RESUMEN
BACKGROUND: The efficacy of daily co-trimoxazole, an antifolate used for malaria chemoprevention in pregnant women living with HIV, is threatened by cross-resistance of Plasmodium falciparum to the antifolate sulfadoxine-pyrimethamine. We assessed whether addition of monthly dihydroartemisinin-piperaquine to daily co-trimoxazole is more effective at preventing malaria infection than monthly placebo plus daily co-trimoxazole in pregnant women living with HIV. METHODS: We did an individually randomised, two-arm, placebo-controlled trial in areas with high-grade sulfadoxine-pyrimethamine resistance in Kenya and Malawi. Pregnant women living with HIV on dolutegravir-based combination antiretroviral therapy (cART) who had singleton pregnancies between 16 weeks' and 28 weeks' gestation were randomly assigned (1:1) by computer-generated block randomisation, stratified by site and HIV status (known positive vs newly diagnosed), to daily co-trimoxazole plus monthly dihydroartemisinin-piperaquine (three tablets of 40 mg dihydroartemisinin and 320 mg piperaquine given daily for 3 days) or daily co-trimoxazole plus monthly placebo. Daily co-trimoxazole consisted of one tablet of 160 mg sulfamethoxazole and 800 mg trimethoprim. The primary endpoint was the incidence of Plasmodium infection detected in the peripheral (maternal) or placental (maternal) blood or tissue by PCR, microscopy, rapid diagnostic test, or placental histology (active infection) from 2 weeks after the first dose of dihydroartemisinin-piperaquine or placebo to delivery. Log-binomial regression was used for binary outcomes, and Poisson regression for count outcomes. The primary analysis was by modified intention to treat, consisting of all randomised eligible participants with primary endpoint data. The safety analysis included all women who received at least one dose of study drug. All investigators, laboratory staff, data analysts, and participants were masked to treatment assignment. This trial is registered with ClinicalTrials.gov, NCT04158713. FINDINGS: From Nov 11, 2019, to Aug 3, 2021, 904 women were enrolled and randomly assigned to co-trimoxazole plus dihydroartemisinin-piperaquine (n=448) or co-trimoxazole plus placebo (n=456), of whom 895 (99%) contributed to the primary analysis (co-trimoxazole plus dihydroartemisinin-piperaquine, n=443; co-trimoxazole plus placebo, n=452). The cumulative risk of any malaria infection during pregnancy or delivery was lower in the co-trimoxazole plus dihydroartemisinin-piperaquine group than in the co-trimoxazole plus placebo group (31 [7%] of 443 women vs 70 [15%] of 452 women, risk ratio 0·45, 95% CI 0·30-0·67; p=0·0001). The incidence of any malaria infection during pregnancy or delivery was 25·4 per 100 person-years in the co-trimoxazole plus dihydroartemisinin-piperaquine group versus 77·3 per 100 person-years in the co-trimoxazole plus placebo group (incidence rate ratio 0·32, 95% CI 0·22-0·47, p<0·0001). The number needed to treat to avert one malaria infection per pregnancy was 7 (95% CI 5-10). The incidence of serious adverse events was similar between groups in mothers (17·7 per 100 person-years in the co-trimoxazole plus dihydroartemisinin-piperaquine group [23 events] vs 17·8 per 100 person-years in the co-trimoxazole group [25 events]) and infants (45·4 per 100 person-years [23 events] vs 40·2 per 100 person-years [21 events]). Nausea within the first 4 days after the start of treatment was reported by 29 (7%) of 446 women in the co-trimoxazole plus dihydroartemisinin-piperaquine group versus 12 (3%) of 445 women in the co-trimoxazole plus placebo group. The risk of adverse pregnancy outcomes did not differ between groups. INTERPRETATION: Addition of monthly intermittent preventive treatment with dihydroartemisinin-piperaquine to the standard of care with daily unsupervised co-trimoxazole in areas of high antifolate resistance substantially improves malaria chemoprevention in pregnant women living with HIV on dolutegravir-based cART and should be considered for policy. FUNDING: European and Developing Countries Clinical Trials Partnership 2; UK Joint Global Health Trials Scheme (UK Foreign, Commonwealth and Development Office; Medical Research Council; National Institute for Health Research; Wellcome); and Swedish International Development Cooperation Agency.
Asunto(s)
Antimaláricos , Artemisininas , Antagonistas del Ácido Fólico , Infecciones por VIH , Malaria , Piperazinas , Quinolinas , Femenino , Humanos , Lactante , Embarazo , Antimaláricos/efectos adversos , Quimioprevención , Antagonistas del Ácido Fólico/uso terapéutico , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Infecciones por VIH/tratamiento farmacológico , Kenia/epidemiología , Malaria/epidemiología , Malaria/prevención & control , Malaui/epidemiología , Placenta , Resultado del Embarazo , Mujeres Embarazadas , Combinación Trimetoprim y Sulfametoxazol/uso terapéutico , Método Doble CiegoRESUMEN
BACKGROUND: The RTS,S/AS01E malaria vaccine (RTS,S) was introduced by national immunisation programmes in Ghana, Kenya, and Malawi in 2019 in large-scale pilot schemes. We aimed to address questions about feasibility and impact, and to assess safety signals that had been observed in the phase 3 trial that included an excess of meningitis and cerebral malaria cases in RTS,S recipients, and the possibility of an excess of deaths among girls who received RTS,S than in controls, to inform decisions about wider use. METHODS: In this prospective evaluation, 158 geographical clusters (66 districts in Ghana; 46 sub-counties in Kenya; and 46 groups of immunisation clinic catchment areas in Malawi) were randomly assigned to early or delayed introduction of RTS,S, with three doses to be administered between the ages of 5 months and 9 months and a fourth dose at the age of approximately 2 years. Primary outcomes of the evaluation, planned over 4 years, were mortality from all causes except injury (impact), hospital admission with severe malaria (impact), hospital admission with meningitis or cerebral malaria (safety), deaths in girls compared with boys (safety), and vaccination coverage (feasibility). Mortality was monitored in children aged 1-59 months throughout the pilot areas. Surveillance for meningitis and severe malaria was established in eight sentinel hospitals in Ghana, six in Kenya, and four in Malawi. Vaccine uptake was measured in surveys of children aged 12-23 months about 18 months after vaccine introduction. We estimated that sufficient data would have accrued after 24 months to evaluate each of the safety signals and the impact on severe malaria in a pooled analysis of the data from the three countries. We estimated incidence rate ratios (IRRs) by comparing the ratio of the number of events in children age-eligible to have received at least one dose of the vaccine (for safety outcomes), or age-eligible to have received three doses (for impact outcomes), to that in non-eligible age groups in implementation areas with the equivalent ratio in comparison areas. To establish whether there was evidence of a difference between girls and boys in the vaccine's impact on mortality, the female-to-male mortality ratio in age groups eligible to receive the vaccine (relative to the ratio in non-eligible children) was compared between implementation and comparison areas. Preliminary findings contributed to WHO's recommendation in 2021 for widespread use of RTS,S in areas of moderate-to-high malaria transmission. FINDINGS: By April 30, 2021, 652â673 children had received at least one dose of RTS,S and 494â745 children had received three doses. Coverage of the first dose was 76% in Ghana, 79% in Kenya, and 73% in Malawi, and coverage of the third dose was 66% in Ghana, 62% in Kenya, and 62% in Malawi. 26â285 children aged 1-59 months were admitted to sentinel hospitals and 13â198 deaths were reported through mortality surveillance. Among children eligible to have received at least one dose of RTS,S, there was no evidence of an excess of meningitis or cerebral malaria cases in implementation areas compared with comparison areas (hospital admission with meningitis: IRR 0·63 [95% CI 0·22-1·79]; hospital admission with cerebral malaria: IRR 1·03 [95% CI 0·61-1·74]). The impact of RTS,S introduction on mortality was similar for girls and boys (relative mortality ratio 1·03 [95% CI 0·88-1·21]). Among children eligible for three vaccine doses, RTS,S introduction was associated with a 32% reduction (95% CI 5-51%) in hospital admission with severe malaria, and a 9% reduction (95% CI 0-18%) in all-cause mortality (excluding injury). INTERPRETATION: In the first 2 years of implementation of RTS,S, the three primary doses were effectively deployed through national immunisation programmes. There was no evidence of the safety signals that had been observed in the phase 3 trial, and introduction of the vaccine was associated with substantial reductions in hospital admission with severe malaria. Evaluation continues to assess the impact of four doses of RTS,S. FUNDING: Gavi, the Vaccine Alliance; the Global Fund to Fight AIDS, Tuberculosis and Malaria; and Unitaid.
