Dihydroartemisinin-piperaquine versus chloroquine to treat vivax malaria in Afghanistan: an open randomized, non-inferiority, trial

Ghulam Rahim Awab, Sasithon Pukrittayakamee, Mallika Imwong, Arjen M Dondorp, Charles J Woodrow, Sue Jean Lee, Nicholas P J Day, Pratap Singhasivanon, Nicholas J White, Faizullah Kaker, Ghulam Rahim Awab, Sasithon Pukrittayakamee, Mallika Imwong, Arjen M Dondorp, Charles J Woodrow, Sue Jean Lee, Nicholas P J Day, Pratap Singhasivanon, Nicholas J White, Faizullah Kaker

Abstract

Background: Afghanistan's national guidelines recommend chloroquine for the treatment of Plasmodium vivax infection, the parasite responsible for the majority of its malaria burden. Chloroquine resistance in P. vivax is emerging in Asia. Therapeutic responses across Afghanistan have not been evaluated in detail.

Methods: Between July 2007 and February 2009, an open-label, randomized controlled trial of chloroquine and dihydroartemisinin-piperaquine in patients aged three months and over with slide-confirmed P. vivax mono-infections was conducted. Consistent with current national guidelines, primaquine was not administered. Subjects were followed up daily during the acute phase of illness (days 0-3) and weekly until day 56. The primary endpoint was the overall cumulative parasitological failure rate at day 56 after the start of treatment, with the hypothesis being that dihydroartemisinin-piperaquine was non-inferior compared to chloroquine (Delta = 5% difference in proportion of failures).

Results: Of 2,182 individuals with positive blood films for P. vivax, 536 were enrolled in the trial. The day 28 cure rate was 100% in both treatment groups. Parasite clearance was more rapid with dihydroartemisinin-piperaquine than chloroquine. At day 56, there were more recurrent infections in the chloroquine arm (8.9%, 95% CI 6.0-13.1%) than the dihydroartemisinin-piperaquine arm (2.8%, 95% CI 1.4-5.8%), a difference in cumulative recurrence rate of 6.1% (2-sided 90%CI +2.6 to +9.7%). The log-rank test comparing the survival curves confirmed the superiority of dihydroartemisinin-piperaquine over chloroquine (p = 0.003). Multivariate analysis showed that a lower initial haemoglobin concentration was also independently associated with recurrence. Both regimens were well tolerated and no serious adverse events were reported.

Conclusions: Chloroquine remains an efficacious treatment for the treatment of vivax malaria in Afghanistan. In a setting where radical therapy cannot be administered, dihydroartemisinin-piperaquine provides additional benefit in terms of post-treatment prophylaxis, reducing the incidence of recurrence from 4-8 weeks after treatment.

Trial registration: ClinicalTrials.gov NCT00682578.

Figures

Figure 1
Figure 1
Trial flow.
Figure 2
Figure 2
Survival curves. The proportion of subjects free from recurrence of P. vivax is displayed according to treatment arm; dihydroartemisinin-piperaquine (DP) and chloroquine (CQ).
Figure 3
Figure 3
Analysis of primary outcome (cumulative failure rate at day 56). Non-inferiority analysis refers to the pre-specified survival analysis.
Figure 4
Figure 4
Proportion with clearance of parasites (a) and fever (b) at day 1-3 after treatment.

