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  • 1.
    Abdulla, Salim
    et al.
    Ifakara Hlth Inst, Dar Es Salaam, Tanzania..
    Ashley, Elizabeth A.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Mahidol Oxford Trop Med Res Unit MORU, Fac Trop Med, Bangkok 10700, Thailand..
    Bassat, Quique
    Univ Barcelona, Ctr Invest Saude Manhica Manhica Mozamb & ISGloba, Barcelona Ctr Int Hlth Res CRESIB, Hosp Clin, Barcelona, Spain..
    Bethell, Delia
    AFRIMS, Dept Immunol & Med, Bangkok, Thailand..
    Bjorkman, Anders
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Malaria Res, Stockholm, Sweden..
    Borrmann, Steffen
    Kenya Govt Med Res Ctr, Wellcome Trust Res Programme, Kilifi, Kenya.;Univ Magdeburg, Sch Med, D-39106 Magdeburg, Germany..
    D'Alessandro, Umberto
    Inst Trop Med, Unit Malariol, B-2000 Antwerp, Belgium.;MRC Unit, Fajara, Gambia..
    Dahal, Prabin
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England..
    Day, Nicholas P.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Mahidol Oxford Trop Med Res Unit MORU, Fac Trop Med, Bangkok 10700, Thailand..
    Diakite, Mahamadou
    Univ Bamako, Malaria Res & Training Ctr, Bamako, Mali..
    Djimde, Abdoulaye A.
    Dondorp, Arjen M.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Mahidol Oxford Trop Med Res Unit MORU, Fac Trop Med, Bangkok 10700, Thailand..
    Duong, Socheat
    Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia..
    Edstein, Michael D.
    Fairhurst, Rick M.
    NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA..
    Faiz, M. Abul
    Malaria Res Grp MRG & Dev Care Fdn, Dhaka, Bangladesh..
    Falade, Catherine
    Univ Ibadan, Coll Med, Ibadan, Nigeria..
    Flegg, Jennifer A.
    Monash Univ, Sch Math Sci, Clayton, Vic 3800, Australia..
    Fogg, Carole
    Univ Portsmouth, Portsmouth, Hants, England..
    Gonzalez, Raquel
    Ctr Invest Saude Manhica Manhica Mozamb, Barcelona, Spain.;CRESIB, Barcelona, Spain..
    Greenwood, Brian
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London WC1, England..
    Guerin, Philippe J.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England..
    Guthmann, Jean-Paul
    Epicentre, Paris, France..
    Hamed, Kamal
    Novartis Pharmaceut, E Hanover, NJ USA..
    Hien, Tran Tinh
    Htut, Ye
    Dept Med Res, Lower Myanmar, Yangon, Myanmar..
    Juma, Elizabeth
    Kenya Govt Med Res Ctr, Nairobi, Kenya..
    Lim, Pharath
    NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA.;US & Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Karolinska Inst, Dept Microbiol Cell & Tumour Biol, Dept Publ Hlth Sci, Malaria Res, Stockholm, Sweden..
    Mayxay, Mayfong
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahosot Hosp, Lao Oxford Mahosot Hosp, Wellcome Trust Res Unit LOMWRU, Viangchan, Laos.;Univ Hlth Sci, Fac Postgrad Studies, Viangchan, Laos..
    Mokuolu, Olugbenga A.
    Univ Ilorin, Dept Paediat & Child Hlth, Ilorin, Nigeria..
    Moreira, Clarissa
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England..
    Newton, Paul
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahosot Hosp, Lao Oxford Mahosot Hosp, Wellcome Trust Res Unit LOMWRU, Viangchan, Laos..
    Noedl, Harald
    Med Univ Vienna, Inst Specif Prophylaxis & Trop Med, Vienna, Austria..
    Nosten, Francois
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Shoklo Malaria Res Unit, Mahidol Oxford Trop Med Res Unit, Fac Trop Med, Bangkok 10700, Thailand..
    Ogutu, Bernhards R.
    Kenya Govt Med Res Ctr, US Army Med Res Unit, Kisumu, Kenya..
    Onyamboko, Marie A.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Kinshasa Sch Publ Hlth, Kinshasa, DEM REP CONGO..
    Owusu-Agyei, Seth
    Kintampo Hlth Res Ctr, Kintampo, Ghana..
    Phyo, Aung Pyae
    Mahidol Univ, Shoklo Malaria Res Unit, Mahidol Oxford Trop Med Res Unit, Fac Trop Med, Bangkok 10700, Thailand..
    Premji, Zul
    Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania..
    Price, Ric N.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Menzies Sch Hlth Res, Global & Trop Hlth Div, Darwin, NT, Australia.;Charles Darwin Univ, Darwin, NT 0909, Australia..
    Pukrittayakamee, Sasithon
    Mahidol Univ, Fac Trop Med, Bangkok 10700, Thailand..
    Ramharter, Michael
    Med Univ Vienna, Div Infect Dis & Trop Med, Dept Med 1, Vienna, Austria.;Univ Tubingen, Inst Tropenmed, Tubingen, Germany.;Ctr Rech Med Lambarene, Lambarene, Gabon..
    Sagara, Issaka
    Univ Bamako, Fac Med Pharm & Odontostomatol, Dept Epidemiol Parasit Dis, Malaria Res & Training Ctr, Bamako, Mali..
    Se, Youry
    AFRIMS, Phnom Penh, Cambodia..
    Suon, Seila
    Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia..
    Stepniewska, Kasia
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England..
    Ward, Stephen A.
    Univ Liverpool, Liverpool Sch Trop Med, Dept Parasitol, Liverpool L3 5QA, Merseyside, England..
    White, Nicholas J.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Mahidol Oxford Trop Med Res Unit MORU, Fac Trop Med, Bangkok 10700, Thailand..
    Winstanley, Peter A.
    Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England..
    Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative: an individual patient data meta-analysis2015In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, article id 359Article in journal (Refereed)
    Abstract [en]

    Background: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up. Methods: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive. Results: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 > 5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrudescence. In western Cambodia, the region with the highest prevalence of artemisinin resistance, there was no evidence for increasing PC1/2 since 2007. Conclusions: Several factors affect PC1/2. As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC1/2 data. Studies with frequent parasite count measurements to characterize PC1/2 should be encouraged. In western Cambodia, where PC1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.

  • 2. Awor, Phyllis
    et al.
    Wamani, Henry
    Tylleskar, Thorkild
    Peterson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Drug seller adherence to clinical protocols with integrated management of malaria, pneumonia and diarrhoea at drug shops in Uganda2015In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, article id 277Article in journal (Refereed)
    Abstract [en]

    Background: Drug shops are usually the first source of care for febrile children in Uganda although the quality of care they provide is known to be poor. Within a larger quasi-experimental study introducing the WHO/UNICEF recommended integrated community case management (iCCM) of malaria, pneumonia and diarrhoea intervention for community health workers in registered drug shops, the level of adherence to clinical protocols by drug sellers was determined. Methods: All drug shops (N = 44) in the intervention area were included and all child visits (N = 7,667) from October 2011-June 2012 to the participating drug shops were analysed. Drug shops maintained a standard iCCM register where they recorded the children seen, their symptoms, diagnostic test performed, treatments given and actions taken. The proportion of children correctly assessed and treated was determined from the registers. Results: Malaria management: 6,140 of 7,667 (80.1%) total visits to drug shops were of children with fever. 5986 (97.5%) children with fever received a malaria rapid diagnostic test (RDT) and the RDT positivity rate was 78% (95% CI 77-79). 4,961/5,307 (93.4%) children with a positive RDT received artemisinin combination therapy. Pneumonia management: after respiratory rate assessment of children with cough and fast/difficult breathing, 3,437 (44.8%) were categorized as "pneumonia", 3,126 (91.0%) of whom received the recommended drug-amoxicillin. Diarrhoea management: 2,335 (30.5%) child visits were for diarrhoea with 2,068 (88.6%) correctly treated with oral rehydration salts and zinc sulphate. Dual/Triple classification: 2,387 (31.1%) children had both malaria and pneumonia and 664 (8.7%) were classified as having three illnesses. Over 90% of the children with dual or triple classification were treated appropriately. Meanwhile, 381 children were categorized as severely sick (with a danger sign) with 309 (81.1%) of them referred for appropriate management. Conclusion: With the introduction of the iCCM intervention at drug shops in Eastern Uganda, it was possible to achieve high adherence to the treatment protocols, which is likely compatible with increased quality of care.

  • 3. Carlsson, Anja M
    et al.
    Ngasala, Billy E
    Dahlström, Sabina
    Membi, Christopher
    Veiga, Isabel M
    Rombo, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Abdulla, Salim
    Premji, Zul
    Gil, J Pedro
    Björkman, Anders
    Mårtensson, Andreas
    Plasmodium falciparum population dynamics during the early phase of anti-malarial drug treatment in Tanzanian children with acute uncomplicated malaria2011In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 10, p. 380-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    This study aimed to explore Plasmodium falciparum population dynamics during the early phase of anti-malarial drug treatment with artemisinin-based combination therapy in children with clinical malaria in a high transmission area in Africa.

    METHODS:

    A total of 50 children aged 1-10 years with acute uncomplicated P. falciparum malaria in Bagamoyo District, Tanzania, were enrolled. Participants were hospitalized and received supervised standard treatment with artemether-lumefantrine according to body weight in six doses over 3 days. Blood samples were collected 11 times, i.e. at time of diagnosis (-2 h) and 0, 2, 4, 8, 16, 24, 36, 48, 60 and 72 h after initiation of treatment. Parasite population dynamics were assessed using nested polymerase chain reaction (PCR)-genotyping of merozoite surface protein (msp) 1 and 2.

    RESULTS:

    PCR-analyses from nine sequential blood samples collected after initiation of treatment identified 20 and 21 additional genotypes in 15/50 (30%) and 14/50 (28%) children with msp1 and msp2, respectively, non-detectable in the pre-treatment samples (-2 and 0 h combined). Some 15/20 (75%) and 14/21 (67%) of these genotypes were identified within 24 h, whereas 17/20 (85%) and 19/21 (90%) within 48 h for msp1 and msp2, respectively. The genotype profile was diverse, and varied considerably over time both within and between patients, molecular markers and their respective families.

    CONCLUSION:

    PCR analyses from multiple blood samples collected during the early treatment phase revealed a complex picture of parasite sub-populations. This underlines the importance of interpreting PCR-outcomes with caution and suggests that the present use of PCR-adjustment from paired blood samples in anti-malarial drug trials may overestimate assessment of drug efficacy in high transmission areas in Africa.The study is registered at http://www.clinicaltrials.gov with identifier NCT00336375.

  • 4. Cook, Jackie
    et al.
    Aydin-Schmidt, Berit
    Gonzalez, Iveth J.
    Bell, David
    Edlund, Elin
    Nassor, Majda H.
    Msellem, Mwinyi
    Ali, Abdullah
    Abass, Ali K.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Bjorkman, Anders
    Loop-mediated isothermal amplification (LAMP) for point-of-care detection of asymptomatic low-density malaria parasite carriers in Zanzibar2015In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, p. 43-Article in journal (Refereed)
    Abstract [en]

    Background: Asymptomatic, low parasite density malaria infections are difficult to detect with currently available point-of-care diagnostics. This study piloted a loop-mediated isothermal amplification (LAMP) kit for field-friendly, high-throughput detection of asymptomatic malaria infections during mass screening and treatment (MSAT) in Zanzibar, a malaria pre-elimination setting. Methods: Screening took place in three known hotspot areas prior to the short rains in November. Finger-prick blood was taken for screening by rapid diagnostic test (RDT) and LAMP and collected on filter paper for subsequent polymerase chain reaction (PCR) analyses. LAMP results were compared to RDT and to PCR using McNemar's test. Results: Approximately 1,000 people were screened. RDT detected ten infections (1.0% (95% CI 0.3-1.6)) whilst both LAMP and PCR detected 18 (1.8% (95% CI 0.9-2.6)) infections. However, PCR identified three infections that LAMP did not detect and vice versa. LAMP testing was easy to scale-up in field conditions requiring minimal training and equipment, with results ready one to three hours after screening. Conclusions: Despite lower than expected prevalence, LAMP detected a higher number of infections than the currently used diagnostic, RDT. LAMP is a field-friendly, sensitive diagnostic test that could be useful for MSAT malaria campaigns which require quick results to enable prompt treatment.

  • 5.
    Cotter, Chris
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition. Univ Calif San Francisco, Global Hlth Grp, Malaria Eliminat Initiat, 550 16th St,3rd Floor, San Francisco, CA 94158 USA.
    Sudathip, Prayuth
    Minist Publ Hlth, Dept Dis Control, Bur Vector Borne Dis, Nonthaburi, Thailand.
    Herdiana, Herdiana
    UN Childrens Fund UNICEF, Aceh Field Off, Banda Aceh, Indonesia;Paritrana Asia Fdn, Jakarta, Indonesia.
    Cao, Yuanyuan
    Jiangsu Inst Parasit Dis, Jiangsu Prov Key Lab Parasite & Vector Control Te, Key Lab, Natl Hlth & Family Planning Commiss Parasit Dis C, Wuxi, Jiangsu, Peoples R China.
    Liu, Yaobao
    Jiangsu Inst Parasit Dis, Jiangsu Prov Key Lab Parasite & Vector Control Te, Key Lab, Natl Hlth & Family Planning Commiss Parasit Dis C, Wuxi, Jiangsu, Peoples R China.
    Luo, Alex
    Univ Calif San Francisco, Global Hlth Sci, San Francisco, CA 94158 USA.
    Ranasinghe, Neil
    Thomson Reuters Ltd, London, England.
    Bennett, Adam
    Univ Calif San Francisco, Global Hlth Grp, Malaria Eliminat Initiat, 550 16th St,3rd Floor, San Francisco, CA 94158 USA;Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA 94158 USA.
    Cao, Jun
    Jiangsu Inst Parasit Dis, Jiangsu Prov Key Lab Parasite & Vector Control Te, Key Lab, Natl Hlth & Family Planning Commiss Parasit Dis C, Wuxi, Jiangsu, Peoples R China.
    Gosling, Roly D.
    Univ Calif San Francisco, Global Hlth Grp, Malaria Eliminat Initiat, 550 16th St,3rd Floor, San Francisco, CA 94158 USA;Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA 94158 USA.
    Piloting a programme tool to evaluate malaria case investigation and reactive case detection activities: results from 3 settings in the Asia Pacific2017In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 16, article id 347Article in journal (Refereed)
    Abstract [en]

    Background: Case investigation and reactive case detection (RACD) activities are widely-used in low transmission settings to determine the suspected origin of infection and identify and treat malaria infections nearby to the index patient household. Case investigation and RACD activities are time and resource intensive, include methodologies that vary across eliminating settings, and have no standardized metrics or tools available to monitor and evaluate them. Methods: In response to this gap, a simple programme tool was developed for monitoring and evaluating (M&E) RACD activities and piloted by national malaria programmes. During the development phase, four modules of the RACD M&E tool were created to assess and evaluate key case investigation and RACD activities and costs. A pilot phase was then carried out by programme implementers between 2013 and 2015, during which malaria surveillance teams in three different settings (China, Indonesia, Thailand) piloted the tool over a period of 3 months each. This study describes summary results of the pilots and feasibility and impact of the tool on programmes. Results: All three study areas implemented the RACD M&E tool modules, and pilot users reported the tool and evaluation process were helpful to identify gaps in RACD programme activities. In the 45 health facilities evaluated, 71.8% (97/135; min 35.3-max 100.0%) of the proper notification and reporting forms and 20.0% (27/135; min 0.0-max 100.0%) of standard operating procedures (SOPs) were available to support malaria elimination activities. The tool highlighted gaps in reporting key data indicators on the completeness for malaria case reporting (98.8%; min 93.3-max 100.0%), case investigations (65.6%; min 61.8-max 78.4%) and RACD activities (70.0%; min 64.7-max 100.0%). Evaluation of the SOPs showed that knowledge and practices of malaria personnel varied within and between study areas. Average monthly costs for conducting case investigation and RACD activities showed variation between study areas (min USD $844.80-max USD $2038.00) for the malaria personnel, commodities, services and other costs required to carry out the activities. Conclusion: The RACD M&E tool was implemented in the three pilot areas, identifying key gaps that led to impacts on programme decision making. Study findings support the need for routine M&E of malaria case reporting, case investigation and RACD activities. Scale-up of the RACD M&E tool in malaria-eliminating settings will contribute to improved programme performance to the high level that is required to reach elimination.

