Factors associated with access and adherence to artemisinin-based combination therapy (ACT) for children under five: a secondary analysis of a national survey in Sierra Leone.

BACKGROUND: Access and adherence to artemisinin-based combination therapy (ACT) are key challenges to effective malaria treatment. A secondary analysis of the Sierra Leone malaria Knowledge, Attitudes, and Practices (mKAP) survey was conducted to investigate access and adherence to ACT for the treatment of fever in children under-five. METHODS: The mKAP was a nationally representative, two-stage cluster-sample survey, conducted in 2012. Thirty primary sampling units per district were randomly selected using probability proportionate to size, based on national census estimates; 14 households were subsequently randomly selected and enrolled per sampling unit. The analysis was restricted to children under-five with fever in the past two weeks. Factors associated with access and adherence were assessed using multivariate logistic regression. RESULTS: Of 5169 enrolled households, 1456 reported at least one child under-five with fever in the past two weeks. Of the 1641 children from these households, 982 (59.8%) received any treatment for fever and were analysed for access to ACT; 469 (47.6%) received ACT and 466 were analysed for treatment adherence. Only 222 (47.4%) febrile children received ACT and completed 3-day treatment. In an adjusted analysis, factors associated with ACT access included knowledge of ACT (odds ratio [OR] 2.78, 95% CI 2.02-3.80; p < 0.001), knowledge of insecticide-treated nets (ITNs) (OR 1.84, 95% CI 1.29-2.63; p = 0.001), source of care (public health facility vs. other; OR 1.86, 95% CI 1.27-2.72, p = 0.001), geographic region (East vs. West; OR 2.30, 95% CI 1.20-4.44; p = 0.025), and age (24-59 vs. 0-23 months; OR 1.45, 95% CI 1.07-1.96; p = 0.016). The only factor associated with ACT adherence was time to treatment; children treated within 24 h were less likely to adhere (OR 0.55, 95% CI 0.34-0.89; p = 0.015). CONCLUSIONS: In 2012, access and adherence to ACT remained low in Sierra Leone. Knowledge of ACT and ITNs, and seeking care in the public sector, were most strongly associated with ACT access. National surveys provide important information on anti-malarial access and could be expanded to measure treatment adherence.

Adherence to treatment with artemether-lumefantrine or amodiaquine-artesunate for uncomplicated malaria in children in Sierra Leone: a randomized trial.

BACKGROUND: Prompt, effective treatment of confirmed malaria cases with artemisinin-based combination therapy (ACT) is a cornerstone of malaria control. Maximizing adherence to ACT medicines is key to ensuring treatment effectiveness. METHODS: This open-label, randomized trial evaluated caregiver adherence to co-formulated artemether-lumefantrine (AL) and fixed-dose amodiaquine-artesunate (AQAS) in Sierra Leone. Children aged 6-59 months diagnosed with malaria were recruited from two public clinics, randomized to receive AL or AQAS, and visited at home the day after completing treatment. Analyses were stratified by site, due to differences in participant characteristics and outcomes. RESULTS: Of the 784 randomized children, 680 (85.6%) were included in the final per-protocol analysis (340 AL, 340 AQAS). Definite adherence (self-reported adherence plus empty package) was higher for AL than AQAS at both sites (Site 1: 79.4% AL vs 63.4% AQAS, odds ratio [OR] 2.16, compared to probable adherence plus probable or definite non-adherence, 95% confidence interval [CI] 1.34-3.49; p = 0.001; Site 2: 52.1% AL vs 37.5% AQAS, OR 1.53, 95% CI 1.00-2.33, p = 0.049). However, self-reported adherence (ignoring drug package inspection) was higher for both regimens at both sites and there was no strong evidence of variation by treatment (Site 1: 96.6% AL vs 95.9% AQAS, OR 1.19, 95% CI 0.39-3.63, p = 0.753; Site 2: 91.5% AL vs 96.4% AQAS, OR 0.40, 95% CI 0.15-1.07, p = 0.067). In Site 2, correct treatment (correct dose + timing + duration) was lower for AL than AQAS (75.8% vs 88.1%, OR 0.42, 95% CI 0.23-0.76, p = 0.004). In both sites, more caregivers in the AQAS arm reported adverse events (Site 1: 3.4% AL vs 15.7% AQAS, p < 0.001; Site 2: 15.2% AL vs 24.4% AQAS, p = 0.039). CONCLUSIONS: Self-reported adherence was high for both AL and AQAS, but varied by site. These results suggest that each regimen has potential disadvantages that might affect adherence; AL was less likely to be taken correctly at one site, but was better tolerated than AQAS at both sites. Measuring adherence to anti-malarials remains challenging, but important. Future research should focus on comparative studies of new drug regimens, and improving the methodology of measuring adherence. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01967472. Retrospectively registered 18 October 2013, https://clinicaltrials.gov/ct2/show/NCT01967472.

