Recurrent Plasmodium falciparum Parasitemia and Drug Resistance Mutations During Intermittent Preventive Treatment of Malaria in Pregnancy in Uganda

Jimmy Kizza; Thomas Katairo; Abel Kakuru; Bienvenu Nsengimaana; Trevor Esilu; Innocent Wiringilimaana; Francis D. Semakuba; Inna Gerlovina; Nicholas Hathaway; Jessica Briggs; Stephen Tukwasibwe; Steven M. Kiwuwa; Moses R. Kamya; Joaniter I. Nankabirwa; Grant Dorsey; Philip J. Rosenthal

doi:10.1093/infdis/jiag074

Recurrent Plasmodium falciparum Parasitemia and Drug Resistance Mutations During Intermittent Preventive Treatment of Malaria in Pregnancy in Uganda

Jimmy Kizza
, Thomas Katairo
, Abel Kakuru
, Bienvenu Nsengimaana
, Trevor Esilu
, Innocent Wiringilimaana
, Francis D. Semakuba
, Inna Gerlovina
, Nicholas Hathaway
, Jessica Briggs
, Stephen Tukwasibwe
, Steven M. Kiwuwa
, Moses R. Kamya
, Joaniter I. Nankabirwa
, Grant Dorsey
, Philip J. Rosenthal

Infectious Diseases Research Collaboration
Makerere University
Busitema University
University of California at San Francisco

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Intermittent preventive treatment with monthly sulfadoxine-pyrimethamine (IPTp-SP) is recommended during pregnancy in malaria-endemic countries. However, widespread resistance of Plasmodium falciparum to SP has compromised its efficacy, and the alternative dihydroartemisinin-piperaquine (DP) is under study. Potential selection of drug resistance is important.

Methods: We sequenced 1377 samples collected from pregnant women enrolled in a trial comparing monthly SP, DP, and DP + SP for IPTp in Busia, Uganda and with asymptomatic parasitemia at the time of IPTp administration. We characterized known markers of drug resistance and assessed the 28-day cumulative risk of recurrent parasitemia, with genotyping to distinguish recrudescence from new infections.

Results: Among 771 samples collected on the day IPTp was initiated, the prevalences of 5 resistance mutations in P. falciparum dihydrofolate reductase (PfDHFR) and dihydropteroate synthase (PfDHPS) were nearly 100%, and the PfDHFR I164L and PfDHPS A581G mutations, associated with high-level resistance, had combined prevalence of 26.5%. The cumulative risks of recurrent parasitemia (SP 57.8%, DP 4.1%, DP + SP 3.9%), symptomatic malaria (SP 9.3%, DP 1.1%, DP + SP 0.3%), and recrudescent parasitemia (SP 40.1%, DP 2.0%, DP + SP 0.8%) were all significantly greater in the SP arm, with risks greatest in primigravidae. In the IPT-SP arm, the combined prevalence of the PfDHFR I164L and PfDHPS A581G mutations increased significantly from 24.9% at initiation of IPTp to 35.2% after receipt of IPTp-SP. Infection with mutant parasites was associated with non-significant increases in risks of recrudescence.

Conclusions: Intermittent preventive treatment with monthly sulfadoxine-pyrimethamine had poor antimalarial preventive efficacy and selected for increased drug resistance, questioning the value of this intervention.

Original language	English
Pages (from-to)	1110-1119
Number of pages	10
Journal	Journal of Infectious Diseases
Volume	233
Issue number	6
DOIs	https://doi.org/10.1093/infdis/jiag074
Publication status	Published - 15 Jun 2026
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

dihydroartemisinin-piperaquine
intermittent preventive treatment
malaria
Plasmodium falciparum
pregnancy
resistance
sulfadoxine-pyrimethamine
Uganda

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10.1093/infdis/jiag074

Cite this

Kizza, J., Katairo, T., Kakuru, A., Nsengimaana, B., Esilu, T., Wiringilimaana, I., Semakuba, F. D., Gerlovina, I., Hathaway, N., Briggs, J., Tukwasibwe, S., Kiwuwa, S. M., Kamya, M. R., Nankabirwa, J. I., Dorsey, G., & Rosenthal, P. J. (2026). Recurrent Plasmodium falciparum Parasitemia and Drug Resistance Mutations During Intermittent Preventive Treatment of Malaria in Pregnancy in Uganda. Journal of Infectious Diseases, 233(6), 1110-1119. https://doi.org/10.1093/infdis/jiag074

