Episodes Of Uncomplicated Malaria Research Articles

Artemether-lumefantrine efficacy among adults on antiretroviral therapy in Malawi

BackgroundWhen people with human immunodeficiency virus (HIV) infection (PWH) develop malaria, they are at risk of poor anti-malarial treatment efficacy resulting from impairment in the immune response and/or drug-drug interactions that alter anti-malarial metabolism. The therapeutic efficacy of artemether-lumefantrine was evaluated in a cohort of PWH on antiretroviral therapy (ART) and included measurement of day 7 lumefantrine levels in a subset to evaluate for associations between lumefantrine exposure and treatment response.MethodsAdults living with HIV (≥ 18 years), on ART for ≥ 6 months with undetectable HIV RNA viral load and CD4 count ≥ 250/mm3 were randomized to daily trimethoprim-sulfamethoxazole (TS), weekly chloroquine (CQ) or no prophylaxis. After diagnosis of uncomplicated Plasmodium falciparum malaria, a therapeutic efficacy monitoring was conducted with PCR-correction according to WHO guidelines. The plasma lumefantrine levels on day 7 in 100 episodes of uncomplicated malaria was measured. A frailty proportional hazards model with random effects models to account for clustering examined the relationship between participant characteristics and malaria treatment failure within 28 days. Pearson’s Chi—squared test was used to compare lumefantrine concentrations among patients with treatment failure and adequate clinical and parasitological response (ACPR).Results411 malaria episodes were observed among 186 participants over 5 years. The unadjusted ACPR rate was 81% (95% CI 77–86). However, after PCR correction to exclude new infections, ACPR rate was 94% (95% CI 92–97). Increasing age and living in Ndirande were associated with decreased hazard of treatment failure. In this population of adults with HIV on ART, 54% (51/94) had levels below a previously defined optimal day 7 lumefantrine level of 200 ng/ml. This occurred more commonly among participants who were receiving an efavirenz-based ART compared to other ART regimens (OR 5.09 [95% CI 1.52–7.9]). Participants who experienced treatment failure had lower day 7 median lumefantrine levels (91 ng/ml [95% CI 48–231]) than participants who experienced ACPR (190 ng/ml [95% CI 101–378], p-value < 0.008).ConclusionRecurrent malaria infections are frequent in this population of PWH on ART. The PCR-adjusted efficacy of AL meets the WHO criteria for acceptable treatment efficacy. Nevertheless, lumefantrine levels tend to be low in this population, particularly in those on efavirenz-based regimens, with lower concentrations associated with more frequent malaria infections following treatment. These results highlight the importance of understanding drug-drug interactions when diseases commonly co-occur.

Economic Burdens of Uncomplicated Malaria in Primary Health Care (PHC) Facilities of Plateau State, Nigeria: Patients' Perspectives.

This study aims at evaluating the costs incurred by patients in Primary Healthcare facilities of Plateau State, Nigeria, due to uncomplicated malaria management. Patients' information on resources used and absence from the labour market due to uncomplicated malaria illness were collected using the self-reported cost of illness instruments across 24 selected Primary Health Care (PHC) facilities in Plateau State. The collated data were used to estimate the direct medical and non-medical costs incurred by patients through the summation of the various costs paid out of pocket for the services; while the indirect cost was estimated using the human capital theory. All analyses were conducted through Microsoft Excel and IBM Statistical Package for Social Sciences (SPSS®) version 23 software. The average direct cost per episode of uncomplicated malaria was estimated at NGN 2808.37/USD 7.39, while the indirect average money equivalence of the time lost due to the ailment was estimated at NGN 2717/USD 7.55, giving an average cost of treating uncomplicated malaria borne by patients in Plateau State per episode to be NGN 5525.37/USD 14.94. The projected annual cost of the disease was NGN 9, 921,671,307.22 (USD 27, 560,198.08). The study showed substantial financial costs borne by patients due to uncomplicated malaria in Plateau State, comprising 50.83% of direct cost and 49.17% of the indirect cost of medications.

House design and risk of malaria, acute respiratory infection and gastrointestinal illness in Uganda: A cohort study.

House construction is rapidly modernizing across Africa but the potential benefits for human health are poorly understood. We hypothesised that improvements to housing would be associated with reductions in malaria, acute respiratory infection (ARI) and gastrointestinal illness in an area of low malaria endemicity in Uganda. Data were analysed from a cohort study of male and female child and adult residents (n = 531) of 80 randomly-selected households in Nagongera sub-county, followed for 24 months (October 4, 2017 to October 31, 2019). Houses were classified as modern (brick walls, metal roof and closed eaves) or traditional (all other homes). Light trap collections of mosquitoes were done every two weeks in all sleeping rooms. Every four weeks, we measured malaria infection (using microscopy and qPCR to detect malaria parasites), incidence of malaria, ARI and gastrointestinal illness. We collected 15,780 adult female Anopheles over 7,631 nights. We collected 13,277 blood samples of which 10.2% (1,347) were positive for malaria parasites. Over 958 person years we diagnosed 38 episodes of uncomplicated malaria (incidence 0.04 episodes per person-year at risk), 2,553 episodes of ARI (incidence 2.7 episodes per person-year) and 387 episodes of gastrointestinal illness (incidence 0.4 episodes per person-year). Modern houses were associated with a 53% lower human biting rate compared to traditional houses (adjusted incidence rate ratio [aIRR] 0.47, 95% confidence interval [CI] 0.32-0.67, p<0.001) and a 24% lower incidence of gastrointestinal illness (aIRR 0.76, 95% CI 0.59-0.98, p = 0.04) but no changes in malaria prevalence, malaria incidence nor ARI incidence. House improvements may reduce mosquito-biting rates and gastrointestinal illness among children and adults. For the health sector to leverage Africa's housing modernization, research is urgently needed to identify the healthiest house designs and to assess their effectiveness across a range of epidemiological settings in sub-Saharan Africa.

