Dataset Information

Relapse of Plasmodium vivax and Plasmodium ovale Malaria With and Without Primaquine Treatment in a Nonendemic Area.

ABSTRACT:

Background

The effect of primaquine in preventing Plasmodium vivax relapses from dormant stages is well established. For Plasmodium ovale, the relapse characteristics and the use of primaquine is not as well studied. We set to evaluate the relapsing properties of these 2 species, in relation to primaquine use among imported malaria cases in a nonendemic setting.

Methods

We performed a nationwide retrospective study of malaria diagnosed in Sweden 1995-2019, by reviewing medical records of 3254 cases. All episodes of P. vivax (n = 972) and P. ovale (n = 251) were selected for analysis.

Results

First time relapses were reported in 80/857 (9.3%) P. vivax and 9/220 (4.1%) P. ovale episodes, respectively (P < .01). Without primaquine, the risk for relapse was higher in P. vivax, 20/60 (33.3%), compared to 3/30 (10.0%) in P. ovale (hazard ratio [HR] 3.5, 95% confidence interval [CI] 1.0-12.0). In P. vivax, patients prescribed primaquine had a reduced risk of relapse compared to episodes without relapse preventing treatment, 7.1% vs 33.3% (HR 0.2, 95% CI .1-.3). In P. ovale, the effect of primaquine on the risk of relapse did not reach statistical significance, with relapses seen in 2.8% of the episodes compared to 10.0% in patients not receiving relapse preventing treatment (HR 0.3, 95% CI .1-1.1).

Conclusions

The risk of relapse was considerably lower in P. ovale than in P. vivax infections indicating different relapsing features between the two species. Primaquine was effective in preventing P. vivax relapse. In P. ovale, relapse episodes were few, and the supportive evidence for primaquine remains limited.

SUBMITTER: Wangdahl A

PROVIDER: S-EPMC8994585 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Publications

Relapse of Plasmodium vivax and Plasmodium ovale Malaria With and Without Primaquine Treatment in a Nonendemic Area.

Wångdahl Andreas A Sondén Klara K Wyss Katja K Stenström Christine C Björklund David D Zhang Jessica J Hervius Askling Helena H Carlander Christina C Hellgren Urban U Färnert Anna A

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20220401 7

<h4>Background</h4>The effect of primaquine in preventing Plasmodium vivax relapses from dormant stages is well established. For Plasmodium ovale, the relapse characteristics and the use of primaquine is not as well studied. We set to evaluate the relapsing properties of these 2 species, in relation to primaquine use among imported malaria cases in a nonendemic setting.<h4>Methods</h4>We performed a nationwide retrospective study of malaria diagnosed in Sweden 1995-2019, by reviewing medical rec ...[more]

PMID: 34216464

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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: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:BackgroundDespite increased efforts to control and ultimately eradicate human malaria, Plasmodium ovale malaria is for the most part outside the focus of research or public health programmes. Importantly, the understanding of P. ovale-nowadays regarded as the two distinct species P. ovale wallikeri and P. ovale curtisi-largely stems from case reports and case series lacking study designs providing high quality evidence. Consecutively, there is a lack of systematic evaluation of the clinical presentation, appropriate treatment and relapse characteristics of P. ovale malaria. The aim of this systematic review is to provide a systematic appraisal of the current evidence for severe manifestations, relapse characteristics and treatment options for human P. ovale malaria.Methods and resultsThis systematic review was performed according to the PRISMA guidelines and registered in the international prospective register for systematic reviews (PROSPERO 2016:CRD42016039214). P. ovale mono-infection was a strict inclusion criterion. Of 3454 articles identified by the literature search, 33 articles published between 1922 and 2015 met the inclusion criteria. These articles did not include randomized controlled trials. Five prospective uncontrolled clinical trials were performed on a total of 58 participants. P. ovale was sensitive to all tested drugs within the follow-up periods and on interpretable in vitro assays. Since its first description in 1922, only 18 relapsing cases of P. ovale with a total of 28 relapse events were identified in the scientific literature. There was however no molecular evidence for a causal relationship between dormant liver stages and subsequent relapses. A total of 22 severe cases of P. ovale malaria were published out of which five were fatal. Additionally, two cases of congenital P. ovale malaria were reported.ConclusionsCurrent knowledge of P. ovale malaria is based on small trials with minor impact, case reports and clinical observations. This systematic review highlights that P. ovale is capable of causing severe disease, severe congenital malaria and may even lead to death. Evidence for relapses in patients with P. ovale malaria adds up to only a handful of cases. Nearly 100 years after P. ovale's first description by Stephens the evidence for the clinical characteristics, relapse potential and optimal treatments for P. ovale malaria is still scarce.