  • 6.
    Dahal, Prabin
    et al.
    World Wide Antimalarial Resistance Network WWARN, Oxford, England;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, WorldWide Antimalarial Resistance Network WWARN, Oxford, England.
    Simpson, Julie Anne
    Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostatist, Melbourne, Vic, Australia.
    Abdulla, Salim
    Ifakara Hlth Inst, Dar Es Salaam, Tanzania.
    Achan, Jane
    MRC Unit, Banjul, Gambia.
    Adam, Ishag
    Univ Khartoum, Fac Med, Khartoum, Sudan.
    Agarwal, Aarti
    Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, Atlanta, GA USA.
    Allan, Richard
    Mentor Initiat, Fajara, Gambia.
    Anvikar, Anupkumar R.
    Natl Inst Malaria Res, Sector 8, Dwarka, New Delhi 110077, India.
    Arinaitwe, Emmanuel
    Infect Dis Res Collaborat, Kampala, Uganda.
    Ashley, Elizabeth A.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Myanmar Oxford Clin Res Unit, Yangon, Myanmar.
    Awab, Ghulam Rahim
    Mahidol Univ, Fac Trop Med, Bangkok, Thailand;Minist Publ Hlth, Islam Republ Afghanistan, Kabul, Afghanistan.
    Bassat, Quique
    Ctr Investigacao Saude Manhica CISM, Maputo, Mozambique;Univ Barcelona, Hosp Clin, ISGlobal, Barcelona, Spain;ICREA, Pg Lluis Companys 23, Barcelona 08010, Spain.
    Bjorkman, Anders
    Karolinska Inst, Depatment Microbiol Tumour & Cell Biol, Stockholm, Sweden.
    Bompart, Francois
    Sanofi Access Med, Gentilly, France.
    Borrmann, Steffen
    Kenya Med Res Inst Kilifi, Kilifi, Kenya;Wellcome Trust Res Programme, Kilifi, Kenya;Heidelberg Univ, Sch Med, Dept Infect Dis, Heidelberg, Germany.
    Bousema, Teun
    Radboud Inst Hlth Sci, Radboudumc Nijmegen, Nijmegen, Netherlands;Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, Nijmegen, Netherlands.
    Broek, Ingrid
    Centrum Infectieziektebestrijding, Epidemioloog Epidemiol Surveillance RIVM, Bilthoven, Netherlands.
    Bukirwa, Hasifa
    African Field Epidemiol Network, Kampala, Uganda.
    Carrara, Verena I.
    Shoklo Malaria Res Unit, Mae Sot, Bangkok, Thailand;Mahidol Oxford Univ Res Unit, Bangkok, Thailand.
    Corsi, Marco
    Private Consultancy Drug Dev Trop Dis, Sigma Tau SpA Ind Farmaceutiche Riunite, Pomezia, Rome, Italy.
    Cot, Michel
    Univ Paris 05, Sorbonne Paris Cite, MERIT, IRD, F-75006 Paris, France.
    D'Alessandro, Umberto
    MRC Unit, Fajara, Gambia;London Sch Hyg & Trop Med, London, England.
    Davis, Timothy M. E.
    Univ Western Australia, Sch Med & Pharmacol, Crawley, WA, Australia.
    de Wit, Marit
    Med Sans Frontieres Operat Ctr Amsterdam, Geneva, Switzerland.
    Deloron, Philippe
    Univ Paris 05, Sorbonne Paris Cite, MERIT, IRD, F-75006 Paris, France.
    Desai, Meghna
    Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, Atlanta, GA USA.
    Dimbu, Pedro Rafael
    Natl Malaria Control Program, Luanda, Angola.
    Djalle, Djibrine
    Inst Pasteur, BP 923, Bangui, Cent Afr Republ.
    Djimde, Abdoulaye
    Univ Sci Techn & Technol Bamako, Fac Pharm, Malaria Res & Training Ctr, Dept Epidemiol Parasit Dis, Bamako, Mali.
    Dorsey, Grant
    Univ Calif San Francisco, Dept Med, San Francisco, CA USA.
    Doumbo, Ogobara K.
    Univ Sci Techn & Technol Bamako, Malaria Res & Training Ctr, Dept Epidemiol Parasit Dis, Fac Med & Odonto Stomatol, Bamako, Mali.
    Drakeley, Chris J.
    London Sch Hyg & Trop Med, Dept Infect & Immun, London, England.
    Duparc, Stephan
    Med Malaria Venture, Geneva, Switzerland.
    Edstein, Michael D.
    Australian Army Malaria Inst, Brisbane, Qld, Australia.
    Espie, Emmanuelle
    R&D Ctr, GSK Vaccines, Clin & Epidemiol Dept, Epicentre, Ave Fleming 20,1300 Wavre,8 Rue St Sabin, F-75011 Paris, France.
    Faiz, Abul
    Malaria Res Grp, Chittagong, Bangladesh;Dev Care Fdn, Dhaka, Bangladesh.
    Falade, Catherine
    Univ Ibadan, Coll Med, Dept Pharmacol & Therapeut, Ibadan, Nigeria.
    Fanello, Caterina
    Univ Oxford, Nuffield Dept Med, Ctr Global Hlth, Oxford, England.
    Faucher, Jean-Francois
    Besancon Univ Med Ctr, Dept Infect Dis, Mother & Child Hlth Trop Res Unit, Inst Rech Dev IRD, Besancon, France.
    Faye, Babacar
    Univ Cheikh Anta Diop, Fac Med, Dept Med Parasitol, Dakar, Senegal.
    Fortes, Filomeno de Jesus
    Natl Malaria Control Program, Luanda, Angola.
    Gadalla, Nahla B.
    Sudanese Amer Med Assoc, Fairfax, VA USA.
    Gaye, Oumar
    Univ Cheikh Anta Diop, Dept Med Parasitol, Fac Med, Dakar, Senegal.
    Gil, J. Pedro
    Karolinska Inst, Div Pharmacogenet, Dept Physiol & Pharmacol, Drug Resistance Unit, Stockholm, Sweden;Univ Lisbon, Ctr Biodivers Funct & Integrat Gen, Fac Ciencias, Lisbon, Portugal.
    Greenwood, Brian
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London, England.
    Grivoyannis, Anastasia
    Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA.
    Hamed, Kamal
    Basilea Pharmaceut Int Ltd, Basel, Switzerland;Novartis Pharmaceut, E Hanover, NJ USA.
    Hien, Tran Tinh
    Oxford Univ Clin Res Unit OUCRU, Ctr Trop Med, Wellcome Trust Major Overseas Program MOP, Oxford, England.
    Hughes, David
    Novartis Int AG, Basel, Switzerland.
    Humphreys, Georgina
    Wellcome Trust Res Labs, London, England;World Wide Antimalarial Resistance Network WWARN, London, England.
    Hwang, Jimee
    US Centers Dis Control & Prevent, Div Parasit Dis & Malaria, US Presidents Malaria Initiat Malaria Branch, Atlanta, GA USA;Univ Calif San Francisco, San Francisco, CA 94143 USA;Global Hlth Grp, San Francisco, CA 94143 USA.
    Ibrahim, Maman Laminou
    Ctr Rech Med & Saniataire CERMES, Niamey, Niger.
    Janssens, Bart
    Medecins Sans Frontieres, Phnom Penh, Belgium.
    Jullien, Vincent
    Univ Paris 05, Assistance Publique Hop Paris, Serv Pharmacol Clin, Paris, France;Grp Hosp Cochin Saint Vincent Paul, Inserm U663, WWARN, Paris, France.
    Juma, Elizabeth
    Kenya Govt Med Res Ctr, Nairobi, Kenya.
    Kamugisha, Erasmus
    Weill Bugando Univ Coll Hlth Sci, Mwanza, Tanzania.
    Karema, Corine
    Minist Hlth, Natl Malaria Control Program TRAC Plus, Kigali, Rwanda.
    Karunajeewa, Harin A.
    Walter & Eliza Hall Inst Med Res, Parkville, Vic, Australia.
    Kiechel, Jean R.
    Drugs Neglected Dis initiat, Geneva, Switzerland.
    Kironde, Fred
    Islam Univ Uganda, Habib Med Sch, Kampala, Uganda.
    Kofoed, Poul-Erik
    Bandim Hlth Project, Indepth Network, Apartado 861, Bissau, Guinea Bissau;Lillebaelt Hosp, Hlth Serv Res Unit, Vejle, Denmark;IRS Univ Southern Denmark, Vejle, Denmark;Kolding Cty Hosp, Dept Paediat, Kolding, Denmark.
    Kremsner, Peter G.
    Univ Tubingen, Inst Trop Med, Tubingen, Germany;Ctr Recherches Medic Lambarene, Lambarene, Gabon.
    Lameyre, Valerie
    Sanofi Access Med, Gentilly, France.
    Lee, Sue J.
    Mahidol Univ, Fac Trop Med, Bangkok, Thailand;Churchill Hosp, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England.
    Marsh, Kevin
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Wellcome Trust Res Programme, Kilifi, Kenya;Kenya Govt Med Res Ctr, Kilifi, Kenya.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Mayxay, Mayfong
    Mahosot Hosp, Lao Oxford Mahosot Hospital, Wellcome Trust Res Unit, Microbiol Lab, Viangchan, Laos.
    Menan, Herve
    Univ Cocody, Dept Parasitol, Fac Pharm, Abidjan, Cote Ivoire;Univ Hlth Sci, Minist Hlth, Fac Postgraduate Studies, Viangchan, Laos.
    Mens, Petra
    Acad Med Ctr, Med Microbiol Parasitol, Amsterdam, Netherlands.
    Mutabingwa, Theonest K.
    Hubert Kairuki Mem Univ, Dar Es Salaam, Tanzania;London Sch Hyg & Trop Med, Dept Infect & Trop Dis, London, England.
    Ndiaye, Jean-Louis
    Univ Cheikh Anta Diop, Fac Med, Parasitol & Mycol Lab, Dakar, Senegal.
    Ngasala, Billy E.
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol, Dar Es Salaam, Tanzania;Karolinska Inst, Dept Med Solna, Infect Dis Unit, Malaria Res, Stockholm, Sweden.
    Noedl, Harald
    Med Univ Vienna, Vienna, Austria.
    Nosten, Francois
    Univ Oxford, Nuffield Dept Med Res Bldg, Ctr Trop Med & Global Hlth, Old Rd Campus, Oxford, England;Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Shoklo Malaria Res Unit, Mae Sot, Thailand.
    Offianan, Andre Toure
    Inst Pasteur Cote Ivoire, Malariol Dept, Abidjan, Cote Ivoire.
    Oguike, Mary
    London Sch Hyg & Trop Med, Dept Immunol & Infect, London, England.
    Ogutu, Bernhards R.
    Kenya Govt Med Res Ctr, Kisumu, Kenya;US Army Med Res Unit, Kisumu, Kenya.
    Olliaro, Piero
    UNICEF, UNDP, World Bank, WHO TDR, Geneva, Switzerland.
    Ouedraogo, Jean Bosco
    Inst Rech Sci Sante, Direct Regionale Ouest, Bobo Dioulasso, Burkina Faso;Ctr Muraz Bobo Dioulasso, Non Transmissible Dis Dept, Bobo Dioulasso, Burkina Faso.
    Piola, Patrice
    Inst Pasteur Cambodge, Phnom Penh, Cambodia.
    Plowe, Christopher V.
    Duke Univ, Duke Global Hlth Inst, Durham, NC USA.
    Plucinski, Mateusz M.
    US Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, US Presidents Malaria Initiat, Atlanta, GA USA;Ctr Dis Control & Prevent, Epidem Intelligence Serv, Atlanta, GA USA.
    Pratt, Oliver James
    Minist Hlth & Social Welf, Natl Malaria Control Program, Monrovia, Liberia.
    Premji, Zulfikarali
    Muhimbili Univ Coll Hlth Sci, Dar Es Salaam, Tanzania.
    Ramharter, Michael
    Univ Med Ctr Hamburg Eppendorf, Dept Med 1, Bernhard Nocht Inst Trop Med, Dept Trop Med, Hamburg, Germany.
    Rogier, Christophe
    Div Expertise & Def Hlth strategy, Cent Directorate, French Mil Hlth Serv, Paris, France;IRBA, Bretigny Sur Orge, France;URMITE, UMR 6236, Marseille, France.
    Rombo, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Rosenthal, Philip J.
    Univ Calif San Francisco, Dept Med, San Francisco, CA USA.
    Sawa, Patrick
    Human Hlth Div, Int Ctr Insect Physiol & Ecol, Mbita, Kenya.
    Schramm, Birgit
    Epicentre, Paris, France.
    Sibley, Carol
    WWARN, Oxford, England;Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA.
    Sinou, Veronique
    Aix Marseille Univ, INSERM, SSA, IRBA,MCT, Marseille, France.
    Sirima, Sodiomon
    GRAS, 06 BP 10248, Ouagadougou 06, Burkina Faso.
    Smithuis, Frank
    Myanmar Oxford Clin Res Unit, Oxford, England.
    Staedke, Sarah G.
    Infect Dis Res Collaborat, Kampala, Uganda;London Sch Hyg & Trop Med, Dept Clin Res, London, England.
    Sutanto, Inge
    Univ Indonesia, Dept Parasitol, Fac Med, 6 Salemba Raya, Jakarta 10430, Indonesia.
    Talisuna, Ambrose Otau
    WHO, Reg Off Afr, Brazzaville, Rep Congo;Univ Oxford, Nuffield Dept Med, Ctr Trop Med & Global Hlth, Oxford, England.
    Tarning, Joel
    WorldWide Antimalarial Resistance Network, Oxford, England;Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand.
    Taylor, Walter R. J.
    Mahidol Univ, Fac Trop Med, Bangkok, Thailand.
    Temu, Emmanuel
    MENTOR Initiat, Crawley, England.
    Thriemer, Kamala L.
    Charles Darwin Univ, Menzies Sch Hlth Res, Global & Trop Hlth Div, Darwin, NT, Australia.
    Thuy, Nhien Nguyen
    Oxford Univ Clin Res Unit OUCRU, Wellcome Trust Major Overseas Program MOP, Ctr Trop Med, Oxford, England.
    Udhayakumar, Venkatachalam
    Ctr Dis Control & Prevent, Ctr Global Hlth, Div Parasit Dis & Malaria, Malaria Branch & Presidents Malaria Initiat, Atlanta, GA USA.
    Ursing, Johan
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC C1, Solna, Sweden;Danderyd Hosp, Dept Infect Dis, Danderyd, Sweden.
    van Herp, Michel
    Operat Ctr Brussels, Med Sans Frontieres, Brussels, Belgium;Univ Amsterdam, Acad Med Ctr, Div Infect Dis, Ctr Trop Med & Travel Med, Amsterdam, Netherlands.
    van Vugt, Michele
    Whitty, Christopher
    London Sch Hyg & Trop Med, Dept Infect & Trop Dis, Malaria Partnership, London, England.
    William, Yavo
    Univ Cocody, Dept Parasitol, Fac Pharm, Abidjan, Cote Ivoire.
    Winnips, Cornelis
    NovartisInternat AG, Basel, Switzerland.
    Zongo, Issaka
    Inst Rech Sci Sante, Direct Regionale lOuest, Bobo Dioulasso, Burkina Faso.
    Guerin, Philippe
    World Wide Antimalarial Resistance Network WWARN, Oxford, England;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England.
    Price, Ric N.
    World Wide Antimalarial Resistance Network WWARN, Oxford, England;Menzies Sch Hlth Res Charles Darwin Univ, Darwin, NT, Australia;Churchill Hosp, Ctr Clin Vaccinol & Trop Med, Oxford, England.
    Stepniewska, Kasia
    World Wide Antimalarial Resistance Network WWARN, Oxford, England;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, WorldWide Antimalarial Resistance Network WWARN, Oxford, England.
    Competing risk events in antimalarial drug trials in uncomplicated Plasmodium falciparum malaria: a WorldWide Antimalarial Resistance Network individual participant data meta-analysis2019In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 18, article id 225Article in journal (Refereed)
    Abstract [en]

    Background: Therapeutic efficacy studies in uncomplicated Plasmodium falciparum malaria are confounded by new infections, which constitute competing risk events since they can potentially preclude/pre-empt the detection of subsequent recrudescence of persistent, sub-microscopic primary infections.

