#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Artemisinin-Naphthoquine versus Artemether-Lumefantrine for Uncomplicated Malaria in Papua New Guinean Children: An Open-Label Randomized Trial


Background:
Artemisinin combination therapies (ACTs) with broad efficacy are needed where multiple Plasmodium species are transmitted, especially in children, who bear the brunt of infection in endemic areas. In Papua New Guinea (PNG), artemether-lumefantrine is the first-line treatment for uncomplicated malaria, but it has limited efficacy against P. vivax. Artemisinin-naphthoquine should have greater activity in vivax malaria because the elimination of naphthoquine is slower than that of lumefantrine. In this study, the efficacy, tolerability, and safety of these ACTs were assessed in PNG children aged 0.5–5 y.

Methods and Findings:
An open-label, randomized, parallel-group trial of artemether-lumefantrine (six doses over 3 d) and artemisinin-naphthoquine (three daily doses) was conducted between 28 March 2011 and 22 April 2013. Parasitologic outcomes were assessed without knowledge of treatment allocation. Primary endpoints were the 42-d P. falciparum PCR-corrected adequate clinical and parasitologic response (ACPR) and the P. vivax PCR-uncorrected 42-d ACPR. Non-inferiority and superiority designs were used for falciparum and vivax malaria, respectively. Because the artemisinin-naphthoquine regimen involved three doses rather than the manufacturer-specified single dose, the first 188 children underwent detailed safety monitoring. Of 2,542 febrile children screened, 267 were randomized, and 186 with falciparum and 47 with vivax malaria completed the 42-d follow-up. Both ACTs were safe and well tolerated. P. falciparum ACPRs were 97.8% and 100.0% in artemether-lumefantrine and artemisinin-naphthoquine-treated patients, respectively (difference 2.2% [95% CI −3.0% to 8.4%] versus −5.0% non-inferiority margin, p = 0.24), and P. vivax ACPRs were 30.0% and 100.0%, respectively (difference 70.0% [95% CI 40.9%–87.2%], p<0.001). Limitations included the exclusion of 11% of randomized patients with sub-threshold parasitemias on confirmatory microscopy and direct observation of only morning artemether-lumefantrine dosing.

Conclusions:
Artemisinin-naphthoquine is non-inferior to artemether-lumefantrine in PNG children with falciparum malaria but has greater efficacy against vivax malaria, findings with implications in similar geo-epidemiologic settings within and beyond Oceania.

Trial registration:
Australian New Zealand Clinical Trials Registry ACTRN12610000913077

Please see later in the article for the Editors' Summary


Vyšlo v časopise: Artemisinin-Naphthoquine versus Artemether-Lumefantrine for Uncomplicated Malaria in Papua New Guinean Children: An Open-Label Randomized Trial. PLoS Med 11(12): e32767. doi:10.1371/journal.pmed.1001773
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pmed.1001773

Souhrn

Background:
Artemisinin combination therapies (ACTs) with broad efficacy are needed where multiple Plasmodium species are transmitted, especially in children, who bear the brunt of infection in endemic areas. In Papua New Guinea (PNG), artemether-lumefantrine is the first-line treatment for uncomplicated malaria, but it has limited efficacy against P. vivax. Artemisinin-naphthoquine should have greater activity in vivax malaria because the elimination of naphthoquine is slower than that of lumefantrine. In this study, the efficacy, tolerability, and safety of these ACTs were assessed in PNG children aged 0.5–5 y.