Adherence to artemisinin-based combination therapy for the treatment of malaria: a systematic review of the evidence.

BACKGROUND: Increasing access to and targeting of artemisinin-based combination therapy (ACT) is a key component of malaria control programmes. To maximize efficacy of ACT and ensure adequate treatment outcomes, patient and caregiver adherence to treatment guidelines is essential. This review summarizes the current evidence base on ACT adherence, including definitions, measurement methods, and associated factors. METHODS: A systematic search of the published literature was undertaken in November 2012 and updated in April 2013. Bibliographies of manuscripts were also searched and additional references identified. Studies were included if they involved at least one form of ACT and reported an adherence measurement. RESULTS: The search yielded 1,412 records, 37 of which were found to measure adherence to ACT. Methods to measure adherence focused on self-report, pill counts and bioassays with varying definitions for adherence. Most studies only reported whether medication regimens were completed, but did not assess how the treatment was taken by the patient (i.e. timing, frequency and dose). Adherence data were available for four different ACT formulations: artemether-lumefantrine (AL) (range 39-100%), amodiaquine plus artesunate (AQ + AS) (range 48-94%), artesunate plus sulphadoxine-pyrimethamine (AS + SP) (range 39-75%) and artesunate plus mefloquine (AS + MQ) (range 77-95%). Association between demographic factors, such as age, gender, education and socio-economic status and adherence to ACT regimens was not consistent. Some evidence of positive association between adherence and patient age, caregiver education levels, drug preferences, health worker instructions, patient/caregiver knowledge and drug packaging were also observed. CONCLUSIONS: This review highlights the weak evidence base on ACT adherence. Results suggest that ACT adherence levels varied substantially between study populations, but comparison between studies was challenging due to differences in study design, definitions, and methods used to measure adherence. Standardising methodologies for both self-report and bioassays used for evaluating adherence of different formulations across diverse contexts would improve the evidence base on ACT adherence and effectiveness; namely, specific and measurable definitions for adherence are needed for both methodologies. Additionally, further studies of the individual factors and barriers associated with non-adherence to ACT are needed in order to make informed policy choices and to improve the delivery of effective malaria treatment.

Knowledge, attitudes and practices of malaria control among communities from the health district of Forécariah in the Republic of Guinea, West Africa.

BACKGROUND & OBJECTIVES: Malaria is the leading cause of death in children under 5-yr of age in the Republic of Guinea. This study aimed at investigating the knowledge, attitudes and practices of malaria control in urban and rural communities in Guinea in order to better target future health interventions. METHODS: A cross-sectional survey of 200 randomly selected households was conducted in an urban site and in three rural villages within the health district of Forιcariah using two semi-structured questionnaires. RESULTS: Only 18.5% of the respondents were aware of the role of mosquitoes in the transmission of malaria in both urban and rural households. Mosquito nets were identified as a malaria prevention method by 11.5% of the participants and only 8.5% of the respondents mentioned stagnant water as a potential mosquito breeding site. Households' heads were more aware of mosquito control methods, with 56 and 42% of the respondents recognizing that bednets or insecticidal coils can protect from mosquitoes, respectively. Despite the limited knowledge of malaria transmission and prevention, 55% of the households owned at least one long-lasting insecticide-treated net (LLIN) and 79% of the net-owning households slept under a net/LLIN the night before the survey. INTERPRETATION & CONCLUSION: In order to maximize the benefits of malaria control strategies, health education should be implemented, building on the higher awareness of mosquito control methods and stressing the role of vectors in transmitting the disease.

Participant perspectives to improve tenofovir adherence in the prevention of mother-to-child transmission of hepatitis B virus in Kinshasa, DRC.

