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Estimating the Proportion of Plasmodium vivax Recurrences Caused by Relapse: A Systematic Review and Meta-Analysis.

ABSTRACT: Plasmodium vivax and Plasmodium ovale form dormant liver hypnozoites that can reactivate weeks to months following initial infection. Malaria recurrences caused by relapses are an important cause of morbidity and source of transmission. To estimate the proportions of P. vivax malaria recurrences caused by relapses in different geographical locations, we systematically reviewed clinical efficacy studies of uncomplicated P. vivax malaria, in which patients were randomized to treatment with or without radical cure primaquine regimens and were followed up for 1 year. The minimum proportion of recurrences caused by relapses was estimated for each study site by assuming primaquine prevented all relapses and did not augment blood-stage efficacy. Of the 261 studies identified, six were eligible enrolling 4,092 patients from 14 treatment arm comparisons across seven countries. Of the 2,735 patients treated with primaquine, 24.3% received low dose (2.5 to < 5.0 mg/kg total) and 75.7% received high-dose primaquine (? 5.0 mg/kg total). The overall pooled incidence rate ratio of P. vivax relapses for patients treated with primaquine versus no primaquine was 0.15 (95% CI: 0.10-0.21; I 2 = 83.3%), equating to a minimum of 79% of recurrences attributable to relapse. Country-specific incidence rate ratios ranged from 0.05 (95% CI: 0.01-0.34; one estimate) in Pakistan to 0.34 in Nepal (95% CI: 0.12-0.83; one estimate) and Afghanistan (95% CI: 0.22-0.51; three estimates). Relapses account for a very high proportion of recurrent infections following schizontocidal treatment of acute P. vivax malaria across diverse geographic locations. This emphasizes the importance of implementing hypnozoitocidal treatment.

SUBMITTER: Commons RJ

PROVIDER: S-EPMC7470578 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Estimating the Proportion of Plasmodium vivax Recurrences Caused by Relapse: A Systematic Review and Meta-Analysis.

Commons Robert J RJ Simpson Julie A JA Watson James J White Nicholas J NJ Price Ric N RN

The American journal of tropical medicine and hygiene 20200901 3

Plasmodium vivax and Plasmodium ovale form dormant liver hypnozoites that can reactivate weeks to months following initial infection. Malaria recurrences caused by relapses are an important cause of morbidity and source of transmission. To estimate the proportions of P. vivax malaria recurrences caused by relapses in different geographical locations, we systematically reviewed clinical efficacy studies of uncomplicated P. vivax malaria, in which patients were randomiz ...[more]

PMID: 32524950

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Project description:Plasmodium vivax has the widest geographic distribution of the human malaria parasites and nearly 2.5 billion people live at risk of infection. The control of P. vivax in individuals and populations is complicated by its ability to relapse weeks to months after initial infection. Strains of P. vivax from different geographical areas are thought to exhibit varied relapse timings. In tropical regions strains relapse quickly (three to six weeks), whereas those in temperate regions do so more slowly (six to twelve months), but no comprehensive assessment of evidence has been conducted. Here observed patterns of relapse periodicity are used to generate predictions of relapse incidence within geographic regions representative of varying parasite transmission.A global review of reports of P. vivax relapse in patients not treated with a radical cure was conducted. Records of time to first P. vivax relapse were positioned by geographic origin relative to expert opinion regions of relapse behaviour and epidemiological zones. Mixed-effects meta-analysis was conducted to determine which geographic classification best described the data, such that a description of the pattern of relapse periodicity within each region could be described. Model outputs of incidence and mean time to relapse were mapped to illustrate the global variation in relapse.Differences in relapse periodicity were best described by a historical geographic classification system used to describe malaria transmission zones based on areas sharing zoological and ecological features. Maps of incidence and time to relapse showed high relapse frequency to be predominant in tropical regions and prolonged relapse in temperate areas.The results indicate that relapse periodicity varies systematically by geographic region and are categorized by nine global regions characterized by similar malaria transmission dynamics. This indicates that relapse may be an adaptation evolved to exploit seasonal changes in vector survival and therefore optimize transmission. Geographic patterns in P. vivax relapse are important to clinicians treating individual infections, epidemiologists trying to infer P. vivax burden, and public health officials trying to control and eliminate the disease in human populations.