Hepatic safety of repeated treatment with pyronaridine\u2010artesunate versus artemether\u2013lumefantrine in patients with uncomplicated malaria: a secondary analysis of the WANECAM 1 data from Bobo-Dioulasso, Burkina Faso

BackgroundThe use of pyronaridine-artesunate (PA) has been associated with scarce transaminitis in patients. This analysis aimed to evaluate the hepatic safety profile of repeated treatment with PA versus artemether–lumefantrine (AL) in patients with consecutive uncomplicated malaria episodes in Bobo-Dioulasso, Burkina Faso.MethodsThis study analysed data from a clinical trial conducted from 2012 to 2015, in which participants with uncomplicated malaria were assigned to either PA or AL arms and followed up to 42 days. Subsequent malaria episodes within a 2-years follow up period were also treated with the same ACT initially allocated. Transaminases (AST/ALT), alkaline phosphatase (ALP), total and direct bilirubin were measured at days 0 (baseline), 3, 7, 28 and on some unscheduled days if required. The proportions of non-clinical hepatic adverse events (AEs) following first and repeated treatments with PA and AL were compared within study arms. The association of these AEs with retreatment in each arm was also determined using a logistic regression model.ResultsA total of 1379 malaria episodes were included in the intention to treat analysis with 60% of all cases occurring in the AL arm. Overall, 179 non-clinical hepatic AEs were recorded in the AL arm versus 145 in the PA arm. Elevated ALT was noted in 3.05% of treated malaria episodes, elevated AST 3.34%, elevated ALP 1.81%, and elevated total and direct bilirubin in 7.90% and 7.40% respectively. Retreated participants were less likely to experience elevated ALT and AST than first episode treated participants in both arms. One case of Hy’s law condition was recorded in a first treated participant of the PA arm. Participants from the retreatment group were 76% and 84% less likely to have elevated ALT and AST, respectively, in the AL arm and 68% less likely to present elevated ALT in the PA arm. In contrast, they were almost 2 times more likely to experience elevated total bilirubin in both arms.ConclusionsPyronaridine-artesunate and artemether–lumefantrine showed similar hepatic safety when used repeatedly in participants with uncomplicated malaria. Pyronaridine-artesunate represents therefore a suitable alternative to the current first line anti-malarial drugs in use in endemic areas.Trial registration Pan African Clinical Trials Registry. PACTR201105000286876

Efficacy and risk of harms of repeat ivermectin mass drug administrations for control of malaria (RIMDAMAL): a cluster-randomised trial

SummaryBackgroundIvermectin is widely used in mass drug administrations for controlling neglected parasitic diseases, and can be lethal to malaria vectors that bite treated humans. Therefore, it could be a new tool to reduce plasmodium transmission. We tested the hypothesis that frequently repeated mass administrations of ivermectin to village residents would reduce clinical malaria episodes in children and would be well tolerated with minimal harms.MethodsWe invited villages (clusters) in Burkina Faso to participate in a single-blind (outcomes assessor), parallel-assignment, two-arm, cluster-randomised trial over the 2015 rainy season. Villages were assigned (1:1) by random draw to either the intervention group or the control group. In both groups, all eligible participants who consented to the treatment and were at least 90 cm in height received single oral doses of ivermectin (150–200 μg/kg) and albendazole (400 mg), and those in the intervention group received five further doses of ivermectin alone at 3-week intervals thereafter over the 18-week treatment phase. The primary outcome was cumulative incidence of uncomplicated malaria episodes over 18 weeks (analysed on a cluster intention-to-treat basis) in an active case detection cohort of children aged 5 years or younger living in the study villages. This trial is registered with ClinicalTrials.gov, number NCT02509481.FindingsEight villages agreed to participate, and four were randomly assigned to each group. 2712 participants (1333 [49%] males and 1379 [51%] females; median age 15 years [IQR 6–34]), including 590 children aged 5 years or younger, provided consent and were enrolled between May 22 and July 20, 2015 (except for 77 participants enrolled after these dates because of unavailability before the first mass drug administration, travel into the village during the trial, or birth), with 1447 enrolled into the intervention group and 1265 into the control group. 330 (23%) participants in the intervention group and 233 (18%) in the control group met the exclusion criteria for mass drug administration. Most children in the active case detection cohort were not treated because of height restrictions. 14 (4%) children in the intervention group and 10 (4%) in the control group were lost to follow-up. Cumulative malaria incidence was reduced in the intervention group (648 episodes among 327 children; estimated mean 2·00 episodes per child) compared with the control group (647 episodes among 263 children; 2·49 episodes per child; risk difference −0·49 [95% CI −0·79 to −0·21], p=0·0009, adjusted for sex and clustering). The risk of adverse events among all participants did not differ between groups (45 events [3%] among 1447 participants in the intervention group vs 24 events [2%] among 1265 in the control group; risk ratio 1·63 [1·01 to 2·67]; risk difference 1·21 [0·04 to 2·38], p=0·060), and no adverse reactions were reported.InterpretationFrequently repeated mass administrations of ivermectin during the malaria transmission season can reduce malaria episodes among children without significantly increasing harms in the populace.FundingBill & Melinda Gates Foundation.