Prevention of mother-to-child transmission (PMTCT) programs for hepatitis B virus (HBV) are critical to reach the World Health Organization's 2030 HBV elimination goals. Despite demonstrated feasibility utilizing HIV infrastructure, HBV PMTCT programs are not implemented in many African settings, including in the Democratic Republic of Congo (DRC). In a previous pilot of HBV PMTCT implementation in DRC's capital, Kinshasa, we observed low TDF metabolite levels at delivery among women with high-risk HBV who were given tenofovir disoproxil fumarate (TDF) antiviral therapy. As such, we conducted qualitative interviews with women who received TDF to understand facilitators and barriers of medication adherence. We used a modified Information-Motivation-Behavioral Skills model (IMB+) as a framework for thematic content analysis. We found that trust in healthcare workers, familial support, and improved awareness of the disease and treatment options were important facilitators of TDF adherence; pill size, social stigma, and low HBV knowledge were barriers to adherence. While overall acceptance of TDF was high in this pilot, improved TDF adherence is needed in order to reach efficacious levels for preventing transmission from mothers to newborns. We suggest ongoing HBV sensitization within existing maternity and HIV care infrastructure would address gaps in knowledge and stigma identified here. Additionally, given the trust women have towards maternity center staff and volunteers, scaled HBV PMTCT interventions should include specific sensitization and education for healthcare affiliates, who currently receive no HBV prevention or information in DRC. This study is timely as TDF, particularly future long-acting formulations, could be considered as an alternate rather than adjuvant to birth-dose vaccination for HBV PMTCT in sub-Saharan Africa.

Epidemiology of Plasmodium malariae and Plasmodium ovale spp. in a highly malaria-endemic country: a longitudinal cohort study in Kinshasa Province, Democratic Republic of Congo.

Background: Increasing reports suggest that non-falciparum species are an underappreciated cause of malaria in sub-Saharan Africa, but their epidemiology is not well-defined. This is particularly true in regions of high P. falciparum endemicity such as the Democratic Republic of Congo (DRC), where 12% of the world's malaria cases and 13% of deaths occur. Methods and Findings: The cumulative incidence and prevalence of P. malariae and P. ovale spp. infection detected by real-time PCR were estimated among children and adults within a longitudinal study conducted in seven rural, peri-urban, and urban sites from 2015-2017 in Kinshasa Province, DRC. Participants were sampled at biannual household survey visits (asymptomatic) and during routine health facility visits (symptomatic). Participant-level characteristics associated with non-falciparum infections were estimated for single- and mixed-species infections. Among 9,089 samples collected from 1,565 participants over a 3-year period, the incidence of P. malariae and P. ovale spp. infection was 11% (95% CI: 9%-12%) and 7% (95% CI: 5%-8%) by one year, respectively, compared to a 67% (95% CI: 64%-70%) one-year cumulative incidence of P. falciparum infection. Incidence continued to rise in the second year of follow-up, reaching 26% and 15% in school-age children (5-14yo) for P. malariae and P. ovale spp., respectively. Prevalence of P. malariae, P. ovale spp., and P. falciparum infections during household visits were 3% (95% CI: 3%-4%), 1% (95% CI: 1%-2%), and 35% (95% CI: 33%-36%), respectively. Non-falciparum malaria was more prevalent in rural and peri-urban vs. urban sites, in school-age children, and among those with P. falciparum co-infection. A crude association was detected between P. malariae and any anemia in the symptomatic clinic population, although this association did not hold when stratified by anemia severity. No crude associations were detected between non-falciparum infection and fever prevalence. Conclusions: P. falciparum remains the primary driver of malaria morbidity and mortality in the DRC. However, non-falciparum species also pose an infection risk across sites of varying urbanicity and malaria endemicity within Kinshasa, DRC, particularly among children under 15 years of age. As P. falciparum interventions gain traction in high-burden settings like the DRC, continued surveillance and improved understanding of non-falciparum infections are warranted.

Epidemiology of Plasmodium malariae and Plasmodium ovale spp. in Kinshasa Province, Democratic Republic of Congo.

