Browsing by Author "Nsobya, Samuel L."

Now showing 1 - 4 of 4
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    Associations between red blood cell variants and malaria among children and adults from three areas of Uganda: a prospective cohort study
    (Malaria Journal, 2020) Kakande, Elijah; Greenhouse, Bryan; Bajunirwe, Francis; Drakeley, Chris; Nankabirwa, Joaniter I.; Walakira, Andrew; Nsobya, Samuel L.; Katureebe, Agaba; Rek, John; Arinaitwe, Emmanuel; Rosenthal, Philip J.; Kamya, Moses R.; Dorsey, Grant; Rodriguez‑Barraquer, Isabel
    Multiple red blood cell (RBC) variants appear to offer protection against the most severe forms of Plasmodium falciparum malaria. Associations between these variants and uncomplicated malaria are less clear. Data from a longitudinal cohort study conducted in 3 sub-counties in Uganda was used to quantify associations between three red blood cell variants Hb [AA, AS, S (rs334)], alpha thalassaemia 3.7 kb deletion, and glucose-6-phosphate dehydrogenase deficiency A—(G6PD 202A genotype) and malaria incidence, parasite prevalence, parasite density (a measure of anti-parasite immunity) and body temperature adjusted for parasite density (a measure of anti-disease immunity). All analyses were adjusted for age, average household entomological inoculation rate, and study site. Results for all variants were compared to those for wild type genotypes.
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    Evolution of Partial Resistance to Artemisinins in Malaria Parasites in Uganda
    (Massachusetts Medical Society, 2024-08) Conrad, Melissa D.; Asua, Victor; Garg, Shreeya; Giesbrecht, David; Niaré, Karamoko; Smith, Sawyer; Namuganga, Jane F; Katairo, Thomas; Legac, Jennifer; Crudale, Rebecca M; Tumwebaze, Patrick K; Nsobya, Samuel L.; Cooper, Roland A; Kamya, Moses R; Dorsey, Grant; Bailey; Jeffrey A.; Rosenthal, Philip J.
    Partial resistance of to the artemisinin component of artemisinin-based combination therapies, the most important malaria drugs, emerged in Southeast Asia and now threatens East Africa. Partial resistance, which manifests as delayed clearance after therapy, is mediated principally by mutations in the kelch protein K13 (PfK13). Limited longitudinal data are available on the emergence and spread of artemisinin resistance in Africa. We performed annual surveillance among patients who presented with uncomplicated malaria at 10 to 16 sites across Uganda from 2016 through 2022. We sequenced the gene encoding kelch 13 ( ) and analyzed relatedness using molecular methods. We assessed malaria metrics longitudinally in eight Ugandan districts from 2014 through 2021. By 2021-2022, the prevalence of parasites with validated or candidate resistance markers reached more than 20% in 11 of the 16 districts where surveillance was conducted. The PfK13 469Y and 675V mutations were seen in far northern Uganda in 2016-2017 and increased and spread thereafter, reaching a combined prevalence of 10 to 54% across much of northern Uganda, with spread to other regions. The 469F mutation reached a prevalence of 38 to 40% in one district in southwestern Uganda in 2021-2022. The 561H mutation, previously described in Rwanda, was first seen in southwestern Uganda in 2021, reaching a prevalence of 23% by 2022. The 441L mutation reached a prevalence of 12 to 23% in three districts in western Uganda in 2022. Genetic analysis indicated local emergence of mutant parasites independent of those in Southeast Asia. The emergence of resistance was observed predominantly in areas where effective malaria control had been discontinued or transmission was unstable. Data from Uganda showed the emergence of partial resistance to artemisinins in multiple geographic locations, with increasing prevalence and regional spread over time. (Funded by the National Institutes of Health.).