\u201cI feel so bad but have nothing to do.\u201d Exploring Ugandan caregivers\u2019 experiences of parenting a child with severe malaria and subsequent repeated uncomplicated malaria

BackgroundSevere malaria in children is often associated with long-term behavioural and cognitive problems. A sizeable minority of children go on to experience repeated malaria due to the high transmission and infection rates in the region. The purpose of this study was to explore caregivers’ experiences of parenting a child with a history of severe malaria followed by repeated episodes of uncomplicated malaria in comparison to healthy community children.MethodsThirty-one caregivers were enrolled in the study. These included caregivers of children previously exposed to severe malaria and who had experienced repeated uncomplicated malaria attacks (SM with RMA, n = 15), caregivers of children exposed to severe malaria who did not experience repeated episodes (SM, n = 10), and caregivers of healthy community children (CC, n = 6) were purposively selected.ResultsThematic-content analysis generated eight areas of concern, six of which were noted only by caregivers of children with SM or SM with RMA: (1) a sense of helplessness; (2) challenges with changes in behaviour; (3) responses to a child’s behaviour; (4) family life disruptions, including breakdown of relationships and inadequate male-spouse involvement in child care; (5) disagreements in seeking healthcare; (6) societal burden; and two by caregivers of children with SM, SM with RMA and also CC; (7) concern about academic achievement; and, (8) balancing work and family life.ConclusionsThe study findings suggest that severe malaria, especially when followed by repeated malaria episodes, affects not only children who have the illness but also their caregivers. The effects on caregivers can decrease their social functioning and isolate them from other parents and may disrupt families. Interventions to support caregivers by counselling the ongoing problems that might be expected in children who have had severe malaria and repeated episodes of malaria, and how to manage these problems, may provide a way to improve behavioural and mental health outcomes for those children and their caregivers.

Pyronaridine–artesunate or dihydroartemisinin–piperaquine versus current first-line therapies for repeated treatment of uncomplicated malaria: a randomised, multicentre, open-label, longitudinal, controlled, phase 3b/4 trial