    Methods: Antimalarial studies typically report the risk of recrudescence derived using the Kaplan-Meier (K-M) method, which considers new infections acquired during the follow-up period as censored. Cumulative Incidence Function (CIF) provides an alternative approach for handling new infections, which accounts for them as a competing risk event. The complement of the estimate derived using the K-M method (1 minus K-M), and the CIF were used to derive the risk of recrudescence at the end of the follow-up period using data from studies collated in the WorldWide Antimalarial Resistance Network data repository. Absolute differences in the failure estimates derived using these two methods were quantified. In comparative studies, the equality of two K-M curves was assessed using the log-rank test, and the equality of CIFs using Gray's k-sample test (both at 5% level of significance). Two different regression modelling strategies for recrudescence were considered: cause-specific Cox model and Fine and Gray's sub-distributional hazard model.

    Results: Data were available from 92 studies (233 treatment arms, 31,379 patients) conducted between 1996 and 2014. At the end of follow-up, the median absolute overestimation in the estimated risk of cumulative recrudescence by using 1 minus K-M approach was 0.04% (interquartile range (IQR): 0.00-0.27%, Range: 0.00-3.60%). The overestimation was correlated positively with the proportion of patients with recrudescence [Pearson's correlation coefficient (rho): 0.38, 95% Confidence Interval (CI) 0.30-0.46] or new infection [rho: 0.43; 95% CI 0.35-0.54]. In three study arms, the point estimates of failure were greater than 10% (the WHO threshold for withdrawing antimalarials) when the K-M method was used, but remained below 10% when using the CIF approach, but the 95% confidence interval included this threshold.

    Conclusions: The 1 minus K-M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efficacy declined, particularly when the observed proportion of new infection was high. The CIF approach provides an alternative approach for derivation of failure estimates in antimalarial trials, particularly in high transmission settings.

  • 7. Golassa, Lemu
    et al.
    Enweji, Nizar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Erko, Berhanu
    Aseffa, Abraham
    Swedberg, Göte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Detection of a substantial number of sub-microscopic Plasmodium falciparum infections by polymerase chain reaction: a potential threat to malaria control and diagnosis in Ethiopia2013In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 12, p. 352-Article in journal (Refereed)
    Abstract [en]

    Background: Prompt and effective malaria diagnosis not only alleviates individual suffering, but also decreases malaria transmission at the community level. The commonly used diagnostic methods, microscopy and rapid diagnostic tests, are usually insensitive at very low-density parasitaemia. Molecular techniques, on the other hand, allow the detection of low-level, sub-microscopic parasitaemia. This study aimed to explore the presence of sub-microscopic Plasmodium falciparum infections using polymerase chain reaction (PCR). The PCR-based parasite prevalence was compared against microscopy and rapid diagnostic test (RDT). Methods: This study used 1,453 blood samples collected from clinical patients and sub-clinical subjects to determine the prevalence of sub-microscopic P. falciparum carriages. Subsets of RDT and microscopy negative blood samples were tested by PCR while all RDT and microscopically confirmed P. falciparum-infected samples were subjected to PCR. Finger-prick blood samples spotted on filter paper were used for parasite genomic DNA extraction. Results: The prevalence of sub-microscopic P. falciparum carriage was 19.2% (77/400) (95% CI = 15.4-23.1). Microscopy-based prevalence of P. falciparum infection was 3.7% (54/1,453) while the prevalence was 6.9% (100/1,453) using RDT alone. Using microscopy and PCR, the estimated parasite prevalence was 20.6% if PCR were performed in 1,453 blood samples. The prevalence was estimated to be 22.7% if RDT and PCR were used. Of 54 microscopically confirmed P. falciparum-infected subjects, PCR detected 90.7% (49/54). Out of 100 RDT-confirmed P. falciparum infections; PCR detected 80.0% (80/100). The sensitivity of PCR relative to microscopy and RDT was, therefore, 90.7% and 80%, respectively. The sensitivity of microscopy and RDT relative to PCR was 16.5 (49/299) and 24.2% (80/330), respectively. The overall PCR-based prevalence of P. falciparum infection was 5.6- and 3.3 fold higher than that determined by microscopy and RDT, respectively. None of the sub-microscopic subjects had severe anaemia, though 29.4% had mild anaemia (10-11.9 g/dl). Conclusions: Asymptomatic, low-density malaria infection was common in the study area and PCR may be a better tool for measuring Plasmodium prevalence than microscopy and RDT. The inadequate sensitivity of the diagnostic methods to detect substantial number of sub-microscopic parasitaemia would undoubtedly affect malaria control efforts, making reduction of transmission more difficult. RDT and microscopy-based prevalence studies and subsequent reports of reduction in malaria incidence underestimate the true pictures of P. falciparum infections in the community. PCR, on the other hand, seems to have reasonable sensitivity to detect a higher number of infected subjects with low and sub-microscopic parasite densities than RDTs or microscopy.

  • 8. Golassa, Lemu
    et al.
    Enweji, Nizar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Erko, Berhanu
    Aseffa, Abraham
    Swedberg, Göte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    High prevalence of pfcrt-CVIET haplotype in isolates from asymptomatic and symptomatic patients in south-central Oromia, Ethiopia2014In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 13, p. 120-Article in journal (Refereed)
    Abstract [en]

    Background: As a result of extensive chloroquine resistance (CQR) in Plasmodium falciparum in late 1990s, Ethiopia replaced CQ with sulphadoxine-pyrimethamine (SP) as first-line drug, which in turn was replaced by artemisinin combination therapy in 2004. Plasmodium falciparum resistance to CQ is determined by the mutation at K76T of the P. falciparum chloroquine resistance transporter (pfcrt) gene. Understanding diversity in the P. falciparum genome is crucial since it has the potential to influence important phenotypes of the parasite such as drug resistance. Limited data is available regarding the type of pfcrt mutant allelic type, the effect of CQ withdrawal and diversity of the parasite population in south-central Oromia, Ethiopia. Methods: Finger-pricked blood spotted on Whatman 3MM filter papers were collected from falciparum malaria patients. Parasite DNA was extracted from individual blood spots on the filter papers. The presence of K76T mutations was determined using nested PCR for all isolates. Complete sequencing of mutations in pfcrt 72-76 was done for a set of randomly selected resistant isolates. Four microsatellite (MS) markers were analysed to determine the heterozygosity. Results: Although CQ was withdrawn for more than a decade, 100% of the parasites still carried the pfcrt K76T mutation. All isolates were mutant at the K76T polymorphism. Based on combinations of MS markers, seven different Ethiopian CQR variants (E1-E7) were identified. Heterozygosity (He) for MS flanking the pfcrt chloroquine resistance allele ranged from 0.00 (mscrt -29, -29.268 kb) to 0.21 (mscrt -2, -2.814 kb). H-e ranged from 0.00 (msint 3, 0 kb) to 0.19 (msint 2, 0 kb) for MS within the pfcrt gene. Both intronic and MS flanking the pfcrt gene showed low levels of diversity. Conclusion: pfcrt CQR allele seems to be fixed in the study area. Of the different haplotypes associated with CQR, only the CVIET genotype was identified. No reversal to the wild-type has occurred in Ethiopia unlike in many Africa countries where CQR parasites declined after cessation of CQ use. Decreased diversity in CQR isolates surrounding pfcrt suggests CQ selection and homogenization among CQR parasite population. While mutation in msint 3 and mscrt -29 of the mutant pfcrt allele is being fixed, it seems that mutations in msint 2 and mscrt -2 are still evolving and may indicate the start of re-diversification of the population from a fixed 76 T population.

  • 9. Golassa, Lemu
    et al.
    Erko, Berhanu
    Baliraine, Frederick N.
    Aseffa, Abraham
    Swedberg, Göte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Polymorphisms in chloroquine resistance-associated genes in Plasmodium vivax in Ethiopia2015In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, article id 164Article in journal (Refereed)
    Abstract [en]

    Background: Evidence for decreasing chloroquine (CQ) efficacy against Plasmodium vivax has been reported from many endemic countries in the world. In Ethiopia, P. vivax accounts for 40% of all malaria cases and CQ is the first-line drug for vivax malaria. Mutations in multidrug resistance 1 (pvmdr-1) and K10 insertion in the pvcrt-o genes have been identified as possible molecular markers of CQ-resistance (CQR) in P. vivax. Despite reports of CQ treatment failures, no data are currently available on the prevalence of molecular markers of P. vivax resistance in Ethiopia. The objective of this study was to determine the prevalence of mutations in the pvmdr-1 and K10 insertion in the pvcrt-o genes. Methods: A total of 36 P. vivax clinical isolates were collected from West Arsi district in Ethiopia. Sequencing was used to analyse polymorphisms of the pvcrt-o and pvmdr-1 genes. Results: Sequencing results of the pvmdr-1 fragment showed the presence of two non-synonymous mutations at positions 976 and 1076. The Y -> F change at codon 976 (TAC -> TTC) was observed in 21 (75%) of 28 the isolates while the F -> L change (at codon 1076), which was due to a single mutation (TTT -> CTT), was observed in 100% of the isolates. Of 33 samples successfully amplified for the pvcrt-o, the majority of the isolates (93.9%) were wild type, without K10 insertion. Conclusions: High prevalence of mutations in candidate genes conferring CQR in P. vivax was identified. The fact that CQ is still the first-line treatment for vivax malaria, the significance of mutations in the pvcrt-o and pvmdr-1 genes and the clinical response of the patients' to CQ treatment and whether thus an association exists between point mutations of the candidate genes and CQR requires further research in Ethiopia.

  • 10. Golassa, Lemu
    et al.
    Kamugisha, Erasmus
    Ishengoma, Deus S.
    Baraka, Vito
    Shayo, Alex
    Baliraine, Frederick N.
    Enweji, Nizar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Erko, Berhanu
    Aseffa, Abraham
    Choy, Angel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Swedberg, Göte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Identification of large variation in pfcrt, pfmdr-1 and pfubp-1 markers in Plasmodium falciparum isolates from Ethiopia and Tanzania2015In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, article id 264Article in journal (Refereed)
    Abstract [en]

    Background: Plasmodium falciparum resistance to anti-malarials is a major drawback in effective malaria control and elimination globally. Artemisinin-combination therapy (ACT) is currently the key first-line treatment for uncomplicated falciparum malaria. Plasmodium falciparum genetic signatures at pfmdr-1, pfcrt, and pfubp-1 loci are known to modulate in vivo and in vitro parasite response to ACT. The objective of this study was to assess the distribution of these resistance gene markers in isolates collected from different malaria transmission intensity in Ethiopia and Tanzania. Methods: Plasmodium falciparum clinical isolates were collected from different regions of Ethiopia and Tanzania. Genetic polymorphisms in the genes pfcrt, pfmdr-1 and pfubp-1 were analysed by PCR and sequencing. Frequencies of the different alleles in the three genes were compared within and between regions, and between the two countries. Results: The majority of the isolates from Ethiopia were mutant for the pfcrt 76 and wild-type for pfmdr-1 86. In contrast, the majority of the Tanzanian samples were wild-type for both pfcrt and pfmdr-1 loci. Analysis of a variable linker region in pfmdr-1 showed substantial variation in isolates from Tanzania as compared to Ethiopian isolates that had minimal variation. Direct sequencing of the pfubp-1 region showed that 92.8% (26/28) of the Ethiopian isolates had identical genome sequence with the wild type reference P. falciparum strain 3D7. Of 42 isolates from Tanzania, only 13 (30.9%) had identical genome sequences with 3D7. In the Tanzanian samples, 10 variant haplotypes were identified. Conclusion: The majority of Ethiopian isolates carried the main marker for chloroquine (CQ) resistance, while the majority of the samples from Tanzania carried markers for CQ susceptibility. Polymorphic genes showed substantially more variation in Tanzanian isolates. The low variability in the polymorphic region of pfmdr-1 in Ethiopia may be a consequence of low transmission intensity as compared to high transmission intensity and large variations in Tanzania.