References

    1. Price RN, Tjitra E, Guerra CA, Yeung S, White NJ, Anstey NM. Vivax malaria: neglected and not benign. Am J Trop Med Hyg. 2007;77:79–87.
    1. Mendis K, Sina BJ, Marchesini P, Carter R. The neglected burden of Plasmodium vivax malaria. Am J Trop Med Hyg. 2001;64:97–106.
    1. Nosten F, McGready R, Simpson JA, Thwai KL, Balkan S, Cho T, Hkirijaroen L, Looareesuwan S, White NJ. Effects of Plasmodium vivax malaria in pregnancy. Lancet. 1999;354:546–549. doi: 10.1016/S0140-6736(98)09247-2.
    1. Baird JK. Resistance to therapies for infection by Plasmodium vivax. Clin Microbiol Rev. 2009;22:508–534. doi: 10.1128/CMR.00008-09.
    1. Karunajeewa HA, Mueller I, Senn M, Lin E, Law I, Gomorrai PS, Oa O, Griffin S, Kotab K, Suano P, Tarongka N, Ura A, Lautu D, Page-Sharp M, Wong R, Salman S, Siba P, Ilett KF, Davis TM. A trial of combination antimalarial therapies in children from Papua New Guinea. N Engl J Med. 2008;359:2545–2557. doi: 10.1056/NEJMoa0804915.
    1. Sumawinata IW, Bernadeta, Leksana B, Sutamihardja A, Purnomo, Subianto B, Sekartuti, Fryauff DJ, Baird JK. Very high risk of therapeutic failure with chloroquine for uncomplicated Plasmodium falciparum and P. vivax malaria in Indonesian Papua. Am J Trop Med Hyg. 2003;68:416–420.
    1. Leslie T, Kaur H, Mohammed N, Kolaczinski K, Ord RL, Rowland M. Epidemic of Plasmodium falciparum malaria involving substandard antimalarial drugs, Pakistan, 2003. Emerg Infect Dis. 2009;15:1753–1759.
    1. Durrani N, Leslie T, Rahim S, Graham K, Ahmad F, Rowland M. Efficacy of combination therapy with artesunate plus amodiaquine compared to monotherapy with chloroquine, amodiaquine or sulfadoxine-pyrimethamine for treatment of uncomplicated Plasmodium falciparum in Afghanistan. Trop Med Int Health. 2005;10:521–529. doi: 10.1111/j.1365-3156.2005.01429.x.
    1. Kolaczinski K, Durrani N, Rahim S, Rowland M. Sulfadoxine-pyrimethamine plus artesunate compared with chloroquine for the treatment of vivax malaria in areas co-endemic for Plasmodium falciparum and P. vivax: a randomised non-inferiority trial in eastern Afghanistan. Trans R Soc Trop Med Hyg. 2007;101:1081–1087. doi: 10.1016/j.trstmh.2007.06.015.
    1. Leslie T, Mayan MI, Hasan MA, Safi MH, Klinkenberg E, Whitty CJ, Rowland M. Sulfadoxine-pyrimethamine, chlorproguanil-dapsone, or chloroquine for the treatment of Plasmodium vivax malaria in Afghanistan and Pakistan: a randomized controlled trial. JAMA. 2007;297:2201–2209. doi: 10.1001/jama.297.20.2201.
    1. Ezard N, Nellepalli P, Asha AW. Sulfadoxine-pyrimethamine remains efficacious against uncomplicated, Plasmodium falciparum malaria in north-eastern Afghanistan. Ann Trop Med Parasitol. 2004;98:85–88. doi: 10.1179/000349804225003019.
    1. Zakeri S, Afsharpad M, Ghasemi F, Raeisi A, Safi N, Butt W, Atta H, Djadid ND. Molecular surveillance of Plasmodium vivax dhfr and dhps mutations in isolates from Afghanistan. Malar J. p. 75.
    1. Denis MB, Davis TM, Hewitt S, Incardona S, Nimol K, Fandeur T, Poravuth Y, Lim C, Socheat D. Efficacy and safety of dihydroartemisinin-piperaquine (Artekin) in Cambodian children and adults with uncomplicated falciparum malaria. Clin Infect Dis. 2002;35:1469–1476. doi: 10.1086/344647.
    1. Ratcliff A, Siswantoro H, Kenangalem E, Maristela R, Wuwung RM, Laihad F, Ebsworth EP, Anstey NM, Tjitra E, Price RN. Two fixed-dose artemisinin combinations for drug-resistant falciparum and vivax malaria in Papua, Indonesia: an open-label randomised comparison. Lancet. 2007;369:757–765. doi: 10.1016/S0140-6736(07)60160-3.
    1. Hasugian AR, Purba HL, Kenangalem E, Wuwung RM, Ebsworth EP, Maristela R, Penttinen PM, Laihad F, Anstey NM, Tjitra E, Price RN. Dihydroartemisinin-piperaquine versus artesunate-amodiaquine: superior efficacy and posttreatment prophylaxis against multidrug-resistant Plasmodium falciparum and Plasmodium vivax malaria. Clin Infect Dis. 2007;44:1067–1074. doi: 10.1086/512677.
    1. Faulde MK, Hoffmann R, Fazilat KM, Hoerauf A. Malaria reemergence in northern Afghanistan. Emerg Infect Dis. 2007;13:1402–1404.
    1. Dhir SL, Rahim A. Malaria and its control in Afghanistan (1950-1954) Indian J Malariol. 1957;11:73–126.
    1. Kolaczinski J, Graham K, Fahim A, Brooker S, Rowland M. Malaria control in Afghanistan: progress and challenges. Lancet. 2005;365:1506–1512. doi: 10.1016/S0140-6736(05)66423-9.
    1. Brooker S, Leslie T, Kolaczinski K, Mohsen E, Mehboob N, Saleheen S, Khudonazarov J, Freeman T, Clements A, Rowland M, Kolaczinski J. Spatial epidemiology of Plasmodium vivax, Afghanistan. Emerg Infect Dis. 2006;12:1600–1602.
    1. World Malaria Report, Afghanistan.