SummaryBackgroundArtemether–lumefantrine and artesunate–amodiaquine are used as first-line artemisinin-based combination therapies (ACTs) in west Africa. Pyronaridine–artesunate and dihydroartemisinin–piperaquine are potentially useful for diversification of ACTs in this region, but further safety and efficacy data are required on malaria retreatment.MethodsWe did a randomised, multicentre, open-label, longitudinal, controlled phase 3b/4 clinical trial at seven tertiary centres in Burkina Faso, Guinea, and Mali. Eligible participants for first malaria episode and all retreatment episodes were adults and children aged 6 months and older with microscopically confirmed Plasmodium spp malaria (>0 to <200 000 parasites per μL of blood) and fever or history of fever in the previous 24 h. Individuals with severe or complicated malaria, an alanine aminotransferase concentration of more than twice the upper limit of normal, or a QTc greater than 450 ms were excluded. Using a randomisation list for each site, masked using sealed envelopes, participants were assigned to either pyronaridine–artesunate or dihydroartemisinin–piperaquine versus either artesunate–amodiaquine or artemether–lumefantrine. Block sizes were two or four if two treatments were allocated, and three or six if three treatments were allocated. Microscopists doing the parasitological assessments were masked to treatment allocation. All treatments were once-daily or twice-daily tablets or granules given orally and dosed by bodyweight over 3 days at the study centre. Patients were followed up as outpatients up to day 42, receiving clinical assessments on days 0, 1, 2, 3, 7, 14, 21, 28, 35, and 42. Two primary outcomes were compared for non-inferiority: the 2-year incidence rate of all microscopically confirmed, complicated and uncomplicated malaria episodes in patients in the intention-to-treat population (ITT; non-inferiority margin 20%); and adequate clinical and parasitological response (ACPR) in uncomplicated malaria across all episodes (unadjusted and PCR-adjusted for Plasmodium falciparum and unadjusted for other Plasmodium spp) in the per-protocol population on days 28 and 42 (non-inferiority margin 5%). Safety was assessed in all participants who received one dose of study drug. This study is registered at the Pan African Clinical Trials Registry (PACTR201105000286876).FindingsBetween Oct 24, 2011, and Feb 1, 2016, we assigned 4710 eligible participants to the different treatment strategies: 1342 to pyronaridine–artesunate, 967 to artemether–lumefantrine, 1061 to artesunate–amodiaquine, and 1340 to dihydroartemisinin–piperaquine. The 2-year malaria incidence rate in the ITT population was non-inferior for pyronaridine–artesunate versus artemether–lumefantrine (1·77, 95% CI 1·63–1·93 vs 1·87, 1·72–2·03; rate ratio [RR] 1·05, 95% CI 0·94–1·17); and versus artesunate–amodiaquine (1·39, 95% CI 1·22–1·59 vs 1·35, 1·18–1·54; RR 0·97, 0·87–1·07). Similarly, this endpoint was non-inferior for dihydroartemisinin–piperaquine versus artemether–lumefantrine (1·16, 95% CI 1·01–1·34 vs 1·42 1·25–1·62; RR 1·22, 95% CI 1·06–1·41) and versus artesunate–amodiaquine (1·35, 1·21–1·51 vs 1·68, 1·51–1·88; RR 1·25, 1·02–1·50). For uncomplicated P falciparum malaria, PCR-adjusted ACPR was greater than 99·5% at day 28 and greater than 98·6% at day 42 for all ACTs; unadjusted ACPR was higher for pyronaridine–artesunate versus comparators at day 28 (96·9% vs 82·3% for artemether–lumefantrine and 95·6% vs 89·0% for artesunate–amodiaquine) and for dihydroartemisinin-piperaquine versus comparators (99·5% vs 81·6% for artemether–lumefantrine and 99·0% vs 89·0% for artesunate–amodiaquine). For non-falciparum species, unadjusted ACPR was greater than 98% for all study drugs at day 28 and at day 42 was greater than 83% except for artemether–lumefantrine against Plasmodium ovale (in ten [62·5%] of 16 patients) and against Plasmodium malariae (in nine [75·0%] of 12 patients). Nine deaths occurred during the study, none of which were related to the study treatment. Mostly mild transient elevations in transaminases occurred with pyronaridine–artesunate versus comparators, and mild QTcF prolongation with dihydroartemisinin-piperaquine versus comparators.InterpretationPyronaridine–artesunate and dihydroartemisinin–piperaquine treatment and retreatment of malaria were well tolerated with efficacy that was non-inferior to first-line ACTs. Greater access to these efficacious treatments in west Africa is justified.FundingThe European and Developing Countries Clinical Trial Partnership, Medicines for Malaria Venture (Geneva, Switzerland), the UK Medical Research Council, the Swedish International Development Cooperation Agency, German Ministry for Education and Research, University Claude Bernard (Lyon, France), University of Science, Techniques and Technologies of Bamako (Bamako, Mali), the Centre National de Recherche et de Formation sur le Paludisme (Burkina Faso), Institut de Recherche en Sciences de la Santé (Bobo-Dioulasso, Burkina Faso), and Centre National de Formation et de Recherche en Santé Rurale (Republic of Guinea).

High Sporozoite Antibody Titers in Conjunction with Microscopically Detectable Blood Infection Display Signatures of Protection from Clinical Malaria.

Immunoepidemiological studies typically reveal slow, age-dependent acquisition of immune responses against Plasmodium falciparum sporozoites. Naturally acquired immunity against preerythrocytic stages is considered inadequate to confer protection against clinical malaria. To explore previously unrecognized antisporozoite responses, we measured serum levels of naturally acquired antibodies to whole Plasmodium falciparum sporozoites (Pfspz) and the immunodominant (NANP)5 repeats of the major sporozoite surface protein, circumsporozoite protein, in a well-characterized Kenyan cohort. Sera were sampled at the start of the malaria transmission season, and all subjects were prospectively monitored for uncomplicated clinical malaria in the ensuing 6 months. We used Kaplan–Meier analysis and multivariable regression to investigate the association of antisporozoite immunity with incidence of clinical malaria. Although naturally acquired humoral responses against Pfspz and (NANP)5 were strongly correlated (p < 0.0001), 37% of Pfspz responders did not recognize (NANP)5. The prevalence and magnitude of antisporozoite responses increased with age, although some high Pfspz responders were identified among children. Survival analysis revealed a reduced risk of and increased time to first or only episode of clinical malaria among Pfspz or (NANP)5 responders carrying microscopically detectable Plasmodium falciparum (Pf) parasitemia at the start of the transmission season (p < 0.03). Our Cox regression interaction models indicated a potentially protective interaction between high anti-Pfspz (p = 0.002) or anti-(NANP)5 (p = 0.001) antibody levels and microscopically detectable Pf parasitemia on the risk of subsequent clinical malaria. Our findings indicate that robust antisporozoite immune responses can be naturally acquired already at an early age. A potentially protective role of high levels of anti-Pfspz antibodies against clinical episodes of uncomplicated malaria was detected, suggesting that antibody-mediated preerythrocytic immunity might indeed contribute to protection in nature.