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Estudios de Factibilidad , Programas de Inmunización , Vacunas contra la Malaria , Malaria Cerebral , Humanos , Ghana/epidemiología , Malaui/epidemiología , Lactante , Femenino , Kenia/epidemiología , Vacunas contra la Malaria/administración & dosificación , Vacunas contra la Malaria/efectos adversos , Masculino , Preescolar , Malaria Cerebral/epidemiología , Malaria Cerebral/mortalidad , Estudios Prospectivos , Malaria Falciparum/prevención & control , Malaria Falciparum/epidemiología , Meningitis/epidemiología , Meningitis/prevención & controlRESUMEN
BACKGROUND: The RTS,S/AS01E (RTS,S) malaria vaccine is recommended for children in malaria endemic areas. This phase 2b trial evaluates RTS,S fractional- and full-dose regimens in Ghana and Kenya. METHODS: In total, 1500 children aged 5-17 months were randomized (1:1:1:1:1) to receive RTS,S or rabies control vaccine. RTS,S groups received 2 full RTS,S doses at months 0 and 1 and either full (groups R012-20, R012-14-26) or fractional doses (one-fifth; groups Fx012-14-26, Fx017-20-32). RESULTS: At month 32 post-dose 1, vaccine efficacy against clinical malaria (all episodes) ranged from 38% (R012-20; 95% confidence interval [CI]: 24%-49%) to 53% (R012-14-26; 95% CI: 42%-62%). Vaccine impact (cumulative number of cases averted/1000 children vaccinated) was 1344 (R012-20), 2450 (R012-14-26), 2273 (Fx012-14-26), and 2112 (Fx017-20-32). To account for differences in vaccine volume (fractional vs full dose; post hoc analysis), we estimated cases averted/1000 RTS,S full-dose equivalents: 336 (R012-20), 490 (R012-14-26), 874 (Fx012-14-26), and 880 (Fx017-20-32). CONCLUSIONS: Vaccine efficacy was similar across RTS,S groups. Vaccine impact accounting for full-dose equivalence suggests that using fractional-dose regimens could be a viable dose-sparing strategy. If maintained through trial end, these observations underscore the means to reduce cost per regimen thus maximizing impact and optimizing supply. CLINICAL TRIALS REGISTRATION: NCT03276962 (ClinicalTrials.gov).
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Vacunas contra la Malaria , Malaria Falciparum , Eficacia de las Vacunas , Humanos , Vacunas contra la Malaria/administración & dosificación , Vacunas contra la Malaria/inmunología , Ghana , Lactante , Kenia , Femenino , Masculino , Malaria Falciparum/prevención & control , Malaria Falciparum/epidemiología , Esquemas de Inmunización , Malaria/prevención & control , Plasmodium falciparum/inmunologíaRESUMEN
BACKGROUND: Malaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisinin-based combination therapies (ACTs) are a highly effective, first-line treatment for uncomplicated Plasmodium falciparum malaria, except in the first trimester of pregnancy, when quinine with clindamycin is recommended due to concerns about the potential embryotoxicity of artemisinins. We compared adverse pregnancy outcomes after artemisinin-based treatment (ABT) versus non-ABTs in the first trimester of pregnancy. METHODS: For this systematic review and individual patient data (IPD) meta-analysis, we searched MEDLINE, Embase, and the Malaria in Pregnancy Library for prospective cohort studies published between Nov 1, 2015, and Dec 21, 2021, containing data on outcomes of pregnancies exposed to ABT and non-ABT in the first trimester. The results of this search were added to those of a previous systematic review that included publications published up until November, 2015. We included pregnancies enrolled before the pregnancy outcome was known. We excluded pregnancies with missing estimated gestational age or exposure information, multiple gestation pregnancies, and if the fetus was confirmed to be unviable before antimalarial treatment. The primary endpoint was adverse pregnancy outcome, defined as a composite of either miscarriage, stillbirth, or major congenital anomalies. A one-stage IPD meta-analysis was done by use of shared-frailty Cox models. This study is registered with PROSPERO, number CRD42015032371. FINDINGS: We identified seven eligible studies that included 12 cohorts. All 12 cohorts contributed IPD, including 34 178 pregnancies, 737 with confirmed first-trimester exposure to ABTs and 1076 with confirmed first-trimester exposure to non-ABTs. Adverse pregnancy outcomes occurred in 42 (5·7%) of 736 ABT-exposed pregnancies compared with 96 (8·9%) of 1074 non-ABT-exposed pregnancies in the first trimester (adjusted hazard ratio [aHR] 0·71, 95% CI 0·49-1·03). Similar results were seen for the individual components of miscarriage (aHR=0·74, 0·47-1·17), stillbirth (aHR=0·71, 0·32-1·57), and major congenital anomalies (aHR=0·60, 0·13-2·87). The risk of adverse pregnancy outcomes was lower with artemether-lumefantrine than with oral quinine in the first trimester of pregnancy (25 [4·8%] of 524 vs 84 [9·2%] of 915; aHR 0·58, 0·36-0·92). INTERPRETATION: We found no evidence of embryotoxicity or teratogenicity based on the risk of miscarriage, stillbirth, or major congenital anomalies associated with ABT during the first trimester of pregnancy. Given that treatment with artemether-lumefantrine was associated with fewer adverse pregnancy outcomes than quinine, and because of the known superior tolerability and antimalarial effectiveness of ACTs, artemether-lumefantrine should be considered the preferred treatment for uncomplicated P falciparum malaria in the first trimester. If artemether-lumefantrine is unavailable, other ACTs (except artesunate-sulfadoxine-pyrimethamine) should be preferred to quinine. Continued active pharmacovigilance is warranted. FUNDING: Medicines for Malaria Venture, WHO, and the Worldwide Antimalarial Resistance Network funded by the Bill & Melinda Gates Foundation.
