articles up to 11 February 2021. We also communicated with researchers to identify additional published and unpublished studies., Selection Criteria: Randomized controlled trials (RCTs) and non-randomized studies comparing MDA to no MDA with balanced co-interventions across study arms and at least two geographically distinct sites per study arm., Data Collection and Analysis: Two review authors independently assessed trials for eligibility and extracted data. We calculated relative risk (RR) and rate ratios with corresponding 95% confidence intervals (CIs) to compare prevalence and incidence, respectively, in MDA compared to no-MDA groups. We stratified analyses by malaria transmission and by malaria species. For cluster-randomized controlled trials (cRCTs), we adjusted standard errors using the intracluster correlation coefficient. We assessed the certainty of the evidence using the GRADE approach. For non-randomized controlled before-and-after (CBA) studies, we summarized the data using difference-in-differences (DiD) analyses., Main Results: Thirteen studies met our criteria for inclusion. Ten were cRCTs and three were CBAs. Cluster-randomized controlled trials Moderate- to high-endemicity areas (prevalence ≥ 10%) We included data from two studies conducted in The Gambia and Zambia.  At one to three months after MDA, the Plasmodium falciparum (hereafter, P falciparum) parasitaemia prevalence estimates may be higher compared to control but the CIs included no effect (RR 1.76, 95% CI 0.58 to 5.36; Zambia study; low-certainty evidence); parasitaemia incidence was probably lower (RR 0.61, 95% CI 0.40 to 0.92; The Gambia study; moderate-certainty evidence); and confirmed malaria illness incidence may be substantially lower,  but the CIs included no effect (rate ratio 0.41, 95% CI 0.04 to 4.42; Zambia study; low-certainty evidence).  At four to six months after MDA, MDA showed little or no effect on P falciparum parasitaemia prevalence (RR 1.18, 95% CI 0.89 to 1.56; The Gambia study; moderate-certainty evidence) and, no persisting effect was demonstrated with parasitaemia incidence (rate ratio 0.91, 95% CI 0.55 to 1.50; The Gambia study). Very low- to low-endemicity areas (prevalence < 10%) Seven studies from Cambodia, Laos, Myanmar (two studies), Vietnam, Zambia, and Zanzibar evaluated the effects of multiple rounds of MDA on P falciparum. Immediately following MDA (less than one month after MDA), parasitaemia prevalence was reduced (RR 0.12, 95% CI 0.03 to 0.52; one study; low-certainty evidence). At one to three months after MDA, there was a reduction in both parasitaemia incidence (rate ratio 0.37, 95% CI 0.21 to 0.55; 1 study; moderate-certainty evidence) and prevalence (RR 0.25, 95% CI 0.15 to 0.41; 7 studies; low-certainty evidence). For confirmed malaria incidence, absolute rates were low, and it is uncertain whether MDA had an effect on this outcome (rate ratio 0.58, 95% CI 0.12 to 2.73; 2 studies; very low-certainty evidence).  For P falciparum prevalence, the relative differences declined over time, from RR 0.63 (95% CI 0.36 to 1.12; 4 studies) at four to six months after MDA, to RR 0.86 (95% CI 0.55 to 1.36; 5 studies) at 7 to 12 months after MDA. Longer-term prevalence estimates showed overall low absolute risks, and relative effect estimates of the effect of MDA on prevalence varied from RR 0.82 (95% CI 0.20 to 3.34) at 13 to 18 months after MDA, to RR 1.25 (95% CI 0.25 to 6.31) at 31 to 36 months after MDA in one study. Five studies from Cambodia, Laos, Myanmar (2 studies), and Vietnam evaluated the effect of MDA on Plasmodium vivax (hereafter, P vivax). One month following MDA, P vivax prevalence was lower (RR 0.18, 95% CI 0.08 to 0.40; 1 study; low-certainty evidence). At one to three months after MDA, there was a reduction in P vivax prevalence (RR 0.15, 95% CI 0.10 to 0.24; 5 studies; low-certainty evidence). The immediate reduction on P vivax prevalence was not sustained over time, from RR 0.78 (95% CI 0.63 to 0.95; 4 studies) at four to six months after MDA, to RR 1.12 (95% CI 0.94 to 1.32; 5 studies) at 7 to 12 months after MDA. One of the studies in Myanmar provided estimates of longer-term effects, where overall absolute risks were low, ranging from RR 0.81 (95% CI 0.44 to 1.48) at 13 to 18 months after MDA, to RR 1.20 (95% CI 0.44 to 3.29) at 31 to 36 months after MDA. Non-randomized studies Three CBA studies were conducted in moderate- to high-transmission areas in Burkina Faso, Kenya, and Nigeria. There was a reduction in P falciparum parasitaemia prevalence in MDA groups compared to control groups during MDA (DiD range: -15.8 to -61.4 percentage points), but the effect varied at one to three months after MDA (DiD range: 14.9 to -41.1 percentage points).  AUTHORS' CONCLUSIONS: In moderate- to high-transmission settings, no studies reported important effects on P falciparum parasitaemia prevalence within six months after MDA. In very low- to low-transmission settings, parasitaemia prevalence and incidence were reduced initially for up to three months for both P falciparum and P vivax; longer-term data did not demonstrate an effect after four months, but absolute risks in both intervention and control groups were low. No studies provided evidence of interruption of malaria transmission., (Copyright © 2021 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Background: Malaria transmission is high in western Kenya and the asymptomatic infected population plays a significant role in driving the transmission. Mathematical modelling and simulation programs suggest that interventions targeting asymptomatic infections through mass testing and treatment (MTaT) or mass drug administration (MDA) have the potential to reduce malaria transmission when combined with existing interventions., Objective: This paper describes the study site, capacity development efforts required, and lessons learned for implementing a multi-year community-based cluster-randomized controlled trial to evaluate the impact of MTaT for malaria transmission reduction in an area of high transmission in western Kenya., Methods: The study partnered with Kenya's Ministry of Health (MOH) and other organizations on community sensitization and engagement to mobilize, train and deploy community health volunteers (CHVs) to deliver MTaT in the community. Within the health facilities, the study availed staff, medical and laboratory supplies and strengthened health information management system to monitor progress and evaluate impact of intervention., Results: More than 80 Kenya MOH CHVs, 13 clinical officers, field workers, data and logistical staff were trained to carry out MTaT three times a year for 2 years in a population of approximately 90,000 individuals. A supply chain management was adapted to meet daily demands for large volumes of commodities despite the limitation of few MOH facilities having ideal storage conditions. Modern technology was adapted more to meet the needs of the high daily volume of collected data., Conclusions: In resource-constrained settings, large interventions require capacity building and logistical planning. This study found that investing in relationships with the communities, local governments, and other partners, and identifying and equipping the appropriate staff with the skills and technology to perform tasks are important factors for success in delivering an intervention like MTaT.

Background: The response to antimalarial treatment is assessed using serial microscopy. New techniques for accurate measurement of the Plasmodium falciparum histidine-rich protein 2 (HRP2) antigen have allowed for monitoring of the antigen concentration over time, offering a potential alternative for assessing treatment response., Methods: Posttreatment HRP2 concentrations were measured in samples obtained longitudinally from 537 individuals with P. falciparum malaria who were participating in efficacy trials in Angola, Tanzania, and Senegal. The HRP2 half-life was estimated using a first-order kinetics clearance model. The association between the HRP2 concentration 3 days after treatment and recrudescence of infection was assessed., Results: Despite substantial variation in HRP2 concentrations among participants at baseline, concentrations consistently showed a first-order exponential decline. The median half-life of HRP2 was estimated to be 4.5 days (interquartile range [IQR], 3.3-6.6 days) in Angola, 4.7 days (IQR, 4.0-5.9 days) in Tanzania, and 3.0 days (IQR, 2.1-4.5 days) in Senegal. The day 3 HRP2 concentration was predictive of eventual recrudescence, with an area under the receiver operating characteristic curve of 0.86 (95% confidence interval, .73-.99)., Conclusions: Consistent HRP2 clearance dynamics following successful antimalarial treatment imply a common underlying mechanism of biological clearance. Patients who ultimately did not respond to treatment did not exhibit this same pattern of clearance, even in the absence of other indications of inadequate response to treatment., (Published by Oxford University Press for the Infectious Diseases Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Infections with the malaria parasite Plasmodium falciparum typically comprise multiple strains, especially in high-transmission areas where infectious mosquito bites occur frequently. However, little is known about the dynamics of mixed-strain infections, particularly whether strains sharing a host compete or grow independently. Competition between drug-sensitive and drug-resistant strains, if it occurs, could be a crucial determinant of the spread of resistance. We analysed 1341 P. falciparum infections in children from Angola, Ghana and Tanzania and found compelling evidence for competition in mixed-strain infections: overall parasite density did not increase with additional strains, and densities of individual chloroquine-sensitive (CQS) and chloroquine-resistant (CQR) strains were reduced in the presence of competitors. We also found that CQR strains exhibited low densities compared with CQS strains (in the absence of chloroquine), which may underlie observed declines of chloroquine resistance in many countries following retirement of chloroquine as a first-line therapy. Our observations support a key role for within-host competition in the evolution of drug-resistant malaria. Malaria control and resistance-management efforts in high-transmission regions may be significantly aided or hindered by the effects of competition in mixed-strain infections. Consideration of within-host dynamics may spur development of novel strategies to minimize resistance while maximizing the benefits of control measures., (© 2016 The Author(s).)