Reports suggest non-falciparum species are an underappreciated cause of malaria in sub-Saharan Africa but their epidemiology is ill-defined, particularly in highly malaria-endemic regions. We estimated incidence and prevalence of PCR-confirmed non-falciparum and Plasmodium falciparum malaria infections within a longitudinal study conducted in Kinshasa, Democratic Republic of Congo (DRC) between 2015-2017. Children and adults were sampled at biannual household surveys and routine clinic visits. Among 9,089 samples from 1,565 participants, incidences of P. malariae, P. ovale spp., and P. falciparum infections by 1-year were 7.8% (95% CI: 6.4%-9.1%), 4.8% (95% CI: 3.7%-5.9%) and 57.5% (95% CI: 54.4%-60.5%), respectively. Non-falciparum prevalences were higher in school-age children, rural and peri-urban sites, and P. falciparum co-infections. P. falciparum remains the primary driver of malaria in the DRC, though non-falciparum species also pose an infection risk. As P. falciparum interventions gain traction in high-burden settings, continued surveillance and improved understanding of non-falciparum infections are warranted.

Plasmodium falciparum with pfhrp2/3 Deletion Not Detected in a 2018-2021 Malaria Longitudinal Cohort Study in Kinshasa Province, Democratic Republic of the Congo.

Histidine-rich protein 2- (HRP2-) based rapid diagnostic tests (RDTs) are widely used to detect Plasmodium falciparum in sub-Saharan Africa. Reports of parasites with pfhrp2 and/or pfhrp3 (pfhrp2/3) gene deletions in Africa raise concerns about the long-term viability of HRP2-based RDTs. We evaluated changes in pfhrp2/3 deletion prevalence over time using a 2018-2021 longitudinal study of 1,635 enrolled individuals in Kinshasa Province, Democratic Republic of the Congo (DRC). Samples collected during biannual household visits with ≥ 100 parasites/µL by quantitative real-time polymerase chain reaction were genotyped using a multiplex real-time PCR assay. Among 2,726 P. falciparum PCR-positive samples collected from 993 participants during the study period, 1,267 (46.5%) were genotyped. No pfhrp2/3 deletions or mixed pfhrp2/3-intact and -deleted infections were identified in our study. Pfhrp2/3-deleted parasites were not detected in Kinshasa Province; ongoing use of HRP2-based RDTs is appropriate.

The Systems Analysis and Improvement Approach: specifying core components of an implementation strategy to optimize care cascades in public health.

BACKGROUND: Healthcare systems in low-resource settings need simple, low-cost interventions to improve services and address gaps in care. Though routine data provide opportunities to guide these efforts, frontline providers are rarely engaged in analyzing them for facility-level decision making. The Systems Analysis and Improvement Approach (SAIA) is an evidence-based, multi-component implementation strategy that engages providers in use of facility-level data to promote systems-level thinking and quality improvement (QI) efforts within multi-step care cascades. SAIA was originally developed to address HIV care in resource-limited settings but has since been adapted to a variety of clinical care systems including cervical cancer screening, mental health treatment, and hypertension management, among others; and across a variety of settings in sub-Saharan Africa and the USA. We aimed to extend the growing body of SAIA research by defining the core elements of SAIA using established specification approaches and thus improve reproducibility, guide future adaptations, and lay the groundwork to define its mechanisms of action. METHODS: Specification of the SAIA strategy was undertaken over 12 months by an expert panel of SAIA-researchers, implementing agents and stakeholders using a three-round, modified nominal group technique approach to match core SAIA components to the Expert Recommendations for Implementing Change (ERIC) list of distinct implementation strategies. Core implementation strategies were then specified according to Proctor's recommendations for specifying and reporting, followed by synthesis of data on related implementation outcomes linked to the SAIA strategy across projects. RESULTS: Based on this review and clarification of the operational definitions of the components of the SAIA, the four components of SAIA were mapped to 13 ERIC strategies. SAIA strategy meetings encompassed external facilitation, organization of provider implementation meetings, and provision of ongoing consultation. Cascade analysis mapped to three ERIC strategies: facilitating relay of clinical data to providers, use of audit and feedback of routine data with healthcare teams, and modeling and simulation of change. Process mapping matched to local needs assessment, local consensus discussions and assessment of readiness and identification of barriers and facilitators. Finally, continuous quality improvement encompassed tailoring strategies, developing a formal implementation blueprint, cyclical tests of change, and purposefully re-examining the implementation process. CONCLUSIONS: Specifying the components of SAIA provides improved conceptual clarity to enhance reproducibility for other researchers and practitioners interested in applying the SAIA across novel settings.

Impact of malaria diagnostic choice on monitoring of Plasmodium falciparum prevalence estimates in the Democratic Republic of the Congo and relevance to control programs in high-burden countries.