  • 11.
    Ishengoma, Deus S.
    et al.
    Natl Inst Med Res, Tanga Res Ctr, Tanga, Tanzania.
    Mandara, Celine I.
    Natl Inst Med Res, Tanga Res Ctr, Tanga, Tanzania;Kilimanjaro Christian Med Univ Coll, Kilimanjaro Christian Med Ctr, Moshi, Tanzania.
    Francis, Filbert
    Natl Inst Med Res, Tanga Res Ctr, Tanga, Tanzania.
    Talundzic, Eldin
    Ctr Dis Control & Prevent, Malaria Branch, Div Parasit Dis & Malaria, Atlanta, GA USA.
    Lucchi, Naomi W.
    Ctr Dis Control & Prevent, Malaria Branch, Div Parasit Dis & Malaria, Atlanta, GA USA.
    Ngasala, Billy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition. Muhimbili Univ Hlth & Allied Sci, Dept Parasitol, Sch Publ Hlth, Dar Es Salaam, Tanzania.
    Kabanywanyi, Abdunoor M.
    Ifakara Hlth Inst, Dar Es Salaam, Tanzania.
    Mahende, Muhidin K.
    Ifakara Hlth Inst, Dar Es Salaam, Tanzania.
    Kamugisha, Erasmus
    Catholic Univ Hlth & Allied Sci, Bugando Med Ctr, Mwanza, Tanzania.
    Kavishe, Reginald A.
    Kilimanjaro Christian Med Univ Coll, Kilimanjaro Christian Med Ctr, Moshi, Tanzania.
    Muro, Florida
    Kilimanjaro Christian Med Univ Coll, Kilimanjaro Christian Med Ctr, Moshi, Tanzania.
    Mohamed, Ally
    Natl Malaria Control Programme, Ocean Rd Luthuli Ave NIMR Complex, Dar Es Salaam, Tanzania.
    Mandike, Renata
    Natl Malaria Control Programme, Ocean Rd Luthuli Ave NIMR Complex, Dar Es Salaam, Tanzania.
    Mkude, Sigsbert
    Natl Malaria Control Programme, Ocean Rd Luthuli Ave NIMR Complex, Dar Es Salaam, Tanzania.
    Chacky, Frank
    Natl Malaria Control Programme, Ocean Rd Luthuli Ave NIMR Complex, Dar Es Salaam, Tanzania.
    Paxton, Lynn
    Ctr Dis Control & Prevent, Malaria Branch, Div Parasit Dis & Malaria, Atlanta, GA USA.
    Greer, George
    US Embassy, US Presidents Malaria Initiat, US Agcy Int Dev, Dar Es Salaam, Tanzania.
    Kitojo, Chonge A.
    US Embassy, US Presidents Malaria Initiat, US Agcy Int Dev, Dar Es Salaam, Tanzania.
    Njau, Ritha
    WHO, Country Off, Dar Es Salaam, Tanzania.
    Martin, Troy
    Fred Hutchinson Canc Res Ctr, HIV Vaccine Trials Network, 1124 Columbia St, Seattle, WA 98104 USA.
    Venkatesan, Meera
    US Agcy Int Dev, US Presidents Malaria Initiat, Washington, DC 20523 USA.
    Warsame, Marian
    WHO, Global Malaria Programme, 20 Ave Appia, CH-1211 Geneva 27, Switzerland;Gothenburg Univ, Gothenburg, Sweden.
    Halsey, Eric S.
    Ctr Dis Control & Prevent, Malaria Branch, Div Parasit Dis & Malaria, Atlanta, GA USA;Ctr Dis Control & Prevent, US Presidents Malaria Initiat, Atlanta, GA USA.
    Udhayakumar, Venkatachalam
    Ctr Dis Control & Prevent, Malaria Branch, Div Parasit Dis & Malaria, Atlanta, GA USA.
    Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated malaria and prevalence of Pfk13 and Pfmdr1 polymorphisms after a decade of using artemisinin-based combination therapy in mainland Tanzania2019In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 18, article id 88Article in journal (Refereed)
    Abstract [en]

    Background: The World Health Organization recommends regular therapeutic efficacy studies (TES) to monitor the performance of first and second-line anti-malarials. In 2016, efficacy and safety of artemether-lumefantrine (AL) for the treatment of uncomplicated falciparum malaria were assessed through a TES conducted between April and October 2016 at four sentinel sites of Kibaha, Mkuzi, Mlimba, and Ujiji in Tanzania. The study also assessed molecular markers of artemisinin and lumefantrine (partner drug) resistance.

    Methods: Eligible patients were enrolled at the four sites, treated with standard doses of AL, and monitored for 28 days with clinical and laboratory assessments. The main outcomes were PCR corrected cure rates, day 3 positivity rates, safety of AL, and prevalence of single nucleotide polymorphisms in Plasmodium falciparum kelch 13 (Pfk13) (codon positions: 440-600) and P. falciparum multi-drug resistance 1 (Pfmdr1) genes (codons: N86Y, Y184F and D1246Y), markers of artemisinin and lumefantrine resistance, respectively.

    Results: Of 344 patients enrolled, three withdrew, six were lost to follow-up; and results were analysed for 335 (97.4%) patients. Two patients had treatment failure (one early treatment failure and one recrudescent infection) after PCR correction, yielding an adequate clinical and parasitological response of > 98%. Day 3 positivity rates ranged from 0 to 5.7%. Common adverse events included cough, abdominal pain, vomiting, and diarrhoea. Two patients had serious adverse events; one died after the first dose of AL and another required hospitalization after the second dose of AL (on day 0) but recovered completely. Of 344 samples collected at enrolment (day 0), 92.7% and 100% were successfully sequenced for Pfk13 and Pfmdr1 genes, respectively. Six (1.9%) had non-synonymous mutations in Pfk13, none of which had been previously associated with artemisinin resistance. For Pfmdr1, the NFD haplotype (codons N86, 184F and D1246) was detected in 134 (39.0%) samples; ranging from 33.0% in Mlimba to 45.5% at Mkuzi. The difference among the four sites was not significant (p = 0.578). All samples had a single copy of the Pfmdr1 gene.

    Conclusion: The study indicated high efficacy of AL and the safety profile was consistent with previous reports. There were no known artemisinin-resistance Pfk13 mutations, but there was a high prevalence of a Pfmdr1 haplotype associated with reduced sensitivity to lumefantrine (but no reduced efficacy was observed in the subjects). Continued TES and monitoring of markers of resistance to artemisinin and partner drugs is critical for early detection of resistant parasites and to inform evidence-based malaria treatment policies.

  • 12.
    Johansson, Emily White
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Gething, Peter W
    Spatial Ecology and Epidemiology Group, Department of Zoology, University of Oxford, UK.
    Hildenwall, Helena
    Global Health - Health Systems and Policy, Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden.
    Mappin, Bonnie
    Spatial Ecology and Epidemiology Group, Department of Zoology, University of Oxford, UK.
    Petzold, Max
    University of Gothenburg, The Sahlgrenska Academy, Health Metrics, Gothenburg, Sweden.
    Peterson, Stefan Swartling
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Ekholm Selling, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Effect of diagnostic testing on medicines used by febrile children less than five years in 12 malaria-endemic African countries: a mixed-methods study2015In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, article id 194Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In 2010, WHO revised guidelines to recommend testing all suspected malaria cases prior to treatment. Yet, evidence to assess programmes is largely derived from limited facility settings in a limited number of countries. National surveys from 12 sub-Saharan African countries were used to examine the effect of diagnostic testing on medicines used by febrile children under five years at the population level, including stratification by malaria risk, transmission season, source of care, symptoms, and age.

    METHODS: Data were compiled from 12 Demographic and Health Surveys in 2010-2012 that reported fever prevalence, diagnostic test and medicine use, and socio-economic covariates (n = 16,323 febrile under-fives taken to care). Mixed-effects logistic regression models quantified the influence of diagnostic testing on three outcomes (artemisinin combination therapy (ACT), any anti-malarial or any antibiotic use) after adjusting for data clustering and confounding covariates. For each outcome, interactions between diagnostic testing and the following covariates were separately tested: malaria risk, season, source of care, symptoms, and age. A multiple case study design was used to understand varying results across selected countries and sub-national groups, which drew on programme documents, published research and expert consultations. A descriptive typology of plausible explanations for quantitative results was derived from a cross-case synthesis.

    RESULTS: Significant variability was found in the effect of diagnostic testing on ACT use across countries (e.g., Uganda OR: 0.84, 95% CI: 0.66-1.06; Mozambique OR: 3.54, 95% CI: 2.33-5.39). Four main themes emerged to explain results: available diagnostics and medicines; quality of care; care-seeking behaviour; and, malaria epidemiology.

    CONCLUSIONS: Significant country variation was found in the effect of diagnostic testing on paediatric fever treatment at the population level, and qualitative results suggest the impact of diagnostic scale-up on treatment practices may not be straightforward in routine conditions given contextual factors (e.g., access to care, treatment-seeking behaviour or supply stock-outs). Despite limitations, quantitative results could help identify countries (e.g., Mozambique) or issues (e.g., malaria risk) where facility-based research or programme attention may be warranted. The mixed-methods approach triangulates different evidence to potentially provide a standard framework to assess routine programmes across countries or over time to fill critical evidence gaps.

  • 13.
    Johansson, Emily White
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Kitutu, Freddy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH). Makerere University School of Public Health, College of Health Sciences.
    Mayora, Chrispus
    Makerere University School of Public Health, College of Health Sciences.
    Awor, Phyllis
    Makerere University School of Public Health, College of Health Sciences.
    Peterson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Wamani, Henry
    Makerere University School of Public Health, College of Health Sciences.
    Hildenwall, Helena
    Karolinska Institutet, Global Health - Health Systems and Policy Research Group.
    "It could be viral, but you don't know. You have not diagnosed it": Health worker challenges in managing non-malaria pediatric fevers in the low transmission area of Mbarara District, Uganda2016In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 15, article id 197Article in journal (Refereed)
    Abstract [en]

    Background: In 2012, Uganda initiated nationwide deployment of malaria rapid diagnostic tests (RDT) as recommended by national guidelines. Yet growing concerns about RDT non-compliance in various settings have spurred calls to deploy RDT as part of enhanced support packages. An understanding of how health workers currently manage non-malaria fevers, particularly for children, and challenges faced in this work should also inform efforts.

    Methods: A qualitative study was conducted in the low transmission area of Mbarara District (Uganda). In-depth interviews with 20 health workers at lower level clinics focused on RDT perceptions, strategies to differentiate non-malaria pediatric fevers, influences on clinical decisions, desires for additional diagnostics, and any challenges in this work. Seven focus group discussions were conducted with caregivers of children less than five years in facility catchment areas to elucidate their RDT perceptions, understandings of non-malaria pediatric fevers and treatment preferences. Data were extracted into meaning units to inform codes and themes in order to describe response patterns using a content analysis approach. 

    Findings: Differential diagnosis strategies included studying fever patterns, taking histories, assessing symptoms and analyzing other factors such as child’s age or home environment. If no alternative cause was found, malaria treatment was reportedly often prescribed despite a negative result. Other reasons for malaria over-treatment stemmed from RDT perceptions, system constraints and provider-client interactions. RDT perceptions included mistrust driven largely by expectations of false negative results due to low parasite/antigen loads, previous anti-malarial treatment or test detection of only one species. System constraints included poor referral systems, working alone without opportunity to confer on difficult cases, and lacking skills and/or tools for differential diagnosis. Provider-client interactions included reported caregiver RDT mistrust, demand for certain drugs, and desire to know the ‘exact’ disease cause if not malaria. Many health workers expressed uncertainty about how to manage non-malaria pediatric fevers, feared doing wrong and patient death, worried caregivers would lose trust, or felt unsatisfied without a clear diagnosis.  

    Conclusions: Enhanced support is needed to improve RDT adoption at lower level clinics that focuses on empowering providers to successfully manage non-severe non-malaria pediatric fevers without referral. This includes building trust in negative results, reinforcing integrated care initiatives (e.g. Integrated Management of Childhood Illness) and fostering communities of practice according to the Diffusion of Innovation model.

     

  • 14.
    Johansson, Emily White
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Selling, Katarina Ekholm
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Nsona, Humphreys
    Minist Hlth, Integrated Management Childhood Illness IMCI Unit, Lilongwe, Malawi..
    Mappin, Bonnie
    Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford, England..
    Gething, Peter W.
    Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford, England..
    Petzold, Max
    Univ Gothenburg, Ctr Appl Biostat, Sahlgrenska Acad, Gothenburg, Sweden..
    Peterson, Stefan Swartling
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH). Karolinska Inst, Dept Publ Hlth Sci, Global Hlth Hlth Syst & Policy Res Grp, Stockholm, Sweden.;Makerere Univ, Coll Hlth Sci, Sch Publ Hlth, Kampala, Uganda..
    Hildenwall, Helena
    Karolinska Inst, Dept Publ Hlth Sci, Global Hlth Hlth Syst & Policy Res Grp, Stockholm, Sweden..
    Integrated paediatric fever management and antibiotic over-treatment in Malawi health facilities: data mining a national facility census2016In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 15, article id 396Article in journal (Refereed)
    Abstract [en]

    Background: There are growing concerns about irrational antibiotic prescription practices in the era of test-based malaria case management. This study assessed integrated paediatric fever management using malaria rapid diagnostic tests (RDT) and Integrated Management of Childhood Illness (IMCI) guidelines, including the relationship between RDT-negative results and antibiotic over-treatment in Malawi health facilities in 2013-2014.

    Methods: A Malawi national facility census included 1981 observed sick children aged 2-59 months with fever complaints. Weighted frequencies were tabulated for other complaints, assessments and prescriptions for RDT-confirmed malaria, IMCI-classified non-severe pneumonia, and clinical diarrhoea. Classification trees using model-based recursive partitioning estimated the association between RDT results and antibiotic over-treatment and learned the influence of 38 other input variables at patient-, provider- and facility-levels.

    Results: Among 1981 clients, 72 % were tested or referred for malaria diagnosis and 85 % with RDT-confirmed malaria were prescribed first-line anti-malarials. Twenty-eight percent with IMCI-pneumonia were not prescribed antibiotics (under-treatment) and 59 % 'without antibiotic need' were prescribed antibiotics (over-treatment). Few clients had respiratory rates counted to identify antibiotic need for IMCI-pneumonia (18 %). RDT-negative children had 16.8 (95 % CI 8.6-32.7) times higher antibiotic over-treatment odds compared to RDT-positive cases conditioned by cough or difficult breathing complaints.

    Conclusions: Integrated paediatric fever management was sub-optimal for completed assessments and antibiotic targeting despite common compliance to malaria treatment guidelines. RDT-negative results were strongly associated with antibiotic over-treatment conditioned by cough or difficult breathing complaints. A shift from malaria-focused 'test and treat' strategies toward 'IMCI with testing' is needed to improve quality fever care and rational use of both anti-malarials and antibiotics in line with recent global commitments to combat resistance.

  • 15.
    Jovel, Irina T.
    et al.
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Malaria Res, Stockholm, Sweden..
    Björkman, Anders
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Malaria Res, Stockholm, Sweden..
    Roper, Cally
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London, England..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Ursing, Johan
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Malaria Res, Stockholm, Sweden.;Danderyd Hosp, Dept Infect Dis, Stockholm, Sweden..
    Unexpected selections of Plasmodium falciparum polymorphisms in previously treatment-naive areas after monthly presumptive administration of three different anti-malarial drugs in Liberia 1976-782017In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 16, article id 113Article in journal (Refereed)
    Abstract [en]

    Background: To assess the effect on malaria prevalence, village specific monthly administrations of pyrimethamine, chlorproguanil, chloroquine or placebo were given to children in four previously treatment-naive Liberian villages, 1976-78. Plasmodium falciparum in vivo resistance developed to pyrimethamine only. Selection of molecular markers of P.falciparum resistance after 2 years of treatment are reported. Methods: Blood samples were collected from 191 study children in a survey in 1978. Polymorphisms in pfcrt, pfmdr1, pfdhfr, pfdhps, pfmrp1 and pfnhe1 genes were determined using PCR-based methods. Results: Pfcrt 72-76 CVIET was found in one chloroquine village sample, all remaining samples had pfcrt CVMNK. Pfmdr1 N86 prevalence was 100%. A pfmdr1 T1069(ACT -> ACG) synonymous polymorphism was found in 30% of chloroquine village samples and 3% of other samples (P = 0.008). Variations in pfnhe1 block I were found in all except the chloroquine treated village (P < 0.001). Resistance associated pfdhfr 108N prevalence was 2% in the pyrimethamine village compared to 45-65% elsewhere, including the placebo village (P = 0.001). Conclusions: Chloroquine treatment possibly resulted in the development of pfcrt 72-76 CVIET. Selection of pfmdr1 T1069(ACG) and a pfnhe1 block 1 genotypes indicates that chloroquine treatment exerted a selective pressure on P. falciparum. Pyrimethamine resistance associated pfdhfr 108N was present prior to the introduction of any drug. Decreased pfdhfr 108N frequency concurrent with development of pyrimethamine resistance suggests a non-pfdhfr polymorphisms mediated resistance mechanism.

