Browsing by Author "Asua, Victor"

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    Associations between Aminoquinoline Resistance Genotypes and Clinical Presentations of Plasmodium falciparum Infection in Uganda
    (Antimicrobial Agents and Chemotherapy, 2020) Cuu, Gloria; Asua, Victor; Tukwasibwe, Stephen; Nsobya, Sam L.; Nanteza, Ann; Kimuda, Magambo Phillip; Mpimbaza, Arthur; Rosenthal, Philip J.
    Mutations that mediate resistance of Plasmodium falciparum to aminoquinoline antimalarials are selected by prior drug use and may alter parasite fitness, but associations with clinical presentations are uncertain. We evaluated genotypes in samples from a case-control study of determinants of severe malaria in Ugandan children 4 months to 10 years of age. We studied 274 cases with severe malaria matched by age and geography to 275 uncomplicated malaria controls and 179 asymptomatic parasitemic controls. The overall prevalence of mutations of interest (considering mixed results as mutant) was 67.0% for PfCRT K76T, 8.5% for PfMDR1 N86Y, 71.5% for PfMDR1 Y184F, and 14.7% for PfMDR1 D1246Y. Compared to asymptomatic controls, the odds of mutant PfCRT 76T were lower for uncomplicated (odds ratio, 0.42 [95% confidence interval, 0.24 to 0.72]; P < 0.001) or severe (0.56 [0.32 to 0.97]; P = 0.031) malaria; the odds of mutant PfMDR1 86Y were lower for uncomplicated (0.33 [0.16 to 0.65]; P < 0.001) or severe (0.21 [0.09 to 0.45]; P < 0.001) malaria; and the odds of mutant PfMDR1 1246Y were higher for uncomplicated (1.83 [0.90 to 3.98]; P = 0.076) or severe (2.06 [1.01 to 4.55]; P = 0.033) malaria. The odds of mutant PfMDR1 184F were lower in severe than asymptomatic (0.59 [0.37 to 0.92]; P = 0.016) or uncomplicated (0.61 [0.41 to 0.90]; P = 0.009) malaria. Overall, the PfCRT 76T and PfMDR1 86Y mutations were associated with decreased risk of symptomatic malaria, PfMDR1 1246Y was associated with increased risk of symptomatic malaria, and PfMDR1 184F was associated with decreased risk of severe malaria. These results offer insights into parasite genotypes in children with different presentations, although the basis for the identified associations is likely complex.
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    Efficacy and safety of artemether‑lumefantrine and dihydroartemisinin‑piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria and prevalence of molecular markers associated with artemisinin and partner drug resistance in Uganda
    (Malaria Journal, 2022) Ebong, Chris; Sserwanga, Asadu; Frances Namuganga, Jane; Kapisi, James; Mpimbaza, Arthur; Gonahasa, Samuel; Asua, Victor; Gudoi, Sam; Kigozi, Ruth; Tibenderana, James; Bwanika, John Bosco; Bosco, Agaba; Rubahika, Denis; Kyabayinze, Daniel; Opigo, Jimmy; Rutazana, Damian; Sebikaari, Gloria; Belay, Kassahun; Niang, Mame; Halsey, Eric S.; Moriarty, Leah F.; Lucchi, Naomi W.; Svigel Souza, Samaly S.; Nsobya, Sam L.; Kamya, Moses R.; Yeka, Adoke
    In Uganda, artemether-lumefantrine (AL) is first-line therapy and dihydroartemisinin-piperaquine (DP) second-line therapy for the treatment of uncomplicated malaria. This study evaluated the efficacy and safety of AL and DP in the management of uncomplicated falciparum malaria and measured the prevalence of molecular markers of resistance in three sentinel sites in Uganda from 2018 to 2019. Methods: This was a randomized, open-label, phase IV clinical trial. Children aged 6 months to 10 years with uncomplicated falciparum malaria were randomly assigned to treatment with AL or DP and followed for 28 and 42 days, respectively. Genotyping was used to distinguish recrudescence from new infection, and a Bayesian algorithm was used to assign each treatment failure a posterior probability of recrudescence. For monitoring resistance, Pfk13 and Pfmdr1 genes were Sanger sequenced and plasmepsin-2 copy number was assessed by qPCR. Results: There were no early treatment failures. The uncorrected 28-day cumulative efficacy of AL ranged from 41.2 to 71.2% and the PCR-corrected cumulative 28-day efficacy of AL ranged from 87.2 to 94.4%. The uncorrected 28-day cumulative efficacy of DP ranged from 95.8 to 97.9% and the PCR-corrected cumulative 28-day efficacy of DP ranged from 98.9 to 100%. The uncorrected 42-day efficacy of DP ranged from 73.5 to 87.4% and the PCR-corrected 42-day efficacy of DP ranged from 92.1 to 97.5%. There were no reported serious adverse events associated with any of the regimens. No resistance-associated mutations in the Pfk13 gene were found in the successfully sequenced samples. In the AL arm, the NFD haplotype (N86Y, Y184F, D1246Y) was the predominant Pfmdr1 haplotype, present in 78 of 127 (61%) and 76 of 110 (69%) of the day 0 and day of failure samples, respectively. All the day 0 samples in the DP arm had one copy of the plasmepsin-2 gene. Conclusions: DP remains highly effective and safe for the treatment of uncomplicated malaria in Uganda. Recurrent infections with AL were common. In Busia and Arua, the 95% confidence interval for PCR-corrected AL efficacy fell below 90%. Further efficacy monitoring for AL, including pharmacokinetic studies, is recommended. Trial registration The trial was also registered with the Pan African Clinical Trial Registry (https:// pactr. samrc. ac. za/) with study Trial No. PACTR201811640750761.
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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.).