Malaria programs rely upon a variety of diagnostic assays, including rapid diagnostic tests (RDTs), microscopy, polymerase chain reaction (PCR), and bead-based immunoassays (BBA), to monitor malaria prevalence and support control and elimination efforts. Data comparing these assays are limited, especially from high-burden countries like the Democratic Republic of the Congo (DRC). Using cross-sectional and routine data, we compared diagnostic performance and Plasmodium falciparum prevalence estimates across health areas of varying transmission intensity to illustrate the relevance of assay performance to malaria control programs. Data and samples were collected between March-June 2018 during a cross-sectional household survey across three health areas with low, moderate, and high transmission intensities within Kinshasa Province, DRC. Samples from 1,431 participants were evaluated using RDT, microscopy, PCR, and BBA. P. falciparum parasite prevalence varied between diagnostic methods across all health areas, with the highest prevalence estimates observed in Bu (57.4-72.4% across assays), followed by Kimpoko (32.6-53.2%), and Voix du Peuple (3.1-8.4%). Using latent class analysis to compare these diagnostic methods against an "alloyed gold standard," the most sensitive diagnostic method was BBA in Bu (high prevalence) and Voix du Peuple (low prevalence), while PCR diagnosis was most sensitive in Kimpoko (moderate prevalence). RDTs were consistently the most specific diagnostic method in all health areas. Among 9.0 million people residing in Kinshasa Province in 2018, the estimated P. falciparum prevalence by microscopy, PCR, and BBA were nearly double that of RDT. Comparison of malaria RDT, microscopy, PCR, and BBA results confirmed differences in sensitivity and specificity that varied by endemicity, with PCR and BBA performing best for detecting any P. falciparum infection. Prevalence estimates varied widely depending on assay type for parasite detection. Inherent differences in assay performance should be carefully considered when using community survey and surveillance data to guide policy decisions.

Exploring Barriers and Facilitators of Adherence to Artemisinin-Based Combination Therapies for the Treatment of Uncomplicated Malaria in Children in Freetown, Sierra Leone.

Medication adherence is an essential step in the malaria treatment cascade. We conducted a qualitative study embedded within a randomized controlled trial comparing the adherence to the recommended dosing of two artemisinin-based combination therapies (ACT) to treat uncomplicated malaria in Freetown, Sierra Leone. This study explored the circumstances and factors that influenced caregiver adherence to the ACT prescribed for their child in the trial. In-depth interviews were conducted with 49 caregivers; all interviews were recorded, transcribed, and translated. Transcripts were coded and aggregated into themes, applying a thematic content approach. We identified four key factors that influenced optimal treatment adherence: (1) health system influences, (2) health services, (3) caregivers' experiences with malaria illness and treatment, and (4) medication characteristics. Specifically, caregivers reported confidence in the health system as facilities were well maintained and care was free. They also felt that health workers provided quality care, leading them to trust the health workers and believe the test results. Ease of medication administration and perceived risk of side effects coupled with caregivers' prior experience treating malaria influenced how medications were administered. To ensure ACTs achieve maximum effectiveness, consideration of these contextual factors and further development of child-friendly antimalarials are needed.

Evaluation of Interceptor long-lasting insecticidal nets in eight communities in Liberia.

BACKGROUND: By 2008, the WHO Pesticide Evaluation Scheme (WHOPES) recommended five long-lasting insecticidal nets (LLINs) for the prevention of malaria: Olyset((R)), PermaNet 2.0((R)), Netprotect((R)), Duranet((R)) and Interceptor((R)). Field information is available for both Olyset(R) and PermaNet((R)), with limited data on the newer LLINs. To address this gap, a field evaluation was carried out to determine the acceptability and durability of Interceptor((R)) LLINs. METHODS: A one-year prospective field study was conducted in eight rural returnee villages in Liberia. Households were randomized to receive Interceptor((R)) LLINs or conventionally treated nets (CTNs). Primary outcomes were levels of residual alpha-cypermethrin measured by HPLC and participant utilization/acceptability of the ITNs. RESULTS: A total of 398 nets were analysed for residual alpha-cypermethrin. The median baseline concentrations of insecticide were 175.5 mg/m2 for the Interceptor((R)) LLIN and 21.8 mg/m2 for the CTN. Chemical residue loss after a one year follow-up period was 22% and 93% respectively. Retention and utilization of nets remained high (94%) after one year, irrespective of type, while parasitaemia prevalence decreased from 29.7% at baseline to 13.6% during the follow up survey (p = < 0.001). Interview and survey data show perceived effectiveness of ITNs was just as important as other physical attributes in influencing net utilization. CONCLUSION: Interceptor((R)) LLINs are effective and desirable in rural communities in Liberia. Consideration for end user preferences should be incorporated into product development of all LLINs in the future, in order to achieve optimum retention and utilization.

