Efficacy of Single-Dose Primaquine With Artemisinin Combination Therapy on Plasmodium Falciparum Gametocytes and Transmission: An Individual Patient Meta-Analysis

Background: Since the World Health Organization recommended single low-dose (0.25 mg/kg) primaquine (PQ) in combination with artemisinin-based combination therapies (ACTs) in areas of low transmission or artemisinin-resistant Plasmodium falciparum, several single-site studies have been conducted to assess efficacy.

Methods: An individual patient meta-analysis to assess gametocytocidal and transmission-blocking efficacy of PQ in combination with different ACTs was conducted. Random effects logistic regression was used to quantify PQ effect on (1) gametocyte carriage in the first 2 weeks post treatment; and (2) the probability of infecting at least 1 mosquito or of a mosquito becoming infected.

Results: In 2574 participants from 14 studies, PQ reduced PCR-determined gametocyte carriage on days 7 and 14, most apparently in patients presenting with gametocytemia on day 0 (odds ratio [OR], 0.22; 95% confidence interval [CI], .17-.28 and OR, 0.12; 95% CI, .08-.16, respectively). Rate of decline in gametocyte carriage was faster when PQ was combined with artemether-lumefantrine (AL) compared to dihydroartemisinin-piperaquine (DP) (P = .010 for day 7). Addition of 0.25 mg/kg PQ was associated with near complete prevention of transmission to mosquitoes.

Conclusions: Transmission blocking is achieved with 0.25 mg/kg PQ. Gametocyte persistence and infectivity are lower when PQ is combined with AL compared to DP.

Citing Articles

Anti-infectivity efficacy and pharmacokinetics of WHO recommended single low-dose primaquine in children with acute Plasmodium falciparum in Burkina Faso: study protocol.

Ouedraogo A, Pouplin J, Mukaka M, Kaendiao T, Ruecker A, Millet P Trials. 2024; 25(1):583.

PMID: 39227956 PMC: 11373093. DOI: 10.1186/s13063-024-08428-8.

Therapeutic efficacy and safety of artemether-lumefantrine combination therapy for the treatment of uncomplicated Plasmodium falciparum malaria at Teda Health Centre, Northwest Ethiopia, 2022/23.

Woldesenbet D, Birhanie M, Abere A, Zeleke A, Bezabih M, Semaw M Malar J. 2024; 23(1):266.

PMID: 39215366 PMC: 11363363. DOI: 10.1186/s12936-024-05082-y.

Mass drug administration to reduce malaria incidence in a low-to-moderate endemic setting: short-term impact results from a cluster randomised controlled trial in Senegal.

Ba Konko Cire E, Roh M, Diallo A, Gadiaga T, Seck A, Thiam S medRxiv. 2024; .

PMID: 39072042 PMC: 11275686. DOI: 10.1101/2024.07.17.24310593.

The effect of single low-dose primaquine treatment for uncomplicated Plasmodium falciparum malaria on haemoglobin levels in Ethiopia: a longitudinal cohort study.

Habtamu K, Getachew H, Abossie A, Demissew A, Tsegaye A, Degefa T Malar J. 2024; 23(1):208.

PMID: 38997771 PMC: 11245871. DOI: 10.1186/s12936-024-05021-x.

Extension of efficacy range for targeted malaria-elimination interventions due to spillover effects.

Benjamin-Chung J, Li H, Nguyen A, Heitmann G, Bennett A, Ntuku H Nat Med. 2024; 30(10):2813-2820.

PMID: 38965434 PMC: 11483210. DOI: 10.1038/s41591-024-03134-z.

References

Ippolito M, Johnson J, Mullin C, Mallow C, Morgan N, Wallender E . The Relative Effects of Artemether-lumefantrine and Non-artemisinin Antimalarials on Gametocyte Carriage and Transmission of Plasmodium falciparum: A Systematic Review and Meta-analysis. Clin Infect Dis. 2017; 65(3):486-494. PMC: 5850314. DOI: 10.1093/cid/cix336. View

Lin J, Lon C, Spring M, Sok S, Chann S, Ittiverakul M . Single dose primaquine to reduce gametocyte carriage and Plasmodium falciparum transmission in Cambodia: An open-label randomized trial. PLoS One. 2017; 12(6):e0168702. PMC: 5462369. DOI: 10.1371/journal.pone.0168702. View

Camarda G, Jirawatcharadech P, Priestley R, Saif A, March S, Wong M . Antimalarial activity of primaquine operates via a two-step biochemical relay. Nat Commun. 2019; 10(1):3226. PMC: 6642103. DOI: 10.1038/s41467-019-11239-0. View

Dicko A, Roh M, Diawara H, Mahamar A, Soumare H, Lanke K . Efficacy and safety of primaquine and methylene blue for prevention of Plasmodium falciparum transmission in Mali: a phase 2, single-blind, randomised controlled trial. Lancet Infect Dis. 2018; 18(6):627-639. PMC: 5968371. DOI: 10.1016/S1473-3099(18)30044-6. View

van Pelt-Koops J, Pett H, Graumans W, van der Vegte-Bolmer M, van Gemert G, Rottmann M . The spiroindolone drug candidate NITD609 potently inhibits gametocytogenesis and blocks Plasmodium falciparum transmission to anopheles mosquito vector. Antimicrob Agents Chemother. 2012; 56(7):3544-8. PMC: 3393464. DOI: 10.1128/AAC.06377-11. View

