Viewpoint: Evaluating the impact of malaria control efforts on mortality in sub-Saharan Africa

OBJECTIVE To describe an approach for evaluating the impact of malaria control efforts on malaria-associated mortality in sub-Saharan Africa, where disease-specific mortality trends usually cannot be measured directly and most malaria deaths occur among young children. METHODS Methods for evaluating changes in malaria-associated mortality are examined; advantages and disadvantages are presented. RESULTS All methods require a plausibility argument - i.e., an assumption that mortality reductions can be attributed to programmatic efforts if improvements are found in steps of the causal pathway between intervention scale-up and mortality trends. As different methods provide complementary information, they can be used together. We recommend following trends in the coverage of malaria control interventions, other factors influencing childhood mortality, malaria-associated morbidity (especially anaemia), and all-cause childhood mortality. This approach reflects decreases in malaria's direct and indirect mortality burden and can be examined in nearly all countries. Adding other information can strengthen the plausibility argument: trends in indicators of malaria transmission, information from demographic surveillance systems and sentinel sites where malaria diagnostics are systematically used, and verbal autopsies linked to representative household surveys. Health facility data on malaria deaths have well-recognized limitations; however, in specific circumstances, they could produce reliable trends. Model-based predictions can help describe changes in malaria-specific burden and assist with program management and advocacy. CONCLUSIONS Despite challenges, efforts to reduce malaria-associated mortality in Africa can be evaluated with trends in malaria intervention coverage and all-cause childhood mortality. Where there are resources and interest, complementary data on malaria morbidity and malaria-specific mortality could be added

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

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

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)

Different methodological approaches to the assessment of in vivo efficacy of three artemisinin-based combination antimalarial treatments for the treatment of uncomplicated falciparum malaria in African children.

BACKGROUND: Use of different methods for assessing the efficacy of artemisinin-based combination antimalarial treatments (ACTs) will result in different estimates being reported, with implications for changes in treatment policy. METHODS: Data from different in vivo studies of ACT treatment of uncomplicated falciparum malaria were combined in a single database. Efficacy at day 28 corrected by PCR genotyping was estimated using four methods. In the first two methods, failure rates were calculated as proportions with either (1a) reinfections excluded from the analysis (standard WHO per-protocol analysis) or (1b) reinfections considered as treatment successes. In the second two methods, failure rates were estimated using the Kaplan-Meier product limit formula using either (2a) WHO (2001) definitions of failure, or (2b) failure defined using parasitological criteria only. RESULTS: Data analysed represented 2926 patients from 17 studies in nine African countries. Three ACTs were studied: artesunate-amodiaquine (AS+AQ, N = 1702), artesunate-sulphadoxine-pyrimethamine (AS+SP, N = 706) and artemether-lumefantrine (AL, N = 518).Using method (1a), the day 28 failure rates ranged from 0% to 39.3% for AS+AQ treatment, from 1.0% to 33.3% for AS+SP treatment and from 0% to 3.3% for AL treatment. The median [range] difference in point estimates between method 1a (reference) and the others were: (i) method 1b = 1.3% [0 to 24.8], (ii) method 2a = 1.1% [0 to 21.5], and (iii) method 2b = 0% [-38 to 19.3].The standard per-protocol method (1a) tended to overestimate the risk of failure when compared to alternative methods using the same endpoint definitions (methods 1b and 2a). It either overestimated or underestimated the risk when endpoints based on parasitological rather than clinical criteria were applied. The standard method was also associated with a 34% reduction in the number of patients evaluated compared to the number of patients enrolled. Only 2% of the sample size was lost when failures were classified on the first day of parasite recurrence and survival analytical methods were used. CONCLUSION: The primary purpose of an in vivo study should be to provide a precise estimate of the risk of antimalarial treatment failure due to drug resistance. Use of survival analysis is the most appropriate way to estimate failure rates with parasitological recurrence classified as treatment failure on the day it occurs

Artemisinin-based combinations versus amodiaquine plus sulphadoxine-pyrimethamine for the treatment of uncomplicated malaria in Faladje, Mali