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    Impact of Antimalarial Treatment and Chemoprevention on the Drug Sensitivity of Malaria Parasites Isolated from Ugandan Children
    (Antimicrobial agents and chemotherapy, 2015) Tumwebaze, Patrick; Conrad, Melissa D.; Walakira, Andrew; LeClair, Norbert; Byaruhanga, Oswald; Nakazibwe, Christine; Okiring, Jaffer; Kakuru, Abel; Bigira, Victor; Kapisi, James; Kamya, Moses R.; Greenhouse, Bryan; Nsobya, Samuel L.; Rosenthal, Philip J.
    Changing treatment practices may be selecting for changes in the drug sensitivity of malaria parasites. We characterized ex vivo drug sensitivity and parasite polymorphisms associated with sensitivity in 459 Plasmodium falciparum samples obtained from subjects enrolled in two clinical trials in Tororo, Uganda, from 2010 to 2013. Sensitivities to chloroquine and monodesethylamodiaquine varied widely; sensitivities to quinine, dihydroartemisinin, lumefantrine, and piperaquine were generally good. Associations between ex vivo drug sensitivity and parasite polymorphisms included decreased chloroquine and monodesethylamodiaquine sensitivity and increased lumefantrine and piperaquine sensitivity with pfcrt 76T, as well as increased lumefantrine sensitivity with pfmdr1 86Y, Y184, and 1246Y. Over time, ex vivo sensitivity decreased for lumefantrine and piperaquine and increased for chloroquine, the prevalences of pfcrt K76 and pfmdr1 N86 and D1246 increased, and the prevalences of pfdhfr and pfdhps polymorphisms associated with antifolate resistance were unchanged. In recurrent infections, recent prior treatment with artemether-lumefantrine was associated with decreased ex vivo lumefantrine sensitivity and increased prevalence of pfcrt K76 and pfmdr1 N86, 184F, and D1246. In children assigned chemoprevention with monthly dihydroartemisinin-piperaquine with documented circulating piperaquine, breakthrough infections had increased the prevalence of pfmdr1 86Y and 1246Y compared to untreated controls. The noted impacts of therapy and chemoprevention on parasite polymorphisms remained significant in multivariate analysis correcting for calendar time. Overall, changes in parasite sensitivity were consistent with altered selective pressures due to changing treatment practices in Uganda. These changes may threaten the antimalarial treatment and preventive efficacies of artemether-lumefantrine and dihydroartemisinin-piperaquine, respectively.
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    Temporal Changes in Prevalence of Molecular Markers Mediating Antimalarial Drug Resistance in a High Malaria Transmission Setting in Uganda
    (The American journal of tropical medicine and hygiene, 2014) Mbogo, George W.; Nankoberanyi, Sheila; Tukwasibwe, Stephen; Baliraine, Frederick N.; Nsobya, Samuel L.; Conrad, Melissa D.; Arinaitwe, Emmanuel; Kamya, Moses; Tappero, Jordan; Staedke, Sarah G.; Dorsey, Grant
    Standard therapy for malaria in Uganda changed from chloroquine to chloroquine + sulfadoxine-pyrimethamine in 2000, and artemether-lumefantrine in 2004, although implementation of each change was slow. Plasmodium falciparum genetic polymorphisms are associated with alterations in drug sensitivity. We followed the prevalence of drug resistancemediating P. falciparum polymorphisms in 982 samples from Tororo, a region of high transmission intensity, collected from three successive treatment trials conducted during 2003–2012, excluding samples with known recent prior treatment. Considering transporter mutations, prevalence of the mutant pfcrt 76T, pfmdr1 86Y, and pfmdr1 1246Y alleles decreased over time. Considering antifolate mutations, the prevalence of pfdhfr 51I, 59R, and 108N, and pfdhps 437G and 540E were consistently high; pfdhfr 164L and pfdhps 581G were uncommon, but most prevalent during 2008–2010. Our data suggest sequential selective pressures as different treatments were implemented, and they highlight the importance of genetic surveillance as treatment policies change over time.