Efficacy and safety of artemisinin-based combination therapy and chloroquine with concomitant primaquine to treat Plasmodium vivax malaria in Brazil: an open label randomized clinical trial

Daher, André; Pereira, Dhélio Batista; Lacerda, Marcus Vinícius Guimarães; Alexandre, Márcia A. A.; Nascimento, Cristiana Teixeira do; Silva, Julio Castro Alves de Lima e; Tada, Mauro Shugiro; Ruffato, Rosilene; Maia, Ivan; Santos, Tereza Cristina dos; Marchesini, Paola; Santelli, Ana Carolina Faria e Silva; Lalloo, David G.

doi:10.1186/s12936-018-2192-x

Cited by 16 publications

(8 citation statements)

References 29 publications

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“…There were 1,593 patients (79.0%) from 15 studies from the Asia-Pacific region [6,25–38], 341 patients (16.9%) from three studies from Africa [39–41], and 83 patients (4.1%) from one study from The Americas [42] (Table 1 and S1 Fig). In total, 812 patients were treated with DP alone [6,25–27,30,34,37,38], 384 with AL alone [6,26,28,31,36,39–41], 613 with DP plus early PQ [25,29,32,33,35], and 208 with AL plus early PQ [28,36,39,41,42]. Only two studies (from Indonesia and Papua New Guinea) compared treatment with DP and AL directly [6,26].…”

Section: Resultsmentioning

confidence: 99%

“…Only two studies (from Indonesia and Papua New Guinea) compared treatment with DP and AL directly [6,26]. Patients were followed for 28 days in one study ( n = 38, 1.9%) [39], 42–62 days in 10 studies ( n = 814, 40.4%) [6,25,26,28,31,32,36–38,40], 63–84 days in three studies ( n = 390, 19.3%) [27,34,42], and 365 days in five studies ( n = 775, 38.4%) [29,30,33,35,41]. The mg/kg doses of lumefantrine and piperaquine were calculated from the number of tablets given for 1,281 (63.5%) of 2,017 patients, with dosing for the remaining 736 (36.5%) patients calculated from the study protocol (Table 1).…”

Section: Resultsmentioning

confidence: 99%

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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

et al. 2019

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BackgroundArtemisinin-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.Methods and findingsClinical 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.ConclusionsIn this study, we observed the risk of P. vivax recurrence at day 42 to be significantly lower following treatment with DP compared with AL, reflecting the longer period of post-treatment prophylaxis; this risk was reduced substantially by coadministration with PQ. We found that delaying P. vivax recurrence was associated with a small but significant improvement in haemoglobin. These results highlight the benefits of PQ radical cure and also the provision of blood-stage antimalarial agents with prolonged post-treatment prophylaxis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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

et al. 2019

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“…Artemisinin-based combinations or chloroquine in combination with a short course of primaquine have also been shown to be highly effective in the treatment of vivax malaria in Brazil [276]. An FDC of mefloquine combined with artesunate has also been studied in cases of falciparum malaria in the Brazilian Amazon basin and shown to have acceptable efficacy, safety, and tolerability [277].…”

Section: Malaria Including Preventionmentioning

confidence: 99%

Fixed dose drug combinations – are they pharmacoeconomically sound? Findings and implications especially for lower- and middle-income countries

Godman

McCabe

Leong

2020

Expert Review of Pharmacoeconomics & Outcomes Research

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Introduction: There are positive aspects regarding the prescribing of fixed dose combinations (FDCs) versus prescribing the medicines separately. However, these have to be balanced against concerns including increased costs and their irrationality in some cases. Consequently, there is a need to review their value among lower-and middle-income countries (LMICs) which have the greatest prevalence of both infectious and noninfectious diseases and issues of affordability. Areas covered: Review of potential advantages, disadvantages, cost-effectiveness, and availability of FDCs in high priority disease areas in LMICs and possible initiatives to enhance the prescribing of valued FDCs and limit their use where there are concerns with their value. Expert commentary: FDCs are valued across LMICs. Advantages include potentially improved response rates, reduced adverse reactions, increased adherence rates, and reduced costs. Concerns include increased chances of drug:drug interactions, reduced effectiveness, potential for imprecise diagnoses and higher unjustified prices. Overall certain FDCs including those for malaria, tuberculosis, and hypertension are valued and listed in the country's essential medicine lists, with initiatives needed to enhance their prescribing where currently low prescribing rates. Proposed initiatives include robust clinical and economic data to address the current paucity of pharmacoeconomic data. Irrational FDCs persists in some countries which are being addressed.

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“…Moreover, P. vivax resistance to CQ has been occasionally described in countries sharing borders with Brazil, such as Bolivia (11), Peru, and Guyana (12). However, recrudescences at day 28 were not observed following CQ-PQ treatment of vivax malaria in other settings of endemicity in Brazil (13), including Juruá Valley, the region with the highest malaria rates in this country (14).…”

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confidence: 91%

Monitoring the Efficacy of Chloroquine-Primaquine Therapy for Uncomplicated Plasmodium vivax Malaria in the Main Transmission Hot Spot of Brazil

Ladeia‐Andrade

et al. 2019

Antimicrob Agents Chemother

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Emerging Plasmodium vivax resistance to chloroquine (CQ) may undermine malaria elimination efforts in South America. CQ-resistant P. vivax has been found in the major port city of Manaus but not in the main malaria hot spots across the Amazon Basin of Brazil, where CQ is routinely coadministered with primaquine (PQ) for radical cure of vivax malaria. Here we randomly assigned 204 uncomplicated vivax malaria patients from Juruá Valley, northwestern Brazil, to receive either sequential (arm 1) or concomitant (arm 2) CQ-PQ treatment. Because PQ may synergize the blood schizontocidal effect of CQ and mask low-level CQ resistance, we monitored CQ-only efficacy in arm 1 subjects, who had PQ administered only at the end of the 28-day follow-up. We found adequate clinical and parasitological responses in all subjects assigned to arm 2. However, 2.2% of arm 1 patients had microscopy-detected parasite recrudescences at day 28. When PCR-detected parasitemias at day 28 were considered, response rates decreased to 92.1% and 98.8% in arms 1 and 2, respectively. Therapeutic CQ levels were documented in 6 of 8 recurrences, consistent with true CQ resistance in vivo. In contrast, ex vivo assays provided no evidence of CQ resistance in 49 local P. vivax isolates analyzed. CQ-PQ coadministration was not found to potentiate the antirelapse efficacy of PQ over 180 days of surveillance; however, we suggest that larger studies are needed to examine whether and how CQ-PQ interactions, e.g., CQ-mediated inhibition of PQ metabolism, modulate radical cure efficacy in different P. vivax-infected populations. (This study has been registered at ClinicalTrials.gov under identifier NCT02691910.)

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Efficacy and safety of artemisinin-based combination therapy and chloroquine with concomitant primaquine to treat Plasmodium vivax malaria in Brazil: an open label randomized clinical trial

Cited by 16 publications

References 29 publications

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

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

Fixed dose drug combinations – are they pharmacoeconomically sound? Findings and implications especially for lower- and middle-income countries

Monitoring the Efficacy of Chloroquine-Primaquine Therapy for Uncomplicated Plasmodium vivax Malaria in the Main Transmission Hot Spot of Brazil

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