<p>Abstract</p> <p>Background</p> <p>Because of the emergence of chloroquine resistance in Mali, artemether-lumefantrine (AL) or artesunate-amodiaquine (AS+AQ) are recommended as first-line therapy for uncomplicated malaria, but have not been available in Mali until recently because of high costs.</p> <p>Methods</p> <p>From July 2005 to January 2006, a randomized open-label trial of three oral antimalarial combinations, namely AS+AQ, artesunate plus sulphadoxine-pyrimethamine (AS+SP), and amodiaquine plus sulphadoxine-pyrimethamine (AQ+SP), was conducted in Faladje, Mali. Parasite genotyping by polymerase chain reaction (PCR) was used to distinguish new from recrudescent <it>Plasmodium falciparum </it>infections.</p> <p>Results</p> <p>397 children 6 to 59 months of age with uncomplicated <it>Plasmodium falciparum </it>malaria were enrolled, and followed for 28 days to assess treatment efficacy. Baseline characteristics were similar in all three treatment groups. The uncorrected rates of adequate clinical and parasitologic response (ACPR) were 55.7%, 90.8%, and 97.7% in AS+AQ, AS+SP, and AQ+SP respectively (p < 0.001); after PCR correction ACPR rates were similar among treatment groups: 95.4%, 96.9%, and 99.2% respectively (p = 0.17). Mean haemoglobin concentration increased across all treatment groups from Day 0 (9.82 ± 1.68 g/dL) to Day 28 (10.78 ± 1.49 g/dL) (p < 0.001), with the greatest improvement occurring in children treated with AQ+SP. On Day 2, the prevalence of parasitaemia was significantly greater among children treated with AQ+SP (50.8%) than in children treated with AS+AQ (10.5%) or AS+SP (10.8%) (p < 0.001). No significant difference in gametocyte carriage was found between groups during the follow-up period.</p> <p>Conclusion</p> <p>The combination of AQ+SP provides a potentially low cost alternative for treatment of uncomplicated <it>P. falciparum </it>infection in Mali and appears to have the added value of longer protective effect against new infection.</p

Malaria case-management under artemether-lumefantrine treatment policy in Uganda

<p>Abstract</p> <p>Background</p> <p>Case-management with artemether-lumefantrine (AL) is one of the key strategies to control malaria in many African countries. Yet, the reports on translation of AL implementation activities into clinical practice are scarce. Here the quality of AL case-management is reported from Uganda; approximately one year after AL replaced combination of chloroquine and sulphadoxine-pyrimethamine (CQ+SP) as recommended first line treatment for uncomplicated malaria.</p> <p>Methods</p> <p>A cross-sectional survey, using a range of quality of care assessment tools, was undertaken at all government and private-not-for-profit facilities in four Ugandan districts. Main outcome measures were AL prescribing, dispensing and counseling practices in comparison with national guidelines, and factors influencing health workers decision to 1) treat for malaria, and 2) prescribe AL.</p> <p>Results</p> <p>195 facilities, 232 health workers and 1,763 outpatient consultations were evaluated. Of 1,200 patients who needed treatment with AL according to guidelines, AL was prescribed for 60%, CQ+SP for 14%, quinine for 4%, CQ for 3%, other antimalarials for 3%, and 16% of patients had no antimalarial drug prescribed. AL was prescribed in the correct dose for 95% of patients. Only three out of seven AL counseling and dispensing tasks were performed for more than 50% of patients. Patients were more likely to be treated for malaria if they presented with main complaint of fever (OR = 5.22; 95% CI: 3.61–7.54) and if they were seen by supervised health workers (OR = 1.63; 95% CI: 1.06–2.50); however less likely if they were treated by more qualified health workers (OR = 0.61; 95% CI: 0.40–0.93) and presented with skin problem (OR = 0.29; 95% CI: 0.15–0.55). AL was more likely prescribed if the appropriate weight-specific AL pack was in stock (OR = 6.15; 95% CI: 3.43–11.05) and when CQ was absent (OR = 2.16; 95% CI: 1.09–4.28). Routine AL implementation activities were not associated with better performance.</p> <p>Conclusion</p> <p>Although the use of AL was predominant over non-recommended therapies, the quality of AL case-management at the point of care is not yet optimal. There is an urgent need for innovative quality improvement interventions, which should be rigorously tested. Adequate availability of ACTs at the point of care will, however, ultimately determine the success of any performance interventions and ACT policy transitions.</p