Methods and Findings:
An open-label, randomized, parallel-group trial of artemether-lumefantrine (six doses over 3 d) and artemisinin-naphthoquine (three daily doses) was conducted between 28 March 2011 and 22 April 2013. Parasitologic outcomes were assessed without knowledge of treatment allocation. Primary endpoints were the 42-d P. falciparum PCR-corrected adequate clinical and parasitologic response (ACPR) and the P. vivax PCR-uncorrected 42-d ACPR. Non-inferiority and superiority designs were used for falciparum and vivax malaria, respectively. Because the artemisinin-naphthoquine regimen involved three doses rather than the manufacturer-specified single dose, the first 188 children underwent detailed safety monitoring. Of 2,542 febrile children screened, 267 were randomized, and 186 with falciparum and 47 with vivax malaria completed the 42-d follow-up. Both ACTs were safe and well tolerated. P. falciparum ACPRs were 97.8% and 100.0% in artemether-lumefantrine and artemisinin-naphthoquine-treated patients, respectively (difference 2.2% [95% CI −3.0% to 8.4%] versus −5.0% non-inferiority margin, p = 0.24), and P. vivax ACPRs were 30.0% and 100.0%, respectively (difference 70.0% [95% CI 40.9%–87.2%], p<0.001). Limitations included the exclusion of 11% of randomized patients with sub-threshold parasitemias on confirmatory microscopy and direct observation of only morning artemether-lumefantrine dosing.

Conclusions:
Artemisinin-naphthoquine is non-inferior to artemether-lumefantrine in PNG children with falciparum malaria but has greater efficacy against vivax malaria, findings with implications in similar geo-epidemiologic settings within and beyond Oceania.

Trial registration:
Australian New Zealand Clinical Trials Registry ACTRN12610000913077

Please see later in the article for the Editors' Summary


Zdroje

1. MurrayCJ, RosenfeldLC, LimSS, AndrewsKG, ForemanKJ, et al. (2012) Global malaria mortality between 1980 and 2010: a systematic analysis. Lancet 379: 413–431.

2. MendisK, SinaBJ, MarchesiniP, CarterR (2001) The neglected burden of Plasmodium vivax malaria. Am J Trop Med Hyg 64: 97–106.

3. BairdJK (2008) Real-world therapies and the problem of vivax malaria. N Engl J Med 359: 2601–2603.

4. PriceRN, TjitraE, GuerraCA, YeungS, WhiteNJ, et al. (2007) Vivax malaria: neglected and not benign. Am J Trop Med Hyg 77: 79–87.

5. KarunajeewaHA, MuellerI, SennM, LinE, LawI, et al. (2008) A trial of combination antimalarial therapies in children from Papua New Guinea. N Engl J Med 359: 2545–2557.

6. Papua New Guinea National Department of Health (2009) National malaria treatment protocol. Port Moresby: National Department of Health.

7. ManningL, LamanM, LawI, BonaC, AipitS, et al. (2011) Features and prognosis of severe malaria caused by Plasmodium falciparum, Plasmodium vivax and mixed Plasmodium species in Papua New Guinean children. PLoS ONE 6: e29203.

8. WangJY, CaoWC, ShanCQ, ZhangM, LiGF, et al. (2004) Naphthoquine phosphate and its combination with artemisinine. Acta Trop 89: 375–381.

9. HombhanjeFW, HuangQ (2010) Artemisinin-naphthoquine combination (ARCO®): an overview of the progress. Pharmaceuticals 3: 3581–3593.

10. BattyKT, SalmanS, MooreBR, BenjaminJ, LeeST, et al. (2012) Artemisinin-naphthoquine combination therapy for uncomplicated pediatric malaria: a pharmacokinetic study. Antimicrob Agents Chemother 56: 2472–2484.

11. BenjaminJ, MooreB, LeeST, SennM, GriffinS, et al. (2012) Artemisinin-naphthoquine combination therapy for uncomplicated pediatric malaria: a tolerability, safety, and preliminary efficacy study. Antimicrob Agents Chemother 56: 2465–2471.

12. World Health Organization (2010) Guidelines for the treatment of malaria, 2nd edition. Geneva: World Health Organization

13. DavisTM, HungTY, SimIK, KarunajeewaHA, IlettKF (2005) Piperaquine: a resurgent antimalarial drug. Drugs 65: 75–87.

14. BarnadasC, KoepfliC, KarunajeewaHA, SibaPM, DavisTM, et al. (2011) Characterization of treatment failure in efficacy trials of drugs against Plasmodium vivax by genotyping neutral and drug resistance-associated markers. Antimicrob Agents Chemother 55: 4479–4481.

15. World Health Organization (2003) Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria. Geneva: World Health Organization.