Private pharmacy staff in five main towns in Benin, Burkina Faso, and Mali: knowledge and practices concerning malaria care in 2014.

The Global Fund's involvement in the fight against malaria has led to significant improvements, but mostly through programs supporting public-sector health facilities and personnel. The authors report the results of the preliminary survey preceding their intervention with private pharmacies. A simple random sampling technique was used to select the sample of pharmacies in urban areas in Burkina Faso, Benin, and Mali. A pretested questionnaire was administered to the supervisor present in each pharmacy at the time of the survey. Data were collected by local students in the first quarter of 2014. In all, 94 pharmacies were surveyed, representing 17.6% of all the pharmacies in these 5 cities. Among the participants, 84% knew about the national malaria control program, and 77.7% about artemisinin-based combination therapy (ACT), while 38.8% knew the national protocols. Licensed pharmacists had a better knowledge of ACT than their assistants, and training improved knowledge of treatment for uncomplicated malaria episodes. These pharmacists and assistants would like to be more involved in the fight against malaria. They are ready to advise ACT when appropriate after rapid detection tests. It is necessary to find resources for subsidized inputs in the private sector to make these drugs and tests more accessible for all patients.

Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated malaria in the setting of three different chemopreventive regimens.

BackgroundThe burden of malaria remains high for children in parts of Africa despite the use of insecticide-treated bed nets (ITNs). Chemoprevention has the potential of reducing the malaria burden; however, limited data exist on the efficacy and safety of anti-malarial therapy in the setting of chemoprevention.Methods600 children 4–5 months of age were enrolled in Tororo, Uganda, an area of high transmission intensity. Participants were given ITNs, and caregivers instructed to bring their child to a study clinic whenever they were ill. Starting at six months of age, 579 were randomized to no chemoprevention, monthly sulphadoxine-pyrimethamine (SP), daily trimethoprim-sulphamethoxazole (TS), or monthly dihydroartemisinin-piperaquine (DP). Study drugs were administered unsupervised at home until 24 months of age. Episodes of uncomplicated malaria were treated with artemether-lumefantrine (AL) with active follow-up for 28 days. The cumulative risk of recurrent malaria within 84 days and the risk of adverse events within 28 days were compared across study arms using a Cox proportional hazards model and generalized estimating equations, respectively.ResultsA total of 1007, 919, 736, and 451 episodes of malaria were treated in the no chemoprevention, SP, TS, and DP arms, respectively. Only 19 (0.6%) treatments were for severe malaria. Early response to therapy with AL was excellent with 96.5% fever clearance and 99.4% parasite clearance by day 3. However, over 50% of AL treatments were followed by recurrent parasitaemia within 28 days. Compared to the no chemoprevention arm, the cumulative risk of recurrent malaria within 84 days following treatment of uncomplicated malaria with AL was significantly lower in the DP arm (HR = 0.77, 95% CI 0.63-0.95, p = 0.01) but not the SP or TS arms. Compared to the no chemoprevention arm, none of the chemopreventive regimens were associated with an increased risk of adverse events following treatment of malaria with AL.ConclusionsThe risk of severe malaria was very low in this cohort of young children living in a high transmission setting. In the setting of chemoprevention, treatment of uncomplicated malaria with AL was safe and efficacious, with moderate protection against recurrent malaria among children assigned monthly DP.Trial registrationClinicalTrials.gov NCT00948896.

Mind the gap: house structure and the risk of malaria in Uganda.

BackgroundGood house construction may reduce the risk of malaria by limiting the entry of mosquito vectors. We assessed how house design may affect mosquito house entry and malaria risk in Uganda.Methods100 households were enrolled in each of three sub-counties: Walukuba, Jinja district; Kihihi, Kanungu district; and Nagongera, Tororo district. CDC light trap collections of mosquitoes were done monthly in all homes. All children aged six months to ten years (n = 878) were followed prospectively for a total of 24 months to measure parasite prevalence every three months and malaria incidence. Homes were classified as modern (cement, wood or metal walls; and tiled or metal roof; and closed eaves) or traditional (all other homes).ResultsA total of 113,618 female Anopheles were collected over 6,765 nights. 6,816 routine blood smears were taken of which 1,061 (15.6%) were malaria parasite positive. 2,582 episodes of uncomplicated malaria were diagnosed after 1,569 person years of follow-up, giving an overall incidence of 1.6 episodes per person year at risk. The human biting rate was lower in modern homes than in traditional homes (adjusted incidence rate ratio (IRR) 0.48, 95% confidence interval (CI) 0.37–0.64, p<0.001). The odds of malaria infection were lower in modern homes across all the sub-counties (adjusted odds ratio 0.44, 95%CI 0.30–0.65, p<0.001), while malaria incidence was lower in modern homes in Kihihi (adjusted IRR 0.61, 95%CI 0.40–0.91, p = 0.02) but not in Walukuba or Nagongera.ConclusionsHouse design is likely to explain some of the heterogeneity of malaria transmission in Uganda and represents a promising target for future interventions, even in highly endemic areas.

