Dataset Information

Unsupervised primaquine for the treatment of Plasmodium vivax malaria relapses in southern Papua: A hospital-based cohort study.

ABSTRACT:

Background

Primaquine is the only licensed drug for eradicating Plasmodium vivax hypnozoites and, therefore, preventing relapses of vivax malaria. It is a vital component of global malaria elimination efforts. Primaquine is efficacious when supervised in clinical trials, but its effectiveness in real-world settings is unknown. We aimed to determine whether unsupervised primaquine was effective for preventing re-presentation to hospital with vivax malaria in southern Papua, Indonesia.

Methods and findings

Routinely-collected hospital surveillance data were used to undertake a pragmatic comparison of the risk of re-presentation to hospital with vivax malaria in patients prescribed dihydroartemisinin-piperaquine (DHP) combined with primaquine versus those patients prescribed DHP alone. The omission of primaquine was predominantly due to 3 stock outages. Individual clinical, pharmacy, and laboratory data were merged using individual hospital identification numbers and the date of presentation to hospital. Between April 2004 and December 2013, there were 86,797 documented episodes of vivax malaria, of which 62,492 (72.0%) were included in the analysis. The risk of re-presentation with vivax malaria within 1 year was 33.8% (95% confidence Interval [CI] 33.1%-34.5%) after initial monoinfection with P. vivax and 29.2% (95% CI 28.1%-30.4%) after mixed-species infection. The risk of re-presentation with P. vivax malaria was higher in children 1 to <5 years of age (49.6% [95% CI 48.4%-50.9%]) compared to patients 15 years of age or older (24.2% [95% CI 23.4-24.9%]); Adjusted Hazard Ratio (AHR) = 2.23 (95% CI 2.15-2.31), p < 0.001. Overall, the risk of re-presentation was 37.2% (95% CI 35.6%-38.8%) in patients who were prescribed no primaquine compared to 31.6% (95% CI 30.9%-32.3%) in those prescribed either a low (?1.5 mg/kg and <5 mg/kg) or high (?5 mg/kg) dose of primaquine (AHR = 0.90 [95% CI 0.86-0.95, p < 0.001]). Limiting the comparison to high dose versus no primaquine in the period during and 12 months before and after a large stock outage resulted in minimal change in the estimated clinical effectiveness of primaquine (AHR 0.91, 95% CI 0.85-0.97, p = 0.003). Our pragmatic study avoided the clinical influences associated with prospective study involvement but was subject to attrition bias caused by passive follow-up.

Conclusions

Unsupervised primaquine for vivax malaria, prescribed according to the current World Health Organization guidelines, was associated with a minimal reduction in the risk of clinical recurrence within 1 year in Papua, Indonesia. New strategies for the effective radical cure of vivax malaria are needed in resource-poor settings.

SUBMITTER: Douglas NM

PROVIDER: S-EPMC5574534 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Publications

Unsupervised primaquine for the treatment of Plasmodium vivax malaria relapses in southern Papua: A hospital-based cohort study.

Douglas Nicholas M NM Poespoprodjo Jeanne Rini JR Patriani Dewi D Malloy Michael J MJ Kenangalem Enny E Sugiarto Paulus P Simpson Julie A JA Soenarto Yati Y Anstey Nicholas M NM Price Ric N RN

PLoS medicine 20170829 8

<h4>Background</h4>Primaquine is the only licensed drug for eradicating Plasmodium vivax hypnozoites and, therefore, preventing relapses of vivax malaria. It is a vital component of global malaria elimination efforts. Primaquine is efficacious when supervised in clinical trials, but its effectiveness in real-world settings is unknown. We aimed to determine whether unsupervised primaquine was effective for preventing re-presentation to hospital with vivax malaria in southern Papua, Indonesia.<h4> ...[more]