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Aborto Espontáneo , Antimaláricos , Malaria Falciparum , Malaria , Femenino , Embarazo , Humanos , Antimaláricos/efectos adversos , Resultado del Embarazo , Quinina/efectos adversos , Primer Trimestre del Embarazo , Mortinato/epidemiología , Estudios Prospectivos , Arteméter/uso terapéutico , Combinación Arteméter y Lumefantrina/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Malaria/tratamiento farmacológico , Combinación de Medicamentos , Etanolaminas/uso terapéuticoRESUMEN
BACKGROUND: Intermittent preventive treatment in pregnancy (IPTp) with dihydroartemisinin-piperaquine is more effective than IPTp with sulfadoxine-pyrimethamine at reducing malaria infection during pregnancy in areas with high-grade resistance to sulfadoxine-pyrimethamine by Plasmodium falciparum in east Africa. We aimed to assess whether IPTp with dihydroartemisinin-piperaquine, alone or combined with azithromycin, can reduce adverse pregnancy outcomes compared with IPTp with sulfadoxine-pyrimethamine. METHODS: We did an individually randomised, double-blind, three-arm, partly placebo-controlled trial in areas of high sulfadoxine-pyrimethamine resistance in Kenya, Malawi, and Tanzania. HIV-negative women with a viable singleton pregnancy were randomly assigned (1:1:1) by computer-generated block randomisation, stratified by site and gravidity, to receive monthly IPTp with sulfadoxine-pyrimethamine (500 mg of sulfadoxine and 25 mg of pyrimethamine for 1 day), monthly IPTp with dihydroartemisinin-piperaquine (dosed by weight; three to five tablets containing 40 mg of dihydroartemisinin and 320 mg of piperaquine once daily for 3 consecutive days) plus a single treatment course of placebo, or monthly IPTp with dihydroartemisinin-piperaquine plus a single treatment course of azithromycin (two tablets containing 500 mg once daily for 2 consecutive days). Outcome assessors in the delivery units were masked to treatment group. The composite primary endpoint was adverse pregnancy outcome, defined as fetal loss, adverse newborn baby outcomes (small for gestational age, low birthweight, or preterm), or neonatal death. The primary analysis was by modified intention to treat, consisting of all randomised participants with primary endpoint data. Women who received at least one dose of study drug were included in the safety analyses. This trial is registered with ClinicalTrials.gov, NCT03208179. FINDINGS: From March-29, 2018, to July 5, 2019, 4680 women (mean age 25·0 years [SD 6·0]) were enrolled and randomly assigned: 1561 (33%; mean age 24·9 years [SD 6·1]) to the sulfadoxine-pyrimethamine group, 1561 (33%; mean age 25·1 years [6·1]) to the dihydroartemisinin-piperaquine group, and 1558 (33%; mean age 24·9 years [6.0]) to the dihydroartemisinin-piperaquine plus azithromycin group. Compared with 335 (23·3%) of 1435 women in the sulfadoxine-pyrimethamine group, the primary composite endpoint of adverse pregnancy outcomes was reported more frequently in the dihydroartemisinin-piperaquine group (403 [27·9%] of 1442; risk ratio 1·20, 95% CI 1·06-1·36; p=0·0040) and in the dihydroartemisinin-piperaquine plus azithromycin group (396 [27·6%] of 1433; 1·16, 1·03-1·32; p=0·017). The incidence of serious adverse events was similar in mothers (sulfadoxine-pyrimethamine group 17·7 per 100 person-years, dihydroartemisinin-piperaquine group 14·8 per 100 person-years, and dihydroartemisinin-piperaquine plus azithromycin group 16·9 per 100 person-years) and infants (sulfadoxine-pyrimethamine group 49·2 per 100 person-years, dihydroartemisinin-piperaquine group 42·4 per 100 person-years, and dihydroartemisinin-piperaquine plus azithromycin group 47·8 per 100 person-years) across treatment groups. 12 (0·2%) of 6685 sulfadoxine-pyrimethamine, 19 (0·3%) of 7014 dihydroartemisinin-piperaquine, and 23 (0·3%) of 6849 dihydroartemisinin-piperaquine plus azithromycin treatment courses were vomited within 30 min. INTERPRETATION: Monthly IPTp with dihydroartemisinin-piperaquine did not improve pregnancy outcomes, and the addition of a single course of azithromycin did not enhance the effect of monthly IPTp with dihydroartemisinin-piperaquine. Trials that combine sulfadoxine-pyrimethamine and dihydroartemisinin-piperaquine for IPTp should be considered. FUNDING: European & Developing Countries Clinical Trials Partnership 2, supported by the EU, and the UK Joint-Global-Health-Trials-Scheme of the Foreign, Commonwealth and Development Office, Medical Research Council, Department of Health and Social Care, Wellcome, and the Bill-&-Melinda-Gates-Foundation.