Home treatments alone or mixed with modern treatments for malaria in Finkolo AC, South Mali: reported use, outcomes and changes over 10 years.

In 2003, a study in Mali showed that 87% of episodes of uncomplicated malaria were first treated at home. We investigated whether treatment-seeking patterns in Mali had changed 10 years later. In 2013, we repeated the retrospective treatment-outcome study on 400 children with presumed malaria in the same area. Most children with reported uncomplicated malaria were still first treated at home (76% [196/258] in 2013 vs 85% in 2003; p=0.006), rather than in modern health centres (20% [52/258] in 2013 vs 12% in 2003; p=0.01). Overall, 58% of children with uncomplicated malaria were treated with herbal medicine alone, a significant increase from 24% 10 years earlier (p<0.001). This was associated with an increase in use of Argemone mexicana decoction from 8% to 26% (p<0.001), with a reported cure or improvement in 100% of cases among those aged >5 years. For severe malaria, first treatment was sought less often from a traditional healer compared with 10 years earlier (4% vs 32%; p<0.001) and more often from a modern health centre (29% vs 17%; p=0.04). Two trends that emerged are that there is a greater use of modern health facilities for treatment of severe malaria, and a greater use of traditional medicine alone for treatment of uncomplicated malaria.

PIN53 - Cost-Effectiveness Analysis Of Artesunate-Amodiaquine Versus Artemether-Lumefantrine For The Treatment Of Uncomplicated Malaria In Under-Five Year Old Patients In Ghana

Artemisinin combination based therapy (ACT) was started in Ghana in 2002 as a result of failure of monotherapy in the treatment of falciparum malaria. The decision to change was in line with recommendations from the World Health Organisation. ArtesunateAmodiaquine (A-Q) is the preferred combination drug of choice for the treatment of uncomplicated malaria and Artemether-Lumefantrine (A-L) is an alternative first line option. This study evaluates the cost-effectiveness of A-Q compared with A-L among under-five year olds in Ghana. In this study a decision analytic model using a decision tree was developed to assess the cost-effectiveness of the two treatments. Cost of illness and cost of medication (Coartem paediatric and Camoquine plus) were determined using figures from the National Health Insurance Scheme (NHIS) Ghana and from wholesalers respectively. Transportation cost was estimated using exit interviews. With the help of randomized controlled trials we estimated malaria cases averted (using clinical failure rates) over a 28 day period post treatment with each drug. Costs were discounted by 3% over a five year period but malaria cases averted 28 days after treatment was not discounted. Incremental costs per uncomplicated malaria case averted was then determined. The cost of illness per episode of uncomplicated malaria was 7.50 Ghana cedis (bundled NHIS cost) and transportation cost was 3.00 Ghana cedis. The incremental cost effectiveness ratio of artesunate-amodiaquine compared with artemether-lumefantrine was 16 Ghana cedis per uncomplicated malaria case averted. This economic evaluation showed that in the Ghanaian setting, treating uncomplicated malaria in under-five year old children with artesunate-amodiaquine was more cost-effective compared with artemether-lumefantrine.

Artemisinin-based combination therapies are efficacious and safe for treatment of uncomplicated malaria in HIV-infected Ugandan children.

Artemisinin-based combination therapies (ACTs) are highly efficacious and safe, but data from human immunodeficiency virus (HIV)-infected children concurrently receiving antiretroviral therapy (ART) and ACTs are limited. We evaluated 28-day outcomes following malaria treatment with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) in 2 cohorts of HIV-infected Ugandan children taking various ART regimens. In one cohort, children <6 years of age were randomized to lopinavir/ritonavir (LPV/r) or nonnucleoside reverse transcriptase inhibitor-based ART and treated with AL for uncomplicated malaria. In another cohort, children <12 months of age were started on nevirapine-based ART if they were eligible, and randomized to AL or DP for the treatment of their first and all subsequent uncomplicated malaria episodes. There were 773 and 165 treatments for malaria with AL and DP, respectively. Initial response to therapy was excellent, with 99% clearance of parasites and <1% risk of repeat therapy within 3 days. Recurrent parasitemia within 28 days was common following AL treatment. The risk of recurrent parasitemia was significantly lower among children taking LPV/r-based ART compared with children taking nevirapine-based ART following AL treatment (15.3% vs 35.5%, P = .009), and those treated with DP compared with AL (8.6% vs 36.2%, P < .001). Both ACT regimens were safe and well tolerated. Treatment of uncomplicated malaria with AL or DP was efficacious and safe in HIV-infected children taking ART. However, there was a high risk of recurrent parasitemia following AL treatment, which was significantly lower in children taking LPV/r-based ART compared with nevirapine-based ART.