16. BukirwaH, UnnikrishnanB, KramerCV, SinclairD, NairS, et al. (2014) Artesunate plus pyronaridine for treating uncomplicated Plasmodium falciparum malaria. Cochrane Database Syst Rev 3: CD006404.

17. European Medicines Agency (2012) Assessment report. Pyramax—pyronaridine tetraphosphate/artesunate. Procedure No.: EMEA/H/W/002319. Available: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2012/06/WC500129290.pdf. Accessed 19 November 2014.

18. World Health Organization (2000) Severe falciparum malaria. World Health Organization, Communicable Diseases Cluster. Trans R Soc Trop Med Hyg 94 (Suppl 1)S1–S90.

19. KarunajeewaH, LimC, HungTY, IlettKF, DenisMB, et al. (2004) Safety evaluation of fixed combination piperaquine plus dihydroartemisinin (Artekin) in Cambodian children and adults with malaria. Br J Clin Pharmacol 57: 93–99.

20. MooreBR, BenjaminJM, SalmanS, GriffinS, GinnyE, et al. (2014) Effect of co-administered fat on the tolerability, safety and pharmacokinetic properties of dihydroartemisinin-piperaquine in Papua New Guinean children with uncomplicated malaria. Antimicrob Agents Chemother 58: 5784–5794.

21. AshleyEA, StepniewskaK, LindegardhN, AnnerbergA, KhamA, et al. (2007) How much fat is necessary to optimize lumefantrine oral bioavailability? Trop Med Int Health 12: 195–200.

22. CattamanchiA, KyabayinzeD, HubbardA, RosenthalPJ, DorseyG (2003) Distinguishing recrudescence from reinfection in a longitudinal antimalarial drug efficacy study: comparison of results based on genotyping of MSP-1, MSP-2, and GLURP. Am J Trop Med Hyg 68: 133–139.

23. FelgerI, BeckHP (2002) Genotyping of Plasmodium falciparum. PCR-RFLP analysis. Methods Mol Med 72: 117–129.

24. WongRP, SalmanS, IlettKF, SibaPM, MuellerI, et al. (2011) Desbutyl-lumefantrine is a metabolite of lumefantrine with potent in vitro antimalarial activity that may influence artemether-lumefantrine treatment outcome. Antimicrob Agents Chemother 55: 1194–1198.

25. SalmanS, Page-SharpM, GriffinS, KoseK, SibaPM, et al. (2011) Population pharmacokinetics of artemether, lumefantrine, and their respective metabolites in Papua New Guinean children with uncomplicated malaria. Antimicrob Agents Chemother 55: 5306–5313.

26. ManningL, LamanM, TownsendMA, ChubbSP, SibaPM, et al. (2011) Reference intervals for common laboratory tests in Melanesian children. Am J Trop Med Hyg 85: 50–54.

27. BlackwelderWC (1982) “Proving the null hypothesis” in clinical trials. Control Clin Trials 3: 345–353.

28. Pocock SJ (1983) Clinical trials: a practical approach. Chichester: John Wiley.

29. KrudsoodS, ChalermrutK, PengruksaC, SrivilairitS, SilachamroonU, et al. (2003) Comparative clinical trial of two-fixed combinations dihydroartemisinin-napthoquine-trimethoprim (DNP) and artemether-lumefantrine (Coartem/Riamet) in the treatment of acute uncomplicated falciparum malaria in Thailand. Southeast Asian J Trop Med Public Health 34: 316–321.

30. TjitraE, HasugianAR, SiswantoroH, PrasetyoriniB, EkowatiningsihR, et al. (2012) Efficacy and safety of artemisinin-naphthoquine versus dihydroartemisinin-piperaquine in adult patients with uncomplicated malaria: a multi-centre study in Indonesia. Malar J 11: 153.

31. LiuH, YangHL, XuJW, WangJZ, NieRH, et al. (2013) Artemisinin-naphthoquine combination versus chloroquine-primaquine to treat vivax malaria: an open-label randomized and non-inferiority trial in Yunnan Province, China. Malar J 12: 409.