@article{7a45f75993c64e95b0847d588b27280b,

title = "Recurrent Plasmodium falciparum Parasitemia and Drug Resistance Mutations During Intermittent Preventive Treatment of Malaria in Pregnancy in Uganda",

abstract = "Background: Intermittent preventive treatment with monthly sulfadoxine-pyrimethamine (IPTp-SP) is recommended during pregnancy in malaria-endemic countries. However, widespread resistance of Plasmodium falciparum to SP has compromised its efficacy, and the alternative dihydroartemisinin-piperaquine (DP) is under study. Potential selection of drug resistance is important. Methods: We sequenced 1377 samples collected from pregnant women enrolled in a trial comparing monthly SP, DP, and DP + SP for IPTp in Busia, Uganda and with asymptomatic parasitemia at the time of IPTp administration. We characterized known markers of drug resistance and assessed the 28-day cumulative risk of recurrent parasitemia, with genotyping to distinguish recrudescence from new infections. Results: Among 771 samples collected on the day IPTp was initiated, the prevalences of 5 resistance mutations in P. falciparum dihydrofolate reductase (PfDHFR) and dihydropteroate synthase (PfDHPS) were nearly 100\%, and the PfDHFR I164L and PfDHPS A581G mutations, associated with high-level resistance, had combined prevalence of 26.5\%. The cumulative risks of recurrent parasitemia (SP 57.8\%, DP 4.1\%, DP + SP 3.9\%), symptomatic malaria (SP 9.3\%, DP 1.1\%, DP + SP 0.3\%), and recrudescent parasitemia (SP 40.1\%, DP 2.0\%, DP + SP 0.8\%) were all significantly greater in the SP arm, with risks greatest in primigravidae. In the IPT-SP arm, the combined prevalence of the PfDHFR I164L and PfDHPS A581G mutations increased significantly from 24.9\% at initiation of IPTp to 35.2\% after receipt of IPTp-SP. Infection with mutant parasites was associated with non-significant increases in risks of recrudescence. Conclusions: Intermittent preventive treatment with monthly sulfadoxine-pyrimethamine had poor antimalarial preventive efficacy and selected for increased drug resistance, questioning the value of this intervention.",

keywords = "dihydroartemisinin-piperaquine, intermittent preventive treatment, malaria, Plasmodium falciparum, pregnancy, resistance, sulfadoxine-pyrimethamine, Uganda",

author = "Jimmy Kizza and Thomas Katairo and Abel Kakuru and Bienvenu Nsengimaana and Trevor Esilu and Innocent Wiringilimaana and Semakuba, \{Francis D.\} and Inna Gerlovina and Nicholas Hathaway and Jessica Briggs and Stephen Tukwasibwe and Kiwuwa, \{Steven M.\} and Kamya, \{Moses R.\} and Nankabirwa, \{Joaniter I.\} and Grant Dorsey and Rosenthal, \{Philip J.\}",

year = "2026",

month = jun,

day = "15",

doi = "10.1093/infdis/jiag074",

language = "English",

volume = "233",

pages = "1110--1119",

journal = "Journal of Infectious Diseases",

issn = "0022-1899",

publisher = "Oxford University Press",

number = "6",

}

Kizza, J, Katairo, T, Kakuru, A, Nsengimaana, B, Esilu, T, Wiringilimaana, I, Semakuba, FD, Gerlovina, I, Hathaway, N, Briggs, J, Tukwasibwe, S, Kiwuwa, SM, Kamya, MR, Nankabirwa, JI, Dorsey, G & Rosenthal, PJ 2026, 'Recurrent Plasmodium falciparum Parasitemia and Drug Resistance Mutations During Intermittent Preventive Treatment of Malaria in Pregnancy in Uganda', Journal of Infectious Diseases, vol. 233, no. 6, pp. 1110-1119. https://doi.org/10.1093/infdis/jiag074

TY - JOUR

T1 - Recurrent Plasmodium falciparum Parasitemia and Drug Resistance Mutations During Intermittent Preventive Treatment of Malaria in Pregnancy in Uganda

AU - Kizza, Jimmy

AU - Katairo, Thomas

AU - Kakuru, Abel

AU - Nsengimaana, Bienvenu

AU - Esilu, Trevor

AU - Wiringilimaana, Innocent

AU - Semakuba, Francis D.

AU - Gerlovina, Inna

AU - Hathaway, Nicholas

AU - Briggs, Jessica

AU - Tukwasibwe, Stephen

AU - Kiwuwa, Steven M.

AU - Kamya, Moses R.

AU - Nankabirwa, Joaniter I.

AU - Dorsey, Grant

AU - Rosenthal, Philip J.