  • 16.
    Kalyango, Joan N
    et al.
    Department of Public Health Sciences, Global Health (IHCAR), Karolinska Institutet, Stockholm, Sweden.
    Alfven, Tobias
    Department of Public Health Sciences, Global Health (IHCAR), Karolinska Institutet, Stockholm, Sweden.
    Peterson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Mugenyi, Kevin
    African Field Epidemiology Network (AFENET), Kampala, Uganda.
    Karamagi, Charles
    Clinical Epidemiology Unit, Makerere University College of Health Sciences, Kampala, Uganda.
    Rutebemberwa, Elizeus
    Department of Health Policy, Makerere University College of Health Scineces, Kampala, Uganda.
    Integrated community case management of malaria and pneumonia increases prompt and appropriate treatment for pneumonia symptoms in children under five years in Eastern Uganda2013In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 12, p. 340-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Efforts to improve access to treatment for common illnesses in children less than five years initially targeted malaria alone under the home management of malaria strategy. However under this strategy, children with other illnesses were often wrongly treated with anti-malarials. Integrated community case management of common childhood illnesses is now recommended but its effect on promptness of appropriate pneumonia treatment is unclear.ObjectivesTo determine the effect of integrated malaria and pneumonia management on receiving prompt and appropriate antibiotics for pneumonia symptoms and treatment outcomes as well as determine associated factors.

    METHODS: A follow-up study was nested within a cluster-randomized trial that compared under-five mortality in areas where community health workers (CHWs) treated children with malaria and pneumonia (intervention areas) and where they treated children with malaria only (control areas). Children treated by CHWs were enrolled on the day of seeking treatment from CHWs (609 intervention, 667 control) and demographic, illness, and treatment seeking information was collected. Further information on illness and treatment outcomes was collected on day four. The primary outcome was prompt and appropriate antibiotics for pneumonia symptoms and the secondary outcome was treatment outcomes on day four.

    RESULTS: Children in the intervention areas were more likely to receive prompt and appropriate antibiotics for pneumonia symptoms compared to children in the control areas (RR = 3.51, 95%CI = 1.75-7.03). Children in the intervention areas were also less likely to have temperature >=37.5[degree sign]C on day four (RR = 0.29, 95%CI = 0.11-0.78). The decrease in fast breathing between day one and four was greater in the intervention (9.2%) compared to the control areas (4.2%, p-value = 0.01).

    CONCLUSIONS: Integrated community management of malaria and pneumonia increases prompt and appropriate treatment for pneumonia symptoms and improves treatment outcomes. Trial registrationISRCTN: ISRCTN52966230.

  • 17.
    Kalyango, Joan N
    et al.
    Dept of Public Health Sciences, Division of Global Health (IHCAR), Karolinska Institutet, Stockholm, Sweden.
    Rutebemberwa, Elizeus
    Dept of Health Policy, Planning and Management, School of Public Health, Makerere University College of Health Sciences, Kampala, Uganda.
    Alfven, Tobias
    Dept of Public Health Sciences, Division of Global Health (IHCAR), Karolinska Institutet, Stockholm, Sweden.
    Ssali, Sarah
    Dept of Gender and Women Studies, Makerere University College of Health Sciences, Kampala, Uganda.
    Peterson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Karamagi, Charles
    Clinical Epidemiology Unit, Makerere University College of Health Sciences, Kampala, Uganda.
    Performance of community health workers under integrated community case management of childhood illnesses in eastern Uganda2012In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 11, no 1, p. 282-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Curative interventions delivered by community health workers (CHWs) were introduced to increase access to health services for children less than five years and have previously targeted single illnesses. However, CHWs in the integrated community case management of childhood illnesses strategy adopted in Uganda in 2010 will manage multiple illnesses. There is little documentation about the performance of CHWs in the management of multiple illnesses. This study compared the performance of CHWs managing malaria and pneumonia with performance of CHWs managing malaria alone in eastern Uganda and the factors influencing performance.

    METHODS:

    A mixed methods study was conducted among 125 CHWs providing either dual malaria and pneumonia management or malaria management alone for children aged four to 59 months. Performance was assessed using knowledge tests, case scenarios of sick children, review of CHWs' registers, and observation of CHWs in the dual management arm assessing respiratory symptoms. Four focus group discussions with CHWs were also conducted.

    RESULTS:

    CHWs in the dual- and single-illness management arms had similar performance with respect to: overall knowledge of malaria (dual 72 %, single 70 %); eliciting malaria signs and symptoms (50 % in both groups); prescribing anti-malarials based on case scenarios (82 % dual, 80 % single); and correct prescription of anti-malarials from record reviews (dual 99 %, single 100 %). In the dual-illness arm, scores for malaria and pneumonia differed on overall knowledge (72 % vs 40 %, p < 0.001); and correct doses of medicines from records (100 % vs 96 %, p < 0.001). According to records, 82 % of the children with fast breathing had received an antibiotic. From observations 49 % of CHWs counted respiratory rates within five breaths of the physician (gold standard) and 75 % correctly classified the children. The factors perceived to influence CHWs' performance were: community support and confidence, continued training, availability of drugs and other necessary supplies, and cooperation from formal health workers.

    CONCLUSION:

    CHWs providing dual-illness management handled malaria cases as well as CHWs providing single-illness management, and also performed reasonably well in the management of pneumonia. With appropriate training that emphasizes pneumonia assessment, adequate supervision, and provision of drugs and necessary supplies, CHWs can provide integrated treatment for malaria and pneumonia.

  • 18. Kamugisha, Erasmus
    et al.
    Jing, Sun
    Minde, Mercy
    Kataraihya, Johaness
    Kongola, Gilbert
    Kironde, Fred
    Swedberg, Göte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Efficacy of artemether-lumefantrine in treatment of malaria among under-fives and prevalence of drug resistance markers in Igombe-Mwanza, north-western Tanzania2012In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 11, p. 58-Article in journal (Refereed)
    Abstract [en]

    Background: Drug resistance to anti-malarials is a major public health problem worldwide. This study aimed at establishing the efficacy of artemether-lumefantrine (ACT) in Igombe-Mwanza, north-western Tanzania after a few years of ACT use, and establish the prevalence of mutations in key targets for artemisinin, chloroquine and sulphadoxine/pyrimetamine (SP) drugs. Methods: A prospective single cohort study was conducted at Igombe health centre using artemether-lumefantrine combination therapy between February 2010 and March 2011. The follow-up period was 28 days and outcome measures were according to WHO guidelines. Blood was collected on Whatman filter paper for DNA analysis. DNA extraction was done using TRIS-EDTA method, and mutations in Pfcrt, Pfmdr1, Pfdhfr, Pfdhps and Pfatp6 were detected using PCR-RFLP methods established previously. Results: A total of 103 patients completed the 28 days follow-up. The mean haemoglobin was 8.9 g/dl (range 5.0 to 14.5 g/dl) and mean parasite density was 5,608 parasites/mu l. Average parasite clearance time was 34.7 hours and all patients cleared the parasites by day 3. There was no early treatment failure in this study. Late clinical failure was seen in three (2.9%) patients and late parasitological failure (LPF) was seen in two (1.9%). PCR-corrected LPF was 1% and adequate clinical and parasitological response was 96%. The majority of parasites have wild type alleles on pfcrt 76 and pfmdr1 86 positions being 87.8% and 93.7% respectively. Mutant parasites predominated at pfdhfr gene at the main three positions 108, 51 and 59 with prevalence of 94.8%, 75.3% and 82.5% respectively. Post-treatment parasites had more wild types of pfdhps at position 437 and 540 than pre-treatment parasites. No mutation was seen in pfatp6 769 in re-infecting or recrudescing parasites. Conclusion: The efficacy of artemether-lumefantrine for treatment of uncomplicated malaria is still high in the study area although the rate of re-infection is higher than previously reported. Parasite clearance after 48 hours was lower compared to previous studies. The prevalence of wild type allele pfcrt 76 K and pfmdr1 86 N was high in the study area while markers for SP resistance is still high. Artemether-lumefantrine may be selecting for wild type alleles on both positions (437 and 540) of pfdhps.

  • 19.
    Kitutu, Freddy Eric
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Kalyango, Joan Nakayaga
    Mayora, Chrispus
    Ekholm Selling, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Peterson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Wamani, Henry
    Integrated community case management by drug sellers influences appropriate treatment of paediatric febrile illness in South Western Uganda: a quasi-experimental study.2017In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 16, no 1, article id 425Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Fever case management is a major challenge for improved child health globally, despite existence of cheap and effective child survival health technologies. The integrated Community Case Management (iCCM) intervention of paediatric febrile illnesses though adopted by Uganda's Ministry of Health to be implemented by community health workers, has not addressed the inaccess to life-saving medicines and diagnostics. Therefore, the iCCM intervention was implemented in private drug shops and evaluated for its effect on appropriate treatment of paediatric fever in a low malaria transmission setting in South Western Uganda.

    METHODS: From June 2013 to September 2015, the effect of the iCCM intervention on drug seller paediatric fever management and adherence to iCCM guidelines was assessed in a quasi-experimental study in South Western Uganda. A total of 212 care-seeker exit interviews were done before and 285 after in the intervention arm as compared to 216 before and 268 care-seeker interviews at the end of the study period in the comparison arm. The intervention effect was assessed by difference-in-difference analysis of drug seller treatment practices against national treatment recommendations between the intervention and comparison arms. Observed proportions among care-seeker interviews were compared with corresponding proportions from 5795 child visits recorded in patient registries and 49 direct observations of drug seller-care-seeker encounters in intervention drug shops.

    RESULTS: The iCCM intervention increased the appropriate treatment of uncomplicated malaria, pneumonia symptoms and non-bloody diarrhoea by 80.2% (95% CI 53.2-107.2), 65.5% (95% CI 51.6-79.4) and 31.4% (95% CI 1.6-61.2), respectively. Within the intervention arm, drug seller scores on appropriate treatment for pneumonia symptoms and diagnostic test use were the same among care-seeker exit interviews and direct observation. A linear trend (negative slope, - 0.009 p value < 0.001) was observed for proportions of child cases prescribed any antimicrobial medicine in the intervention arm drug shops.

    CONCLUSIONS: The iCCM intervention improved appropriate treatment for uncomplicated malaria, pneumonia symptoms and diarrhoea. Drug seller adherence to iCCM guidelines was high, without causing excessive prescription of antimicrobial medicines in this study. Further research should assess whether this effect is sustained over time and under routine supervision models.

  • 20.
    Kitutu, Freddy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH). Makerere Univ, Coll Hlth Sci, Pharm Dept, Kampala, Uganda.
    Wamani, Henry
    Makerere University School of Public Health.
    Ekholm Selling, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Katabazi, Fred
    Makerere University College of Health Sciences, Department of Medical Microbiology.
    Kuteesa, Ronald
    Makerere University College of Health Sciences, Infectious Disease Institute.
    Peterson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH). Makerere Univ, Coll Hlth Sci, Pharm Dept, Kampala, Uganda; Makerere Univ, Coll Hlth Sci, Infect Dis Inst, Kampala, Uganda.
    Kalyango, Joan
    Makerere University College of Health Sciences, Department of Pharmacy.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Can malaria rapid diagnostic tests by drug sellers under feld conditions classify children 5 years old or less with or without Plasmodium falciparum malaria?: Comparison with nested PCR analysis2018In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 17, article id 365Article in journal (Refereed)
    Abstract [en]

    Background

    Malaria rapid diagnostic tests (RDTs) available as dipsticks or strips, are simple to perform, easily interpretable and do not require electricity nor infrastructural investment. Correct interpretation of and compliance with the malaria RDT results is a challenge to drug sellers. Thus, drug seller interpretation of malaria RDT strips was compared with laboratory scientist re-reading, and PCR analysis of Plasmodium DNA extracted from malaria RDT nitrocellulose strips and Fast Transient Analysis (FTA) cards. Malaria RDT cassettes are also assessed as potential source of Plasmodium DNA.

    Methods

    A total of 212 children aged between 2 and 60 months, 199 of whom had complete records at two study drug shops in south west Uganda participated in the study. Duplicate 5μL samples of capillary blood were picked from the 212 children, dispensed onto the sample well of the CareStartTM Pf-HRP2 RDT cassette and a fast transient analysis (FTA), WhatmanTM 3MM filter paper in parallel. The malaria RDT strip was interpreted by the drug seller within 15 to 20 minutes, visually re-read centrally by laboratory scientist and from it; Plasmodium DNA was recovered and detected by PCR, and compared with FTA recovered P. falciparum DNA PCR detection.

    Results

    Malaria positive samples were 62/199 (31.2% 95% CI 24.9 - 38.3) by drug seller interpretation of malaria RDT strip, 59/212 (27.8% 95% CI 22.2 – 34.3) by laboratory scientist, 55/212 (25.9% 95% CI 20.0 – 32.6) by RDT nitrocellulose strip PCR and 64/212 (30.2% 95% CI 24.4 – 37.7). The overall agreement between the drug seller interpretation and laboratory scientist re-reading of the malaria RDT strip was 93% with kappa value of 0.8 (95 % CI 0.7, 0.9). The drug seller compliance with the reported malaria RDT results and kappa value were 92.5% and 0.8 (95% CI 0.7, 0.9), respectively. The performance of the three diagnostic strategies compared with FTA PCR as the gold standard had sensitivity between 76.6% and 86.9%, specificity above 90%, positive predictive value ranging from 79% to 89.8% and negative predictive value above 90%.

    Conclusion:

    Drug sellers can use of malaria RDTs in field conditions and achieve acceptable accuracy for malaria diagnosis, and they comply with the malaria RDT results. Plasmodium DNA can be recovered from malaria RDT nitrocellulose strips even in the context of drug shops. Future malaria surveillance and diagnostic quality control studies with malaria RDT cassette as a source of Plasmodium DNA are recommended.

  • 21. Kofoed, Poul-Erik
    et al.
    Ursing, Johan
    Rodrigues, Amabelia
    Rombo, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Paracetamol versus placebo in treatment of non-severe malaria in children in Guinea-Bissau: a randomized controlled trial2011In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 10, p. 148-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The current guidelines for treatment of malaria include paracetamol to children with fever. No convincing evidence for the beneficial effects of this practice exists. Studies show that time to parasite clearance is significantly longer in children treated with paracetamol, which questions the policy. Whether this is of clinical importance has not been investigated.

    METHODS:

    Children with Plasmodium falciparum monoinfection and ≥20 parasites per 200 leucocytes at the Bandim Health Centre, Guinea-Bissau were randomized to receive paracetamol or placebo together with chloroquine for three days in a double blind randomized study. Temperature and symptoms were recorded twice daily during treatment and on day 3. The participants were interviewed and a malaria film taken once weekly until day 35. The data is in the form of grouped failure-times, the outcome of interest being time until parasitaemia during follow-up. Mantel-Haenszel weighted odds ratios are given. Other differences between and within the two groups have been tested using the Chi-square test and Mann-Whitney U test.