Background: Quinidine gluconate, the only U.S. Food and Drug Administration-approved treatment for life-threatening malaria in the United States, has a problematic safety profile and is often unavailable in hospitals., Objective: To assess the safety and clinical benefit of intravenous artesunate as an alternative to quinidine., Design: Retrospective case series., Setting: U.S. hospitals., Patients: 102 patients aged 1 to 72 years (90% adults; 61% men) with severe and complicated malaria. Patients received 4 weight-based doses of intravenous artesunate (2.4 mg/kg) under a treatment protocol implemented by the Centers for Disease Control and Prevention between January 2007 and December 2010. At baseline, 35% had evidence of cerebral malaria, and 17% had severe hepatic impairment. Eligibility required the presence of microscopically confirmed malaria, need for intravenous treatment, and an impediment to quinidine., Measurements: Clinical and laboratory data from each patient's hospital records were abstracted retrospectively, including information from baseline through a maximum 7-day follow-up, and presented before a physician committee to evaluate safety and clinical benefit outcomes., Results: 7 patients died (mortality rate, 6.9%). The most frequent adverse events were anemia (65%) and elevated hepatic enzyme levels (49%). All deaths and most adverse events were attributed to the severity of malaria. Patients' symptoms generally improved or resolved within 3 days, and the median time to discharge from the intensive care unit was 4 days, even for patients with severe liver disease or cerebral malaria. More than 100 concomitant medications were used, with no documented drug-drug interactions., Limitation: Potential late-presenting safety issues might occur outside the 7-day follow-up., Conclusion: Artesunate was a safe and clinically beneficial alternative to quinidine.

Mass drug administration (MDA) was a component of many malaria programs during the eradication era, but later was seldomly deployed due to concerns regarding efficacy and feasibility and fear of accelerating drug resistance. Recently, however, there has been renewed interest in the role of MDA as an elimination tool. Following a 2013 Cochrane Review that focused on the quantitative effects of malaria MDA, we have conducted a systematic, qualitative review of published, unpublished, and gray literature documenting past MDA experiences. We have also consulted with field experts, using their historical experience to provide an informed, contextual perspective on the role of MDA in malaria elimination. Substantial knowledge gaps remain and more research is necessary, particularly on optimal target population size, methods to improve coverage, and primaquine safety. Despite these gaps, MDA has been used successfully to control and eliminate Plasmodium falciparum and P. vivax malaria in the past, and should be considered as part of a comprehensive malaria elimination strategy in specific settings., (© The American Society of Tropical Medicine and Hygiene.)

Background: Artemisinin combination therapy (ACT) is first-line treatment for malaria in most endemic countries and is increasingly available in the private sector. Most studies on ACT adherence have been conducted in the public sector, with minimal data from private retailers., Methods: Parallel studies were conducted in Tanzania, in which patients obtaining artemether-lumefantrine (AL) at 40 randomly selected public health facilities and 37 accredited drug dispensing outlets (ADDOs) were visited at home and questioned about doses taken. The effect of sector on adherence, controlling for potential confounders was assessed using logistic regression with a random effect for outlet., Results: Of 572 health facility patients and 450 ADDO patients, 74.5% (95% CI: 69.8, 78.8) and 69.8% (95% CI: 64.6, 74.5), respectively, completed treatment and 46.0% (95% CI: 40.9, 51.2) and 34.8% (95% CI: 30.1, 39.8) took each dose at the correct time ('timely completion'). ADDO patients were wealthier, more educated, older, sought care later in the day, and were less likely to test positive for malaria than health facility patients. Controlling for patient characteristics, the adjusted odds of completed treatment and of timely completion for ADDO patients were 0.65 (95% CI: 0.43, 1.00) and 0.69 (95% CI: 0.47, 1.01) times that of health facility patients. Higher socio-economic status was associated with both adherence measures. Higher education was associated with completed treatment (adjusted OR = 1.68, 95% CI: 1.20, 2.36); obtaining AL in the evening was associated with timely completion (adjusted OR = 0.35, 95% CI: 0.19, 0.64). Factors associated with adherence in each sector were examined separately. In both sectors, recalling correct instructions was positively associated with both adherence measures. In health facility patients, but not ADDO patients, taking the first dose of AL at the outlet was associated with timely completion (adjusted OR = 2.11, 95% CI: 1.46, 3.04)., Conclusion: When controlling for patient characteristics, there was some evidence that the adjusted odds of adherence for ADDO patients was lower than that for public health facility patients. Better understanding is needed of which patient care aspects are most important for adherence, including the role of effective provision of advice.

Artemisinin combination therapies are available in private outlets, but patient adherence might be compromised by poor advice from dispensers. In this cluster randomized trial in drug shops in Tanzania, 42 of 82 selected shops were randomized to receive text message reminders about what advice to provide when dispensing artemether-lumefantrine (AL). Eligible patients purchasing AL at shops in both arms were followed up at home and questioned about each dose taken. Dispensers were interviewed regarding knowledge of AL dispensing practices and receipt of the malaria-related text messages. We interviewed 904 patients and 110 dispensers from 77 shops. Although there was some improvement in dispenser knowledge, there was no difference between arms in adherence measured as completion of all doses (intervention 68.3%, control 69.8%, p [adjusted] = 0.6), or as completion of each dose at the correct time (intervention 33.1%, control 32.6%, p [adjusted] = 0.9). Further studies on the potential of text messages to improve adherence are needed., (© The American Society of Tropical Medicine and Hygiene.)

Background: Throughout Africa, many people seek care for malaria in private-sector drug shops where diagnostic testing is often unavailable. Recently, subsidized artemisinin-based combination therapies (ACTs), a first-line medication for uncomplicated malaria, were made available in these drug shops in Tanzania. This study assessed the prevalence of malaria among and purchase of ACTs by drug shop clients in the setting of a national ACT subsidy program and sub-national drug shop accreditation program., Method and Findings: A cross-sectional survey of drug shop clients was performed in two regions in Tanzania, one with a government drug shop accreditation program and one without, from March-May, 2012. Drug shops were randomly sampled from non-urban districts. Shop attendants were interviewed about their education, training, and accreditation status. Clients were interviewed about their symptoms and medication purchases, then underwent a limited physical examination and laboratory testing for malaria. Malaria prevalence and predictors of ACT purchase were assessed using univariate analysis and multiple logistic regression. Amongst 777 clients from 73 drug shops, the prevalence of laboratory-confirmed malaria was 12% (95% CI: 6-18%). Less than a third of clients with malaria had purchased ACTs, and less than a quarter of clients who purchased ACTs tested positive for malaria. Clients were more likely to have purchased ACTs if the participant was <5 years old (aOR: 6.6; 95% CI: 3.9-11.0) or the shop attendant had >5 years, experience (aOR: 2.8; 95% CI: 1.2-6.3). Having malaria was only a predictor of ACT purchase in the region with a drug shop accreditation program (aOR: 3.4; 95% CI: 1.5-7.4)., Conclusion: Malaria is common amongst persons presenting to drug shops with a complaint of fever. The low proportion of persons with malaria purchasing ACTs, and the high proportion of ACTs going to persons without malaria demonstrates a need to better target who receives ACTs in these drug shops.

Background: 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., Objective: We conducted a systematic review of studies reporting quantitative results on patient adherence to antimalarials obtained for treatment., Results: 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., Conclusion: 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.

Background: Use of artemisinin-based combination therapy (ACT), such as artemether-lumefantrine (AL), requires a strict dosing schedule that follows the drugs' pharmacokinetic properties. The quality of malaria case management was assessed in two areas in rural Tanzania, to ascertain patient characteristics and facility-specific factors that influence correct dosing of AL for management of uncomplicated malaria., Methods: Exit interviews were conducted with patients attending health facilities for initial illness consultation. Information about health workers' training and supervision visits was collected. Health facilities were inventoried for capacity and availability of medical products related to care of malaria patients. The outcome was correct dosing of AL based on age and weight. Logistic regression was used to assess health facility factors and patient characteristics associated with correct dosing of AL by age and weight., Results: A total of 1,531 patients were interviewed, but 60 pregnant women were excluded from the analysis. Only 503 (34.2%) patients who received AL were assessed for correct dosing. Most patients who received AL (85.3%) were seen in public health facilities, 75.7% in a dispensary and 91.1% in a facility that had AL in stock on the survey day. Overall, 92.1% (463) of AL prescriptions were correct by age or weight; but 85.7% of patients received correct dosing by weight alone and 78.5% received correct dosing by age alone. In multivariate analysis, patients in the middle dosing bands in terms of age or weight, had statistically significant lower odds of correct AL dosing (p < 0.05) compared to those in the lowest age or weight group. Other factors such as health worker supervision and training on ACT did not improve the odds of correct AL dosing., Conclusion: Although malaria treatment guidelines indicate AL dosing can be prescribed based on age or weight of the patient, findings from this study show that patients within the middle age and weight dosing bands were least likely to receive a correct dose by either measure. Clinicians should be made aware of AL dosing errors for patients aged three to 12 years and advised to use weight-based prescriptions whenever possible.