Project description:BackgroundA 14-day course of primaquine is used for radical cure of Plasmodium vivax and Plasmodium ovale malaria only. We quantified the risk of P vivax parasitaemia after treatment of Plasmodium falciparum with commonly used antimalarial drugs to assess the potential benefits of radical cure for all patients with uncomplicated malaria in co-endemic regions.MethodsIn this systematic review and meta-analysis, we searched MEDLINE, Embase, Web of Science, and the Cochrane Database of Systematic Reviews for prospective clinical studies in any language, published between Jan 1, 1960, and Jan 5, 2018, assessing drug efficacy in patients with uncomplicated P falciparum malaria in countries co-endemic for P vivax. Studies were included if the presence or absence of P vivax parasitaemia was recorded after treatment. The primary outcome was the risk of P vivax parasitaemia between day 7 and day 42 after initiation of antimalarial treatment for P falciparum, with the pooled risk calculated by random-effects meta-analysis. We compared the risk of P vivax parasitaemia after treatment with different artemisinin-based combination therapies (ACTs). This study is registered with PROSPERO, number CRD42017064838.Findings153 of 891 screened studies were included in the analysis, including 31 262 patients from 323 site-specific treatment groups: 130 (85%) studies were from the Asia-Pacific region, 16 (10%) from the Americas, and seven (5%) from Africa. The risk of P vivax parasitaemia by day 42 was 5·6% (95% CI 4·0-7·4; I2=92·0%; 117 estimates). The risk of P vivax parasitaemia was 6·5% (95% CI 4·6-8·6) in regions of short relapse periodicity compared with 1·9% (0·4-4·0) in regions of long periodicity, and was greater after treatment with a more rapidly eliminated ACT: 15·3% (5·1-29·3) for artemether-lumefantrine compared with 4·5% (1·2-9·3) for dihydroartemisinin-piperaquine and 5·2% (2·9-7·9) for artesunate-mefloquine. Recurrent parasitaemia was delayed in patients treated with ACTs containing mefloquine or piperaquine compared with artemether-lumefantrine, but by day 63 the risk of vivax parasitaemia was more than 15% for all ACTs assessed.InterpretationOur findings show a high risk of vivax parasitaemia after treatment of falciparum malaria, particularly in areas with short relapse periodicity and after rapidly eliminated treatment. In co-endemic regions, universal radical cure for all patients with uncomplicated malaria has the potential to substantially reduce recurrent malaria.FundingAustralian National Health and Medical Research Council, Royal Australasian College of Physicians, Wellcome Trust, and Bill & Melinda Gates Foundation.

Project description:BackgroundPlasmodium vivax is one of the major species of malaria infecting humans. Although emphasis on P. falciparum is appropriate, the burden of vivax malaria should be given due attention. This study aimed to synthesize the evidence on severe malaria in P. vivax infection compared with that in P. falciparum infection.Methods/principal findingsWe searched relevant studies in electronic databases. The main outcomes required for inclusion in the review were mortality, severe malaria (SM) and severe anaemia (SA). The methodological quality of the included studies was assessed using the Newcastle-Ottawa Scale. Overall, 26 studies were included. The main meta-analysis was restricted to the high quality studies. Eight studies (n = 27490) compared the incidence of SM between P. vivax infection and P. falciparum mono-infection; a comparable incidence was found in infants (OR: 0.45, 95% CI:0.04-5.68, I2:98%), under 5 year age group (OR: 2.06, 95% CI: 0.83-5.1, I2:83%), the 5-15 year-age group (OR: 0.6, 95% CI: 0.31-1.16, I2:81%) and adults (OR: 0.83, 95% CI: 0.67-1.03, I2:25%). Six studies reported the incidences of SA in P. vivax infection and P. falciparum mono-infection; a comparable incidence of SA was found among infants (OR: 3.47, 95%:0.64-18.94, I2: 92%), the 5-15 year-age group (OR:0.71, 95% CI: 0.06-8.57, I2:82%). This was significantly lower in adults (OR:0.75, 95% CI: 0.62-0.92, I2:0%). Five studies (n = 71079) compared the mortality rate between vivax malaria and falciparum malaria. A lower rate of mortality was found in infants with vivax malaria (OR:0.61, 95% CI:0.5-0.76, I2:0%), while this was comparable in the 5-15 year- age group (OR: 0.43, 95% CI:0.06-2.91, I2:84%) and the children of unspecified-age group (OR: 0.77, 95% CI:0.59-1.01, I2:0%).ConclusionOverall, the present analysis identified that the incidence of SM in patients infected with P. vivax was considerable, indicating that P. vivax is a major cause of SM. Awareness of the clinical manifestations of vivax malaria should prompt early detection. Subsequent treatment and monitoring of complications can be life-saving.