Cross-border malaria control for internally displaced persons: observational results from a pilot programme in eastern Burma/Myanmar.

OBJECTIVES: To document the feasibility of a cross-border community based integrated malaria control programme implemented by internally displaced persons in eastern Burma/Myanmar. METHODS: This pilot study was conducted from February 2003 through January 2005 in seven villages of displaced ethnic Karen. Interventions comprised early diagnosis of Plasmodium falciparum and treatment with mefloquine and artesunate, distribution of long-lasting insecticide treated nets (LLITNs), and educational messages. The primary outcome measure was P. falciparum prevalence during bi-annual universal screenings with the Paracheck-Pf (Orchid Biomedical Systems, Goa, India) device. Secondary outcomes were P. falciparum incidence and process indicators related to net use and malaria knowledge, attitudes and practices (KAP). RESULTS: P. falciparum prevalence in original programme areas declined from 8.4% [95% confidence interval (CI) 8.3-8.6] at baseline to 1.1% (95% CI 1.1-1.2) in the final screening. Annual incidence in original areas declined from 232 to 70 cases/1000/year [incidence rate ratio 0.30 (95% CI 0.24-0.39)]. The proportion of household members sleeping under a LLITN improved from 0% to 89% and malaria KAP improved in all areas. CONCLUSIONS: Integrated malaria control organized and implemented by displaced persons is feasible in eastern Burma/Myanmar. The decline in P. falciparum prevalence and incidence suggest that it may be possible to reduce the burden of disease and the reservoir of malaria in eastern Burma/Myanmar, with implications for malaria control in the greater Mekong region.

Monitoring antimalarial safety and tolerability in clinical trials: a case study from Uganda.

BACKGROUND: New antimalarial regimens, including artemisinin-based combination therapies (ACTs), have been adopted widely as first-line treatment for uncomplicated malaria. Although these drugs appear to be safe and well-tolerated, experience with their use in Africa is limited and continued assessment of safety is a priority. However, no standardized guidelines for evaluating drug safety and tolerability in malaria studies exist. A system for monitoring adverse events in antimalarial trials conducted in Uganda was developed. Here the reporting system is described, and difficulties faced in analysing and interpreting the safety results are illustrated, using data from the trials. CASE DESCRIPTION: Between 2002 and 2007, eleven randomized, controlled clinical trials were conducted to compare the efficacy, safety, and tolerability of different antimalarial regimens for treatment of uncomplicated malaria in Uganda. The approach to adverse event monitoring was similar in all studies. A total of 5,614 treatments were evaluated in 4,876 patients. Differences in baseline characteristics and patterns of adverse event reporting were noted between the sites, which limited the ability to pool and analyse data. Clinical failure following antimalarial treatment confounded associations between treatment and adverse events that were also common symptoms of malaria, particularly in areas of lower transmission intensity. DISCUSSION AND EVALUATION: Despite prospectively evaluating for adverse events, limitations in the monitoring system were identified. New standardized guidelines for monitoring safety and tolerability in antimalarial trials are needed, which should address how to detect events of greatest importance, including serious events, those with a causal relationship to the treatment, those which impact on adherence, and events not previously reported. CONCLUSION: Although the World Health Organization has supported the development of pharmacovigilance systems in African countries deploying ACTs, additional guidance on adverse events monitoring in antimalarial clinical trials is needed, similar to the standardized recommendations available for assessment of drug efficacy.

Artemisinin versus nonartemisinin combination therapy for uncomplicated malaria: randomized clinical trials from four sites in Uganda.