Background: Mass drug administration (MDA), defined as the empiric administration of a therapeutic antimalarial regimen to an entire population at the same time, has been a historic component of many malaria control and elimination programmes, but is not currently recommended. With renewed interest in MDA and its role in malaria elimination, this review aims to summarize the findings from existing research studies and program experiences of MDA strategies for reducing malaria burden and transmission., Objectives: To assess the impact of antimalarial MDA on population asexual parasitaemia prevalence, parasitaemia incidence, gametocytaemia prevalence, anaemia prevalence, mortality and MDA-associated adverse events., Search Methods: We searched the Cochrane Infectious Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE+, EMBASE, to February 2013. We also searched CABS Abstracts, LILACS, reference lists, and recent conference proceedings., Selection Criteria: Cluster-randomized trials and non-randomized controlled studies comparing therapeutic MDA versus placebo or no MDA, and uncontrolled before-and-after studies comparing post-MDA to baseline data were selected. Studies administering intermittent preventive treatment (IPT) to sub-populations (for example, pregnant women, children or infants) were excluded., Data Collection and Analysis: Two authors independently reviewed studies for inclusion, extracted data and assessed risk of bias. Studies were stratified by study design and then subgrouped by endemicity, by co-administration of 8-aminoquinoline plus schizonticide drugs and by plasmodium species. The quality of evidence was assessed using the GRADE approach., Main Results: Two cluster-randomized trials, eight non-randomized controlled studies and 22 uncontrolled before-and-after studies are included in this review. Twenty-two studies (29 comparisons) compared MDA to placebo or no intervention of which two comparisons were conducted in areas of low endemicity (≤5%), 12 in areas of moderate endemicity (6-39%) and 15 in areas of high endemicity (≥ 40%). Ten studies evaluated MDA plus other vector control measures. The studies used a wide variety of MDA regimens incorporating different drugs, dosages, timings and numbers of MDA rounds. Many of the studies are now more than 30 years old. Areas of low endemicity (≤5%)Within the first month post-MDA, a single uncontrolled before-and-after study conducted in 1955 on a small Taiwanese island reported a much lower prevalence of parasitaemia following a single course of chloroquine compared to baseline (1 study, very low quality evidence). This lower parasite prevalence was still present after more than 12 months (one study, very low quality evidence). In addition, one cluster-randomized trial evaluating MDA in a low endemic setting reported zero episodes of parasitaemia at baseline, and throughout five months of follow-up in both the control and intervention arms (one study, very low quality evidence). Areas of moderate endemicity (6-39%)Within the first month post-MDA, the prevalence of parasitaemia was much lower in three non-randomized controlled studies from Kenya and India in the 1950s (RR 0.03, 95% CI 0.01 to 0.08, three studies, moderate quality evidence), and in three uncontrolled before-and-after studies conducted between 1954 and 1961 (RR 0.29, 95% CI 0.17 to 0.48, three studies,low quality evidence).The longest follow-up in these settings was four to six months. At this time point, the prevalence of parasitaemia remained substantially lower than controls in the two non-randomized controlled studies (RR 0.18, 95% CI 0.10 to 0.33, two studies, low quality evidence). In contrast, the two uncontrolled before-and-after studies found mixed results: one found no difference and one found a substantially higher prevalence compared to baseline (not pooled, two studies, very low quality evidence). Areas of high endemicity (≥40%)Within the first month post-MDA, the single cluster-randomized trial from the Gambia in 1999 found no significant difference in parasite prevalence (one study, low quality evidence). However, prevalence was much lower during the MDA programmes in three non-randomized controlled studies conducted in the 1960s and 1970s (RR 0.17, 95% CI 0.11 to 0.27, three studies, moderate quality evidence), and within one month of MDA in four uncontrolled before-and-after studies (RR 0.37, 95% CI 0.28 to 0.49, four studies,low quality evidence).Four trials reported changes in prevalence beyond three months. In the Gambia, the single cluster-randomized trial found no difference at five months (one trial, moderate quality evidence). The three uncontrolled before-and-after studies had mixed findings with large studies from Palestine and Cambodia showing sustained reductions at four months and 12 months, respectively, and a small study from Malaysia showing no difference after four to six months of follow-up (three studies,low quality evidence). 8-aminoquinolines We found no studies directly comparing MDA regimens that included 8-aminoquinolines with regimens that did not. In a crude subgroup analysis with a limited number of studies, we were unable to detect any evidence of additional benefit of primaquine in moderate- and high-transmission settings. Plasmodium species In studies that reported species-specific outcomes, the same interventions resulted in a larger impact on Plasmodium falciparum compared to P. vivax., Authors' Conclusions: MDA appears to reduce substantially the initial risk of malaria parasitaemia. However, few studies showed sustained impact beyond six months post-MDA, and those that did were conducted on small islands or in highland settings.To assess whether there is an impact of MDA on malaria transmission in the longer term requires more quasi experimental studies with the intention of elimination, especially in low- and moderate-transmission settings. These studies need to address any long-term outcomes, any potential barriers for community uptake, and contribution to the development of drug resistance.

Objectives: Parasitological confirmation of malaria prior to treatment is recommended for patients of all ages, with malaria rapid diagnostic tests (mRDTs) an important tool to target artemisinin-based combination therapies (ACTs) to patients with malaria. To evaluate the impact on case management practices of routine government implementation of mRDTs, we conducted large-scale health facility surveys in three regions of Tanzania before and after mRDT roll-out., Methods: Febrile patients at randomly selected health facilities were interviewed about care received at the facility, and blood samples were collected for reference blood smears. Health facility staff were interviewed about their qualifications and availability of malaria diagnostics and drugs., Results: The percentage of febrile patients tested for malaria at the facility increased from 15.8% in 2010 to 54.9% in 2012. ACTs were obtained by 65.8% of patients positive by reference blood smear in 2010 and by 50.2% in 2012 (P = 0.0675); no antimalarial was obtained by 57.8% of malaria-negative patients in 2010 and by 82.3% in 2012 (P < 0.0001). Overall, ACT use decreased (39.9-21.3%, P < 0.0001) and antibiotic use increased (31.2-48.5%, P < 0.0001)., Conclusion: Roll-out of mRDTs in Tanzania dramatically improved diagnostic testing for malaria and reduced overuse of ACTs for patients without parasitemia. However, post-roll-out almost 50% of febrile patients did not receive a diagnostic test, and almost 50% of patients testing positive did not receive ACTs. Stock-outs of ACTs and mRDTs were important problems. Further investigation is needed to determine reasons for not providing ACTs to patients with malaria and potential for inappropriate antibiotic use., (© 2013 John Wiley & Sons Ltd.)

Background: Anti-malarial regimens containing sulphonamide or artemisinin ingredients are widely used in malaria-endemic countries. However, evidence of the incidence of adverse drug reactions (ADR) to these drugs is limited, especially in Africa, and there is a complete absence of information on the economic burden such ADR place on patients. This study aimed to document ADR incidence and associated household costs in three high malaria transmission districts in rural Tanzania covered by demographic surveillance systems., Methods: Active and passive surveillance methods were used to identify ADR from sulphadoxine-pyrimethamine (SP) and artemisinin (AS) use. ADR were identified by trained clinicians at health facilities (passive surveillance) and through cross-sectional household surveys (active surveillance). Potential cases were followed up at home, where a complete history and physical examination was undertaken, and household cost data collected. Patients were classified as having 'possible' or 'probable' ADR by a physician., Results: A total of 95 suspected ADR were identified during a two-year period, of which 79 were traced, and 67 reported use of SP and/or AS prior to ADR onset. Thirty-four cases were classified as 'probable' and 33 as 'possible' ADRs. Most (53) cases were associated with SP monotherapy, 13 with the AS/SP combination (available in one of the two areas only), and one with AS monotherapy. Annual ADR incidence per 100,000 exposures was estimated based on 'probable' ADR only at 5.6 for AS/SP in combination, and 25.0 and 11.6 for SP monotherapy. Median ADR treatment costs per episode ranged from US$2.23 for those making a single provider visit to US$146.93 for patients with four visits. Seventy-three per cent of patients used out-of-pocket funds or sold part of their farm harvests to pay for treatment, and 19% borrowed money., Conclusion: Both passive and active surveillance methods proved feasible methods for anti-malarial ADR surveillance, with active surveillance being an important complement to facility-based surveillance, given the widespread practice of self-medication. Household costs associated with ADR treatment were high and potentially catastrophic. Efforts should be made to both improve pharmacovigilance across Africa and to identify strategies to reduce the economic burden endured by households suffering from ADR.