    RESULTS:

    In the evening of the day of inclusion, the temperature was slightly, but statistically insignificant, higher in the placebo group and significantly more children complained of headache. At no other time was a significant difference in temperature or symptoms detected. However, 6 children from the placebo-group as compared to two children from the paracetamol-group were admitted to hospital with high fever and convulsions by day 3. No differences in the cumulative percentages of children with adequate clinical and parasitological response were found in the intention-to-treat analysis or in the per-protocol analysis.

    CONCLUSION:

    Fewer children had early treatment failure and the mean temperature was slightly lower in the afternoon on day 0 in the paracetamol group. However, the cumulative adequate clinical and parasitological cure rates were not significantly different during the period of study. It is doubtful whether adding paracetamol to the treatment of uncomplicated malaria in children is beneficial.

    TRIAL REGISTRATION:

    NCT00137566

  • 22. Lalani, Mirza
    et al.
    Kitutu, Freddy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Clarke, Siân E
    Kaur, Harparkash
    Anti-malarial medicine quality field studies and surveys: a systematic review of screening technologies used and reporting of findings2017In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 16, no 1, article id 197Article, review/survey (Refereed)
    Abstract [en]

    BACKGROUND: Assessing the quality of medicines in low-middle income countries (LMICs) relies primarily on human inspection and screening technologies, where available. Field studies and surveys have frequently utilized screening tests to analyse medicines sampled at the point of care, such as health care facilities and medicine outlets, to provide a snap shot of medicine quality in a specific geographical area. This review presents an overview of the screening tests typically employed in surveys to assess anti-malarial medicine quality, summarizes the analytical methods used, how findings have been reported and proposes a reporting template for future studies.

    METHODS: A systematic search of the peer-reviewed and grey literature available in the public domain (including national and multi-national medicine quality surveys) covering the period 1990-2016 was undertaken. Studies were included if they had used screening techniques to assess the quality of anti-malarial medicines. As no standardized set of guidelines for the methodology and reporting of medicine quality surveys exist, the included studies were assessed for their standard against a newly proposed list of criteria.

    RESULTS: The titles and abstracts of 4621 records were screened and only 39 were found to meet the eligibility criteria. These 39 studies utilized visual inspection, disintegration, colorimetry and Thin Layer Chromatography (TLC) either as components of the Global Pharma Health Fund (GPHF) MiniLab(®) or as individual tests. Overall, 30/39 studies reported employing confirmatory testing described in international pharmacopeia to verify the quality of anti-malarials post assessment by a screening test. The authors assigned scores for the 23 criteria for the standard of reporting of each study.

    CONCLUSIONS: There is considerable heterogeneity in study design and inconsistency in reporting of field surveys of medicine quality. A lack of standardization in the design and reporting of studies of medicine quality increases the risk of bias and error, impacting on the generalizability and reliability of study results. The criteria proposed for reporting on the standard of studies in this review can be used in conjunction with existing medicine quality survey guidelines as a checklist for designing and reporting findings of studies. The review protocol has been registered with PROSPERO (CRD42015026782).

  • 23.
    Lohy Das, Jesmin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kyaw, Myat P.
    Department of Medical Research, Yangon, Republic of the Union of Myanmar..
    Nyunt, Myat
    Department of Medical Research, Yangon, Republic of the Union of Myanmar..
    Chit, Khin
    Department of Medical Research, Yangon, Republic of the Union of Myanmar..
    Aye, Kyin
    Department of Medical Research, Yangon, Republic of the Union of Myanmar..
    Aye, Moe
    Department of Medical Research, Yangon, Republic of the Union of Myanmar..
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bergstrand, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Tarning, Joel
    Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand;Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
    Population Pharmacokinetic and Pharmacodynamic Properties of Artesunate in Patients with Artemisinin Resistant Infections in Southern Myanmar2018In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 17, article id 126Article in journal (Refereed)
    Abstract [en]

    Background: Artemisinins are the most effective anti-malarial drugs for uncomplicated and severe Plasmodium falciparum malaria. However, widespread artemisinin resistance in the Greater Mekong Region of Southeast Asia is threatening the possibility to control and eliminate malaria. This work aimed to evaluate the pharmacokinetic and pharmacodynamic properties of artesunate and its active metabolite, dihydroartemisinin, in patients with sensitive and resistant falciparum infections in Southern Myanmar. In addition, a simple nomogram previously developed to identify artemisinin resistant malaria infections was evaluated. Methods: Fifty-three (n = 53) patients were recruited and received daily oral artesunate monotherapy (4 mg/kg) for 7 days. Frequent artesunate and dihydroartemisinin plasma concentration measurements and parasite microscopy counts were obtained and evaluated using nonlinear mixed-effects modelling. Results: The absorption of artesunate was best characterized by a transit-compartment (n = 3) model, followed by one-compartment disposition models for artesunate and dihydroartemisinin. The drug-dependent parasite killing effect of dihydroartemisinin was described using an Emax function, with a mixture model discriminating between artemisinin sensitive and resistant parasites. Overall, 56% of the studied population was predicted to have resistant malaria infections. Application of the proposed nomogram to identify artemisinin-resistant malaria infections demonstrated an overall sensitivity of 90% compared to 55% with the traditional day-3 positivity test. Conclusion: The pharmacokinetic-pharmacodynamic properties of artesunate and dihydroartemisinin were well-characterized with a mixture model to differentiate between drug sensitive and resistant infections in these patients. More than half of all patients recruited in this study had artemisinin-resistant infections. The relatively high sensitivity of the proposed nomogram highlights its potential clinical usefulness.

  • 24.
    Low, Matthew
    et al.
    Swedish Univ Agr Sci, Dept Ecol, Box 7044, S-75007 Uppsala, Sweden..
    Tsegaye, Admasu Tassew
    Univ Addis Ababa, Ethiopian Inst Water Resources, Addis Ababa, Ethiopia..
    Ignell, Rickard
    Swedish Univ Agr Sci, Dept Plant Protect Biol, Unit Chem Ecol, Box 102, S-23053 Alnarp, Sweden..
    Hill, Sharon
    Swedish Univ Agr Sci, Dept Plant Protect Biol, Unit Chem Ecol, Box 102, S-23053 Alnarp, Sweden..
    Elleby, Rasmus
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences. Swedish Univ Agr Sci, Dept Ecol, Box 7044, S-75007 Uppsala, Sweden..
    Feltelius, Vilhelm
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences. Swedish Univ Agr Sci, Dept Ecol, Box 7044, S-75007 Uppsala, Sweden..
    Hopkins, Richard
    Univ Greenwich, Nat Resources Inst, London SE18 6PF, England..
    The importance of accounting for larval detectability in mosquito habitat-association studies2016In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 15, article id 253Article in journal (Refereed)
    Abstract [en]

    Background: Mosquito habitat-association studies are an important basis for disease control programmes and/or vector distribution models. However, studies do not explicitly account for incomplete detection during larval presence and abundance surveys, with potential for significant biases because of environmental influences on larval behaviour and sampling efficiency.

    Methods: Data were used from a dip-sampling study for Anopheles larvae in Ethiopia to evaluate the effect of six factors previously associated with larval sampling (riparian vegetation, direct sunshine, algae, water depth, pH and temperature) on larval presence and detectability. Comparisons were made between: (i) a presence-absence logistic regression where samples were pooled at the site level and detectability ignored, (ii) a success versus trials binomial model, and (iii) a presence-detection mixture model that separately estimated presence and detection, and fitted different explanatory variables to these estimations.

    Results: Riparian vegetation was consistently highlighted as important, strongly suggesting it explains larval presence (-). However, depending on how larval detectability was estimated, the other factors showed large variations in their statistical importance. The presence-detection mixture model provided strong evidence that larval detectability was influenced by sunshine and water temperature (+), with weaker evidence for algae (+) and water depth (-). For larval presence, there was also some evidence that water depth (-) and pH (+) influenced site occupation. The number of dip-samples needed to determine if larvae were likely present at a site was condition dependent: with sunshine and warm water requiring only two dips, while cooler water and cloud cover required 11.

    Conclusions: Environmental factors influence true larval presence and larval detectability differentially when sampling in field conditions. Researchers need to be more aware of the limitations and possible biases in different analytical approaches used to associate larval presence or abundance with local environmental conditions. These effects can be disentangled using data that are routinely collected (i.e., multiple dip samples at each site) by employing a modelling approach that separates presence from detectability.

  • 25.
    Lwanira, Catherine N.
    et al.
    Makerere Univ, Coll Hlth Sci, Sch Biomed Sci, Kampala, Uganda..
    Mukasa, Mark Kaddu
    Makerere Univ, Coll Hlth Sci, Sch Med, Kampala, Uganda..
    Swedberg, Göte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kironde, Fred
    Makerere Univ, Coll Hlth Sci, Sch Biomed Sci, Kampala, Uganda.;Islamic Univ Uganda IUIU, Fac Hlth Sci, Habib Med Sch, Kampala, Uganda..
    Frequency of RANTES gene polymorphisms and their association with incidence of malaria: a longitudinal study on children in Iganga district, Uganda2015In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, article id 341Article in journal (Refereed)
    Abstract [en]

    Background: The severity and outcome of malaria is influenced by host immunity in which chemokines such as Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES) play an important role. Previous studies show that variations in the RANTES gene affect RANTES protein production, hence altering host immunity. In this study, the relationship between presence of mutations in RANTES and incidence of malaria in a cohort of children living in a malaria-endemic area of Uganda was determined. Methods: This was a longitudinal study comprising of 423 children aged between 6 months and 9 years, who were actively followed up for 1 year. Malaria episodes occurring in the cohort children were detected and the affected children treated with national policy drug regimen. Mutations in the RANTES gene were determined by PCR-RFLP method and their frequencies were calculated. A multivariate negative binomial regression model was used to estimate the impact of RANTES mutations on malaria incidence. In all statistical tests, a P-value of <0.05 was considered as significant. Results: The frequencies of the -403A and In1.1C allele were 53.7 and 19.2 %, respectively. No mutations were found at the -28 locus. After adjustment of incidence rates for age, blood group, insecticide-treated bed net (ITN) use, malaria history and the sickle cell trait, 1n1.1T/C heterozygotes and homozygotes showed a non-significant trend towards higher incidence rates compared to wild-type individuals (IRR = 1.10; P = 0.55 and IRR = 1.25; P = 0.60, respectively). Similarly, there was no significant difference in malaria incidence rates between RANTES -403G/A heterozygotes or homozygotes and those without mutations (IRR = 1.09; P = 0.66 and IRR = 1.16; P = 0.50, respectively). No relation was seen between RANTES polymorphisms, baseline parasite densities and the time to first re-infection after administration of anti-malaria drugs. Conclusions: This study showed that the -403A mutation occurs in nearly half of the study population and the In1.1C allele occurs in one in every four children. Despite the high frequency of these mutations, there was no clear association with malaria incidence. Other studies evaluating more markers, that could potentially modulate RANTES gene transcription alongside other genetic modifiers of malaria susceptibility, may provide further explanations to these less dramatic findings.

  • 26.
    Lwanira, Catherine Nassozi
    et al.
    Makerere Univ, Coll Hlth Sci, Sch Biomed Sci, Kampala, Uganda..
    Kironde, Fred
    Islamic Univ Uganda IUIU, Fac Hlth Sci, Habib Med Sch, Kampala Campus, Uganda..
    Kaddumukasa, Mark
    Makerere Univ, Coll Hlth Sci, Sch Med, Kampala, Uganda..
    Swedberg, Göte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Prevalence of polymorphisms in glucose-6-phosphate dehydrogenase, sickle haemoglobin and nitric oxide synthase genes and their relationship with incidence of uncomplicated malaria in Iganga, Uganda2017In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 16, article id 322Article in journal (Refereed)
    Abstract [en]

    Background: Host genetics play an important role in Plasmodium falciparum malaria susceptibility. However, information on host genetic factors and their relationships with malaria in the vaccine trial site of Iganga, Uganda is limited. The main objective of this study was to determine the prevalence of selected host genetic markers and their relationship to malaria incidence in the vaccine trial site of Iganga, Uganda. In a 1-year longitudinal cohort study, 423 children aged below 9 years were recruited and their malaria episodes were investigated. Host genetic polymorphisms were assessed by PCR-RFLP, haemoglobin electrophoresis and DNA sequencing. Using a multivariate negative binomial regression model, estimates of the impact of human genetic polymorphisms on malaria incidence were performed. In all statistical tests, a P value of < 0.05 was considered as significant. Results: The prevalences of sickle cell haemoglobin trait, G6PD c. 202 G > A (rs 1050828) and NOS2 -954 G > C (rs 1800482) variants were 26.6, 22.7 and 17.3%, respectively. Inducible nitric oxide synthase 2 (NOS2 -954 G>C; rs 1800482) heterozygosity was associated with lower incidence of malaria in all age groups {Adjusted incident rates ratio (aIRR) 0.59; 95% CI [0.386-0.887]; P = 0.012)}. About 4% of study subjects had co-existence of sickle cell Hb trait and G6PD deficiency. Sickle cell Hb heterozygotes (Hb AS) aged less than 1 year experienced significantly more malaria episodes annually than children with normal haemoglobin (Hb AA) {aIRR = 1.98; 95% CI [1.240-3.175]; P = 0.004}. There was no significant influence of the sickle cell trait on malaria incidence among older children of 1-9 years. Conclusions: Mutation (NOS2 -954 G > C; rs 1800482) of nitric oxide synthase 2 gene promoter was associated with a lower incidence of acute malaria. The normal haemoglobin (wild genotype; HbAA) was associated with reduced malaria incidence rates during the first year of life. More understanding of the interplay between host genetics and malaria susceptibility is required.

  • 27. Marwa, Karol J.
    et al.
    Schmidt, Theresa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sjögren, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Minzi, Omary M. S.
    Kamugisha, Erasmus
    Swedberg, Göte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Cytochrome P450 single nucleotide polymorphisms in an indigenous Tanzanian population: a concern about the metabolism of artemisinin-based combinations2014In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 13, p. 420-Article in journal (Refereed)
    Abstract [en]

    Background: Artemisinin-based combinations currently recommended for treatment of uncomplicated Plasmodium falciparum malaria in many countries of sub-Saharan Africa are substrates of CYP enzymes. The cytochrome enzyme system is responsible for metabolism of about 80-90% of clinically used drugs. It is, therefore, important to obtain the pharmacogenetics of the population in the region with respect to these combinations and thereby enable practitioners to predict treatment outcomes. The aim of this study was to detect and determine allelic frequencies of CYP2C8*2, CYP2C8*3, CYP3A4*1B, CYP3A5*3 and CYP2B6*6 variant alleles in a Tanzanian indigenous population. Methods: Genomic DNA extraction from blood obtained from 256 participants who escorted patients at Karume Health Centre in Mwanza Tanzania, was carried out using the Gene JET (TM) Genomic DNA purification kit (Thermo Scientific). Genotyping for the cytochrome P450 variant alleles was performed using predesigned primers. Amplification was done by PCR while differentiation between alleles was done by restriction fragment length polymorphism (PCR-RFLP) (for CYP2C8*2, CYP2C8*3) and sequencing (for CYP2B6*6, CYP3A5*3 and CYP3A4*1B). Results: CYP2C8*2, CYP2C8*3, CYP3A5*3, CYP3A4*1B and CYP2B6*6 variant allelic frequencies were found to be 19,10,16,78 and 36% respectively. Conclusion: Prevalence of CYP2C8*2, CYP3A5*3, CYP3A4*1B and CYP2B6*6 mutations in a Tanzanian population/ subjects are common. The impact of these point mutations on the metabolism of anti-malarial drugs, particularly artemisinin-based combinations, and their potential drug-drug interactions (DDIs) needs to be further evaluated.