BACKGROUND: Drug resistance in Plasmodium falciparum poses a major threat to malaria control. Combination antimalarial therapy including artemisinins has been advocated recently to improve efficacy and limit the spread of resistance, but artemisinins are expensive and relatively untested in highly endemic areas. We compared artemisinin-based and other combination therapies in four districts in Uganda with varying transmission intensity. METHODS AND FINDINGS: We enrolled 2,160 patients aged 6 mo or greater with uncomplicated falciparum malaria. Patients were randomized to receive chloroquine (CQ) + sulfadoxine-pyrimethamine (SP); amodiaquine (AQ) + SP; or AQ + artesunate (AS). Primary endpoints were the 28-d risks of parasitological failure either unadjusted or adjusted by genotyping to distinguish recrudescence from new infections. A total of 2,081 patients completed follow-up, of which 1,749 (84%) were under the age of 5 y. The risk of recrudescence after treatment with CQ + SP was high, ranging from 22% to 46% at the four sites. This risk was significantly lower (p < 0.01) after AQ + SP or AQ + AS (7%-18% and 4%-12%, respectively). Compared to AQ + SP, AQ + AS was associated with a lower risk of recrudescence but a higher risk of new infection. The overall risk of repeat therapy due to any recurrent infection (recrudescence or new infection) was similar at two sites and significantly higher for AQ + AS at the two highest transmission sites (risk differences = 15% and 16%, p < 0.003). CONCLUSION: AQ + AS was the most efficacious regimen for preventing recrudescence, but this benefit was outweighed by an increased risk of new infection. Considering all recurrent infections, the efficacy of AQ + SP was at least as efficacious at all sites and superior to AQ + AS at the highest transmission sites. The high endemicity of malaria in Africa may impact on the efficacy of artemisinin-based combination therapy. The registration number for this trial is ISRCTN67520427 (http://www.controlled-trials.com/isrctn/trial/|/0/67520427.html).

Sulfadoxine-pyrimethamine plus chloroquine or amodiaquine for uncomplicated falciparum malaria: a randomized, multisite trial to guide national policy in Uganda.

The use of combinations of inexpensive drugs for the treatment of malaria in Africa has been proposed as an interim policy while awaiting the widespread availability of more effective regimens. We compared sulfadoxine-pyrimethamine plus chloroquine or amodiaquine in three districts in Uganda. Patients aged 6 months or greater with uncomplicated falciparum malaria were enrolled and randomized to therapy. Safety, tolerability, and efficacy outcomes, adjusted by genotyping, were assessed over 28 days. Of 1,105 patients enrolled, 1,057 (96%) completed follow-up. For children less than 5 years old, the risk of clinical treatment failure adjusted by genotyping at the three sites ranged from 34% to 67% with chloroquine plus sulfadoxine-pyrimethamine and from 13% to 35% with amodiaquine plus sulfadoxine-pyrimethamine (risk differences 21-32%, P < 0.0001 at all sites). Serious adverse events were uncommon with both regimens. The risk of treatment failure with chloroquine plus sulfadoxine-pyrimethamine, the current standard in Uganda, was unacceptably high. Amodiaquine plus sulfadoxine-pyrimethamine was significantly more efficacious; however, existing levels of resistance raises concern about the useful therapeutic life-span of this regimen.

Community case management of malaria: exploring support, capacity and motivation of community medicine distributors in Uganda.

BACKGROUND: In Uganda, community services for febrile children are expanding from presumptive treatment of fever with anti-malarials through the home-based management of fever (HBMF) programme, to include treatment for malaria, diarrhoea and pneumonia through Integrated Community Case Management (ICCM). To understand the level of support available, and the capacity and motivation of community health workers to deliver these expanded services, we interviewed community medicine distributors (CMDs), who had been involved in the HBMF programme in Tororo district, shortly before ICCM was adopted. METHODS: Between October 2009 and April 2010, 100 CMDs were recruited to participate by convenience sampling. The survey included questionnaires to gather information about the CMDs' work experience and to assess knowledge of fever case management, and in-depth interviews to discuss experiences as CMDs including motivation, supervision and relationships with the community. All questionnaires and knowledge assessments were analysed. Summary contact sheets were made for each of the 100 interviews and 35 were chosen for full transcription and analysis. RESULTS: CMDs faced multiple challenges including high patient load, limited knowledge and supervision, lack of compensation, limited drugs and supplies, and unrealistic expectations of community members. CMDs described being motivated to volunteer for altruistic reasons; however, the main benefits of their work appeared related to 'becoming someone important', with the potential for social mobility for self and family, including building relationships with health workers. At the time of the survey, over half of CMDs felt demotivated due to limited support from communities and the health system. CONCLUSIONS: Community health worker programmes rely on the support of communities and health systems to operate sustainably. When this support falls short, motivation of volunteers can wane. If community interventions, in increasingly complex forms, are to become the solution to improving access to primary health care, greater attention to what motivates individuals, and ways to strengthen health system support are required.