PMID: 28850568

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Project description:The widespread use of primaquine (PQ) radical cure for P. vivax, is constrained by concerns over its safety. We used routinely collected patient data to compare the overall morbidity and mortality in patients treated with and without PQ without prior testing of Glucose-6-Phosphate-Dehydrogenase (G6PD) deficiency in Papua, Indonesia, where there is a low prevalence of G6PD deficiency. Records were collated from patients older than 1 year, with P. vivax infection, who were treated with an artemisinin combination therapy (ACT). The risks of re-presentation, hospitalization, major fall in haemoglobin and death within 30 days were quantified and compared between patients treated with and without PQ using a Cox regression model. In total 26,216 patients with P. vivax malaria presented to the hospital with malaria during the study period. Overall 27.56% (95% Confidence Interval (95%CI): 26.96-28.16) of 21,344 patients treated with PQ re-presented with any illness within 30 days and 1.69% (1.51-1.88) required admission to hospital. The corresponding risks were higher in the 4,872 patients not treated with PQ; Adjusted Hazard Ratio (AHR) = 0.84 (0.79-0.91; p<0.001) and 0.54 (0.41-0.70; p<0.001) respectively. By day 30, 14.15% (12.45-16.05) of patients who had received PQ had a fall in haemoglobin (Hb) below 7g/dl compared to 20.43% (16.67-24.89) of patients treated without PQ; AHR = 0.66 (0.45-0.97; p = 0.033). A total of 75 (0.3%) patients died within 30 days of treatment with a mortality risk of 0.27% (0.21-0.35) in patients treated with PQ, compared to 0.38% (0.24-0.60) without PQ; AHR = 0.79 (0.43-1.45; p = 0.448). In Papua, Indonesia routine administration of PQ radical cure without prior G6PD testing, was associated with lower risk of all cause hospitalization and other serious adverse clinical outcomes. In areas where G6PD testing is not available or cannot be delivered reliably, the risks of drug induced haemolysis should be balanced against the potential benefits of reducing recurrent P. vivax malaria and its associated morbidity and mortality.

Project description:BackgroundTafenoquine, a single-dose therapy for Plasmodium vivax malaria, has been associated with relapse prevention through the clearance of P. vivax parasitemia and hypnozoites, termed "radical cure."MethodsWe performed a phase 3, prospective, double-blind, double-dummy, randomized, controlled trial to compare tafenoquine with primaquine in terms of safety and efficacy. The trial was conducted at seven hospitals or clinics in Peru, Brazil, Colombia, Vietnam, and Thailand and involved patients with normal glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and female patients with moderate G6PD enzyme deficiency; all patients had confirmed P. vivax parasitemia. The patients were randomly assigned, in a 2:1 ratio, to receive a single 300-mg dose of tafenoquine or 15 mg of primaquine once daily for 14 days (administered under supervision); all patients received a 3-day course of chloroquine and were followed for 180 days. The primary safety outcome was a protocol-defined decrease in the hemoglobin level (>3.0 g per deciliter or ≥30% from baseline or to a level of <6.0 g per deciliter). Freedom from recurrence of P. vivax parasitemia at 6 months was the primary efficacy outcome in a planned patient-level meta-analysis of the current trial and another phase 3 trial of tafenoquine and primaquine (per-protocol populations), and an odds ratio for recurrence of 1.45 (tafenoquine vs. primaquine) was used as a noninferiority margin.ResultsA protocol-defined decrease in the hemoglobin level occurred in 4 of 166 patients (2.4%; 95% confidence interval [CI], 0.9 to 6.0) in the tafenoquine group and in 1 of 85 patients (1.2%; 95% CI, 0.2 to 6.4) in the primaquine group, for a between-group difference of 1.2 percentage points (95% CI, -4.2 to 5.0). In the patient-level meta-analysis, the percentage of patients who were free from recurrence at 6 months was 67.0% (95% CI, 61.0 to 72.3) among the 426 patients in the tafenoquine group and 72.8% (95% CI, 65.6 to 78.8) among the 214 patients in the primaquine group. The efficacy of tafenoquine was not shown to be noninferior to that of primaquine (odds ratio for recurrence, 1.81; 95% CI, 0.82 to 3.96).ConclusionsAmong patients with normal G6PD enzyme activity, the decline in hemoglobin level with tafenoquine did not differ significantly from that with primaquine. Tafenoquine showed efficacy for the radical cure of P. vivax malaria, although tafenoquine was not shown to be noninferior to primaquine. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; GATHER ClinicalTrials.gov number, NCT02216123 .).