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Antimaláricos , Complicaciones Parasitarias del Embarazo , Quinolinas , Recién Nacido , Embarazo , Femenino , Humanos , Adulto , Adulto Joven , Pirimetamina/efectos adversos , Sulfadoxina/efectos adversos , Resultado del Embarazo , Antimaláricos/efectos adversos , Azitromicina/efectos adversos , Complicaciones Parasitarias del Embarazo/tratamiento farmacológico , Complicaciones Parasitarias del Embarazo/prevención & control , Complicaciones Parasitarias del Embarazo/epidemiología , Combinación de Medicamentos , Kenia , TanzaníaRESUMEN
BACKGROUND: Children who have been hospitalized with severe anemia in areas of Africa in which malaria is endemic have a high risk of readmission and death within 6 months after discharge. No prevention strategy specifically addresses this period. METHODS: We conducted a multicenter, two-group, randomized, placebo-controlled trial in nine hospitals in Kenya and Uganda to determine whether 3 months of malaria chemoprevention could reduce morbidity and mortality after hospital discharge in children younger than 5 years of age who had been admitted with severe anemia. All children received standard in-hospital care for severe anemia and a 3-day course of artemether-lumefantrine at discharge. Two weeks after discharge, children were randomly assigned to receive dihydroartemisinin-piperaquine (chemoprevention group) or placebo, administered as 3-day courses at 2, 6, and 10 weeks after discharge. Children were followed for 26 weeks after discharge. The primary outcome was one or more hospital readmissions for any reason or death from the time of randomization to 6 months after discharge. Conditional risk-set modeling for recurrent events was used to calculate hazard ratios with the use of the Prentice-Williams-Peterson total-time approach. RESULTS: From May 2016 through May 2018, a total of 1049 children underwent randomization; 524 were assigned to the chemoprevention group and 525 to the placebo group. From week 3 through week 26, a total of 184 events of readmission or death occurred in the chemoprevention group and 316 occurred in the placebo group (hazard ratio, 0.65; 95% confidence interval [CI], 0.54 to 0.78; P<0.001). The lower incidence of readmission or death in the chemoprevention group than in the placebo group was restricted to the intervention period (week 3 through week 14) (hazard ratio, 0.30; 95% CI, 0.22 to 0.42) and was not sustained after that time (week 15 through week 26) (hazard ratio, 1.13; 95% CI, 0.87 to 1.47). No serious adverse events were attributed to dihydroartemisinin-piperaquine. CONCLUSIONS: In areas with intense malaria transmission, 3 months of postdischarge malaria chemoprevention with monthly dihydroartemisinin-piperaquine in children who had recently received treatment for severe anemia prevented more deaths or readmissions for any reason after discharge than placebo. (Funded by the Research Council of Norway and the Centers for Disease Control and Prevention; ClinicalTrials.gov number, NCT02671175.).
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Anemia/tratamiento farmacológico , Antimaláricos/uso terapéutico , Artemisininas/uso terapéutico , Malaria/prevención & control , Quinolinas/uso terapéutico , Cuidados Posteriores , Preescolar , Combinación de Medicamentos , Enfermedades Endémicas , Femenino , Humanos , Lactante , Kenia/epidemiología , Malaria/epidemiología , Masculino , Readmisión del Paciente/estadística & datos numéricos , Uganda/epidemiologíaRESUMEN
BACKGROUND: Rapid diagnostic tests (RDTs) are effective tools to diagnose and inform the treatment of malaria in adults and children. The recent development of a highly sensitive rapid diagnostic test (HS-RDT) for Plasmodium falciparum has prompted questions over whether it could improve the diagnosis of malaria in pregnancy and pregnancy outcomes in malaria endemic areas. METHODS: This landscape review collates studies addressing the clinical performance of the HS-RDT. Thirteen studies were identified comparing the HS-RDT and conventional RDT (co-RDT) to molecular methods to detect malaria in pregnancy. Using data from five completed studies, the association of epidemiological and pregnancy-related factors on the sensitivity of HS-RDT, and comparisons with co-RDT were investigated. The studies were conducted in 4 countries over a range of transmission intensities in largely asymptomatic women. RESULTS: Sensitivity of both RDTs varied widely (HS-RDT range 19.6 to 85.7%, co-RDT range 22.8 to 82.8% compared to molecular testing) yet HS-RDT detected individuals with similar parasite densities across all the studies including different geographies and transmission areas [geometric mean parasitaemia around 100 parasites per µL (p/µL)]. HS-RDTs were capable of detecting low-density parasitaemias and in one study detected around 30% of infections with parasite densities of 0-2 p/µL compared to the co-RDT in the same study which detected around 15%. CONCLUSION: The HS-RDT has a slightly higher analytical sensitivity to detect malaria infections in pregnancy than co-RDT but this mostly translates to only fractional and not statistically significant improvement in clinical performance by gravidity, trimester, geography or transmission intensity. The analysis presented here highlights the need for larger and more studies to evaluate incremental improvements in RDTs. The HS-RDT could be used in any situation where co-RDT are currently used for P. falciparum diagnosis, if storage conditions can be adhered to.
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Malaria Falciparum , Malaria , Adulto , Embarazo , Niño , Humanos , Femenino , Plasmodium falciparum , Prueba de Diagnóstico Rápido , Sensibilidad y Especificidad , Malaria Falciparum/diagnóstico , Malaria Falciparum/epidemiología , Pruebas Diagnósticas de Rutina/métodos , Antígenos de Protozoos/análisisRESUMEN
BACKGROUND: Entomological surveillance is traditionally conducted by supervised teams of trained technicians. However, it is expensive and limiting in the number of sites visited. Surveillance through community-based collectors (CBC) may be more cost-effective and sustainable for longitudinal entomological monitoring. This study evaluated the efficiency of CBCs in monitoring mosquito densities compared to quality-assured sampling conducted by experienced entomology technicians. METHODS: Entomological surveillance employing CBCs was conducted in eighteen clusters of villages in western Kenya using indoor and outdoor CDC light traps and indoor Prokopack aspiration. Sixty houses in each cluster were enrolled and sampled once every month. Collected mosquitoes were initially identified to the genus level by CBCs, preserved in 70% ethanol and transferred to the laboratory every 2 weeks. Parallel, collections by experienced entomology field technicians were conducted monthly by indoor and outdoor CDC light traps and indoor Prokopack aspiration and served as a quality assurance of the CBCs. RESULTS: Per collection, the CBCs collected 80% fewer Anopheles gambiae sensu lato (s.l.) [RR = 0.2; (95% CI 0.14-0.27)] and Anopheles coustani [RR = 0.2; (95% CI 0.06-0.53)] and 90% fewer Anopheles funestus [RR = 0.1; (95% CI 0.08-0.19)] by CDC light traps compared to the quality assured (QA) entomology teams. Significant positive correlations were however observed between the monthly collections by CBCs and QA teams for both An. gambiae and An. funestus. In paired identifications of pooled mosquitoes, the CBCs identified 4.3 times more Anopheles compared to experienced technicians. The cost per person-night was lower in the community-based sampling at $9.1 compared to $89.3 by QA per collection effort. CONCLUSION: Unsupervised community-based mosquito surveillance collected substantially fewer mosquitoes per trap-night compared to quality-assured collection by experienced field teams, while consistently overestimating the number of Anopheles mosquitoes during identification. However, the numbers collected were significantly correlated between the CBCs and the QA teams suggesting that trends observed by CBCs and QA teams were similar. Further studies are needed to evaluate whether adopting low-cost, devolved supervision with spot checks, coupled with remedial training of the CBCs, can improve community-based collections to be considered a cost-effective alternative to surveillance conducted by experienced entomological technicians.