Background: In vivo efficacy assessments of antimalarials are essential for ensuring effective case management. In Ethiopia, chloroquine (CQ) without primaquine is the first-line treatment for Plasmodium vivax in malarious areas, but artemether-lumefantrine (AL) is also commonly used., Methods and Findings: In 2009, we conducted a 42-day efficacy study of AL or CQ for P. vivax in Oromia Regional State, Ethiopia. Individuals with P. vivax monoinfection were enrolled. Primary endpoint was day 28 cure rate. In patients with recurrent parasitemia, drug level and genotyping using microsatellite markers were assessed. Using survival analysis, uncorrected patient cure rates at day 28 were 75.7% (95% confidence interval (CI) 66.8-82.5) for AL and 90.8% (95% CI 83.6-94.9) for CQ. During the 42 days of follow-up, 41.6% (47/113) of patients in the AL arm and 31.8% (34/107) in the CQ arm presented with recurrent P. vivax infection, with the median number of days to recurrence of 28 compared to 35 days in the AL and CQ arm, respectively. Using microsatellite markers to reclassify recurrent parasitemias with a different genotype as non-treatment failures, day 28 cure rates were genotype adjusted to 91.1% (95% CI 84.1-95.1) for AL and to 97.2% (91.6-99.1) for CQ. Three patients (2.8%) with recurrent parasitemia by day 28 in the CQ arm were noted to have drug levels above 100 ng/ml., Conclusions: In the short term, both AL and CQ were effective and well-tolerated for P. vivax malaria, but high rates of recurrent parasitemia were noted with both drugs. CQ provided longer post-treatment prophylaxis than AL, resulting in delayed recurrence of parasitemia. Although the current policy of species-specific treatment can be maintained for Ethiopia, the co-administration of primaquine for treatment of P. vivax malaria needs to be urgently considered to prevent relapse infections., Trial Registration: ClinicalTrials.gov NCT01052584.

Background: The World Health Organization recommends parasitological confirmation of all malaria cases. Tanzania is implementing a phased rollout of malaria rapid diagnostic tests (RDTs) for routine use in all levels of care as one strategy to increase parasitological confirmation of malaria diagnosis. This study was carried out to evaluated artemisinin combination therapy (ACT) prescribing patterns in febrile patients with and without uncomplicated malaria in one pre-RDT implementation and one post-RDT implementation area., Methods: A cross-sectional health facility surveys was conducted during high and low malaria transmission seasons in 2010 in both areas. Clinical information and a reference blood film on all patients presenting for an initial illness consultation were collected. Malaria was defined as a history of fever in the past 48 h and microscopically confirmed parasitaemia. Routine diagnostic testing was defined as RDT or microscopy ordered by the health worker and performed at the health facility as part of the health worker-patient consultation. Correct diagnostic testing was defined as febrile patient tested with RDT or microscopy. Over-testing was defined as a non-febrile patient tested with RDT or microscopy. Correct treatment was defined as patient with malaria prescribed ACT. Over-treatment was defined as patient without malaria prescribed ACT., Results: A total of 1,247 febrile patients (627 from pre-implementation area and 620 from post-implementation area) were included in the analysis. In the post-RDT implementation area, 80.9% (95% CI, 68.2-89.3) of patients with malaria received recommended treatment with ACT compared to 70.3% (95% CI, 54.7-82.2) of patients in the pre-RDT implementation area. Correct treatment was significantly higher in the post-implementation area during high transmission season (85.9% (95% CI, 72.0-93.6) compared to 58.3% (95% CI, 39.4-75.1) in pre-implementation area (p = 0.01). Over-treatment with ACT of patients without malaria was less common in the post-RDT implementation area (20.9%; 95% CI, 14.7-28.8) compared to the pre-RDT implementation area (45.8%; 95% CI, 37.2-54.6) (p < 0.01) in high transmission. The odds of overtreatment was significantly lower in post- RDT area (adjusted Odds Ratio (OR: 95% CI) 0.57(0.36-0.89); and much higher with clinical diagnosis adjusted OR (95% CI) 2.24(1.37-3.67), Conclusion: Implementation of RDTs increased use of RDTs for parasitological confirmation and reduced over-treatment with ACT during high malaria transmission season in one area in Tanzania. Continued monitoring of the national RDT rollout will be needed to assess whether these changes in case management practices will be replicated in other areas and sustained over time. Additional measures (such as refresher trainings, closer supervisions, etc.) may be needed to improve ACT targeting during low transmission seasons.

Background: Artemisinin-based combination therapy (ACT) has been promoted as a means to reduce malaria transmission due to their ability to kill both asexual blood stages of malaria parasites, which sustain infections over long periods and the immature derived sexual stages responsible for infecting mosquitoes and onward transmission. Early studies reported a temporal association between ACT introduction and reduced malaria transmission in a number of ecological settings. However, these reports have come from areas with low to moderate malaria transmission, been confounded by the presence of other interventions or environmental changes that may have reduced malaria transmission, and have not included a comparison group without ACT. This report presents results from the first large-scale observational study to assess the impact of case management with ACT on population-level measures of malaria endemicity in an area with intense transmission where the benefits of effective infection clearance might be compromised by frequent and repeated re-infection., Methods: A pre-post observational study with a non-randomized comparison group was conducted at two sites in Tanzania. Both sites used sulphadoxine-pyrimethamine (SP) monotherapy as a first-line anti-malarial from mid-2001 through 2002. In 2003, the ACT, artesunate (AS) co-administered with SP (AS + SP), was introduced in all fixed health facilities in the intervention site, including both public and registered non-governmental facilities. Population-level prevalence of Plasmodium falciparum asexual parasitaemia and gametocytaemia were assessed using light microscopy from samples collected during representative household surveys in 2001, 2002, 2004, 2005 and 2006., Findings: Among 37,309 observations included in the analysis, annual asexual parasitaemia prevalence in persons of all ages ranged from 11% to 28% and gametocytaemia prevalence ranged from <1% to 2% between the two sites and across the five survey years. A multivariable logistic regression model was fitted to adjust for age, socioeconomic status, bed net use and rainfall. In the presence of consistently high coverage and efficacy of SP monotherapy and AS + SP in the comparison and intervention areas, the introduction of ACT in the intervention site was associated with a modest reduction in the adjusted asexual parasitaemia prevalence of 5 percentage-points or 23% (p < 0.0001) relative to the comparison site. Gametocytaemia prevalence did not differ significantly (p = 0.30)., Interpretation: The introduction of ACT at fixed health facilities only modestly reduced asexual parasitaemia prevalence. ACT is effective for treatment of uncomplicated malaria and should have substantial public health impact on morbidity and mortality, but is unlikely to reduce malaria transmission substantially in much of sub-Saharan Africa where individuals are rapidly re-infected.

Background: Artemisinin-based combination therapy (ACT) for treating malaria has activity against immature gametocytes. In theory, this property may complement the effect of terminating otherwise lengthy malaria infections and reducing the parasite reservoir in the human population that can infect vector mosquitoes. However, this has never been verified at a population level in a setting with intense transmission, where chronically infectious asymptomatic carriers are common and cured patients are rapidly and repeatedly re-infected., Methods: From 2001 to 2004, malaria vector densities were monitored using light traps in three Tanzanian districts. Mosquitoes were dissected to determine parous and oocyst rates. Plasmodium falciparum sporozoite rates were determined by ELISA. Sulphadoxine-pyrimethamine (SP) monotherapy was used for treatment of uncomplicated malaria in the contiguous districts of Kilombero and Ulanga throughout this period. In Rufiji district, the standard drug was changed to artesunate co-administered with SP (AS + SP) in March 2003. The effects of this change in case management on malaria parasite infection in the vectors were analysed., Results: Plasmodium falciparum entomological inoculation rates exceeded 300 infective bites per person per year at both sites over the whole period. The introduction of AS + SP in Rufiji was associated with increased oocyst prevalence (OR [95%CI] = 3.9 [2.9-5.3], p < 0.001), but had no consistent effect on sporozoite prevalence (OR [95%CI] = 0.9 [0.7-1.2], p = 0.5). The estimated infectiousness of the human population in Rufiji was very low prior to the change in drug policy. Emergence rates and parous rates of the vectors varied substantially throughout the study period, which affected estimates of infectiousness. The latter consequently cannot be explained by the change in drug policy., Conclusions: In high perennial transmission settings, only a small proportion of infections in humans are symptomatic or treated, so case management with ACT may have little impact on overall infectiousness of the human population. Variations in infection levels in vectors largely depend on the age distribution of the mosquito population. Benefits of ACT in suppressing transmission are more likely to be evident where transmission is already low or effective vector control is widely implemented.