Project description:BackgroundThere is a high risk of Plasmodium vivax recurrence in patients treated for Plasmodium falciparum malaria in co-endemic areas. Primaquine radical cure has the potential to reduce P vivax recurrences in patients presenting with P falciparum as well as P vivax malaria but is undermined by poor adherence to the currently recommended 14-day regimen. We aimed to assess the efficacy and safety of supervised versus unsupervised primaquine radical cure in patients presenting with uncomplicated malaria.MethodsWe did a cluster-randomised, controlled, open-label superiority trial in Papua, Indonesia. 21 clusters of village health posts, matched by annual parasite index, were randomly assigned (1:1) to treat patients (age >12 months and body weight >5 kg) presenting with confirmed uncomplicated P falciparum or P vivax malaria with oral dihydroartemisinin-piperaquine plus either a supervised or unsupervised 14-day course of oral primaquine (0·5 mg/kg per day). Patients in the supervised group were supervised taking their primaquine dose on alternate days. Patients were followed-up for 6 months and those who presented again with malaria were retreated with the same drug regimen. Masking was not possible due to the nature of the study. The primary outcome was the incidence risk of P vivax malaria over 6 months, assessed in the modified intention-to-treat population (all patients who were assigned to a treatment group, excluding patients who were lost to follow-up after their first visit). This trial is now complete, and is registered with ClinicalTrials.gov, NCT02787070.FindingsBetween Sept 14, 2016, and July 31, 2018, 436 patients were screened for eligibility and 419 were enrolled; 223 (53%) patients in 11 clusters were assigned to supervised primaquine treatment and 196 (47%) in ten clusters to unsupervised primaquine treatment. 161 (72%) of 223 patients in the supervised group and 151 (77%) of 196 in the unsupervised group completed 6 months of follow-up. At 6 months, the incidence risk of P vivax recurrence in the supervised group was 29·7% (95% CI 16·4-49·9) versus 55·8% (32·3-81·8) in the unsupervised group (hazard ratio 0·23 [95% CI 0·07-0·76]; p=0·016). The incidence rate for P vivax recurrence was 539 (95% CI 390-747) infections per 1000 person-years in the supervised group versus 859 (673-1096) in the unsupervised group (incidence rate ratio 0·63 [95% CI 0·42-0·94]; p=0·025). The corresponding rates in the 224 patients who presented with P falciparum malaria were 346 (95% CI 213-563) and 660 (446-977; incidence rate ratio 0·52 [95% CI 0·28-0·98]; p=0·043). Seven serious adverse events were reported (three in the supervised group, four in the unsupervised group), none of which were deemed treatment-related, and there were no deaths.InterpretationIn this area of moderate malaria transmission, supervision of primaquine radical cure treatment reduced the risk of P vivax recurrence. This finding was apparent for patients presenting with either P falciparum or P vivax malaria. Further studies are warranted to investigate the safety and efficacy of radical cure for patients presenting with uncomplicated falciparum malaria in other co-endemic areas.FundingThe Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Foreign Affairs and Trade of the Australian Government.TranslationFor the Indonesian translation of the abstract see Supplementary Materials section.