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Anopheles , Malaria , Animales , Humanos , Kenia/epidemiología , Mosquitos Vectores , Conducta Alimentaria , Control de MosquitosRESUMEN
BACKGROUND: Low birth weight (LBW) is a significant public health concern given its association with early-life mortality and other adverse health consequences that can impact the entire life cycle. In many countries, accurate estimates of LBW prevalence are lacking due to inaccuracies in collection and gaps in available data. Our study aimed to determine LBW prevalence among facility-born infants in selected areas of Kenya and Tanzania and to assess whether the introduction of an intervention to improve the accuracy of birth weight measurement would result in a meaningfully different estimate of LBW prevalence than current practice. METHODS: We carried out a historically controlled intervention study in 22 health facilities in Kenya and three health facilities in Tanzania. The intervention included: provision of high-quality digital scales, training of nursing staff on accurate birth weight measurement, recording and scale calibration practices, and quality maintenance support that consisted of enhanced supervision and feedback (prospective arm). The historically controlled data were birth weights from the same facilities recorded in maternity registers for the same calendar months from the previous year measured using routine practices and manual scales. We calculated mean birth weight (95% confidence interval CI), mean difference in LBW prevalence, and respective risk ratio (95% CI) between study arms. RESULTS: Between October 2019 and February 2020, we prospectively collected birth weights from 8441 newborns in Kenya and 4294 in Tanzania. Historical data were available from 9318 newborns in Kenya and 12,007 in Tanzania. In the prospective sample, the prevalence of LBW was 12.6% (95% confidence intervals [CI]: 10.9%-14.4%) in Kenya and 18.2% (12.2%-24.2%) in Tanzania. In the historical sample, the corresponding prevalence estimates were 7.8% (6.5%-9.2%) and 10.0% (8.6%-11.4%). Compared to the retrospective sample, the LBW prevalence in the prospective sample was 4.8% points (3.2%-6.4%) higher in Kenya and 8.2% points (2.3%-14.0%) higher in Tanzania, corresponding to a risk ratio of 1.61 (1.38-1.88) in Kenya and 1.81 (1.30-2.52) in Tanzania. CONCLUSION: Routine birth weight records underestimate the risk of LBW among facility-born infants in Kenya and Tanzania. The quality of birth weight data can be improved by a simple intervention consisting of provision of digital scales and supportive training.
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Peso al Nacer , Lactante , Recién Nacido , Embarazo , Femenino , Humanos , Estudios Retrospectivos , Estudios Prospectivos , Tanzanía/epidemiología , Kenia/epidemiologíaRESUMEN
INTRODUCTION: Infant and neonatal mortality estimates are typically derived from retrospective birth histories collected through surveys in countries with unreliable civil registration and vital statistics systems. Yet such data are subject to biases, including under-reporting of deaths and age misreporting, which impact mortality estimates. Prospective population-based cohort studies are an underutilized data source for mortality estimation that may offer strengths that avoid biases. METHODS: We conducted a secondary analysis of data from the Child Health Epidemiology Reference Group, including 11 population-based pregnancy or birth cohort studies, to evaluate the appropriateness of vital event data for mortality estimation. Analyses were descriptive, summarizing study designs, populations, protocols, and internal checks to assess their impact on data quality. We calculated infant and neonatal morality rates and compared patterns with Demographic and Health Survey (DHS) data. RESULTS: Studies yielded 71,760 pregnant women and 85,095 live births. Specific field protocols, especially pregnancy enrollment, limited exclusion criteria, and frequent follow-up visits after delivery, led to higher birth outcome ascertainment and fewer missing deaths. Most studies had low follow-up loss in pregnancy and the first month with little evidence of date heaping. Among studies in Asia and Latin America, neonatal mortality rates (NMR) were similar to DHS, while several studies in Sub-Saharan Africa had lower NMRs than DHS. Infant mortality varied by study and region between sources. CONCLUSIONS: Prospective, population-based cohort studies following rigorous protocols can yield high-quality vital event data to improve characterization of detailed mortality patterns of infants in low- and middle-income countries, especially in the early neonatal period where mortality risk is highest and changes rapidly.
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Mortalidad Infantil , Muerte Perinatal , Lactante , Recién Nacido , Niño , Humanos , Femenino , Embarazo , América Latina/epidemiología , Estudios Prospectivos , Estudios Retrospectivos , África del Sur del Sahara , Asia/epidemiologíaRESUMEN
BACKGROUND: Malaria is a significant public health threat in sub-Saharan Africa, particularly among children. The RTS,S/AS01 malaria vaccine reduces the risk and severity of malaria in children. RTS,S/AS01 was piloted in three African countries, Ghana, Kenya and Malawi, to assess safety, feasibility and cost-effectiveness in real-world settings. A qualitative longitudinal study was conducted as part of the feasibility assessment. This analysis explores RTS,S/AS01 vaccination barriers and identifies potential motivators among caregivers in three sub-counties in western Kenya. METHODS: A cohort of 63 caregivers with a malaria vaccine eligible child was interviewed at three time points over 24 months. A sub-set of 11 caregivers whose eligible children were either partially or non-vaccinated were selected for this sub-analysis. The 5A Taxonomy for root causes of under-vaccination was used to organise the inductively-coded data into categories (awareness, acceptance, access, affordability, and activation) and identify the factors influencing uptake across caregivers. A trajectory analysis was conducted to understand changes in factors over time within each caregiver experience. Caregiver narratives are used to illustrate how the factors influencing uptake were interrelated and changed over time. RESULTS: Lack of awareness, previous negative experiences with routine childhood immunisations and the burden of getting to the health facility contributed to caregivers initially delaying uptake of the vaccine. Over time concerns about vaccine side effects diminished and anticipated vaccination benefits strongly motivated caregivers to vaccinate their children. Persistent health system barriers (e.g., healthcare provider strikes, vaccine stockouts, negative provider attitudes) meant some children missed the first-dose eligibility window by aging-out. CONCLUSIONS: Caregivers in this study believed the RTS,S/AS01 to be effective and were motivated to have their children vaccinated. Despite these positive perceptions of the malaria vaccine, uptake was substantially hindered by persistent health system constraints. Negative provider attitudes emerged as a powerful deterrent to attending immunisation services and hampered uptake of the vaccine. Strategies that focus on improving interpersonal communication skills among healthcare providers are needed.
