The efficacy of dihydroartemisinin-piperaquine and artemether-lumefantrine with and without primaquine on Plasmodium vivax recurrence: A systematic review and individual patient data meta-analysis

• Published in: PLoS medicine 2019-10, Vol.16 (10), p.e1002928-e1002928
• Main Authors: Commons, Robert J, Simpson, Julie A, Thriemer, Kamala, Abreha, Tesfay, Adam, Ishag, Anstey, Nicholas M, Assefa, Ashenafi, Awab, Ghulam R, Baird, J Kevin, Barber, Bridget E, Chu, Cindy S, Dahal, Prabin, Daher, André, Davis, Timothy M E, Dondorp, Arjen M, Grigg, Matthew J, Humphreys, Georgina S, Hwang, Jimee, Karunajeewa, Harin, Laman, Moses, Lidia, Kartini, Moore, Brioni R, Mueller, Ivo, Nosten, Francois, Pasaribu, Ayodhia P, Pereira, Dhelio B, Phyo, Aung P, Poespoprodjo, Jeanne R, Sibley, Carol H, Stepniewska, Kasia, Sutanto, Inge, Thwaites, Guy, Hien, Tran T, White, Nicholas J, William, Timothy, Woodrow, Charles J, Guerin, Philippe J, Price, Ric N
• Format: Article
• Language: English
• Subjects: Analysis; Antimalarial agents; Antimalarials; Antimalarials - administration & dosage; Artemether; Artemether, Lumefantrine Drug Combination - administration & dosage; Artemisinin; Artemisinins - administration & dosage; Biology and Life Sciences; Chloroquine; Clinical medicine; Dihydroartemisinin; Hemoglobin; Hemoglobins; Hospitals; Humans; Infectious diseases; Malaria; Malaria, Vivax - diagnosis; Malaria, Vivax - drug therapy; Medical research; Medicine; Medicine and Health Sciences; Meta-analysis; Patients; Physical Sciences; Plasmodium vivax; Population; Primaquine; Primaquine - administration & dosage; Prophylaxis; Public health; Quinolines - administration & dosage; Recurrence; Recurrence (Disease); Research and Analysis Methods; Retirement benefits; Risk; Risk assessment; Systematic review; Treatment Outcome; Tropical diseases; Vector-borne diseases
• ISSN: 1549-1676; 1549-1277; 1549-1676
• DOI: 10.1371/journal.pmed.1002928

Artemisinin-based combination therapy (ACT) is recommended for uncomplicated Plasmodium vivax malaria in areas of emerging chloroquine resistance. We undertook a systematic review and individual patient data meta-analysis to compare the efficacies of dihydroartemisinin-piperaquine (DP) and artemether-lumefantrine (AL) with or without primaquine (PQ) on the risk of recurrent P. vivax. Clinical efficacy studies of uncomplicated P. vivax treated with DP or AL and published between January 1, 2000, and January 31, 2018, were identified by conducting a systematic review registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42016053310. Investigators of eligible studies were invited to contribute individual patient data that were pooled using standardised methodology. The effect of mg/kg dose of piperaquine/lumefantrine, ACT administered, and PQ on the rate of P. vivax recurrence between days 7 and 42 after starting treatment were investigated by Cox regression analyses according to an a priori analysis plan. Secondary outcomes were the risk of recurrence assessed on days 28 and 63. Nineteen studies enrolling 2,017 patients were included in the analysis. The risk of recurrent P. vivax at day 42 was significantly higher in the 384 patients treated with AL alone (44.0%, 95% confidence interval [CI] 38.7-49.8) compared with the 812 patients treated with DP alone (9.3%, 95% CI 7.1-12.2): adjusted hazard ratio (AHR) 12.63 (95% CI 6.40-24.92), p < 0.001. The rates of recurrence assessed at days 42 and 63 were associated inversely with the dose of piperaquine: AHRs (95% CI) for every 5-mg/kg increase 0.63 (0.48-0.84), p = 0.0013 and 0.83 (0.73-0.94), p = 0.0033, respectively. The dose of lumefantrine was not significantly associated with the rate of recurrence (1.07 for every 5-mg/kg increase, 95% CI 0.99-1.16, p = 0.0869). In a post hoc analysis, in patients with symptomatic recurrence after AL, the mean haemoglobin increased 0.13 g/dL (95% CI 0.01-0.26) for every 5 days that recurrence was delayed, p = 0.0407. Coadministration of PQ reduced substantially the rate of recurrence assessed at day 42 after AL (AHR = 0.20, 95% CI 0.10-0.41, p < 0.001) and at day 63 after DP (AHR = 0.08, 95% CI 0.01-0.70, p = 0.0233). Results were limited by follow-up of patients to 63 days or less and nonrandomised treatment groups. In this study, we observed the risk of P. vivax recurrence at day 42 to be significantly lower following treatment with D