  • 28. Morris, Ulrika
    et al.
    Khamis, Mwinyi
    Aydin-Schmidt, Berit
    Abass, Ali K
    Msellem, Mwinyi I
    Nassor, Majda H
    González, Iveth J
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Ali, Abdullah S
    Björkman, Anders
    Cook, Jackie
    Field deployment of loop-mediated isothermal amplification for centralized mass-screening of asymptomatic malaria in Zanzibar: a pre-elimination setting2015In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, article id 205Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Molecular tools for detection of low-density asymptomatic Plasmodium infections are needed in malaria elimination efforts. This study reports results from the hitherto largest implementation of loop-mediated isothermal amplification (LAMP) for centralized mass screening of asymptomatic malaria in Zanzibar.

    METHODS: Healthy individuals present and willing to participate in randomly selected households in 60 villages throughout Zanzibar were screened for malaria by rapid diagnostic tests (RDT). In 50 % of the study households, participants were asked to provide 60 μL of finger-prick blood for additional LAMP screening. LAMP was conducted in two centralized laboratories in Zanzibar, by trained technicians with limited or no previous experience of molecular methods. The LAMP assay was performed with Loopamp(TM) MALARIA Pan/Pf Detection Kit (Eiken Chemical Company, Japan). Samples positive for Plasmodium genus (Pan)-LAMP were re-tested using Plasmodium falciparum-specific LAMP kits.

    RESULTS: Paired RDT and LAMP samples were available from 3983 individuals. The prevalence of asymptomatic malaria was 0.5 % (CI 95 % 0.1-0.8) and 1.6 % (CI 95 % 1.1-2.2) by RDT and Pan-LAMP, respectively. LAMP detected 3.4 (CI 95 % 2.2-5.2) times more Plasmodium positive samples than RDT. DNA contamination was experienced, but solved by repetitive decontamination of all equipment and reagents.

    CONCLUSIONS: LAMP is a simple and sensitive molecular tool, and has potential in active surveillance and mass-screening programmes for detection of low-density asymptomatic malaria in pre-elimination settings. However, in order to deploy LAMP more effectively in field settings, protocols may need to be adapted for processing larger numbers of samples. A higher throughput, affordable closed system would be ideal to avoid contamination.

  • 29.
    Mubi, Marycelina
    et al.
    Department of Medicine, Malaria Research, Karolinska Institutet, Stockholm, Sweden.
    Kakoko, Deodatus
    Department of Behavioural Sciences, School of Public Health and Social Sciences, Muhimbili University of Health and Allied Sciences, Dar es Saalam, Tanzania.
    Ngasala, Billy
    Department of Parasitology and Medical entomology, School of Public Health and Social Sciences, Muhimbili University of Health and Allied Sciences, Dar es Saalam, Tanzania.
    Premji, Zul
    Department of Parasitology and Medical entomology, School of Public Health and Social Sciences, Muhimbili University of Health and Allied Sciences, Dar es Saalam, Tanzania.
    Peterson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Bjorkman, Anders
    Department of Medicine, Malaria Research, Karolinska Institutet, Stockholm, Sweden.
    Martensson, Andreas
    Department of Medicine, Malaria Research, Karolinska Institutet, Stockholm, Sweden.
    Malaria diagnosis and treatment practices following introduction of rapid diagnostic tests in Kibaha District, Coast Region, Tanzania2013In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 12, p. 293-Article in journal (Refereed)
    Abstract [en]

    Background: The success of the universal parasite-based malaria testing policy for fever patients attending primary health care (PHC) facilities in Tanzania will depend highly on health workers' perceptions and practices. The aim of this study was, therefore, to assess the present use of malaria diagnostics (rapid diagnostic tests (RDTs) and microscopy), prescription behaviour and factors affecting adherence to test results at PHC facilities in Kibaha District, Coast Region, Tanzania. Methods: Exit interviews were conducted with fever patients at PHC facilities and information on diagnostic test performed and treatment prescribed were recorded. Interviews with prescribers to assess their understanding, perceptions and practices related to RDTs were conducted, and health facility inventory performed to assess availability of staff, diagnostics and anti-malarial drugs. Results: The survey was undertaken at ten governmental PHC facilities, eight of which had functional diagnostics. Twenty health workers were interviewed and 195 exit interviews were conducted with patients at the PHC facilities. Of the 168 patients seen at facilities with available diagnostics, 105 (63%) were tested for malaria, 31 (30%) of whom tested positive. Anti-malarial drugs were prescribed to all patients with positive test results, 14% of patients with negative results and 28% of patients not tested for malaria. Antibiotics were more likely to be prescribed to patients with negative test results compared to patients with positive results (81 vs 39%, p < 0.01) and among non-tested compared to those tested for malaria (84 vs 69%, p = 0.01). Stock-outs of RDTs and staff shortage accounted for the low testing rate, and health worker perceptions were the main reason for non-adherence to test results. Conclusions: Anti-malarial prescription to patients with negative test results and those not tested is still practiced in Tanzania despite the universal malaria testing policy of fever patients. The use of malaria diagnostics was also associated with higher prescription of antibiotics among patients with negative results. Strategies to address health system factors and health worker perceptions associated with these practices are needed.

  • 30. Mukanga, David
    et al.
    Tibenderana, James K.
    Peterson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Pariyo, George W.
    Kiguli, Juliet
    Waiswa, Peter
    Babirye, Rebecca
    Ojiambo, Godfrey
    Kasasa, Simon
    Pagnoni, Franco
    Kallander, Karin
    Access, acceptability and utilization of community health workers using diagnostics for case management of fever in Ugandan children: a cross-sectional study2012In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 11, p. 121-Article in journal (Refereed)
    Abstract [en]

    Background: Use of diagnostics in integrated community case management (iCCM) of fever is recognized as an important step in improving rational use of drugs and quality of care for febrile under-five children. This study assessed household access, acceptability and utilization of community health workers (CHWs) trained and provided with malaria rapid diagnostic tests (RDTs) and respiratory rate timers (RRTs) to practice iCCM.

    Methods: A total of 423 households with under-five children were enrolled into the study in Iganga district, Uganda. Households were selected from seven villages in Namungalwe sub-county using probability proportionate to size sampling. A semi-structured questionnaire was administered to caregivers in selected households. Data were entered into Epidata statistical software, and analysed using SPSS Statistics 17.0, and STATA version 10.

    Results: Most (86%, 365/423) households resided within a kilometre of a CHW's home, compared to 26% (111/423) residing within 1 km of a health facility (p<0.001). The median walking time by caregivers to a CHW was 10 minutes (IQR 5-20). The first option for care for febrile children in the month preceding the survey was CHWs (40%, 242/601), followed by drug shops (33%, 196/601). Fifty-seven percent (243/423) of caregivers took their febrile children to a CHW at least once in the three month period preceding the survey. Households located 1-3 km from a health facility were 72% (AOR 1.72; 95% CI 1.11-2.68) more likely to utilize CHW services compared to households within 1 km of a health facility. Households located 1-3 km from a CHW were 81% (AOR 0.19; 95% CI 0.10-0.36) less likely to utilize CHW services compared to those households residing within 1 km of a CHW. A majority (79%, 336/423) of respondents thought CHWs services were better with RDTs, and 89% (375/423) approved CHWs' continued use of RDTs. Eighty-six percent (209/243) of respondents who visited a CHW thought RRTs were useful.

    Conclusion: ICCM with diagnostics is acceptable, increases access, and is the first choice for caregivers of febrile children. More than half of caregivers of febrile children utilized CHW services over a three-month period. However, one-third of caregivers used drug shops in spite of the presence of CHWs.

  • 31.
    Mwaiswelo, Richard
    et al.
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, Dar Es Salaam, Tanzania..
    Ngasala, Billy E.
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, Dar Es Salaam, Tanzania..
    Jovel, Irina
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Gosling, Roland
    Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA.;Univ Calif San Francisco, Global Hlth Grp, San Francisco, CA 94143 USA..
    Premji, Zul
    Aga Khan Univ Hosp, Nairobi, Kenya..
    Poirot, Eugenie
    Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA.;Univ Calif San Francisco, Global Hlth Grp, San Francisco, CA 94143 USA..
    Mmbando, Bruno P.
    Tanga Ctr, Natl Inst Med Res, Tanga, Tanzania..
    Bjorkman, Anders
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Safety of a single low-dose of primaquine in addition to standard artemether-lumefantrine regimen for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania2016In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 15, article id 316Article in journal (Refereed)
    Abstract [en]

    Background: This study assessed the safety of the new World Health Organization (WHO) recommendation of adding a single low-dose of primaquine (PQ) to standard artemisinin-based combination therapy (ACT), regardless of individual glucose-6-phosphate dehydrogenase (G6PD) status, for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania. Methods: Men and non-pregnant, non-lactating women aged >= 1 year with uncomplicated P. falciparum malaria were enrolled and randomized to either standard artemether-lumefantrine (AL) regimen alone or with a 0.25 mg/kg single-dose of PQ. PQ was administered concomitantly with the first AL dose. All drug doses were supervised. Safety was evaluated between days 0 and 28. G6PD status was assessed using rapid test (CareStart (TM)) and molecular genotyping. The primary endpoint was mean percentage relative reduction in haemoglobin (Hb) concentration (g/dL) between days 0 and 7 by genotypic G6PD status and treatment arm. Results: Overall, 220 patients, 110 per treatment arm, were enrolled, of whom 33/217 (15.2 %) were phenotypically G6PD deficient, whereas 15/110 (13.6 %) were genotypically hemizygous males, 5/110 (4.5 %) homozygous females and 22/110 (20 %) heterozygous females. Compared to genotypically G6PD wild-type/normal [ 6.8, 95 % confidence interval (CI) 4.67-8.96], only heterozygous patients in AL arm had significant reduction in day-7 mean relative Hb concentration (14.3, 95 % CI 7.02-21.55, p=0.045), however, none fulfilled the pre-defined haemolytic threshold value of >= 25 % Hb reduction. After adjustment for baseline parasitaemia, Hb, age and sex the mean relative Hb reduction was not statistically significant in both heterozygous and hemizygous/homozygous patients in both arms. A majority of the adverse events (AEs) were mild and unrelated to the study drugs. However, six (4.4 %) episodes, three per treatment arm, of acute haemolytic anaemia occurred between days 0 and 7. Three occurred in phenotypically G6PD deficient patients, two in AL and one in AL + PQ arm, but none in genotypically hemizygous/homozygous patients. All patients with acute haemolytic anaemia recovered without medical intervention. Conclusion: The findings support that the WHO recommendation of adding a single low-dose of PQ to standard AL regimen is safe for the treatment of acute uncomplicated P. falciparum malaria regardless of G6PD status in Tanzania.

  • 32.
    Mwaiswelo, Richard
    et al.
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, Dar Es Salaam, Tanzania..
    Ngasala, Billy
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, Dar Es Salaam, Tanzania..
    Jovel, Irina
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Aydin-Schmidt, Berit
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Gosling, Roland
    Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA.;Univ Calif San Francisco, Global Hlth Grp, San Francisco, CA 94143 USA..
    Premji, Zul
    Aga Khan Univ Hosp, Nairobi, Kenya..
    Mmbando, Bruno
    Natl Inst Med Res, Tanga Ctr, Tanga, Tanzania..
    Bjorkman, Anders
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Adding a single low-dose of primaquine (0.25 mg/kg) to artemether-lumefantrine did not compromise treatment outcome of uncomplicated Plasmodium falciparum malaria in Tanzania: a randomized, single-blinded clinical trial2016In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 15, article id 435Article in journal (Refereed)
    Abstract [en]

    Background: The World Health Organization (WHO) recently recommended the addition of a single low-dose of the gametocytocidal drug primaquine (PQ) to artemisinin-based combination therapy (ACT) in low transmission settings as a component of pre-elimination or elimination programmes. However, it is unclear whether that influences the ACT cure rate. The study assessed treatment outcome of artemether-lumefantrine (AL) plus a single PQ dose (0.25 mg/kg) versus standard AL regimen for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania. Methods: A randomized, single-blinded, clinical trial was conducted in Yombo, Bagamoyo district, Tanzania. Acute uncomplicated P. falciparum malaria patients aged >= 1 year, with the exception of pregnant and lactating women, were enrolled and treated with AL plus a single PQ dose (0.25 mg/kg) or AL alone under supervision. PQ was administered together with the first AL dose. Clinical and laboratory assessments were performed at 0, 8, 24, 36, 48, 60, and 72 h and on days 7, 14, 21, and 28. The primary end-point was a polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) on day 28. Secondary outcomes included: fever and asexual parasitaemia clearance, proportion of patients with PCR-determined parasitaemia on day 3, and proportion of patients with Pfmdr1 N86Y and Pfcrt K76T on days 0, 3 and day of recurrent infection. Results: Overall 220 patients were enrolled, 110 were allocated AL + PQ and AL, respectively. Parasite clearance by microscopy was fast, but PCR detectable parasitaemia on day 3 was 31/109 (28.4 %) and 29/108 (26.9 %) in patients treated with AL + PQ and AL, respectively (p = 0.79). Day 28 PCR-adjusted ACPR and re-infection rate was 105/105 (100 %) and 101/102 (99 %) (p = 0.31), and 5/107 (4.7 %) and 5/8 (4.8 %) (p = 0.95), in AL + PQ and AL arm, respectively. There was neither any statistically significant difference in the proportion of Pfmdr1 N86Y or Pfcrt K76T between treatment arms on days 0, 3 and day of recurrent infection, nor within treatment arms between days 0 and 3 or day 0 and day of recurrent infection. Conclusion: The new WHO recommendation of adding a single low-dose of PQ to AL did not compromise treatment outcome of uncomplicated P. falciparum malaria in Tanzania.

