Betty Balikagala1, Miki Sakurai-Yatsushiro2, Shin-Ichiro Tachibana1, Mie Ikeda1, Masato Yamauchi1, Osbert T Katuro3, Edward H Ntege4, Makoto Sekihara1, Naoyuki Fukuda1, Nobuyuki Takahashi2, Shouki Yatsushiro5, Toshiyuki Mori1, Makoto Hirai1, Walter Opio6, Paul S Obwoya6, Denis A Anywar7, Mary A Auma6, Nirianne M Q Palacpac8, Takafumi Tsuboi4, Emmanuel I Odongo-Aginya7, Eisaku Kimura9, Martin Ogwang6, Toshihiro Horii8, Toshihiro Mita10. 1. Department of Tropical Medicine and Parasitology, School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. 2. Department of International Affairs and Tropical Medicine, School of Medicine, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan. 3. Mildmay Uganda, Nazibwa Hill, Lweza, P.O. Box 24985, Kampala, Uganda. 4. Division of Malaria Research, Proteo-Science Center, Ehime University, 3 Bunkyo-cho, Matsuyama, Ehime, 790-8577, Japan. 5. Health Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 2217-14 Hayashi-cho, Takamatsu, Kagawa, 761-0395, Japan. 6. St. Mary's Hospital Lacor, P.O. Box 180, Gulu, Uganda. 7. Faculty of Science, Gulu University, P.O. Box 166, Gulu, Uganda. 8. Department of Malaria Vaccine Development, Research Institute for Microbial Diseases, Osaka University, 3 Yamadaoka, Suita, Osaka, 565-0871, Japan. 9. Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, Nagasaki, 852-8523, Japan. 10. Department of Tropical Medicine and Parasitology, School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. tmita@juntendo.ac.jp.
Abstract
BACKGROUND: Usage of chloroquine was discontinued from the treatment of Plasmodium falciparum infection in almost all endemic regions because of global spread of resistant parasites. Since the first report in Malawi, numerous epidemiological studies have demonstrated that the discontinuance led to re-emergence of chloroquine-susceptible P. falciparum, suggesting a possible role in future malaria control. However, most studies were cross-sectional, with few studies looking at the persistence of chloroquine recovery in long term. This study fills the gap by providing, for a period of at least 6 years, proof of persistent re-emergence/stable recovery of susceptible parasite populations using both molecular and phenotypic methods. METHODS: Ex vivo drug-susceptibility assays to chloroquine (n = 319) and lumefantrine (n = 335) were performed from 2013 to 2018 in Gulu, Northern Uganda, where chloroquine had been removed from the official malaria treatment regimen since 2006. Genotyping of pfcrt and pfmdr1 was also performed. RESULTS: Chloroquine resistance (≥ 100 nM) was observed in only 3 (1.3%) samples. Average IC50 values for chloroquine were persistently low throughout the study period (17.4-24.9 nM). Parasites harbouring pfcrt K76 alleles showed significantly lower IC50s to chloroquine than the parasites harbouring K76T alleles (21.4 nM vs. 43.1 nM, p-value = 3.9 × 10-8). Prevalence of K76 alleles gradually increased from 71% in 2013 to 100% in 2018. CONCLUSION: This study found evidence of stable persistence of chloroquine susceptibility with the fixation of pfcrt K76 in Northern Uganda after discontinuation of chloroquine in the region. Accumulation of similar evidence in other endemic areas in Uganda could open channels for possible future re-use of chloroquine as an option for malaria treatment or prevention.
BACKGROUND: Usage of chloroquine was discontinued from the treatment of Plasmodium falciparum infection in almost all endemic regions because of global spread of resistant parasites. Since the first report in Malawi, numerous epidemiological studies have demonstrated that the discontinuance led to re-emergence of chloroquine-susceptible P. falciparum, suggesting a possible role in future malaria control. However, most studies were cross-sectional, with few studies looking at the persistence of chloroquine recovery in long term. This study fills the gap by providing, for a period of at least 6 years, proof of persistent re-emergence/stable recovery of susceptible parasite populations using both molecular and phenotypic methods. METHODS: Ex vivo drug-susceptibility assays to chloroquine (n = 319) and lumefantrine (n = 335) were performed from 2013 to 2018 in Gulu, Northern Uganda, where chloroquine had been removed from the official malaria treatment regimen since 2006. Genotyping of pfcrt and pfmdr1 was also performed. RESULTS:Chloroquine resistance (≥ 100 nM) was observed in only 3 (1.3%) samples. Average IC50 values for chloroquine were persistently low throughout the study period (17.4-24.9 nM). Parasites harbouring pfcrt K76 alleles showed significantly lower IC50s to chloroquine than the parasites harbouring K76T alleles (21.4 nM vs. 43.1 nM, p-value = 3.9 × 10-8). Prevalence of K76 alleles gradually increased from 71% in 2013 to 100% in 2018. CONCLUSION: This study found evidence of stable persistence of chloroquine susceptibility with the fixation of pfcrt K76 in Northern Uganda after discontinuation of chloroquine in the region. Accumulation of similar evidence in other endemic areas in Uganda could open channels for possible future re-use of chloroquine as an option for malaria treatment or prevention.
Authors: Natalia Rodriguez-Valero; Isabel Vera; Montse Roldan Torralvo; Teresa De Alba; Elisabeth Ferrer; Daniel Camprubi; Alex Almuedo Riera; Ruth Sotil Gallego; Magdalena Muelas; Maria Jesus Pinazo; Jose Muñoz Journal: Travel Med Infect Dis Date: 2020-04-29 Impact factor: 6.211
Authors: Fredy E Villena; Jorge L Maguiña; Meddly L Santolalla; Edwar Pozo; Carola J Salas; Julia S Ampuero; Andres G Lescano; Danett K Bishop; Hugo O Valdivia Journal: Malar J Date: 2020-12-04 Impact factor: 2.979
Authors: Kennedy Kassaza; Anna C Long; Jennifer M McDaniels; Mharlove Andre; Wasswa Fredrickson; Dan Nyehangane; Patrick Orikiriza; Darwin J Operario; Joel Bazira; Juliet A Mwanga-Amumpaire; Christopher C Moore; Jennifer L Guler; Yap Boum Journal: Malar J Date: 2021-02-25 Impact factor: 2.979