Prevalence of Plasmodium falciparum in active conflict areas of eastern Burma: a summary of cross-sectional data.

BACKGROUND: Burma records the highest number of malaria deaths in southeast Asia and may represent a reservoir of infection for its neighbors, but the burden of disease and magnitude of transmission among border populations of Burma remains unknown. METHODS: Plasmodium falciparum (Pf) parasitemia was detected using a HRP-II antigen based rapid test (Paracheck-Pf(R)). Pf prevalence was estimated from screenings conducted in 49 villages participating in a malaria control program, and four retrospective mortality cluster surveys encompassing a sampling frame of more than 220,000. Crude odds ratios were calculated to evaluate Pf prevalence by age, sex, and dry vs. rainy season. RESULTS: 9,796 rapid tests were performed among 28,410 villagers in malaria program areas through four years (2003: 8.4%, 95% CI: 8.3 - 8.6; 2004: 7.1%, 95% CI: 6.9 - 7.3; 2005:10.5%, 95% CI: 9.3 - 11.8 and 2006: 9.3%, 95% CI: 8.2 - 10.6). Children under 5 (OR = 1.99; 95% CI: 1.93 - 2.06) and those 5 to 14 years (OR = 2.24, 95% CI: 2.18 - 2.29) were more likely to be positive than adults. Prevalence was slightly higher among females (OR = 1.04, 95% CI: 1.02 - 1.06) and in the rainy season (OR = 1.48, 95% CI: 1.16 - 1.88). Among 5,538 rapid tests conducted in four cluster surveys, 10.2% were positive (range 6.3%, 95% CI: 3.9 - 8.8; to 12.4%, 95% CI: 9.4 - 15.4). CONCLUSION: Prevalence of plasmodium falciparum in conflict areas of eastern Burma is higher than rates reported among populations in neighboring Thailand, particularly among children. This population serves as a large reservoir of infection that contributes to a high disease burden within Burma and likely constitutes a source of infection for neighboring regions.

Artemisinin combination therapies for treatment of uncomplicated malaria in Uganda.

OBJECTIVES: To compare the efficacy and safety of artemisinin combination therapies for the treatment of uncomplicated falciparum malaria in Uganda. DESIGN: Randomized single-blind controlled trial. SETTING: Tororo, Uganda, an area of high-level malaria transmission. PARTICIPANTS: Children aged one to ten years with confirmed uncomplicated P. falciparum malaria. INTERVENTIONS: Amodiaquine + artesunate or artemether-lumefantrine. OUTCOME MEASURES: Risks of recurrent symptomatic malaria and recurrent parasitemia at 28 days, unadjusted and adjusted by genotyping to distinguish recrudescences and new infections. RESULTS: Of 408 participants enrolled, 403 with unadjusted efficacy outcomes were included in the per-protocol analysis. Both treatment regimens were highly efficacious; no recrudescences occurred in patients treated with amodiaquine + artesunate, and only two occurred in those treated with artemether-lumefantrine. However, recurrent malaria due to new infections was common. The unadjusted risk of recurrent symptomatic malaria was significantly lower for participants treated with artemether-lumefantrine than for those treated with amodiaquine + artesunate (27% versus 42%, risk difference 15%, 95% CI 5.9%-24.2%). Similar results were seen for the risk of recurrent parasitemia (51% artemether-lumefantrine versus 66% amodiaquine + artesunate, risk difference 16%, 95% CI 6.2%-25.2%). Amodiaquine + artesunate and artemether-lumefantrine were both well-tolerated. Serious adverse events were uncommon with both regimens. CONCLUSIONS: Amodiaquine + artesunate and artemether-lumefantrine were both highly efficacious for treatment of uncomplicated malaria. However, in this holoendemic area, despite the excellent performance of both regimens in terms of efficacy, many patients experienced recurrent parasitemia due to new infections. Artemether-lumefantrine was superior to amodiaquine + artesunate for prevention of new infections. To maximize the benefit of artemisinin combination therapy in Africa, treatment should be integrated with strategies to prevent malaria transmission. The impact of frequent repeated therapy on the efficacy, safety, and cost-effectiveness of new artemisinin regimens should be further investigated.