    1. Faulde MK, Hoffmann R, Fazilat KM, Hoerauf A. Epidemiology of Plasmodium falciparum and P. vivax malaria endemic in northern Afghanistan. J Egypt Soc Parasitol. 2008;38:679–692.
    1. WHO. Severe and complicated malaria. Trans R Soc Trop Med Hyg. 2000;94(Suppl 1):1–90.
    1. Stepniewska K, White NJ. Some considerations in the design and interpretation of antimalarial drug trials in uncomplicated falciparum malaria. Malar J. 2006;5:127. doi: 10.1186/1475-2875-5-127.
    1. Pukrittayakamee S, Chantra A, Simpson JA, Vanijanonta S, Clemens R, Looareesuwan S, White NJ. Therapeutic responses to different antimalarial drugs in vivax malaria. Antimicrob Agents Chemother. 2000;44:1680–1685. doi: 10.1128/AAC.44.6.1680-1685.2000.
    1. Marubini E, Valsecchi MG. Analysing Survival Data from Clinical Trials and Observational Studies. Chichester: John Wiley & Sons; 1995.
    1. Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJ. Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. JAMA. 2006;295:1152–1160. doi: 10.1001/jama.295.10.1152.
    1. Snounou G. Detection and identification of the four malaria parasite species infecting humans by PCR amplification. Methods Mol Biol. 1996;50:263–291.
    1. White NJ. Clinical pharmacokinetics and pharmacodynamics of artemisinin and derivatives. Trans R Soc Trop Med Hyg. 1994;88(Suppl 1):S41–43. doi: 10.1016/0035-9203(94)90471-5.
    1. Baird JK, Wiady I, Fryauff DJ, Sutanihardja MA, Leksana B, Widjaya H, Kysdarmanto, Subianto B. In vivo resistance to chloroquine by Plasmodium vivax and Plasmodium falciparum at Nabire, Irian Jaya, Indonesia. Am J Trop Med Hyg. 1997;56:627–631.
    1. Ratcliff A, Siswantoro H, Kenangalem E, Wuwung M, Brockman A, Edstein MD, Laihad F, Ebsworth EP, Anstey NM, Tjitra E, Price RN. Therapeutic response of multidrug-resistant Plasmodium falciparum and P. vivax to chloroquine and sulfadoxine-pyrimethamine in southern Papua, Indonesia. Trans R Soc Trop Med Hyg. 2007;101:351–359. doi: 10.1016/j.trstmh.2006.06.008.
    1. Sutanto I, Suprijanto S, Nurhayati, Manoempil P, Baird JK. Resistance to chloroquine by Plasmodium vivax at Alor in the Lesser Sundas Archipelago in eastern Indonesia. Am J Trop Med Hyg. 2009;81:338–342.
    1. Chen N, Auliff A, Rieckmann K, Gatton M, Cheng Q. Relapses of Plasmodium vivax infection result from clonal hypnozoites activated at predetermined intervals. J Infect Dis. 2007;195:934–941. doi: 10.1086/512242.
    1. Imwong M, Snounou G, Pukrittayakamee S, Tanomsing N, Kim JR, Nandy A, Guthmann JP, Nosten F, Carlton J, Looareesuwan S, Nair S, Sudimack D, Day NP, Anderson TJ, White NJ. Relapses of Plasmodium vivax infection usually result from activation of heterologous hypnozoites. J Infect Dis. 2007;195:927–933. doi: 10.1086/512241.
    1. Rowland M, Durrani N. Randomized controlled trials of 5- and 14-days primaquine therapy against relapses of vivax malaria in an Afghan refugee settlement in Pakistan. Trans R Soc Trop Med Hyg. 1999;93:641–643. doi: 10.1016/S0035-9203(99)90081-0.
    1. Leslie T, Rab MA, Ahmadzai H, Durrani N, Fayaz M, Kolaczinski J, Rowland M. Compliance with 14-day primaquine therapy for radical cure of vivax malaria--a randomized placebo-controlled trial comparing unsupervised with supervised treatment. Trans R Soc Trop Med Hyg. 2004;98:168–173. doi: 10.1016/S0035-9203(03)00041-5.
    1. Leslie T, Mayan I, Mohammed N, Erasmus P, Kolaczinski J, Whitty CJ, Rowland M. A randomised trial of an eight-week, once weekly primaquine regimen to prevent relapse of Plasmodium vivax in Northwest Frontier Province, Pakistan. PLoS One. 2008;3:e2861. doi: 10.1371/journal.pone.0002861.
    1. Luxemburger C, Nosten F, White NJ. Naturally acquired immunity to vivax malaria. Lancet. 1999;354:162. doi: 10.1016/S0140-6736(05)75295-8.
    1. Pukrittayakamee S, Imwong M, Looareesuwan S, White NJ. Therapeutic responses to antimalarial and antibacterial drugs in vivax malaria. Acta Trop. 2004;89:351–356. doi: 10.1016/j.actatropica.2003.10.012.
    1. White NJ. The assessment of antimalarial drug efficacy. Trends Parasitol. 2004;18:351–356.
    1. Tarning J, Lindegardh N, Annerberg A, Singtoroj T, Day NP, Ashton M, White NJ. Pitfalls in estimating piperaquine elimination. Antimicrob Agents Chemother. 2005;49:5127–5128. doi: 10.1128/AAC.49.12.5127-5128.2005.
    1. Karunajeewa HA, Ilett KF, Mueller I, Siba P, Law I, Page-Sharp M, Lin E, Lammey J, Batty KT, Davis TM. Pharmacokinetics and efficacy of piperaquine and chloroquine in Melanesian children with uncomplicated malaria. Antimicrob Agents Chemother. 2008;52:237–243. doi: 10.1128/AAC.00555-07.

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