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Vacunas contra la Malaria , Malaria Falciparum , Malaria , Niño , Humanos , Lactante , Malaria Falciparum/prevención & control , Kenia , Estudios Longitudinales , Malaria/prevención & control , Malaria/tratamiento farmacológico , VacunaciónRESUMEN
BACKGROUND: We performed an economic analysis of a new technology used in antenatal care (ANC) clinics, the ANC panel. Introduced in 2019-2020 in five Rwandan districts, the ANC panel screens for four infections [hepatitis B virus (HBV), human immunodeficiency virus (HIV), malaria, and syphilis] using blood from a single fingerstick. It increases the scope and sensitivity of screening over conventional testing. METHODS: We developed and applied an Excel-based economic and epidemiologic model to perform cost-effectiveness and cost-benefit analyses of this technology in Kenya, Rwanda, and Uganda. Costs include the ANC panel itself, its administration, and follow-up treatment. Effectiveness models predicted impacts on maternal and infant mortality and other outcomes. Key parameters are the baseline prevalence of each infection and the effectiveness of early treatment using observations from the Rwanda pilot, national and international literature, and expert opinion. For each parameter, we found the best estimate (with 95% confidence bound). RESULTS: The ANC panel averted 92 (69-115) disability-adjusted life years (DALYs) per 1,000 pregnant women in ANC in Kenya, 54 (52-57) in Rwanda, and 258 (156-360) in Uganda. Net healthcare costs per woman ranged from $0.53 ($0.02-$4.21) in Kenya, $1.77 ($1.23-$5.60) in Rwanda, and negative $5.01 (-$6.45 to $0.48) in Uganda. Incremental cost-effectiveness ratios (ICERs) in dollars per DALY averted were $5.76 (-$3.50-$11.13) in Kenya, $32.62 ($17.54-$46.70) in Rwanda, and negative $19.40 (-$24.18 to -$15.42) in Uganda. Benefit-cost ratios were $17.48 ($15.90-$23.71) in Kenya, $6.20 ($5.91-$6.45) in Rwanda, and $25.36 ($16.88-$33.14) in Uganda. All results appear very favorable and cost-saving in Uganda. CONCLUSION: Though subject to uncertainty, even our lowest estimates were still favorable. By combining field data and literature, the ANC model could be applied to other countries.
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Costos de la Atención en Salud , Atención Prenatal , Lactante , Femenino , Embarazo , Humanos , Rwanda/epidemiología , Kenia/epidemiología , Uganda/epidemiología , Análisis Costo-BeneficioRESUMEN
BACKGROUND: Screen-and-treat strategies with sensitive diagnostic tests may reduce malaria-associated adverse pregnancy outcomes. We conducted a diagnostic accuracy study to evaluate new point-of-care tests to screen pregnant women for malaria at their first antenatal visit in western Kenya. METHODS: Consecutively women were tested for Plasmodium infection by expert microscopy, conventional rapid diagnostic test (cRDT), ultra sensitive RDT (usRDT), and loop-mediated isothermal amplification (LAMP). Photoinduced electron-transfer polymerase chain reaction (PET-PCR) served as the reference standard. Diagnostic performance was calculated and modelled at low parasite densities. RESULTS: Between May and September 2018, 172 of 482 screened participants (35.7%) were PET-PCR positive. Relative to PET-PCR, expert microscopy was least sensitive (40.1%; 95% confidence interval [CI], 32.7%-47.9%), followed by cRDT (49.4%; 95% CI, 41.7%-57.1), usRDT (54.7%; 95% CI, 46.9%-62.2%), and LAMP (68.6%; 95% CI, 61.1%-75.5%). Test sensitivities were comparable in febrile women (n = 90). Among afebrile women (n = 392), the geometric-mean parasite density was 29â parasites/µL and LAMP (sensitivity = 61.9%) and usRDT (43.2%) detected 1.74 (95% CI, 1.31-2.30) and 1.21 (95% CI, 88-2.21) more infections than cRDT (35.6%). Per our model, tests performed similarly at densities >200â parasites/µL. At 50â parasites/µL, the sensitivities were 45%, 56%, 62%, and 74% with expert microscopy, cRDT, usRDT, and LAMP, respectively. CONCLUSIONS: This first-generation usRDT provided moderate improvement in detecting low-density infections in afebrile pregnant women compared to cRDTs.
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Malaria Falciparum , Malaria , Pruebas Diagnósticas de Rutina , Femenino , Humanos , Kenia , Malaria/diagnóstico , Malaria Falciparum/diagnóstico , Técnicas de Diagnóstico Molecular , Técnicas de Amplificación de Ácido Nucleico , Plasmodium falciparum/genética , Embarazo , Mujeres Embarazadas , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Since the World Health Organization recommended single low-dose (0.25 mg/kg) primaquine (PQ) in combination with artemisinin-based combination therapies (ACTs) in areas of low transmission or artemisinin-resistant Plasmodium falciparum, several single-site studies have been conducted to assess efficacy. METHODS: An individual patient meta-analysis to assess gametocytocidal and transmission-blocking efficacy of PQ in combination with different ACTs was conducted. Random effects logistic regression was used to quantify PQ effect on (1) gametocyte carriage in the first 2 weeks post treatment; and (2) the probability of infecting at least 1 mosquito or of a mosquito becoming infected. RESULTS: In 2574 participants from 14 studies, PQ reduced PCR-determined gametocyte carriage on days 7 and 14, most apparently in patients presenting with gametocytemia on day 0 (odds ratio [OR],â 0.22; 95% confidence interval [CI], .17-.28 and OR,â 0.12; 95% CI, .08-.16, respectively). Rate of decline in gametocyte carriage was faster when PQ was combined with artemether-lumefantrine (AL) compared to dihydroartemisinin-piperaquine (DP) (Pâ =â .010 for day 7). Addition of 0.25 mg/kg PQ was associated with near complete prevention of transmission to mosquitoes. CONCLUSIONS: Transmission blocking is achieved with 0.25 mg/kg PQ. Gametocyte persistence and infectivity are lower when PQ is combined with AL compared to DP.
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Antimaláricos , Artemisininas , Malaria Falciparum , Animales , Arteméter/farmacología , Arteméter/uso terapéutico , Combinación Arteméter y Lumefantrina/uso terapéutico , Artemisininas/farmacología , Humanos , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum , PrimaquinaRESUMEN
Histidine-rich protein 2 (HRP2)-based rapid diagnostic tests detect Plasmodium falciparum malaria and are used throughout sub-Saharan Africa. However, deletions in the pfhrp2 and related pfhrp3 (pfhrp2/3) genes threaten use of these tests. Therapeutic efficacy studies (TESs) enroll persons with symptomatic P. falciparum infection. We screened TES samples collected during 2016-2018 in Ethiopia, Kenya, Rwanda, and Madagascar for HRP2/3, pan-Plasmodium lactate dehydrogenase, and pan-Plasmodium aldolase antigen levels and selected samples with low levels of HRP2/3 for pfhrp2/3 genotyping. We observed deletion of pfhrp3 in samples from all countries except Kenya. Single-gene deletions in pfhrp2 were observed in 1.4% (95% CI 0.2%-4.8%) of Ethiopia samples and in 0.6% (95% CI 0.2%-1.6%) of Madagascar samples, and dual pfhrp2/3 deletions were noted in 2.0% (95% CI 0.4%-5.9%) of Ethiopia samples. Although this study was not powered for precise prevalence estimates, evaluating TES samples revealed a low prevalence of pfhrp2/3 deletions in most sites.
