Variable piperaquine exposure significantly impacts protective efficacy of monthly dihydroartemisinin-piperaquine for the prevention of malaria in Ugandan children

Kerstin Sundell, Prasanna Jagannathan, Liusheng Huang, Victor Bigira, James Kapisi, Mary M Kakuru, Rada Savic, Moses R Kamya, Grant Dorsey, Francesca Aweeka, Kerstin Sundell, Prasanna Jagannathan, Liusheng Huang, Victor Bigira, James Kapisi, Mary M Kakuru, Rada Savic, Moses R Kamya, Grant Dorsey, Francesca Aweeka

Abstract

Background: Anti-malarial chemoprevention with dihydroartemisinin-piperaquine (DHA/PQ) is a promising tool for malaria control, but its efficacy in children may be limited by inadequate drug exposure.

Methods: Children were enrolled in a non directly-observed trial of DHA/PQ chemoprevention in a high transmission setting in Uganda. Children were randomized at 6 months of age to no chemoprevention (n = 89) or monthly DHA/PQ (n = 87) and followed through 24 months of age, with pharmacokinetic sampling performed at variable times following monthly dosing of DHA/PQ. A previously published pharmacokinetic model was used to estimate piperaquine (PQ) exposure in each child, and associations between PQ exposure and the protective efficacy (PE) of DHA/PQ were explored.

Results: The incidence of malaria was 6.83 and 3.09 episodes per person year at risk in the no chemoprevention and DHA/PQ arms, respectively (PE 54 %, 95 % CI 39-66 %, P < 0.001). Among children randomized to DHA/PQ, 493 pharmacokinetic samples were collected. Despite nearly 100 % reported adherence to study drug administration at home, there was wide variability in PQ exposure, and children were stratified into three groups based on average PQ exposure during the intervention that was determined by model generated percentiles (low, n = 40; medium, n = 37, and high, n = 10). Gender and socioeconomic factors were not significantly associated with PQ exposure. In multivariate models, the PE of DHA/PQ was 31 % in the low PQ exposure group (95 % CI 6-49 %, P = 0.02), 67 % in the medium PQ exposure group (95 % CI 54-76 %, P < 0.001), and 97 % in the high PQ exposure group (95 % CI 89-99 %, P < 0.001).

Conclusions: The protective efficacy of DHA/PQ chemoprevention in young children was strongly associated with higher drug exposure; in children with the highest PQ exposure, monthly DHA/PQ chemoprevention was nearly 100 % protective against malaria. Strategies to ensure good adherence to monthly dosing and optimize drug exposure are critical to maximize the efficacy of this promising malaria control strategy.

Trial registration: Current Controlled Trials Identifier NCT00948896.

Figures

Fig. 1
Fig. 1
Assigned percentile per collected PK measurement and piperaquine exposure scores. Percentiles for each collected plasma sample of piperaquine, plotted against the age of the child at the time of the measurement. The red text displays the percentile boundaries of the piperaquine scores 0, 1, 2 and 3. Solid line represents best fit relationship between days since start of intervention and piperaquine exposure percentile with dotted line showing 95 % confidence intervals
Fig. 2
Fig. 2
Average piperaquine score and the incidence of malaria. The average incidence of malaria per child plotted against the average adherence score. Solid line best fit line of generated data with dotted line showing 95 % confidence intervals. RS Spearman’s rank correlation