Project description:BackgroundEthiopia is one of the scarce African countries where Plasmodium vivax and P. falciparum co-exist. There has been no attempt to derive a robust prevalence estimate of P. vivax in the country although a clear understanding of the epidemiology of this parasite is essential for informed decisions. This systematic review and meta-analysis, therefore, is aimed to synthesize the available evidences on the distribution of P. vivax infection by different locations/regions, study years, eco-epidemiological zones, and study settings in Ethiopia.MethodsThis study was conducted in accordance with Preferred Reposting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. Studies conducted and published over the last two decades (2000 to 2020) that reported an estimate of P. vivax prevalence in Ethiopia were included. The Cochrane Q (χ2) and the I2 tests were used to assess heterogeneity, and the funnel plot and Egger's test were used to examine publication bias. A p-value of the χ2 test <0.05 and an I2 value >75% were considered presence of considerable heterogeneity. Random effect models were used to obtain pooled estimate of P. vivax infection prevalence. This study is registered with PROSPERO (International Prospective Register of Systematic Reviews): ID CRD42020201761.ResultsWe screened 4,932 records and included 79 studies that enrolled 1,676,659 confirmed malaria cases, from which 548,214 (32.69%) were P. vivax infections and 1,116,581 (66.59%) were due to P. falciparum. The rest were due to mixed infections. The pooled estimate of P. vivax prevalence rate was 8.93% (95% CI: 7.98-9.88%) with significant heterogeneity (I2 = 100%, p<0.0001). Regional differences showed significant effects (p<0.0001, and I2 = 99.4%) on the pooled prevalence of P. vivax, while study years (before and after the scaling up of interventional activities) did not show significant differences (p = 0.9, I2 = 0%). Eco-epidemiological zones considered in the analysis did show a significant statistical effect (p<0.001, I2 = 78.5%) on the overall pooled estimate prevalence. Also, the study setting showed significant differences (p = 0.001, and I2 = 90.3%) on the overall prevalence, where significant reduction of P. vivax prevalence (4.67%, 95%CI: 1.41-7.93%, p<0.0001) was observed in studies conducted at the community level. The studies included in the review demonstrated lack of publication bias qualitatively (symmetrical funnel plot) and quantitatively [Egger's test (coefficient) = -2.97, 95% CI: -15.06-9.13, p = 0.62].ConclusionThe estimated prevalence of P. vivax malaria in Ethiopia was 8.93% with P. vivax prevailing in the central west region of Ethiopia, but steadily extending to the western part of the country. Its distribution across the nation varies according to geographical location, study setting and study years.

Project description:Chloroquine (CQ) is the first-line treatment for Plasmodium vivax malaria in most countries where malaria is endemic. Monitoring P. vivax CQ resistance (CQR) is critical but remains challenged by the difficulty to distinguish real treatment failure from reinfection or liver relapse. The therapeutic efficacy of CQ against uncomplicated P. vivax malaria was evaluated in Gia Lai Province, Vietnam. Sixty-seven patients were enrolled and followed for 42 days using microscopy and quantitative PCR. Adequate clinical and parasitological response (ACPR) was 100% (66/66) on day 28 but 75.4% (49/65) on day 42. Eighteen recurrences (27.7%) were detected, with a median time to recurrence of 42 days (interquartile range [IQR], 35 to 42) and blood CQ concentration of <100 ng/ml. Primary infections leading to recurrence occurred in younger individuals (median age for ACPR = 25 years [IQR, 20 to 28]; recurrences = 18 [16 to 21]; P = 0.002) had a longer parasite clearance time (PCT for ACPR = 47.5 h [IQR, 36.2 to 59.8 h]; recurrences = 54.2 [48.4 to 62.0]; P = 0.035) and higher pvcrt gene expression (median relative expression ratio for ACPR = 0.09 [IQR, 0.05 to 0.22]; recurrences = 0.20 [0.15 to 0.56]; P = 0.002), but showed no differences in ex vivo CQ sensitivity. Parasite genotyping by microsatellites, single nucleotide polymorphism (SNP) barcoding, and whole-genome sequencing (WGS) identified a majority of homologous recurrences, with 80% (8/10) showing >98% identity by descent to paired day 0 samples. This study shows that CQ remained largely efficacious to treat P. vivax in Gia Lai; i.e., recurrences occurred late (>day 28) and in the presence of low blood CQ concentrations. However, the combination of both WGS and gene expression analysis (pvcrt) data with clinical data (PCT) allowed us to identify potential emergence of low-grade CQR, which should be closely monitored. (This study has been registered at ClinicalTrials.gov under identifier NCT02610686.).

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Estimating the Proportion of Plasmodium vivax Recurrences Caused by Relapse: A Systematic Review and Meta-Analysis.

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Estimating the Proportion of <i>Plasmodium vivax</i> Recurrences Caused by Relapse: A Systematic Review and Meta-Analysis.

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