Problem/condition: Malaria in humans is caused by intraerythrocytic protozoa of the genus Plasmodium. These parasites are transmitted by the bite of an infective female Anopheles mosquito. The majority of malaria infections in the United States occur among persons who have traveled to areas with ongoing malaria transmission. In the United States, cases can occur through exposure to infected blood products, congenital transmission, or local mosquito-borne transmission. Malaria surveillance is conducted to identify episodes of local transmission and to guide prevention recommendations for travelers., Period Covered: This report summarizes cases in persons with onset of illness in 2010 and summarizes trends during previous years., Description of System: Malaria cases diagnosed by blood film, polymerase chain reaction, or rapid diagnostic tests are mandated to be reported to local and state health departments by health-care providers or laboratory staff. Case investigations are conducted by local and state health departments, and reports are transmitted to CDC through the National Malaria Surveillance System (NMSS), National Notifiable Diseases Surveillance System (NNDSS), or direct CDC consults. Data from these reporting systems serve as the basis for this report., Results: CDC received 1,691 reported cases of malaria, including 1,688 cases classified as imported, one transfusion-related case, and two cryptic cases, with an onset of symptoms in 2010 among persons in the United States. The total number of cases represents an increase of 14% from the 1,484 cases reported for 2009. Plasmodium falciparum, P. vivax, P. malariae, and P. ovale were identified in 58%, 19%, 2%, and 2% of cases, respectively. Thirteen patients were infected by two or more species. The infecting species was unreported or undetermined in 18% of cases. Among the 898 cases in U.S. civilians for whom information on chemoprophylaxis use and travel area was known, 45 (5%) reported that they had followed and adhered to a chemoprophylactic drug regimen recommended by CDC for the areas to which they had traveled. Forty-one cases were reported in pregnant women, among whom only two (5%) adhered to chemoprophylaxis. Among all reported cases, 176 (10%) were classified as severe infections, of which nine were fatal., Interpretation: The number of cases reported in 2010 marked the largest number of cases reported since 1980. Despite the apparent progress in reducing the global burden of malaria, many areas remain malaria endemic and the use of appropriate prevention measures by travelers is still inadequate., Public Health Actions: Travelers visiting friends and relatives (VFR) continue to be a difficult population to reach with effective malaria prevention strategies. Evidence-based prevention strategies that effectively target VFR travelers need to be developed and implemented to have a substantial impact on the numbers of imported malaria cases in the United States. A large number of pregnant travelers diagnosed with malaria did not take any chemoprophylaxis. Pregnant women traveling to areas in which malaria is endemic are at higher risk for severe malaria and must use appropriate malaria prevention strategies including chemoprophylaxis. Malaria prevention recommendations are available online (http://www.cdc.gov/malaria/travelers/drugs.html). Malaria infections can be fatal if not diagnosed and treated promptly with antimalarial medications appropriate for the patient's age and medical history, the likely country of malaria acquisition, and previous use of antimalarial chemoprophylaxis. Clinicians should consult the CDC Guidelines for Treatment of Malaria and contact the CDC's Malaria Hotline for case management advice, when needed. Malaria treatment recommendations can be obtained online (http://www.cdc.gov/malaria/diagnosis&#95;treatment) or by calling the Malaria Hotline (770-488-7788 or toll-free at 855-856-4713).

The antifolate sulphadoxine-pyrimethamine (SP) has been used in the intermittent prevention of malaria in pregnancy (IPTp). SP is an ideal choice for IPTp, however, as resistance of Plasmodium falciparum to SP increases, data are accumulating that SP may no longer provide benefit in areas of high-level resistance. Probenecid was initially used as an adjunctive therapy to increase the blood concentration of penicillin; it has since been used to augment concentrations of other drugs, including antifolates. The addition of probenecid has been shown to increase the treatment efficacy of SP against malaria, suggesting that the combination of probenecid plus SP may prolong the useful lifespan of SP as an effective agent for IPTp. Here, the literature on the pharmacokinetics, adverse reactions, interactions and available data on the use of these drugs in pregnancy is reviewed, and the possible utility of an SP-probenecid combination is discussed. This article concludes by calling for further research into this potentially useful combination., (© 2012 Gutman et al; BioMed Central Ltd.)

Background: In 2007, Malawi replaced the first-line medication for uncomplicated malaria, sulfadoxine-pyrimethamine-a single-dose regimen-with artemether-lumefantrine (AL)-a 6-dose, 3-day regimen. Because of concerns about the complex dosing schedule, we assessed patient adherence to AL 2 years after routine implementation., Methods: Adults and children with uncomplicated malaria were recruited at 3 health centers. We conducted both pill counts and in-home interviews on medication consumption 72 hours after patients received AL. Complete adherence was defined as correctly taking all 6 AL doses, as assessed by pill count and dose recall. We used logistic regression to identify factors associated with complete adherence., Results: Of 386 patients, 65% were completely adherent. Patients were significantly more likely to be completely adherent if they received their first dose of AL as directly observed therapy at the health center (odds ratio [OR], 2.4; P < .01), received instructions using the medication package as a visual aid (OR, 2.5; P = .02), and preferred AL over other antimalarials (OR, 2.7; P < .001). In contrast, children <5 years of age were significantly less likely to be adherent (OR, 0.5; P = .05)., Conclusions: Adherence to AL treatment for uncomplicated malaria was moderate, and children, who are the most likely to die of malaria, were less adherent than adults. Efforts to improve adherence should be focused on this vulnerable group. Interventions including the introduction of child-friendly antimalarial formulations, direct observation of the first dose, use of the AL package as a visual aid for instructions, and enhancing patient preference for AL could potentially increase AL adherence and overall effectiveness.

Background: In vivo efficacy assessments of the first-line treatments for Plasmodium falciparum malaria are essential for ensuring effective case management. In Ethiopia, artemether-lumefantrine (AL) has been the first-line treatment for uncomplicated P. falciparum malaria since 2004., Methods: Between October and November 2009, we conducted a 42-day, single arm, open label study of AL for P. falciparum in individuals >6 months of age at two sites in Oromia State, Ethiopia. Eligible patients who had documented P. falciparum mono-infection were enrolled and followed according to the standard 2009 World Health Organization in vivo drug efficacy monitoring protocol. The primary and secondary endpoints were PCR uncorrected and corrected cure rates, as measured by adequate clinical and parasitological response on days 28 and 42, respectively., Results: Of 4426 patients tested, 120 with confirmed falciparum malaria were enrolled and treated with AL. Follow-up was completed for 112 patients at day 28 and 104 patients at day 42. There was one late parasitological failure, which was classified as undetermined after genotyping. Uncorrected cure rates at both day 28 and 42 for the per protocol analysis were 99.1% (95% CI 95.1-100.0); corrected cure rates at both day 28 and 42 were 100.0%. Uncorrected cure rates at day 28 and 42 for the intention to treat analysis were 93.3% (95% CI 87.2-97.1) and 86.6% (95% CI 79.1-92.1), respectively, while the corrected cure rates at day 28 and 42 were 94.1% (95% CI 88.2-97.6) and 87.3% (95% CI 79.9-92.7), respectively. Using survival analysis, the unadjusted cure rate was 99.1% and 100.0% adjusted by genotyping for day 28 and 42, respectively. Eight P. falciparum patients (6.7%) presented with Plasmodium vivax infection during follow-up and were excluded from the per protocol analysis. Only one patient had persistent parasitaemia at day 3. No serious adverse events were reported, with cough and nausea/vomiting being the most common adverse events., Conclusions: AL remains a highly effective and well-tolerated treatment for uncomplicated falciparum malaria in the study setting after several years of universal access to AL. A high rate of parasitaemia with P. vivax possibly from relapse or new infection was observed., Trial Registration: NCT01052584.

Rapid diagnostic tests (RDTs) were developed as an alternative to microscopy for malaria diagnosis. The RDTs detect malaria parasite antigen(s) in whole blood with high sensitivity and specificity. We assessed health worker malaria treatment practices after the introduction of RDTs in peripheral health facilities without microscopy. From December 2007 to October 2008, we introduced histidine-rich protein II (HRP-2)-based ParaHIT RDTs for routine use in 12 health facilities in Rufiji District, Tanzania. Health workers received training on how to perform RDTs for patients 5 years of age or older with fever or suspected malaria. Children < 5 years of age were to be treated empirically per national guidelines. Among the 30,195 patients seen at these 12 health facilities, 10,737 (35.6%) were tested with an RDT for malaria. 88.3% (9,405/10,648) of tested patients reported fever or history of fever and 2.7% (289/10,677) of all tested individuals were children < 5 years of age. The RDT results were recorded for 10,650 patients (99.2%). Among the 5,488 (51.5%) RDT-positive patients, 5,256 (98.6%) were treated with an appropriate first-line antimalarial per national guidelines (artemether-lumefantrine or quinine). Among the 5,162 RDT-negative patients, only 205 (4.0%) were treated with an antimalarial. Other reported treatments included antibiotics and antipyretics. Implementation of RDTs in rural health facilities resulted in high adherence to national treatment guidelines. Patients testing negative by RDT were rarely treated with antimalarials. Unapproved antimalarials were seldom used. Health workers continued to follow guidelines for the empiric treatment of febrile children.