Project description:Plasmodium ovale is a benign tertian malaria parasite that morphologically resembles Plasmodium vivax. P. ovale also shares similar tertian periodicity and can cause relapse in patients without a radical cure, making it easily misidentified as P. vivax in routine diagnosis. Therefore, its prevalence might be underreported worldwide. The present study aimed to quantify the prevalence of P. ovale misidentified as P. vivax malaria using data from studies reporting confirmed P. ovale cases by molecular methods. Studies reporting the misidentification of P. ovale as P. vivax malaria were identified from three databases, MEDLINE, Web of Science, and Scopus, without language restrictions, but the publication date was restricted to 1993 and 2020. The quality of the included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS). The random-effects model was used to estimate the pooled prevalence of the misidentification of P. ovale as P. vivax malaria by the microscopic method when compared to those with the reference polymerase chain reaction method. Subgroup analysis of participants was also performed to demonstrate the difference between imported and indigenous P. ovale cases. The heterogeneity of the included studies was assessed using Cochran's Q and I2 statistics. Publication bias across the included studies was assessed using the funnel plot and Egger's test, and if required, contour-enhanced funnel plots were used to identify the source(s) of funnel plot asymmetry. Of 641 articles retrieved from databases, 22 articles met the eligibility criteria and were included in the present study. Of the 8,297 malaria-positive cases identified by the PCR method, 453 P. ovale cases were confirmed. The pooled prevalence of misidentification of P. ovale as P. vivax malaria by the microscopic method was 11% (95% CI: 7-14%, I2: 25.46%). Subgroup analysis of the participants demonstrated a higher prevalence of misidentification in indigenous cases (13%, 95% CI: 6-21%, I2: 27.8%) than in imported cases (10%, 95% CI: 6-14%, I2: 24.1%). The pooled prevalence of misidentification of P. vivax as P. ovale malaria by the microscopic method was 1%, without heterogeneity (95% CI: 0-3%, I2: 16.8%). PCR was more sensitive in identifying P. ovale cases than the microscopic method (p < 0.00001, OR: 2.76, 95% CI: 1.83-4.15, I2: 65%). Subgroup analysis of participants demonstrated the better performance of PCR in detecting P. ovale malaria in indigenous cases (p: 0.0009, OR: 6.92, 95% CI: 2.21-21.7%, I2: 68%) than in imported cases (p: 0.0004, OR: 2.15, 95% CI: 1.41-3.29%, I2: 63%). P. ovale infections misidentified as P. vivax malaria by the microscopic method were frequent and led to underreported P. ovale cases. The molecular identification of P. ovale malaria in endemic areas is needed because a higher rate of P. ovale misidentification was found in endemic or indigenous cases than in imported cases. In addition, updated courses, enhanced training, and refreshers for microscopic examinations, particularly for P. ovale identification, are necessary to improve the microscopic identification of Plasmodium species in rural health centres where PCR is unavailable.

Dataset Information

Relapse of Plasmodium vivax and Plasmodium ovale Malaria With and Without Primaquine Treatment in a Nonendemic Area.

Background

Methods

Results

Conclusions

Publications

Relapse of Plasmodium vivax and Plasmodium ovale Malaria With and Without Primaquine Treatment in a Nonendemic Area.

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