New Antenatal Model in Africa and India (NAMAI) study: implementation research to improve antenatal care using WHO recommendations

Background: In 2020, an estimated 287 000 women died globally from pregnancy‐related causes and 2 million babies were stillborn. Many of these outcomes can be prevented by quality healthcare during pregnancy and childbirth. Within the continuum of maternal health, antenatal care (ANC) is a key moment in terms of contact with the health system, yet it remains an underutilized platform. This paper describes the protocol for a study conducted in collaboration with Ministries of Health and country research partners that aims to employ implementation science to systematically introduce and test the applicability of the adapted WHO ANC package in selected sites across four countries. Methods: Study design is a mixed methods stepped-wedge cluster randomized implementation trial with a nested cohort component (in India and Burkina Faso). The intervention is composed of two layers: (i) the country- (or state)-specific ANC package, including evidence-based interventions to improve maternal and newborn health outcomes, and (ii) the co-interventions (or implementation strategies) to help delivery and uptake of the adapted ANC package. Using COM-B model, co-interventions support behaviour change among health workers and pregnant women by (1) training health workers on the adapted ANC package and ultrasound (except in India), (2) providing supplies, (3) conducting mentoring and supervision and (4) implementing community mobilization strategies. In Rwanda and Zambia, a fifth strategy includes a digital health intervention. Qualitative data will be gathered from health workers, women and their families, to gauge acceptability of the adapted ANC package and its components, as well as experience of care. The implementation of the adapted ANC package of interventions, and their related costs, will be documented to understand to what extent the co-interventions were performed as intended, allowing for iteration. Discussion: Results from this study aim to build the global evidence base on how to implement quality ANC across different settings and inform pathways to scale, which will ultimately lead to stronger health systems with better maternal and perinatal outcomes. On the basis of the study results, governments will be able to adopt and plan for national scale-up, aiming to improve ANC nationally. This evidence will inform global guidance. Trial registration number: ISRCTN, ISRCTN16610902. Registered 27 May 2022. https://www.isrctn.com/ISRCTN16610902

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

Increasing malaria hospital admissions in Uganda between 1999 and 2009

<p>Abstract</p> <p>Background</p> <p>Some areas of Africa are witnessing a malaria transition, in part due to escalated international donor support and intervention coverage. Areas where declining malaria rates have been observed are largely characterized by relatively low baseline transmission intensity and rapid scaling of interventions. Less well described are changing patterns of malaria burden in areas of high parasite transmission and slower increases in control and treatment access.</p> <p>Methods</p> <p>Uganda is a country predominantly characterized by intense, perennial malaria transmission. Monthly pediatric admission data from five Ugandan hospitals and their catchments have been assembled retrospectively across 11 years from January 1999 to December 2009. Malaria admission rates adjusted for changes in population density within defined catchment areas were computed across three time periods that correspond to periods where intervention coverage data exist and different treatment and prevention policies were operational. Time series models were developed adjusting for variations in rainfall and hospital use to examine changes in malaria hospitalization over 132 months. The temporal changes in factors that might explain changes in disease incidence were qualitatively examined sequentially for each hospital setting and compared between hospital settings</p> <p>Results</p> <p>In four out of five sites there was a significant increase in malaria admission rates. Results from time series models indicate a significant month-to-month increase in the mean malaria admission rates at four hospitals (trend <it>P </it>< 0.001). At all hospitals malaria admissions had increased from 1999 by 47% to 350%. Observed changes in intervention coverage within the catchments of each hospital showed a change in insecticide-treated net coverage from <1% in 2000 to 33% by 2009 but accompanied by increases in access to nationally recommended drugs at only two of the five hospital areas studied.</p> <p>Conclusions</p> <p>The declining malaria disease burden in some parts of Africa is not a universal phenomena across the continent. Despite moderate increases in the coverage of measures to reduce infection and disease without significant coincidental increasing access to effective medicines to treat disease may not lead to severe disease burden reductions in high transmission areas of Africa. More data is needed from a wider range of malaria settings to provide an honest tracking progress of the impact of scaled intervention coverage in Africa.</p