Background: Pharmacovigilance programmes can monitor and help ensure the safe use of medicines that are critical to the success of global public health programmes. The widespread deployment of artemisinin-based combination therapy (ACT) by national malaria control programmes as part of the overall Global Malaria Action Plan for malaria control to elimination and eradication makes ACT an excellent candidate for pharmacovigilance activities. In 2008, The Roll Back Malaria partnership issued guidelines for inclusion of pharmacovigilance in Global Fund and other related proposals. In light of this recommendation and the rapid scale-up of ACT worldwide, an analysis of Global Fund Round 8 proposals and the President's Malaria Initiative (PMI) 2009 Malaria Operational Plans was conducted to assess if and how pharmacovigilance has been incorporated into countries' national malaria plans and donor budget requests., Methods: The Global Fund-Malaria Round 8 proposals for the 26 countries and the PMI Malaria Operational Plans (MOPs) for fiscal year 2009 for the 15 countries that were approved and received funding from either the Global Fund-Malaria Round 8 or PMI were accessed through the programme websites. The analysis consisted of conducting word counts and key word in context analyses of each proposal and plan., Results: Twelve out of 26 (46%) of the Global Fund proposals mentioned that established pharmacovigilance systems were present in their countries. Four of the fifteen PMI MOPs (27%) mentioned that established pharmacovigilance systems were present in their countries. Only seven of the 26 (27%) Global Fund proposals included a request for funding for new or current pharmacovigilance activities. Seven of 15 (47%) MOPs included a request for funding for pharmacovigilance activities., Conclusions: There were relatively few requests for funding for pharmacovigilance activities, demonstrating a lack of emphasis placed on pharmacovigilance systems in recipient countries. The findings stress the need for more active direction to strengthen active surveillance and passive adverse event reporting systems to augment the issuance of guidance documents.

Histidine-rich protein II (HRP2)-based malaria rapid diagnostic tests (RDTs) have shown high sensitivity and specificity for detecting Plasmodium falciparum malaria in a variety of study settings. However, RDTs are susceptible to heat and humidity and variation in individual performance, which may affect their use in field settings. We evaluated sensitivity and specificity of RDTs during routine use for malaria case management in peripheral health facilities. From December 2007 to October 2008, HRP2-based ParaHIT-f RDTs were introduced in 12 facilities without available microscopy in Rufiji District, Tanzania. Health workers received a single day of instruction on how to perform an RDT and thick blood smear. Job aids, Integrated Management of Childhood Illness guidelines, and national malaria treatment algorithms were reviewed. For quality assurance (QA), thick blood smears for reference microscopy were collected for 2 to 3 days per week from patients receiving RDTs; microscopy was not routinely performed at the health facilities. Slides were stained and read centrally within 72 hours of collection by a reference microscopist. When RDT and blood smear results were discordant, blood smears were read by additional reference microscopists blinded to earlier results. Facilities were supervised monthly by the district laboratory supervisor or a member of the study team. Ten thousand six hundred fifty (10,650) patients were tested with RDTs, and 51.5% (5,488/10,650) had a positive test result. Blood smear results were available for 3,914 patients, of whom 40.1% (1,577/3,914) were positive for P. falciparum malaria. Overall RDT sensitivity was 90.7% (range by facility 85.7-96.5%) and specificity was 73.5% (range 50.0-84.3%). Sensitivity increased with increasing parasite density. Successful implementation of RDTs was achieved in peripheral health facilities with adequate training and supervision. Quality assurance is essential to the adequate performance of any laboratory test. Centralized staining and reading of blood smears provided useful monitoring of RDT performance. However, this level of QA may not be sustainable nationwide.

The impact of market concentration has been little studied in markets for ambulatory care in the developing world, where the retail sector often accounts for a high proportion of treatments. This study begins to address this gap through an analysis of the consumer market for malaria treatment in rural areas of three districts in Tanzania. We developed methods for investigating market definition, sales volumes and concentration, and used these to explore the relationship between antimalarial retail prices and competition.The market was strongly geographically segmented and highly concentrated in terms of antimalarial sales. Antimalarial prices were positively associated with market concentration. High antimalarial prices were likely to be an important factor in the low proportion of care-seekers obtaining appropriate treatment.Retail sector distribution of subsidised antimalarials has been proposed to increase the coverage of effective treatment, but this analysis indicates that local market power may prevent such subsidies from being passed on to rural customers. Policymakers should consider the potential to maintain lower retail prices by decreasing concentration among antimalarial providers and recommending retail price levels., (Copyright (c) 2009 John Wiley & Sons, Ltd.)

Background: Although the molecular basis of resistance to a number of common antimalarial drugs is well known, a geographic description of the emergence and dispersal of resistance mutations across Africa has not been attempted. To that end we have characterised the evolutionary origins of antifolate resistance mutations in the dihydropteroate synthase (dhps) gene and mapped their contemporary distribution., Methods and Findings: We used microsatellite polymorphism flanking the dhps gene to determine which resistance alleles shared common ancestry and found five major lineages each of which had a unique geographical distribution. The extent to which allelic lineages were shared among 20 African Plasmodium falciparum populations revealed five major geographical groupings. Resistance lineages were common to all sites within these regions. The most marked differentiation was between east and west African P. falciparum, in which resistance alleles were not only of different ancestry but also carried different resistance mutations., Conclusions: Resistant dhps has emerged independently in multiple sites in Africa during the past 10-20 years. Our data show the molecular basis of resistance differs between east and west Africa, which is likely to translate into differing antifolate sensitivity. We have also demonstrated that the dispersal patterns of resistance lineages give unique insights into recent parasite migration patterns.

Background: The development of antimalarial drug resistance has led to increasing calls for the introduction of artemisinin-based combination therapy (ACT). However, little evidence is available on the full costs associated with changing national malaria treatment policy. This paper presents findings on the actual drug and non-drug costs associated with deploying ACT in one district in Tanzania, and uses these data to estimate the nationwide costs of implementation in a setting where identification of malaria cases is primarily dependant on clinical diagnosis., Methods: Detailed data were collected over a three year period on the financial costs of providing ACT in Rufiji District as part of a large scale effectiveness evaluation, including costs of drugs, distribution, training, treatment guidelines and other information, education and communication (IEC) materials and publicity. The district-level costs were scaled up to estimate the costs of nationwide implementation, using four scenarios to extrapolate variable costs., Results: The total district costs of implementing ACT over the three year period were slightly over one million USD, with drug purchases accounting for 72.8% of this total. The composite (best) estimate of nationwide costs for the first three years of ACT implementation was 48.3 million USD (1.29 USD per capita), which varied between 21 and 67.1 million USD in the sensitivity analysis (2003 USD). In all estimates drug costs constituted the majority of total costs. However, non-drug costs such as IEC materials, drug distribution, communication, and health worker training were also substantial, accounting for 31.4% of overall ACT implementation costs in the best estimate scenario. Annual implementation costs are equivalent to 9.5% of Tanzania's recurrent health sector budget, and 28.7% of annual expenditure on medical supplies, implying a 6-fold increase in the national budget for malaria treatment., Conclusion: The costs of implementing ACT are substantial. Although drug purchases constituted a majority of total costs, non-drug costs were also considerable. It is clear that substantial external resources will be required to facilitate and sustain effective ACT delivery across Tanzania and other malaria-endemic countries.

Introduction: Retail pharmaceutical products are commonly used to treat fever and malaria in sub-Saharan African countries. Small scale studies have suggested that poor quality antimalarials are widespread throughout the region, but nationwide data are not available that could lead to generalizable conclusions about the extent to which poor quality drugs are available in African communities. This study aimed to assess the quality of antimalarials available from retail outlets across mainland Tanzania., Methods and Findings: We systematically purchased samples of oral antimalarial tablets from retail outlets across 21 districts in mainland Tanzania in 2005. A total of 1080 antimalarial formulations were collected including 679 antifol antimalarial samples (394 sulfadoxine/pyrimethamine and 285 sulfamethoxypyrazine/pyrimethamine), 260 amodiaquine samples, 63 quinine samples, and 51 artemisinin derivative samples. A systematic subsample of 304 products was assessed for quality by laboratory based analysis to determine the amount of the active ingredient and dissolution profile by following the published United States Pharmacopoeia (USP) monogram for the particular tablet being tested. Products for which a published analytical monogram did not exist were assessed on amount of active ingredient alone. Overall 38 or 12.2% of the samples were found to be of poor quality. Of the antifolate antimalarial drugs tested 13.4% were found to be of poor quality by dissolution and content analysis using high-performance liquid chromatography (HPLC). Nearly one quarter (23.8%) of quinine tablets did not comply within the tolerance limits of the dissolution and quantification analysis. Quality of amodiaquine drugs was relatively better but still unacceptable as 7.5% did not comply within the tolerance limits of the dissolution analysis. Formulations of the artemisinin derivatives all contained the stated amount of active ingredient when analysed using HPLC alone., Conclusions: Substandard antimalarial formulations were widely available in Tanzania at the time of this study. No products were detected that did not contain any amount of the stated active ingredient. Quinine and sulfadoxine/pyrimethamine products were the most widely available and also the most likely to be of poor quality. Substandard products were identified in all parts of the country and were labeled as made by both domestic and international manufacturers. With the expansion of the retail pharmaceutical sector as a delivery channel for antimalarial formulations the need for regular nationwide monitoring of their quality will become increasingly important.