Comparative Impacts Over 5 Years of Artemisinin-Based Combination Therapies on Plasmodium falciparum Polymorphisms That Modulate Drug Sensitivity in Ugandan Children

Artemisinin-based combination therapies, including artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP), are recommended to treat uncomplicated falciparum malaria. Sensitivities to components of AL and DP are impacted by polymorphisms in pfmdr1 and pfcrt. We monitored changes in prevalences of polymorphisms in Tororo, Uganda, from 2008 to 2012. Polymorphic loci in pfmdr1 and pfcrt were characterized in samples from 312 children randomized to AL or DP for each episode of uncomplicated malaria (50 samples per arm for each 3-month interval) utilizing a fluorescent microsphere assay. Treatment outcomes and impacts of prior therapies were also characterized. Prevalence increased significantly over time for pfmdr1 N86 (AL: odds ratio [OR], 2.08 [95% confidence interval {CI}, 1.83-2.38]; DP: 1.41 [95% CI, 1.25-1.57]), pfmdr1 D1246 (AL: 1.46 [95% CI, 1.29-1.64]; DP: 1.36 [95% CI, 1.23-1.50]), and pfcrt K76 (AL: 3.37 [95% CI, 1.85-6.16]; DP: 5.84 [95% CI, 1.94-17.53], and decreased for pfmdr1 Y184 (AL: 0.78 [95% CI, .70-.86]; DP: 0.84 [95% CI, .76-1.50]); changes were consistently greater in the AL arm. Recent AL treatment selected for pfmdr1 N86, D1246, and 184F in subsequent episodes; DP selected for the opposite alleles. Genotypes with decreased sensitivity to AL components increased over time. This increase was greater in children receiving AL, suggesting that the choice of treatment regimen can profoundly influence parasite genetics and drug sensitivity. NCT00527800.

A Longitudinal Trial Comparing Chloroquine as Monotherapy or in Combination with Artesunate, Azithromycin or Atovaquone-Proguanil to Treat Malaria

BackgroundThe predominance of chloroquine-susceptible falciparum malaria in Malawi more than a decade after chloroquine's withdrawal permits contemplation of re-introducing chloroquine for targeted uses. We aimed to compare the ability of different partner drugs to preserve chloroquine efficacy and prevent the re-emergence of resistance.Methodology/Principal FindingsChildren with uncomplicated malaria were enrolled at a government health center in Blantyre, Malawi. Participants were randomized to receive chloroquine alone or combined with artesunate, azithromycin or atovaquone-proguanil for all episodes of uncomplicated malaria for one year. The primary outcome was incidence of clinical malaria. Secondary endpoints included treatment efficacy, and incidence of the chloroquine resistance marker pfcrt T76 and of anemia. Of the 640 children enrolled, 628 were included in the intention-to-treat analysis. Malaria incidence (95% confidence interval) was 0.59 (.46–.74), .61 (.49–.76), .63 (.50–.79) and .68 (.54–.86) episodes/person-year for group randomized to receive chloroquine alone or in combination with artesunate, azithromycin or atovaquone-proguanil respectively and the differences were not statistically significant. Treatment efficacy for first episodes was 100% for chloroquine monotherapy and 97.9% for subsequent episodes of malaria. Similar results were seen in each of the chloroquine combination groups. The incidence of pfcrt T76 in pure form was 0%; mixed infections with both K76 and T76 were found in two out of 911 infections. Young children treated with chloroquine-azithromycin had higher hemoglobin concentrations at the study's end than did those in the chloroquine monotherapy group.Conclusion/SignificanceSustained chloroquine efficacy with repeated treatment supports the eventual re-introduction of chloroquine combinations for targeted uses such as intermittent preventive treatment.Trial Registration:ClinicalTrials.gov NCT00379821

Costs and cost-effectiveness of malaria control interventions - a systematic review

BackgroundThe control and elimination of malaria requires expanded coverage of and access to effective malaria control interventions such as insecticide-treated nets (ITNs), indoor residual spraying (IRS), intermittent preventive treatment (IPT), diagnostic testing and appropriate treatment. Decisions on how to scale up the coverage of these interventions need to be based on evidence of programme effectiveness, equity and cost-effectiveness.MethodsA systematic review of the published literature on the costs and cost-effectiveness of malaria interventions was undertaken. All costs and cost-effectiveness ratios were inflated to 2009 USD to allow comparison of the costs and benefits of several different interventions through various delivery channels, across different geographical regions and from varying costing perspectives.ResultsFifty-five studies of the costs and forty three studies of the cost-effectiveness of malaria interventions were identified, 78% of which were undertaken in sub-Saharan Africa, 18% in Asia and 4% in South America. The median financial cost of protecting one person for one year was $2.20 (range $0.88-$9.54) for ITNs, $6.70 (range $2.22-$12.85) for IRS, $0.60 (range $0.48-$1.08) for IPT in infants, $4.03 (range $1.25-$11.80) for IPT in children, and $2.06 (range $0.47-$3.36) for IPT in pregnant women. The median financial cost of diagnosing a case of malaria was $4.32 (range $0.34-$9.34). The median financial cost of treating an episode of uncomplicated malaria was $5.84 (range $2.36-$23.65) and the median financial cost of treating an episode of severe malaria was $30.26 (range $15.64-$137.87). Economies of scale were observed in the implementation of ITNs, IRS and IPT, with lower unit costs reported in studies with larger numbers of beneficiaries. From a provider perspective, the median incremental cost effectiveness ratio per disability adjusted life year averted was $27 (range $8.15-$110) for ITNs, $143 (range $135-$150) for IRS, and $24 (range $1.08-$44.24) for IPT.ConclusionsA transparent evidence base on the costs and cost-effectiveness of malaria control interventions is provided to inform rational resource allocation by donors and domestic health budgets and the selection of optimal packages of interventions by malaria control programmes.