Chaumeau V, Kajeechiwa L, Fustec B, Landier J, Naw Nyo S, Hsel S . Contribution of Asymptomatic Plasmodium Infections to the Transmission of Malaria in Kayin State, Myanmar. J Infect Dis. 2018; 219(9):1499-1509. PMC: 6467188. DOI: 10.1093/infdis/jiy686. View

White N . Qinghaosu (artemisinin): the price of success. Science. 2008; 320(5874):330-4. DOI: 10.1126/science.1155165. View

von Seidlein L, Peto T, Landier J, Nguyen T, Tripura R, Phommasone K . The impact of targeted malaria elimination with mass drug administrations on falciparum malaria in Southeast Asia: A cluster randomised trial. PLoS Med. 2019; 16(2):e1002745. PMC: 6377128. DOI: 10.1371/journal.pmed.1002745. View

Konate D, Diawara S, Toure M, Diakite S, Guindo A, Traore K . Effect of routine seasonal malaria chemoprevention on malaria trends in children under 5 years in Dangassa, Mali. Malar J. 2020; 19(1):137. PMC: 7137428. DOI: 10.1186/s12936-020-03202-y. View

10.

Landier J, Kajeechiwa L, Thwin M, Parker D, Chaumeau V, Wiladphaingern J . Safety and effectiveness of mass drug administration to accelerate elimination of artemisinin-resistant falciparum malaria: A pilot trial in four villages of Eastern Myanmar. Wellcome Open Res. 2017; 2:81. PMC: 5635445. DOI: 10.12688/wellcomeopenres.12240.1. View

11.

Pett H, Bradley J, Okebe J, Dicko A, Tiono A, Goncalves B . Polymorphisms and the Safety and Gametocytocidal Activity of Single-Dose Primaquine for Plasmodium falciparum. Antimicrob Agents Chemother. 2019; 63(10). PMC: 6761544. DOI: 10.1128/AAC.00538-19. View

12.

Kumar N, Zheng H . Stage-specific gametocytocidal effect in vitro of the antimalaria drug qinghaosu on Plasmodium falciparum. Parasitol Res. 1990; 76(3):214-8. DOI: 10.1007/BF00930817. View

13.

Bastiaens G, Tiono A, Okebe J, Pett H, Coulibaly S, Goncalves B . Safety of single low-dose primaquine in glucose-6-phosphate dehydrogenase deficient falciparum-infected African males: Two open-label, randomized, safety trials. PLoS One. 2018; 13(1):e0190272. PMC: 5764271. DOI: 10.1371/journal.pone.0190272. View

14.

White N, Ashley E, Recht J, Delves M, Ruecker A, Smithuis F . Assessment of therapeutic responses to gametocytocidal drugs in Plasmodium falciparum malaria. Malar J. 2014; 13:483. PMC: 4295364. DOI: 10.1186/1475-2875-13-483. View

15.

Tadesse F, Slater H, Chali W, Teelen K, Lanke K, Belachew M . The Relative Contribution of Symptomatic and Asymptomatic Plasmodium vivax and Plasmodium falciparum Infections to the Infectious Reservoir in a Low-Endemic Setting in Ethiopia. Clin Infect Dis. 2018; 66(12):1883-1891. DOI: 10.1093/cid/cix1123. View

16.

Sawa P, Shekalaghe S, Drakeley C, Sutherland C, Mweresa C, Baidjoe A . Malaria transmission after artemether-lumefantrine and dihydroartemisinin-piperaquine: a randomized trial. J Infect Dis. 2013; 207(11):1637-45. DOI: 10.1093/infdis/jit077. View

17.

Feachem R, Chen I, Akbari O, Bertozzi-Villa A, Bhatt S, Binka F . Malaria eradication within a generation: ambitious, achievable, and necessary. Lancet. 2019; 394(10203):1056-1112. DOI: 10.1016/S0140-6736(19)31139-0. View

18.

Bousema T, Okell L, Shekalaghe S, Griffin J, Omar S, Sawa P . Revisiting the circulation time of Plasmodium falciparum gametocytes: molecular detection methods to estimate the duration of gametocyte carriage and the effect of gametocytocidal drugs. Malar J. 2010; 9:136. PMC: 2881938. DOI: 10.1186/1475-2875-9-136. View

19.

Mwaiswelo R, Ngasala B, Jovel I, Gosling R, Premji Z, Poirot E . Safety of a single low-dose of primaquine in addition to standard artemether-lumefantrine regimen for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania. Malar J. 2016; 15:316. PMC: 4901409. DOI: 10.1186/s12936-016-1341-3. View

20.

Bousema T, Dinglasan R, Morlais I, Gouagna L, van Warmerdam T, Awono-Ambene P . Mosquito feeding assays to determine the infectiousness of naturally infected Plasmodium falciparum gametocyte carriers. PLoS One. 2012; 7(8):e42821. PMC: 3425579. DOI: 10.1371/journal.pone.0042821. View