PY - 2026/6/15

Y1 - 2026/6/15

N2 - Background: Intermittent preventive treatment with monthly sulfadoxine-pyrimethamine (IPTp-SP) is recommended during pregnancy in malaria-endemic countries. However, widespread resistance of Plasmodium falciparum to SP has compromised its efficacy, and the alternative dihydroartemisinin-piperaquine (DP) is under study. Potential selection of drug resistance is important. Methods: We sequenced 1377 samples collected from pregnant women enrolled in a trial comparing monthly SP, DP, and DP + SP for IPTp in Busia, Uganda and with asymptomatic parasitemia at the time of IPTp administration. We characterized known markers of drug resistance and assessed the 28-day cumulative risk of recurrent parasitemia, with genotyping to distinguish recrudescence from new infections. Results: Among 771 samples collected on the day IPTp was initiated, the prevalences of 5 resistance mutations in P. falciparum dihydrofolate reductase (PfDHFR) and dihydropteroate synthase (PfDHPS) were nearly 100%, and the PfDHFR I164L and PfDHPS A581G mutations, associated with high-level resistance, had combined prevalence of 26.5%. The cumulative risks of recurrent parasitemia (SP 57.8%, DP 4.1%, DP + SP 3.9%), symptomatic malaria (SP 9.3%, DP 1.1%, DP + SP 0.3%), and recrudescent parasitemia (SP 40.1%, DP 2.0%, DP + SP 0.8%) were all significantly greater in the SP arm, with risks greatest in primigravidae. In the IPT-SP arm, the combined prevalence of the PfDHFR I164L and PfDHPS A581G mutations increased significantly from 24.9% at initiation of IPTp to 35.2% after receipt of IPTp-SP. Infection with mutant parasites was associated with non-significant increases in risks of recrudescence. Conclusions: Intermittent preventive treatment with monthly sulfadoxine-pyrimethamine had poor antimalarial preventive efficacy and selected for increased drug resistance, questioning the value of this intervention.

AB - Background: Intermittent preventive treatment with monthly sulfadoxine-pyrimethamine (IPTp-SP) is recommended during pregnancy in malaria-endemic countries. However, widespread resistance of Plasmodium falciparum to SP has compromised its efficacy, and the alternative dihydroartemisinin-piperaquine (DP) is under study. Potential selection of drug resistance is important. Methods: We sequenced 1377 samples collected from pregnant women enrolled in a trial comparing monthly SP, DP, and DP + SP for IPTp in Busia, Uganda and with asymptomatic parasitemia at the time of IPTp administration. We characterized known markers of drug resistance and assessed the 28-day cumulative risk of recurrent parasitemia, with genotyping to distinguish recrudescence from new infections. Results: Among 771 samples collected on the day IPTp was initiated, the prevalences of 5 resistance mutations in P. falciparum dihydrofolate reductase (PfDHFR) and dihydropteroate synthase (PfDHPS) were nearly 100%, and the PfDHFR I164L and PfDHPS A581G mutations, associated with high-level resistance, had combined prevalence of 26.5%. The cumulative risks of recurrent parasitemia (SP 57.8%, DP 4.1%, DP + SP 3.9%), symptomatic malaria (SP 9.3%, DP 1.1%, DP + SP 0.3%), and recrudescent parasitemia (SP 40.1%, DP 2.0%, DP + SP 0.8%) were all significantly greater in the SP arm, with risks greatest in primigravidae. In the IPT-SP arm, the combined prevalence of the PfDHFR I164L and PfDHPS A581G mutations increased significantly from 24.9% at initiation of IPTp to 35.2% after receipt of IPTp-SP. Infection with mutant parasites was associated with non-significant increases in risks of recrudescence. Conclusions: Intermittent preventive treatment with monthly sulfadoxine-pyrimethamine had poor antimalarial preventive efficacy and selected for increased drug resistance, questioning the value of this intervention.

KW - dihydroartemisinin-piperaquine

KW - intermittent preventive treatment

KW - malaria

KW - Plasmodium falciparum

KW - pregnancy

KW - resistance

KW - sulfadoxine-pyrimethamine

KW - Uganda

U2 - 10.1093/infdis/jiag074

DO - 10.1093/infdis/jiag074

M3 - Article

C2 - 41679334

AN - SCOPUS:105042028923

SN - 0022-1899

VL - 233

SP - 1110

EP - 1119

JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

IS - 6

ER -

Recurrent Plasmodium falciparum Parasitemia and Drug Resistance Mutations During Intermittent Preventive Treatment of Malaria in Pregnancy in Uganda

Abstract

UN SDGs

Keywords

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