32. HungTY, DavisTM, IlettKF, KarunajeewaH, HewittS, et al. (2004) Population pharmacokinetics of piperaquine in adults and children with uncomplicated falciparum or vivax malaria. Br J Clin Pharmacol 57: 253–262.

33. KarunajeewaHA, IlettKF, MuellerI, SibaP, LawI, et al. (2008) Pharmacokinetics and efficacy of piperaquine and chloroquine in Melanesian children with uncomplicated malaria. Antimicrob Agents Chemother 52: 237–243.

34. SalmanS, Page-SharpM, BattyKT, KoseK, GriffinS, et al. (2012) Pharmacokinetic comparison of two piperaquine-containing artemisinin combination therapies in Papua New Guinean children with uncomplicated malaria. Antimicrob Agents Chemother 56: 3288–3297.

35. EzzetF, MullR, KarbwangJ (1998) Population pharmacokinetics and therapeutic response of CGP 56697 (artemether + benflumetol) in malaria patients. Br J Clin Pharmacol 46: 553–561.

36. WorldWide Antimalarial Resistance Network (WWARN) DP Study Group (2013) The effect of dosing regimens on the antimalarial efficacy of dihydroartemisinin-piperaquine: a pooled analysis of individual patient data. PLoS Med 10: e1001564.

37. Hassan AlinM, AshtonM, KihamiaCM, MteyGJ, BjorkmanA (1996) Multiple dose pharmacokinetics of oral artemisinin and comparison of its efficacy with that of oral artesunate in falciparum malaria patients. Trans R Soc Trop Med Hyg 90: 61–65.

38. van AgtmaelMA, Cheng-QiS, QingJX, MullR, van BoxtelCJ (1999) Multiple dose pharmacokinetics of artemether in Chinese patients with uncomplicated falciparum malaria. Int J Antimicrob Agents 12: 151–158.

39. SkinnerTS, ManningLS, JohnstonWA, DavisTM (1996) In vitro stage-specific sensitivity of Plasmodium falciparum to quinine and artemisinin drugs. Int J Parasitol 26: 519–525.

40. MooreBR, SalmanS, BenjaminJ, Page-SharpM, RobinsonLJ, et al. (2014) Pharmacokinetic properties of single-dose primaquine in Papua New Guinean children: feasibility of abbreviated high-dose regimens for radical cure of vivax malaria. Antimicrob Agents Chemother 58: 432–439.

41. WongRP, LautuD, TavulL, HackettSL, SibaP, et al. (2010) In vitro sensitivity of Plasmodium falciparum to conventional and novel antimalarial drugs in Papua New Guinea. Trop Med Int Health 15: 342–349.

42. KurthF, BelardS, BasraA, RamharterM (2011) Pyronaridine-artesunate combination therapy for the treatment of malaria. Curr Opin Infect Dis 24: 564–569.

43. WhiteNJ (2007) Cardiotoxicity of antimalarial drugs. Lancet Infect Dis 7: 549–558.

44. BustosMD, GayF, DiquetB, ThomareP, WarotD (1994) The pharmacokinetics and electrocardiographic effects of chloroquine in healthy subjects. Trop Med Parasitol 45: 83–86.

45. LwinKM, PhyoAP, TarningJ, HanpithakpongW, AshleyEA, et al. (2012) Randomized, double-blind, placebo-controlled trial of monthly versus bimonthly dihydroartemisinin-piperaquine chemoprevention in adults at high risk of malaria. Antimicrob Agents Chemother 56: 1571–1577.

46. BorsiniF, CrumbW, PaceS, UbbenD, WibleB, et al. (2012) In vitro cardiovascular effects of dihydroartemisin-piperaquine combination compared with other antimalarials. Antimicrob Agents Chemother 56: 3261–3270.

47. Van DornCS, JohnsonJN, TaggartNW, ThorkelsonL, AckermanMJ (2011) QTc values among children and adolescents presenting to the emergency department. Pediatrics 128: e1395–1401.

48. European Medicines Agency (2011) Annex I: summary of product characteristics. Available: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001199/WC500118113.pdf. Accessed 25 November 2014.

Štítky
Interné lekárstvo

Článok vyšiel v časopise

PLOS Medicine


2014 Číslo 12
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#