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. M alaria, in particular disease caused by Plasmodium falciparum, remains an overwhelming problem in most of subSaharan Africa (1, 2). Malaria control was greatly limited by resistance to chloroquine (CQ) and sulfadoxine-pyrimethamine (SP), leading to adoption of artemisinin-based combination therapy (ACT) as the standard treatment for uncomplicated falciparum malaria in the last decade (3). ACT consists of a rapid-acting artemisinin derivative plus a longer-acting partner drug that clears parasites not eliminated by the artemisinin component and limits selection of artemisinin resistance (4, 5). In nearly all countries in sub-Saharan Africa, either artemether-lumefantrine (AL) or artesunate-amodiaquine (AS-AQ) is recommended to treat uncomplicated malaria (6). Other ACTs are dihydroartemisinin (DHA)-piperaquine (DP), a first-line therapy in some countries in Asia, with particular promise for malaria prevention due to the extended halflife of piperaquine (7), and artesunate-mefloquine (AS-MQ), which is used in some countries in Asia and South America. In Uganda, AL was named the national ma...

Tumwebaze, P.; Tukwasibwe, S.; Taylor, A.; Conrad, M.; Ruhamyankaka, E.; Asua, V.; Walakira, A.; Nankabirwa, J.; Yeka, A.; Staedke, S.G.; Greenhouse, B.; Nsobya, S.L.; Kamya, M.R.; Dorsey, G.; Rosenthal, P.J. (2016) We assessed Plasmodium falciparum drug resistance markers in parasites collected in 2012, 40

BackgroundIntermittent preventive treatment during pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is widely recommended in sub-Saharan Africa to reduce the risk of malaria and improve birth outcomes. However, there are reports that the efficacy of IPTp with SP is waning, especially in parts of Africa where antimalarial resistance to this drug has become widespread.Methodology/Principal FindingsWe conducted a cross-sectional study of 565 HIV-uninfected women giving birth at Tororo District Hospital in southeastern Uganda. The primary objective of the study was to measure associations between use of SP during pregnancy from antenatal records and the risk of adverse outcomes including placental malaria, low birth weight, maternal parasitemia and maternal anemia. The proportion of women who reported taking 0, 1, 2, and 3 doses of SP during pregnancy was 5.7%, 35.8%, 56.6% and 2.0% respectively. Overall, the prevalence of placental malaria was 17.5%, 28.1%, and 66.2% by placental smear, PCR, and histopathology, respectively. In multivariate analyses controlling for potential confounders, ≥2 doses of SP was associated with non-significant trends towards lower odds of placental malaria by placental smear (OR = 0.75, p = 0.25), placental malaria by PCR (OR = 0.93, p = 0.71), placental malaria by histopathology (OR = 0.75, p = 0.16), low birth weight (OR = 0.63, p = 0.11), maternal parasitemia (OR = 0.88, p = 0.60) and maternal anemia (OR = 0.88, p = 0.48). Using a composite outcome, ≥2doses of SP was associated with a significantly lower odds of placental malaria, low birth weight, maternal parasitemia, or maternal anemia (OR = 0.52, p = 0.01).Conclusions/SignificanceIn this area of Uganda with intense malaria transmission, the prevalence of placental malaria by histopathology was high even among women who reported taking at least 2 doses of SP during pregnancy. The reported use of ≥2 doses of SP was not associated with protection against individual birth and maternal outcome measures but did protect against a composite measure of any adverse outcome.

Contributions of species other than to human malaria in sub-Saharan Africa are uncertain. We collected blood from children aged 6 months to 10 years diagnosed with malaria by Giemsa-stained blood smears (176 subjects) or histidine rich protein-2-based rapid diagnostic tests (323 subjects) in 2016; 50 samples from each of 10 sites across Uganda were studied to identify infecting species. Of 499 available samples, 474 demonstrated plasmodial infection by polymerase chain reaction amplification of 18S ribosomal RNA genes, including in 472, in 22, in 15, and in four; 435 were pure, two did not contain , and the remainder were mixed infections including. The prevalence of nonfalciparum species varied geographically. Stratifying based on recent history of indoor residual spraying (IRS) of insecticides, nonfalciparum infections were seen in 27/189 (14.8%) samples from sites that received and 13/285 (4.6%) samples from sites that did not receive IRS since 2010 ( = 0.0013). Overall, 39/474 (8.2%) samples from individuals diagnosed with malaria included nonfalciparum infections. Thus, a substantial proportion of episodes of malaria in Uganda include infections with plasmodial species other than .