  • 33. Ngasala, Billy E.
    et al.
    Malmberg, Maja
    Carlsson, Anja M.
    Ferreira, Pedro E.
    Petzold, Max G.
    Blessborn, Daniel
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Bergqvist, Yngve
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Gil, Jose P.
    Premji, Zul
    Mårtensson, Andreas
    Effectiveness of artemether-lumefantrine provided by community health workers in under-five children with uncomplicated malaria in rural Tanzania: an open label prospective study2011In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 10, p. 64-Article in journal (Refereed)
    Abstract [en]

    Background: Home-management of malaria (HMM) strategy improves early access of anti-malarial medicines to high-risk groups in remote areas of sub-Saharan Africa. However, limited data are available on the effectiveness of using artemisinin-based combination therapy (ACT) within the HMM strategy. The aim of this study was to assess the effectiveness of artemether-lumefantrine (AL), presently the most favoured ACT in Africa, in under-five children with uncomplicated Plasmodium falciparum malaria in Tanzania, when provided by community health workers (CHWs) and administered unsupervised by parents or guardians at home. Methods: An open label, single arm prospective study was conducted in two rural villages with high malaria transmission in Kibaha District, Tanzania. Children presenting to CHWs with uncomplicated fever and a positive rapid malaria diagnostic test (RDT) were provisionally enrolled and provided AL for unsupervised treatment at home. Patients with microscopy confirmed P. falciparum parasitaemia were definitely enrolled and reviewed weekly by the CHWs during 42 days. Primary outcome measure was PCR corrected parasitological cure rate by day 42, as estimated by Kaplan-Meier survival analysis. This trial is registered with ClinicalTrials.gov, number NCT00454961. Results: A total of 244 febrile children were enrolled between March-August 2007. Two patients were lost to follow up on day 14, and one patient withdrew consent on day 21. Some 141/241 (58.5%) patients had recurrent infection during follow-up, of whom 14 had recrudescence. The PCR corrected cure rate by day 42 was 93.0% (95% CI 88.3%-95.9%). The median lumefantrine concentration was statistically significantly lower in patients with recrudescence (97 ng/mL [IQR 0-234]; n = 10) compared with reinfections (205 ng/mL [114-390]; n = 92), or no parasite reappearance (217 [121-374] ng/mL; n = 70; p <= 0.046). Conclusions: Provision of AL by CHWs for unsupervised malaria treatment at home was highly effective, which provides evidence base for scaling-up implementation of HMM with AL in Tanzania.

  • 34.
    Pathak, Ashish
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Gawariker, Sudhir
    Department of Medicine, R D Gardi Medical College, Surasa, Ujjain, India.
    Mandliya, Jagdish
    Department of Pediatrics, R D Gardi Medical College, Surasa, Ujjain, India.
    Sharma, Ashish
    Department of Medicine, R D Gardi Medical College, Surasa, Ujjain, India.
    Diwan, Vishal
    Department of Public Health Sciences (Global Health/IHCAR), Karolinska Institutet, Stockholm, Sweden.
    Ursing, Johan
    Malaria Research, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Characterization of drug resistance associated genetic polymorphisms among Plasmodium falciparum field isolates in Ujjain, Madhya Pradesh, India.2014In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 13, p. 182-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Since 2011, artesunate + sulphadoxine-pyrimethamine (ASP), instead of chloroquine, has been recommended for treatment of uncomplicated malaria in India. In Ujjain, central India, with an annual parasite index <0.1, the prevalence of drug-resistant Plasmodium falciparum is unknown. In other parts of India chloroquine and sulphadoxine-pyrimethamine-resistant P. falciparum is prevalent. The aim of this study was to determine the prevalence of anti-malarial drug resistance-associated genetic polymorphisms in P. falciparum collected in Ujjain in 2009 and 2010, prior to the introduction of ASP.

    METHODS: Blood samples from 87 patients with P. falciparum mono-infection verified by microscopy were collected on filter-paper at all nine major pathology laboratories in Ujjain city. Codons Pfcrt 72-76, pfmdr1 1034-1246, pfdhfr 16-185, pfdhps 436-632 and pfnhe1 ms4760 haplotypes were identified by sequencing. Pfcrt K76T and pfmdr1 N86Y were identified by restriction fragment length polymorphism, and pfmdr1 gene copy number by real-time PCR.

    RESULTS: Sulphadoxine-pyrimethamine resistance-associated pfdhfr 108 N and 59R alleles were found in 75/78 (96%) and 70/78 (90%) samples, respectively, and pfdhps 437G was found in 7/77 (9%) samples. Double mutant pfdhfr 59R + 108 N were found in 62/76 (82%) samples. Triple mutant pfdhfr 59R + 108 N and pfdhps 437G were found in 6/76 (8%) samples. Chloroquine-resistance-associated pfcrt 76 T was found in 82/87 (94%). The pfcrt 72-76 haplotypes found were: 80/84 (95%) SVMNT, 3/84 (4%) CVMNK and 1/84 (1%) CVMNT. Pfmdr1 N86 and 86Y were identified in 70/83 (84%) and 13/83 (16%) samples, respectively. Pfmdr1 S1034 + N1042 + D1246 were identified together in 70/72 (97%) of successfully sequenced samples. One pfmdr1 gene copy was found in 74/75 (99%) successfully amplified samples.

    CONCLUSION: This is the first characterization of key anti-malarial drug resistance-associated genetic markers among P. falciparum collected in Ujjain, Madhya Pradesh, India. The results indicate that the efficacy of standard dose chloroquine at the time of the study was likely to be poor, whereas ASP was likely to be efficacious, supporting the changed drug treatment policy. However, P. falciparum with reduced susceptibility to sulphadoxine-pyrimethamine is highly prevalent, highlighting the need for continuous surveillance of ASP efficacy in the study area.

  • 35.
    Rutebemberwa, Elizeus
    et al.
    Dept of Healht Policy, Planning and Management, Makerere University School of Public Health, Kampala, Uganda.
    Nsabagasani, Xavier
    Pariyo, George
    Tomson, Göran
    Peterson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Kallander, Karin
    Use of drugs, perceived drug efficacy and preferred providers for febrile children: implications for home management of fever2009In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 8, no 1, p. 131-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Community distribution of anti-malarials and antibiotics has been recommended as a strategy to reduce the under-five mortality due to febrile illnesses in sub-Saharan Africa. However, drugs distributed in these interventions have been considered weak by some caretakers and utilization of community medicine distributors has been low. The aim of the study was to explore caretakers' use of drugs, perceptions of drug efficacy and preferred providers for febrile children in order to make suggestions for community management of pneumonia and malaria. METHODS: The study was conducted in eastern Uganda using four focus group discussions with fathers and mothers of children under five; and eight key informant interviews with health workers in government and non-governmental organization facilities, community medicine distributors, and attendants in drug shops and private clinics. Caretakers were asked the drugs they use for treatment of fever, why they considered them efficacious, and the providers they go to and why they go there. Health providers were interviewed on their opinions of caretakers' perceptions of drugs and providers. Analysis was done using content analysis. RESULTS: Drugs that have been phased out as first-line treatment for malaria, such as chloroquine and sulphadoxine/pyrimethamine, are still perceived as efficacious. Use of drugs depended on perception of the disease, cost and drug availability. There were divergent views about drug efficacy concerning drug combinations, side effects, packaging, or using drugs over time. Bitter taste and high cost signified high efficacy for anti-malarials. Government facilities were preferred for conducting diagnostic investigations and attending to serious illnesses, but often lacked drugs and did not treat people fast. Drug shops were preferred for having a variety of drugs, attending to clients promptly and offering treatment on credit. However, drug shops were considered disadvantageous since they lacked diagnostic capability and had unqualified providers. CONCLUSION: Community views about drug efficacy are divergent and some may divert caretakers from obtaining efficacious drugs for febrile illness. Interventions should address these perceptions, equip community medicine distributors with capacity to do diagnostic investigations and provide a constant supply of drugs. Subsidized efficacious drugs could be made available in the private sector.

  • 36.
    Rutebemberwa, Elizeus
    et al.
    Dept of Health Policy Planning and Management, Makerere University School of Public Health, Kampala, Uganda.
    Pariyo, George
    Peterson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Tomson, Göran
    Kallander, Karin
    Utilization of public or private health care providers by febrile children after user fee removal in Uganda2009In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 8, p. 45-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Despite investments in providing free government health services in Uganda, many caretakers still seek treatment from the drug shops/private clinics. The study aimed to assess determinants for use of government facilities or drug shops/private clinics for febrile illnesses in children under five. METHODS: Structured questionnaires were administered to caretakers in 1078 randomly selected households in the Iganga - Mayuge Demographic Surveillance site. Those with children who had had fever in the previous two weeks and who had sought care from outside the home were interviewed on presenting symptoms and why they chose the provider they went to. Symptoms children presented with and reasons for seeking care from government facilities were compared with those of drug shops/private clinics. RESULTS: Of those who sought care outside the home, 62.7% (286/456) had first gone to drug shops/private clinics and 33.1% (151/456) first went to government facilities. Predictors of having gone to government facilities with a febrile child were child presenting with vomiting (OR 2.07; 95% CI 1.10 - 3.89) and perceiving that the health providers were qualified (OR 10.32; 95% CI 5.84 - 18.26) or experienced (OR 1.93; 95% CI 1.07 - 3.48). Those who took the febrile child to drug shops/private clinics did so because they were going there to get first aid (OR 0.20; 95% CI 0.08 - 0.52). CONCLUSION: Private providers offer 'first aid' to caretakers with febrile children. Government financial assistance to health care providers should not stop at government facilities. Multi-faceted interventions in the private sector and implementation of community case management of febrile children through community medicine distributors could increase the proportion of children who access quality care promptly.

  • 37.
    Sundell, Kerstin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jagannathan, Prasanna
    Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, San Francisco, CA 94143 USA..
    Huang, Liusheng
    Univ Calif San Francisco, Dept Clin Pharm, San Francisco, CA USA..
    Bigira, Victor
    Infect Dis Res Collaborat, Kampala, Uganda..
    Kapisi, James
    Infect Dis Res Collaborat, Kampala, Uganda..
    Kakuru, Mary M.
    Infect Dis Res Collaborat, Kampala, Uganda..
    Savic, Rada
    Univ Calif San Francisco, Dept Bioengn & Therapeut, San Francisco, CA USA..
    Kamya, Moses R.
    Makerere Univ, Coll Hlth Sci, Dept Med, Kampala, Uganda..
    Dorsey, Grant
    Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, San Francisco, CA 94143 USA..
    Aweeka, Francesca
    Univ Calif San Francisco, Dept Clin Pharm, San Francisco, CA USA..
    Variable piperaquine exposure significantly impacts protective efficacy of monthly dihydroartemisinin-piperaquine for the prevention of malaria in Ugandan children2015In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, article id 368Article in journal (Refereed)
    Abstract [en]

    Background: Anti-malarial chemoprevention with dihydroartemisinin-piperaquine (DHA/PQ) is a promising tool for malaria control, but its efficacy in children may be limited by inadequate drug exposure. Methods: Children were enrolled in a non directly-observed trial of DHA/PQ chemoprevention in a high transmission setting in Uganda. Children were randomized at 6 months of age to no chemoprevention (n = 89) or monthly DHA/PQ (n = 87) and followed through 24 months of age, with pharmacokinetic sampling performed at variable times following monthly dosing of DHA/PQ. A previously published pharmacokinetic model was used to estimate piperaquine (PQ) exposure in each child, and associations between PQ exposure and the protective efficacy (PE) of DHA/PQ were explored. Results: The incidence of malaria was 6.83 and 3.09 episodes per person year at risk in the no chemoprevention and DHA/PQ arms, respectively (PE 54 %, 95 % CI 39-66 %, P < 0.001). Among children randomized to DHA/PQ, 493 pharmacokinetic samples were collected. Despite nearly 100 % reported adherence to study drug administration at home, there was wide variability in PQ exposure, and children were stratified into three groups based on average PQ exposure during the intervention that was determined by model generated percentiles (low, n = 40; medium, n = 37, and high, n = 10). Gender and socioeconomic factors were not significantly associated with PQ exposure. In multivariate models, the PE of DHA/PQ was 31 % in the low PQ exposure group (95 % CI 6-49 %, P = 0.02), 67 % in the medium PQ exposure group (95 % CI 54-76 %, P < 0.001), and 97 % in the high PQ exposure group (95 % CI 89-99 %, P < 0.001). Conclusions: The protective efficacy of DHA/PQ chemoprevention in young children was strongly associated with higher drug exposure; in children with the highest PQ exposure, monthly DHA/PQ chemoprevention was nearly 100 % protective against malaria. Strategies to ensure good adherence to monthly dosing and optimize drug exposure are critical to maximize the efficacy of this promising malaria control strategy.

  • 38.
    Sylvester, Boniphace
    et al.
    Muhimbili Univ Hlth & Allied Sci, Sch Publ Hlth & Social Sci, Dept Parasitol & Med Entomol, POB 65001, Dar Es Salaam, Tanzania..
    Gasarasi, Dinah B.
    Muhimbili Univ Hlth & Allied Sci, Sch Publ Hlth & Social Sci, Dept Parasitol & Med Entomol, POB 65001, Dar Es Salaam, Tanzania..
    Aboud, Said
    Muhimbili Univ Hlth & Allied Sci, Sch Med, Dept Microbiol & Immunol, POB 65001, Dar Es Salaam, Tanzania..
    Tarimo, Donath
    Muhimbili Univ Hlth & Allied Sci, Sch Publ Hlth & Social Sci, Dept Parasitol & Med Entomol, POB 65001, Dar Es Salaam, Tanzania..
    Massawe, Siriel
    Muhimbili Univ Hlth & Allied Sci, Sch Med, Dept Obstet & Gynaecol, POB 65001, Dar Es Salaam, Tanzania..
    Mpembeni, Rose
    Muhimbili Univ Hlth & Allied Sci, Sch Publ Hlth & Social Sci, Dept Community Med, POB 65001, Dar Es Salaam, Tanzania..
    Swedberg, Göte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Prenatal exposure to Plasmodium falciparum increases frequency and shortens time from birth to first clinical malaria episodes during the first two years of life: prospective birth cohort study2016In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 15, article id 379Article in journal (Refereed)
    Abstract [en]

    Background: Prenatal exposure to Plasmodium falciparum affects development of protective immunity and susceptibility to subsequent natural challenges with similar parasite antigens. However, the nature of these effects has not been fully elucidated. The aim of this study was to determine the effect of prenatal exposure to P. falciparum on susceptibility to natural malaria infection, with a focus on median time from birth to first clinical malaria episode and frequency of clinical malaria episodes in the first 2 years of life.

    Methods: A prospective birth cohort study was conducted in Rufiji district in Tanzania, between January 2013 and December 2015. Infants born to mothers with P. falciparum in the placenta at time of delivery were defined as exposed, and infants born to mothers without P. falciparum parasites in placenta were defined as unexposed. Placental infection was established by histological techniques. Out of 206 infants recruited, 41 were in utero exposed to P. falciparum and 165 infants were unexposed. All infants were monitored for onset of clinical malaria episodes in the first 2 years of life. The outcome measure was time from birth to first clinical malaria episode, defined by fever (>= 37 degrees C) and microscopically determined parasitaemia. Median time to first clinical malaria episode between exposed and unexposed infants was assessed using Kaplan-Meier survival analysis and comparison was done by log rank. Association of clinical malaria episodes with prenatal exposure to P. falciparum was assessed by multivariate binary logistic regression. Comparative analysis of mean number of clinical malaria episodes between exposed and unexposed infants was done using independent sample t test.

    Results: The effect of prenatal exposure to P. falciparum infection on clinical malaria episodes was statistically significant (Odds Ratio of 4.79, 95 % CI 2.21-10.38, p < 0.01) when compared to other confounding factors. Median time from birth to first clinical malaria episode for exposed and unexposed infants was 32 weeks (95 % CI 30.88-33.12) and 37 weeks (95 % CI 35.25-38.75), respectively, and the difference was statistically significant (p = 0.003). The mean number of clinical malaria episodes in exposed and unexposed infants was 0.51 and 0.30 episodes/infant, respectively, and the difference was statistically significant (p = 0.038).

    Conclusions: Prenatal exposure to P. falciparum shortens time from birth to first clinical malaria episode and increases frequency of clinical malaria episodes in the first 2 years of life.

1 - 38 of 38
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