Background: Malaria control strategies emphasize the need for prompt and effective treatment of malaria episodes. To increase treatment efficacy, Tanzania changed its first-line treatment from chloroquine to sulphadoxine-pyrimethamine (SP) in 2001. The effect of this policy change on the availability of antimalarials was studied in rural south-eastern Tanzania., Methods: In 2001 and 2004, the study area was searched for commercial outlets selling drugs and their stocks were recorded. Household information was obtained from the local Demographic Surveillance System., Results: From 2001 to 2004, the number of general shops stocking drugs increased by 15% and the number of drug stores nearly doubled. However, the proportion of general shops stocking antimalarials dropped markedly, resulting in an almost 50% decrease of antimalarial selling outlets. This led to more households being located farther from a treatment source. In 2004, five out of 25 studied villages with a total population of 13,506 (18%) had neither a health facility, nor a shop as source of malaria treatment., Conclusion: While the change to SP resulted in a higher treatment efficacy, it also led to a decreased antimalarial availability in the study area. Although there was no apparent impact on overall antimalarial use, the decline in access may have disproportionately affected the poorest and most remote groups. In view of the imminent policy change to artemisinin-based combination therapy these issues need to be addressed urgently if the benefits of this new class of antimalarials are to be extended to the whole population.

Background: Recently global health advocates have called for the introduction of artemisinin-containing antimalarial combination therapies to help curb the impact of drug-resistant malaria in Africa. Retail trade in artemisinin monotherapies could undermine efforts to restrict this class of medicines to more theoretically sound combination treatments., Methods: This paper describes a systematic search for artemisinin-containing products at a random sample of licensed pharmacies in Dar-es-Salaam, Tanzania in July 2005., Results: Nineteen different artemisinin-containing oral pharmaceutical products, including one co-formulated product, one co-packaged product, and 17 monotherapies were identified. All but one of the products were legally registered and samples of each product were obtained without a prescription. Packaging and labeling of the products seldom included local language or illustrated instructions for low-literate clients. Packaging and inserts compared reasonably well with standards recommended by the national regulatory authority with some important exceptions. Dosing instructions were inconsistent, and most recommended inadequate doses based on international standards. None of the monotherapy products mentioned potential benefits of combining the treatment with another antimalarial drug., Conclusion: The findings confirm the widespread availability of artemisinin monotherapies that led the World Health Organization to call for the voluntary withdrawal of these drugs in malaria-endemic countries. As the global public health community gathers resources to deploy artemisinin-containing combination therapies in Africa, planners should be mindful that these drugs will coexist with artemisinin monotherapies in an already well-established market place. In particular, regulatory authorities should be incorporated urgently into the process of planning for rational deployment of artemisinin-containing antimalarial combination therapies.

We have measured microsatellite diversity at 26 markers around the dhfr gene in pyrimethamine-sensitive and -resistant parasites collected in southeast Africa. Through direct comparison with diversity on sensitive chromosomes we have found significant loss of diversity across a region of 70 kb around the most highly resistant allele which is evidence of a selective sweep attributable to selection through widespread use of pyrimethamine (in combination with sulfadoxine) as treatment for malaria. Retrospective analysis through four years of direct and continuous selection from use of sulfadoxine-pyrimethamine as first-line malaria treatment on a Plasmodium falciparum population in KwaZulu Natal, South Africa, has revealed how recombination significantly narrowed the margins of the selective sweep over time. A deterministic model incorporating selection coefficients measured during the same interval indicates that the transition was toward a state of recombination-selection equilibrium. We compared loss of diversity around the same resistance allele in two populations at either extreme of the range of entomological inoculation rates (EIRs), namely, under one infective bite per year in Mpumalanga, South Africa, and more than one per day in southern Tanzania. EIRs determine effective recombination rates and are expected to profoundly influence the dimensions of the selective sweep. Surprisingly, the dimensions were broadly consistent across both populations. We conclude that despite different recombination rates and contrasting drug selection histories in neighboring countries, the region-wide movement of resistant parasites has played a key role in the establishment of resistance in these populations and the dimensions of the selective sweep are dominated by the influence of high initial starting frequencies.

Artemisinin-containing antimalarial combination therapies are recommended to confront drug-resistant Plasmodium falciparum malaria. Among the questions surrounding whether these complex multidose treatments will be practical is to what extent patients complete the recommended doses. Combination therapy through coadministration of sulfadoxine-pyrimethamine plus artesunate was introduced as a first-line treatment for uncomplicated malaria in one district in Tanzania. Interventions to optimize correct use were also implemented. We observed 453 patient encounters at one health facility and recorded key practices as health workers dispensed the combination. A total of 253 patients were followed-up at 24 or 48 hours. Complete adherence measured at 48 hours reached 75.0%, based on self-report and tablet counts. This is substantially better than reported elsewhere and compares favorably with intervention studies to optimize adherence to chloroquine. Counseling about what to do if a patient vomits appears to have been an independent risk factor for nonadherence.

Objectives: To characterize availability of fever and malaria medicines within the retail sector in rural Tanzania, assess the likely public health implications, and identify opportunities for policy interventions to increase the coverage of effective treatment., Methods: A census of retailers selling drugs was undertaken in the areas under demographic surveillance in four Tanzanian districts, using a structured questionnaire., Results: Drugs were stocked by two types of retailer: a large number of general retailers (n = 675) and a relatively small number of drug shops (n = 43). Almost all outlets stocked antipyretics/painkillers. One-third of general retailers stocking drugs had antimalarials, usually chloroquine alone. Almost all drug shops stocked antimalarials (98%): nearly all had chloroquine, 42% stocked quinine, 37% sulphadoxine-pyrimethamine and 30% amodiaquine. A large number of antimalarial brands were available. Population ratios indicate the relative accessibility of retail drug providers compared with health facilities. Drug shop staff generally travelled long distances to buy from drugs wholesalers or pharmacies. General retailers bought mainly from local general wholesalers, with a few general wholesalers accounting for a high proportion of all sources cited., Conclusions: Drugs were widely available from a large number of retail outlets. Potential negative implications include provision of ineffective drugs, confusion over brand names, uncontrolled use of antimalarials, and the availability of components of potential combination therapy regimens as monotherapies. On the other hand, this active and highly accessible retail market provides opportunities for improving the coverage of effective antimalarial treatment. Interventions targeted at all drug retailers are likely to be costly to deliver and difficult to sustain, but two promising points for targeted intervention are drug shops and selected general wholesalers. Retail quality may also be improved through consumer education, and modification of the chemical quality, packaging and price of products entering the retail distribution chain.

Malaria is a leading cause of death in children aged < 5 years in Malawi. As part of the Roll Back Malaria initiative, African heads of state have pledged that by 2005, 60% of children will receive an effective antimalarial drug within 24 h of developing fever. In 1993, Malawi switched from chloroquine to sulfadoxine-pyrimethamine (SP) in its recommendations of home treatment of febrile illness in children. To study care seeking behaviour and home treatment in Blantyre District, and provide valuable follow-up to the chloroquine to SP transition, we performed a 2-stage cluster-sample survey in February 2000. Our sample of 1080 households included 672 households with children aged < 5 years; 292 (32.2%, 95% CI 28.7-35.8%) of the 912 children in these households had completed a febrile episode within the past 14 d. Among recently febrile children, 210 (72.0%, 95% CI 67.0-77.1%) received medication at home during their illness, but only 36 (12.2%, 95% CI 8.4-16.0%) received an appropriate antimalarial drug. Overall, 111 (37.4%, 95% CI 30.9-43.9%) received prompt, appropriate treatment. Only rural location was statistically associated with failure to receive prompt appropriate treatment (risk ratio estimate 1.2, 95% CI 1.01-1.5). A greater effort to improve the quality of malaria home treatment or to expand health facility utilization will be necessary to achieve Roll Back Malaria goals before 2005 in Blantyre District. Current care seeking practices suggest interventions should stress promptness of health facility visits, improved access to appropriate drugs, and accurate dosing for home-based treatments.