Effect of α+-thalassaemia on episodes of fever due to malaria and other causes: a community-based cohort study in Tanzania

BackgroundIt is controversial to what degree α+-thalassaemia protects against episodes of uncomplicated malaria and febrile disease due to infections other than Plasmodium.MethodsIn Tanzania, in children aged 6-60 months and height-for-age z-score < -1.5 SD (n = 612), rates of fevers due to malaria and other causes were compared between those with heterozygous or homozygotes α+-thalassaemia and those with a normal genotype, using Cox regression models that accounted for multiple events per child.ResultsThe overall incidence of malaria was 3.0/child-year (1, 572/526 child-years); no differences were found in malaria rates between genotypes (hazard ratios, 95% CI: 0.93, 0.82-1.06 and 0.91, 0.73-1.14 for heterozygotes and homozygotes respectively, adjusted for baseline factors that were predictive for outcome). However, this association strongly depended on age: among children aged 6-17 months, those with α+-thalassaemia experienced episodes more frequently than those with a normal genotype (1.30, 1.02-1.65 and 1.15, 0.80-1.65 for heterozygotes and homozygotes respectively), whereas among their peers aged 18-60 months, α+-thalassaemia protected against malaria (0.80, 0.68-0.95 and 0.78, 0.60-1.03; p-value for interaction 0.001 and 0.10 for hetero- and homozygotes respectively). No effect was observed on non-malarial febrile episodes.ConclusionsIn this population, the association between α+-thalassaemia and malaria depends on age. Our data suggest that protection by α+-thalassaemia is conferred by more efficient acquisition of malaria-specific immunity.

Is parasite clearance clinically important after malaria treatment in a high transmission area? A 3-month follow-up of home-based management with herbal medicine or ACT

Argemone mexicana (AM), a validated herbal medicine for uncomplicated malaria, seems to prevent severe malaria without completely clearing parasites in most patients. This study, in a high transmission area of South Mali, explores whether residual parasitaemia at day 28 was associated with subsequent malaria episodes and/or anaemia. Three hundred and one patients were randomly assigned to AM or artesunate/amodiaquine as first line treatment, of whom 294 were followed up beyond the standard 28 days, to 84 days. From day 29 to day 84, there were no significant differences between treatment groups in new clinical episodes of uncomplicated malaria (0.33 vs 0.31 episodes/patient), severe malaria (<6% per month of patients aged ≤5 years) or moderate anaemia (hematocrit <24%: 1.1% in both groups at day 84). Total parasite clearance at day 28 was not correlated with incidence of uncomplicated or severe malaria or of moderate anaemia over the subsequent two months. Total parasite clearance at day 28 was not clinically important in the context of high transmission. If this finding can be confirmed, some antimalarials which are clinically effective but do not completely clear parasites could nevertheless be appropriate in high transmission areas. Such a policy could be tested as a way to delay resistance to artemisinin combination therapies.

Nitric oxide generation in children with malaria and the NOS2G-954C promoter polymorphism

Previous epidemiological studies have demonstrated a protective association between the NOS2G-954C (NOS2(Lambaréné)) polymorphism in inducible nitric oxide synthase and severe malaria. The polymorphism is commoner in children with uncomplicated compared with severe malaria. We now show that the likely mechanism for such protection is increased flux of nitrogen from arginine to nitric oxide (NO) during episodes of malaria. Forty-seven boys with uncomplicated malaria received an infusion of (15)N-arginine to measure directly whole body in vivo NO production. The NOS2G-954C genotype previously associated with reduced risk of severe malaria in Gabon was also assessed. Evaluable data were obtained from 40 boys, of whom 6 were NOS2G-954C heterozygotes. Heterozygotes had higher urinary (15)N nitrate enrichments, 2.3 ± 0.6 vs. 1.4 ± 0.5 atoms percent excess (P = 0.001) and higher ratios of (15)N between urine nitrate and plasma arginine (87 ± 11 vs. 57 ± 18%, P = 0.001) consistent with accelerated NO production. We also derived total NO production rates, combining data with total urine production rate and nitrate concentration; these showed no difference by genotype (0.62 ± 0.36, n = 6 vs. 0.83 ± 0.50 μmol/kg·h, n = 16; P = 0.36), but data were confounded by very high variability in measurements of urine output and nitrate concentrations. This study supports the idea that NOS2 genotype protects against severe malaria by increasing NO production during episodes of uncomplicated malaria.