Project description:BACKGROUND:Plasmodium vivax malaria is characterized by the presence of dormant liver-stage parasites, called hypnozoites, which can cause malaria relapses after an initial attack. Primaquine, which targets liver hypnozoites, must be used in combination with a schizonticidal agent to get the radical cure. However, relapses can sometimes occur in spite of correct treatment, due to different factors such as a diminished metabolization of primaquine. CASE PRESENTATION:In January 2019, a 21 years old woman with residence in Madrid, returning from a trip to Venezuela with clinical symptoms compatible with malaria infection, was diagnosed with vivax malaria. Chloroquine for 3 days plus primaquine for 14 days was the elected treatment. Two months later and after a second trip to Venezuela, the patient presented a second P. vivax infection, which was treated as the previous one. A third P. vivax malaria episode was diagnosed 2 months later, after returning from a trip to Morocco, receiving chloroquine for 3 days but increasing to 28 days the primaquine regimen, and with no more relapses after 6 months of follow up. The genotyping of P. vivax in the three malaria episodes revealed that the same strain was present in the different relapses. Upon confirmation of correct adherence to the treatment, non-description of resistance in the infection area and the highly unlikely re-infection on subsequent trips or stays in Spain, a possible metabolic failure was considered. CYP2D6 encodes the human cytochrome P450 isoenzyme 2D6 (CYP2D6), responsible for primaquine activation. The patient was found to have a CYP2D6*4/*1 genotype, which turns out in an intermediate metabolizer phenotype, which has been related to P. vivax relapses. CONCLUSIONS:The impairment in CYP2D6 enzyme could be the most likely cause of P. vivax relapses in this patient. This highlights the importance of considering the analysis of CYP2D6 gene polymorphisms in cases of P. vivax relapses after a correct treatment and, especially, it should be considered in any study of dosage and duration of primaquine treatment.

Project description:Plasmodium vivax has the ability to relapse from dormant parasites in the liver weeks or months after inoculation, causing further blood-stage infection and potential onward transmission. Estimates of the force of blood-stage infections arising from primary infections and relapses are important for designing intervention strategies. However, in endemic settings their relative contributions are unclear. Infections are frequently asymptomatic, many individuals harbor multiple infections, and while high-resolution genotyping of blood samples enables individual infections to be distinguished, primary infections and relapses cannot be identified. We develop a model and fit it to longitudinal genotyping data from children in Papua New Guinea to estimate the incidence and seasonality of P vivax primary infection and relapse. The children, aged one to three years at enrolment, were followed up over 16 months with routine surveys every two months. Blood samples were taken at the routine visits and at other times if the child was ill. Samples positive by microscopy or a molecular method for species detection were genotyped using high-resolution capillary electrophoresis for P vivax MS16 and msp1F3, and P falciparum msp2. The data were summarized as longitudinal patterns of success or failure to detect a genotype at each routine time-point (eg 001000001). We assume that the seasonality of P vivax primary infection is similar to that of P falciparum since they are transmitted by the same vectors and, because P falciparum does not have the ability to relapse, the seasonality can be estimated. Relapses occurring during the study period can be a consequence of infections occurring prior to the study: we assume that the seasonal pattern of primary infections repeats over time. We incorporate information from parasitological and entomology studies to gain leverage for estimating the parameters, and take imperfect detection into account. We estimate the force of P vivax primary infections to be 11.5 (10.5, 12.3) for a three-year old child per year and the mean number of relapses per infection to be 4.3 (4.0, 4.6) over 16 months. The peak incidence of relapses occurred in the two month interval following the peak interval for primary infections: the contribution to the force of blood-stage infection from relapses is between 71% and 90% depending on the season. Our estimates contribute to knowledge of the P vivax epidemiology and have implications for the timing of intervention strategies targeting different stages of the life cycle.

Dataset Information

Unsupervised primaquine for the treatment of Plasmodium vivax malaria relapses in southern Papua: A hospital-based cohort study.

Background

Methods and findings

Conclusions

Publications

Unsupervised primaquine for the treatment of Plasmodium vivax malaria relapses in southern Papua: A hospital-based cohort study.

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