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Malaria Falciparum , Malaria , Antígenos de Protozoos/genética , Pruebas Diagnósticas de Rutina , Etiopía/epidemiología , Eliminación de Gen , Humanos , Kenia/epidemiología , Madagascar/epidemiología , Malaria Falciparum/diagnóstico , Malaria Falciparum/epidemiología , Plasmodium falciparum/genética , Proteínas Protozoarias/genética , Rwanda/epidemiologíaRESUMEN
Antimalarial resistance threatens global malaria control efforts. The World Health Organization (WHO) recommends routine antimalarial efficacy monitoring through a standardized therapeutic efficacy study (TES) protocol. From June 2016 to March 2017, children with uncomplicated P. falciparum mono-infection in Siaya County, Kenya were enrolled into a standardized TES and randomized (1:1 ratio) to a 3-day course of artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP). Efficacy outcomes were measured at 28 and 42 days. A total of 340 children were enrolled. All but one child cleared parasites by day 3. PCR-corrected adequate clinical and parasitological response (ACPR) was 88.5% (95% CI: 80.9 to 93.3%) at day 28 for AL and 93.0% (95% CI: 86.9 to 96.4%) at day 42 for DP. There were 9.6 times (95% CI: 3.4 to 27.2) more reinfections in the AL arm compared to the DP arm at day 28, and 3.1 times (95% CI: 1.9 to 4.9) more reinfections at day 42. Both AL and DP were efficacious (per WHO 90% cutoff in the confidence interval) and well tolerated for the treatment of uncomplicated malaria in western Kenya, but AL efficacy appears to be waning. Further efficacy monitoring for AL, including pharmacokinetic studies, is recommended.
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Antimaláricos , Artemisininas , Antagonistas del Ácido Fólico , Malaria Falciparum , Malaria , Quinolinas , Antimaláricos/efectos adversos , Arteméter/uso terapéutico , Combinación Arteméter y Lumefantrina/uso terapéutico , Artemisininas/efectos adversos , Niño , Combinación de Medicamentos , Etanolaminas/efectos adversos , Etanolaminas/uso terapéutico , Fluorenos/efectos adversos , Fluorenos/uso terapéutico , Humanos , Lactante , Kenia , Malaria/tratamiento farmacológico , Malaria Falciparum/tratamiento farmacológico , Piperazinas , Plasmodium falciparum , Quinolinas/efectos adversos , ReinfecciónRESUMEN
BACKGROUND: Understanding the age patterns of disease is necessary to target interventions to maximise cost-effective impact. New malaria chemoprevention and vaccine initiatives target young children attending routine immunisation services. Here we explore the relationships between age and severity of malaria hospitalisation versus malaria transmission intensity. METHODS: Clinical data from 21 surveillance hospitals in East Africa were reviewed. Malaria admissions aged 1 month to 14 years from discrete administrative areas since 2006 were identified. Each site-time period was matched to a model estimated community-based age-corrected parasite prevalence to provide predictions of prevalence in childhood (PfPR2-10). Admission with all-cause malaria, severe malaria anaemia (SMA), respiratory distress (RD) and cerebral malaria (CM) were analysed as means and predicted probabilities from Bayesian generalised mixed models. RESULTS: 52,684 malaria admissions aged 1 month to 14 years were described at 21 hospitals from 49 site-time locations where PfPR2-10 varied from < 1 to 48.7%. Twelve site-time periods were described as low transmission (PfPR2-10 < 5%), five low-moderate transmission (PfPR2-10 5-9%), 20 moderate transmission (PfPR2-10 10-29%) and 12 high transmission (PfPR2-10 ≥ 30%). The majority of malaria admissions were below 5 years of age (69-85%) and rare among children aged 10-14 years (0.7-5.4%) across all transmission settings. The mean age of all-cause malaria hospitalisation was 49.5 months (95% CI 45.1, 55.4) under low transmission compared with 34.1 months (95% CI 30.4, 38.3) at high transmission, with similar trends for each severe malaria phenotype. CM presented among older children at a mean of 48.7 months compared with 39.0 months and 33.7 months for SMA and RD, respectively. In moderate and high transmission settings, 34% and 42% of the children were aged between 2 and 23 months and so within the age range targeted by chemoprevention or vaccines. CONCLUSIONS: Targeting chemoprevention or vaccination programmes to areas where community-based parasite prevalence is ≥10% is likely to match the age ranges covered by interventions (e.g. intermittent presumptive treatment in infancy to children aged 2-23 months and current vaccine age eligibility and duration of efficacy) and the age ranges of highest disease burden.
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Malaria Cerebral , Malaria Falciparum , Adolescente , África Oriental/epidemiología , Teorema de Bayes , Niño , Preescolar , Hospitalización , Humanos , Lactante , Malaria Cerebral/epidemiología , Malaria Falciparum/epidemiología , FenotipoRESUMEN
BACKGROUND: In 2012, the World Health Organization (WHO) recommended single low-dose (SLD, 0.25 mg/kg) primaquine to be added as a Plasmodium (P.) falciparum gametocytocide to artemisinin-based combination therapy (ACT) without glucose-6-phosphate dehydrogenase (G6PD) testing, to accelerate malaria elimination efforts and avoid the spread of artemisinin resistance. Uptake of this recommendation has been relatively slow primarily due to safety concerns. METHODS: A systematic review and individual patient data (IPD) meta-analysis of single-dose (SD) primaquine studies for P. falciparum malaria were performed. Absolute and fractional changes in haemoglobin concentration within a week and adverse effects within 28 days of treatment initiation were characterised and compared between primaquine and no primaquine arms using random intercept models. RESULTS: Data comprised 20 studies that enrolled 6406 participants, of whom 5129 (80.1%) had received a single target dose of primaquine ranging between 0.0625 and 0.75 mg/kg. There was no effect of primaquine in G6PD-normal participants on haemoglobin concentrations. However, among 194 G6PD-deficient African participants, a 0.25 mg/kg primaquine target dose resulted in an additional 0.53 g/dL (95% CI 0.17-0.89) reduction in haemoglobin concentration by day 7, with a 0.27 (95% CI 0.19-0.34) g/dL haemoglobin drop estimated for every 0.1 mg/kg increase in primaquine dose. Baseline haemoglobin, young age, and hyperparasitaemia were the main determinants of becoming anaemic (Hb < 10 g/dL), with the nadir observed on ACT day 2 or 3, regardless of G6PD status and exposure to primaquine. Time to recovery from anaemia took longer in young children and those with baseline anaemia or hyperparasitaemia. Serious adverse haematological events after primaquine were few (9/3, 113, 0.3%) and transitory. One blood transfusion was reported in the primaquine arms, and there were no primaquine-related deaths. In controlled studies, the proportions with either haematological or any serious adverse event were similar between primaquine and no primaquine arms. CONCLUSIONS: Our results support the WHO recommendation to use 0.25 mg/kg of primaquine as a P. falciparum gametocytocide, including in G6PD-deficient individuals. Although primaquine is associated with a transient reduction in haemoglobin levels in G6PD-deficient individuals, haemoglobin levels at clinical presentation are the major determinants of anaemia in these patients. TRIAL REGISTRATION: PROSPERO, CRD42019128185.