References

    1. Jagannathan P, Muhindo MK, Kakuru A, Arinaitwe E, Greenhouse B, Tappero J, et al. Increasing incidence of malaria in children despite insecticide-treated bed nets and prompt anti-malarial therapy in Tororo, Uganda. Malar J. 2012;11:435. doi: 10.1186/1475-2875-11-435.
    1. Mukonka VM, Chanda E, Haque U, Kamuliwo M, Mushinge G, Chileshe J, et al. High burden of malaria following scale-up of control interventions in Nchelenge District, Luapula Province, Zambia. Malar J. 2014;13:153. doi: 10.1186/1475-2875-13-153.
    1. Greenwood BM, Bojang K, Whitty CJ, Targett GAT. Malaria. Lancet. 2005;365:1487–1498. doi: 10.1016/S0140-6736(05)66420-3.
    1. Enayati A, Hemingway J. Malaria management: past, present, and future. Annu Rev Entomol. 2010;55:569–591. doi: 10.1146/annurev-ento-112408-085423.
    1. Nosten F, White NJ. Artemisinin-based combination treatment of falciparum malaria. Am J Trop Med Hyg. 2007;77(6 Suppl):181–192.
    1. WHO . Guidelines for the treatment of malaria. Geneva: World Health Organization; 2010.
    1. ter Kuile FO, van Eijk AM, Filler SJ. Effect of sulfadoxine-pyrimethamine resistance on the efficacy of intermittent preventive therapy for malaria control during pregnancy: a systematic review. JAMA. 2007;297:2603–2616. doi: 10.1001/jama.297.23.2603.
    1. WHO . World malaria report 2012. Geneva: World Health Organization; 2012.
    1. Konate AT, Yaro JB, Ouedraogo AZ, Diarra A, Gansane A, Soulama I, et al. Intermittent preventive treatment of malaria provides substantial protection against malaria in children already protected by an insecticide-treated bednet in Burkina Faso: a randomised, double-blind, placebo-controlled trial. PLoS Med. 2011;8:e1000408. doi: 10.1371/journal.pmed.1000408.
    1. Tarning J, Ashley EA, Lindegardh N, Stepniewska K, Phaiphun L, Day NP, et al. Population pharmacokinetics of piperaquine after two different treatment regimens with dihydroartemisinin-piperaquine in patients with Plasmodium falciparum malaria in Thailand. Antimicrob Agents Chemother. 2008;52:1052–1061. doi: 10.1128/AAC.00955-07.
    1. Lwin KM, Phyo AP, Tarning J, Hanpithakpong W, Ashley EA, Lee SJ, et al. Randomized, double-blind, placebo-controlled trial of monthly versus bimonthly dihydroartemisinin-piperaquine chemoprevention in adults at high risk of malaria. Antimicrob Agents Chemother. 2012;56:1571–1577. doi: 10.1128/AAC.05877-11.
    1. Nankabirwa JI, Wandera B, Amuge P, Kiwanuka N, Dorsey G, Rosenthal PJ, et al. Impact of intermittent preventive treatment with dihydroartemisinin-piperaquine on malaria in ugandan schoolchildren: a randomized, placebo-controlled trial. Clin Infect Dis. 2014;58:1404–1412. doi: 10.1093/cid/ciu150.
    1. Bigira V, Kapisi J, Clark TD, Kinara S, Mwangwa F, Muhindo MK, et al. Protective efficacy and safety of three antimalarial regimens for the prevention of malaria in young ugandan children: a randomized controlled trial. PLoS Med. 2014;11:e1001689. doi: 10.1371/journal.pmed.1001689.
    1. Kjellin LL, Dorsey G, Rosenthal PJ, Aweeka F, Huang L. Determination of the antimalarial drug piperaquine in small volume pediatric plasma samples by LC-MS/MS. Bioanalysis. 2014;6:3081–3089. doi: 10.4155/bio.14.254.
    1. Tarning J, Zongo I, Some FA, Rouamba N, Parikh S, Rosenthal PJ, et al. Population pharmacokinetics and pharmacodynamics of piperaquine in children with uncomplicated falciparum malaria. Clin Pharmacol Ther. 2012;91:497–505. doi: 10.1038/clpt.2011.254.
    1. Snyman K, Mwangwa F, Bigira V, Kapisi J, Clark TD, Osterbauer B, et al. Poor housing construction associated with increased malaria incidence in a cohort of young Ugandan children. Am J Trop Med Hyg. 2015;92:1207–1213. doi: 10.4269/ajtmh.14-0828.
    1. Bergstrand M, Nosten F, Lwin KM, Karlsson MO, White NJ, Tarning J. Characterization of an in vivo concentration-effect relationship for piperaquine in malaria chemoprevention. Sci Transl Med. 2014
    1. Eastman RT, Dharia NV, Winzeler EA, Fidock DA. Piperaquine resistance is associated with a copy number variation on chromosome 5 in drug-pressured Plasmodium falciparum parasites. Antimicrob Agents Chemother. 2011;55:3908–3916. doi: 10.1128/AAC.01793-10.
    1. Tumwebaze P, Conrad MD, Walakira A, LeClair N, Byaruhanga O, Nakazibwe C, et al. Impact of antimalarial treatment and chemoprevention on the drug sensitivity of malaria parasites isolated from ugandan children. Antimicrob Agents Chemother. 2015;59:3018–3030. doi: 10.1128/AAC.05141-14.
    1. Nsobya SL, Kiggundu M, Nanyunja S, Joloba M, Greenhouse B, Rosenthal PJ. In vitro sensitivities of Plasmodium falciparum to different antimalarial drugs in Uganda. Antimicrob Agents Chemother. 2010;54:1200–1206. doi: 10.1128/AAC.01412-09.

Source: PubMed

3
S'abonner