Background: Recent efforts in malaria control have resulted in great gains in reducing the burden of Plasmodium falciparum, but P. vivax has been more refractory. Its ability to form dormant liver stages confounds control and elimination efforts. To compare the efficacy and safety of primaquine regimens for radical cure, we undertook a randomized controlled trial in Ethiopia.Methods and Findings: Patients with normal glucose-6-phosphate dehydrogenase status with symptomatic P. vivax mono-infection were enrolled and randomly assigned to receive either chloroquine (CQ) or artemether-lumefantrine (AL), alone or in combination with 14 d of semi-supervised primaquine (PQ) (3.5 mg/kg total). A total of 398 patients (n = 104 in the CQ arm, n = 100 in the AL arm, n = 102 in the CQ+PQ arm, and n = 92 in the AL+PQ arm) were followed for 1 y, and recurrent episodes were treated with the same treatment allocated at enrolment. The primary endpoints were the risk of P. vivax recurrence at day 28 and at day 42. The risk of recurrent P. vivax infection at day 28 was 4.0% (95% CI 1.5%-10.4%) after CQ treatment and 0% (95% CI 0%-4.0%) after CQ+PQ. The corresponding risks were 12.0% (95% CI 6.8%-20.6%) following AL alone and 2.3% (95% CI 0.6%-9.0%) following AL+PQ. On day 42, the risk was 18.7% (95% CI 12.2%-28.0%) after CQ, 1.2% (95% CI 0.2%-8.0%) after CQ+PQ, 29.9% (95% CI 21.6%-40.5%) after AL, and 5.9% (95% CI 2.4%-13.5%) after AL+PQ (overall p < 0.001). In those not prescribed PQ, the risk of recurrence by day 42 appeared greater following AL treatment than CQ treatment (HR = 1.8 [95% CI 1.0-3.2]; p = 0.059). At the end of follow-up, the incidence rate of P. vivax was 2.2 episodes/person-year for patients treated with CQ compared to 0.4 for patients treated with CQ+PQ (rate ratio: 5.1 [95% CI 2.9-9.1]; p < 0.001) and 2.3 episodes/person-year for AL compared to 0.5 for AL+PQ (rate ratio: 6.4 [95% CI 3.6-11.3]; p < 0.001). There was no difference in the occurrence of adverse events between treatment arms. The main limitations of the study were the early termination of the trial and the omission of haemoglobin measurement after day 42, resulting in an inability to estimate the cumulative risk of anaemia.Conclusions: Despite evidence of CQ-resistant P. vivax, the risk of recurrence in this study was greater following treatment with AL unless it was combined with a supervised course of PQ. PQ combined with either CQ or AL was well tolerated and reduced recurrence of vivax malaria by 5-fold at 1 y.Trial Registration: ClinicalTrials.gov NCT01680406. [ABSTRACT FROM AUTHOR]

Background: The Affordable Medicines Facility - malaria (AMFm) is primarily an artemisinin combination therapy (ACT) subsidy, aimed at increasing availability, affordability, market share and use of quality-assured ACTs (QAACTs). Mainland Tanzania was one of eight national scale programmes where AMFm was introduced in 2010. Here we present findings from outlet and household surveys before and after AMFm implementation to evaluate its impact from both the supply and demand side. Methods: Outlet surveys were conducted in 49 randomly selected wards throughout mainland Tanzania in 2010 and 2011, and data on outlet characteristics and stocking patterns were collected from outlets stocking antimalarials. Household surveys were conducted in 240 randomly selected enumeration areas in three regions in 2010 and 2012. Questions about treatment seeking for fever and drugs obtained were asked of individuals reporting fever in the previous two weeks. Results: The availability of QAACTs increased from 25.5% to 69.5% among all outlet types, with the greatest increase among pharmacies and drug stores, together termed specialised drug sellers (SDSs), where the median QAACT price fell from $5.63 to $0.94. The market share of QAACTs increased from 26.2% to 42.2%, again with the greatest increase in SDSs. Household survey results showed a shift in treatment seeking away from the public sector towards SDSs. Overall, there was no change in the proportion of people with fever obtaining an antimalarial or ACT from baseline to endline. However, when broken down by treatment source, ACT use increased significantly among clients visiting SDSs. Discussion: Unchanged ACT use overall, despite increases in QAACT availability, affordability and market share in the private sector, reflected a shift in treatment seeking towards private providers. The reasons for this shift are unclear, but likely reflect both persistent stockouts in public facilities, and the increased availability of subsidised ACTs in the private sector. [ABSTRACT FROM AUTHOR]

Background: In vivo efficacy assessments of antimalarials are essential for ensuring effective case management. In Ethiopia, chloroquine (CQ) without primaquine is the first-line treatment for Plasmodium vivax in malarious areas, but artemether-lumefantrine (AL) is also commonly used. Methods and Findings: In 2009, we conducted a 42-day efficacy study of AL or CQ for P. vivax in Oromia Regional State, Ethiopia. Individuals with P. vivax monoinfection were enrolled. Primary endpoint was day 28 cure rate. In patients with recurrent parasitemia, drug level and genotyping using microsatellite markers were assessed. Using survival analysis, uncorrected patient cure rates at day 28 were 75.7% (95% confidence interval (CI) 66.8–82.5) for AL and 90.8% (95% CI 83.6–94.9) for CQ. During the 42 days of follow-up, 41.6% (47/113) of patients in the AL arm and 31.8% (34/107) in the CQ arm presented with recurrent P. vivax infection, with the median number of days to recurrence of 28 compared to 35 days in the AL and CQ arm, respectively. Using microsatellite markers to reclassify recurrent parasitemias with a different genotype as non-treatment failures, day 28 cure rates were genotype adjusted to 91.1% (95% CI 84.1–95.1) for AL and to 97.2% (91.6–99.1) for CQ. Three patients (2.8%) with recurrent parasitemia by day 28 in the CQ arm were noted to have drug levels above 100 ng/ml. Conclusions: In the short term, both AL and CQ were effective and well-tolerated for P. vivax malaria, but high rates of recurrent parasitemia were noted with both drugs. CQ provided longer post-treatment prophylaxis than AL, resulting in delayed recurrence of parasitemia. Although the current policy of species-specific treatment can be maintained for Ethiopia, the co-administration of primaquine for treatment of P. vivax malaria needs to be urgently considered to prevent relapse infections. Trial Registration: ClinicalTrials.gov NCT01052584 [ABSTRACT FROM AUTHOR]

Background: Since 2000, the World Health Organization has recommended a package of interventions to prevent malaria during pregnancy and its sequelae that includes the promotion of insecticide-treated bed nets (ITNs), intermittent preventive treatment in pregnancy (IPTp), and effective case management of malarial illness. It is recommended that pregnant women in malaria-endemic areas receive at least two doses of sulphadoxine-pyrimethamine in the second and third trimesters of pregnancy. This study assessed the prevalence of placental malaria at delivery in women during 1st or 2nd pregnancy, who did not receive intermittent preventive treatment for malaria (IPTp) in a malaria-endemic area with high bed net coverage. Methods: A hospital-based cross-sectional study was done in Ifakara, Tanzania, where bed net coverage is high. Primi- and secundigravid women, who presented to the labour ward and who reported not using IPTp were included in the study. Self-report data were collected by questionnaire; whereas neonatal birth weight and placenta parasitaemia were measured directly at the time of delivery. Results: Overall, 413 pregnant women were enrolled of which 91% reported to have slept under a bed net at home the previous night, 43% reported history of fever and 62% were primigravid. Malaria parasites were detected in 8% of the placenta samples; the geometric mean (95%CI) placental parasite density was 3,457 (1,060-11,271) parasites/µl in primigravid women and 2,178 (881-5,383) parasites/µl in secundigravid women. Fifteen percent of newborns weighed <2,500 g at delivery. Self-reported bed net use was statistically associated with lower risk for low birth weight [OR 0.34 (95% CI: 0.16-0.74) and OR 0.22 (95% CI: 0.08-0.59) for untreated and treated bed nets, respectively], but was not associated with placental parasitaemia [OR 0.74 (0.21-2.68) and OR 1.64 (0.44-6.19) for untreated and treated bed nets, respectively]. Conclusion: The observed incidence of LBW and prevalence of placental parasitaemia at delivery suggests that malaria remains a problem in pregnancy in this area with high bed net coverage when eligible women do not receive IPTp. Delivery of IPTp should be emphasized at all levels of implementation to achieve maximum community coverage. [ABSTRACT FROM AUTHOR]

In 1996, Zambia's Ministry of Health made sulfadoxine-pyrimethamine (SP) available as a second-line antimalarial. SP differs from chloroquine (CQ) in ways that might affect parents' acceptance of the drug, resulting in possible delays in seeking treatment if parents perceive SP as less efficacious. A multifaceted study consisting of a rapid community ethnographic assessment to examine local attitudes and perceptions toward malaria, a 14-day in vivo drug efficacy study comparing clinical and parasitological efficacy of CQ, SP, and SP with paracetamol (PCM) in children under five, and a qualitative study examining caretakers' perceptions of drug efficacy helped to guide implementation of the new drug policy. The rapid ethnographic study indicated that the community was aware of malaria as an illness best treated with modern medicines, particularly CQ. The drug efficacy study demonstrated a 25% level of clinical failures compared to none with SP, and 30% of the children treated with CQ had either RIII or RII parasitological failures whereas none occurred in children treated with SP. Most parents perceived that their children were improving and that the drugs were working. Parents in the SP groups were most pleased and readily accepted SP as a new drug. The addition of PCM did not improve perceptions of SP efficacy, contradicting conventional wisdom regarding the need for direct antipyretic action for parents to perceive a drug as efficacious. The combined results reflected a community that was in the beginning stages of evaluating a new malaria therapy mostly unknown to them. Perceptions of efficacy of CQ were beginning to shift, indicating a readiness for accepting a new drug based on its shown biological efficacy. Parasitological and clinical failure rates reinforced the need to fully implement the changed national policy as soon as possible, and to consider a change in first-line therapy. [ABSTRACT FROM AUTHOR]