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Antimaláricos , Artemisininas , Malaria Falciparum , Primaquina , Antimaláricos/uso terapéutico , Artemisininas/uso terapéutico , Niño , Preescolar , Glucosafosfato Deshidrogenasa , Hemoglobinas/análisis , Humanos , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum , Primaquina/uso terapéuticoRESUMEN
BACKGROUND: Detection of malaria parasitaemia in samples that are negative by rapid diagnostic tests (RDTs) requires resource-intensive molecular tools. While pooled testing using a two-step strategy provides a cost-saving alternative to the gold standard of individual sample testing, statistical adjustments are needed to improve accuracy of prevalence estimates for a single step pooled testing strategy. METHODS: A random sample of 4670 malaria RDT negative dried blood spot samples were selected from a mass testing and treatment trial in Asembo, Gem, and Karemo, western Kenya. Samples were tested for malaria individually and in pools of five, 934 pools, by one-step quantitative polymerase chain reaction (qPCR). Maximum likelihood approaches were used to estimate subpatent parasitaemia (RDT-negative, qPCR-positive) prevalence by pooling, assuming poolwise sensitivity and specificity was either 100% (strategy A) or imperfect (strategy B). To improve and illustrate the practicality of this estimation approach, a validation study was constructed from pools allocated at random into main (734 pools) and validation (200 pools) subsets. Prevalence was estimated using strategies A and B and an inverse-variance weighted estimator and estimates were weighted to account for differential sampling rates by area. RESULTS: The prevalence of subpatent parasitaemia was 14.5% (95% CI 13.6-15.3%) by individual qPCR, 9.5% (95% CI (8.5-10.5%) by strategy A, and 13.9% (95% CI 12.6-15.2%) by strategy B. In the validation study, the prevalence by individual qPCR was 13.5% (95% CI 12.4-14.7%) in the main subset, 8.9% (95% CI 7.9-9.9%) by strategy A, 11.4% (95% CI 9.9-12.9%) by strategy B, and 12.8% (95% CI 11.2-14.3%) using inverse-variance weighted estimator from poolwise validation. Pooling, including a 20% validation subset, reduced costs by 52% compared to individual testing. CONCLUSIONS: Compared to individual testing, a one-step pooled testing strategy with an internal validation subset can provide accurate prevalence estimates of PCR-positivity among RDT-negatives at a lower cost.
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Malaria Falciparum , Malaria , Humanos , Pruebas Diagnósticas de Rutina , Kenia/epidemiología , Funciones de Verosimilitud , Malaria/diagnóstico , Malaria/epidemiología , Malaria Falciparum/epidemiología , Técnicas de Diagnóstico Molecular , Parasitemia/diagnóstico , Parasitemia/epidemiología , Prevalencia , Sensibilidad y Especificidad , Ensayos Clínicos como AsuntoRESUMEN
BACKGROUND: Over the last two decades, the scale-up of vector control and changes in the first-line anti-malarial, from chloroquine (CQ) to sulfadoxine-pyrimethamine (SP) and then to artemether-lumefantrine (AL), have resulted in significant decreases in malaria burden in western Kenya. This study evaluated the long-term effects of control interventions on molecular markers of Plasmodium falciparum drug resistance using parasites obtained from humans and mosquitoes at discrete time points. METHODS: Dried blood spot samples collected in 2012 and 2017 community surveys in Asembo, Kenya were genotyped by Sanger sequencing for markers associated with resistance to SP (Pfdhfr, Pfdhps), CQ, AQ, lumefantrine (Pfcrt, Pfmdr1) and artemisinin (Pfk13). Temporal trends in the prevalence of these markers, including data from 2012 to 2017 as well as published data from 1996, 2001, 2007 from same area, were analysed. The same markers from mosquito oocysts collected in 2012 were compared with results from human blood samples. RESULTS: The prevalence of SP dhfr/dhps quintuple mutant haplotype C50I51R59N108I164/S436G437E540A581A613 increased from 19.7% in 1996 to 86.0% in 2012, while an increase in the sextuple mutant haplotype C50I51R59N108I164/H436G437E540A581A613 containing Pfdhps-436H was found from 10.5% in 2012 to 34.6% in 2017. Resistant Pfcrt-76 T declined from 94.6% in 2007 to 18.3% in 2012 and 0.9% in 2017. Mutant Pfmdr1-86Y decreased across years from 74.8% in 1996 to zero in 2017, mutant Pfmdr1-184F and wild Pfmdr1-D1246 increased from 17.9% to 58.9% in 2007 to 55.9% and 90.1% in 2017, respectively. Pfmdr1 haplotype N86F184S1034N1042D1246 increased from 11.0% in 2007 to 49.6% in 2017. No resistant mutations in Pfk13 were found. Prevalence of Pfdhps-436H was lower while prevalence of Pfcrt-76 T was higher in mosquitoes than in human blood samples. CONCLUSION: This study showed an increased prevalence of dhfr/dhps resistant markers over 20 years with the emergence of Pfdhps-436H mutant a decade ago in Asembo. The reversal of Pfcrt from CQ-resistant to CQ-sensitive genotype occurred following 19 years of CQ withdrawal. No Pfk13 markers associated with artemisinin resistance were detected, but the increased haplotype of Pfmdr1 N86F184S1034N1042D1246 was observed. The differences in prevalence of Pfdhps-436H and Pfcrt-76 T SNPs between two hosts and the role of mosquitoes in the transmission of drug resistant parasites require further investigation.