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International Journal of Infectious... Sep 2020Diagnosis is a challenging issue for eliminating malaria. Loop-mediated isothermal amplification (LAMP) could be an alternative to conventional methods. This study aimed... (Comparative Study)
Comparative Study Meta-Analysis
Systematic review and meta-analysis of diagnostic accuracy of loop-mediated isothermal amplification (LAMP) methods compared with microscopy, polymerase chain reaction and rapid diagnostic tests for malaria diagnosis.
BACKGROUND
Diagnosis is a challenging issue for eliminating malaria. Loop-mediated isothermal amplification (LAMP) could be an alternative to conventional methods. This study aimed to evaluate the diagnostic accuracy of LAMP for malaria compared with microscopy, polymerase chain reaction (PCR) and rapid diagnostic tests (RDTs).
METHODS AND DESIGN
MEDLINE, Web of Science and Scopus were searched from inception to 1 July 2019. Prospective and retrospective, randomised and non-randomised, mono-center and multi-center studies, including symptomatic or asymptomatic patients, that reported one LAMP method and one comparator (microscopy, RDT or PCR) were included. PROSPERO registration number: CRD42017075186.
RESULTS
Sixty-six studies published between 2006 and 2019 were included, leading to the analysis of 30,641 LAMP tests. The pooled sensitivity of LAMP remained between 96% and 98%, whichever the comparator. The pooled specificity of LAMP was around 95%, but was a little higher if the best PCR studies were considered. The AUC was found to be >0.98, whichever the subgroup of studies was considered. Diagnostic odds ratio (DOR) was found to be around 1000 for all subgroups, except for Plasmodium vivax.
CONCLUSION
This meta-analysis confirmed that the LAMP method is robust for diagnosing malaria, both in symptomatic and asymptomatic people. Thus, the impact of LAMP for controlling malaria is expected to be important.
Topics: Diagnostic Tests, Routine; Humans; Malaria; Microscopy; Nucleic Acid Amplification Techniques; Plasmodium; Polymerase Chain Reaction; Prospective Studies; Retrospective Studies; Sensitivity and Specificity
PubMed: 32659450
DOI: 10.1016/j.ijid.2020.07.009 -
The American Journal of Tropical... Sep 2020and form dormant liver hypnozoites that can reactivate weeks to months following initial infection. Malaria recurrences caused by relapses are an important cause of... (Meta-Analysis)
Meta-Analysis
and 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 malaria recurrences caused by relapses in different geographical locations, we systematically reviewed clinical efficacy studies of uncomplicated 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 relapses for patients treated with primaquine versus no primaquine was 0.15 (95% CI: 0.10-0.21; = 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 malaria across diverse geographic locations. This emphasizes the importance of implementing hypnozoitocidal treatment.
Topics: Antimalarials; Geography; Humans; Malaria; Malaria, Vivax; Plasmodium vivax; Primaquine; Recurrence
PubMed: 32524950
DOI: 10.4269/ajtmh.20-0186 -
BMC Infectious Diseases May 2020Plasmodium vivax rarely develops severe complications when compared to severe falciparum malaria. However, severe vivax malaria also needs urgent, intensive care and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Plasmodium vivax rarely develops severe complications when compared to severe falciparum malaria. However, severe vivax malaria also needs urgent, intensive care and treatment as severe falciparum malaria. This systematic review aimed to explore pooled prevalence of severe vivax malaria and to identify factors related to poor outcome of patients who developed severe manifestation.
METHODS
The systematic review conducted by two reviewers independently through searching of research publications related to severe P. vivax malaria in three databases including MEDLINE, Web of Science (ISI), and Scopus until October, 22 2019. The pooled prevalence of severe vivax malaria was achieved using STATA and RevMan 5 Software. Factors related to poor outcome of patients with severe vivax malaria were analyzed using SPSS 11.5 Software.
RESULTS
Among 2615 research publications retrieved from three databases, 49 articles reporting on 42,325 severity cases were selected for calculating pooled prevalence. Seventy-six patients from case reports, case series, letter to editors, and research communications were collected to identify factors related to poor outcome of patients with severe vivax malaria. The results showed that severe anemia, jaundice, respiratory distress, impaired consciousness, and renal failure were the most common major manifestations of severe malaria guided by the World Health Organization (WHO) criterion. The meta-analysis indicated that severe malaria was less frequent in patient with P. vivax compared to those with P. falciparum (P -value < 0.00001, OR = 0.38, 95% CI = 0.25-0.56, I = 87%). In addition, thrombocytopenia, anemia, hepatitis, and severe thrombocytopenia were the most common minor complications. Analysis of cases indicated that convulsion, respiratory distress, renal failure, jaundice, anuria/oliguria, and complication during treatment impacted on longer hospital stays compared to other severe complications (P-value < 0.05). Respiratory distress was frequently found after first treatment with anti-malarial drugs (P-value = 0.002). Renal failure was frequently found before treatment with anti-malarial drugs (P-value = 0.016). Mean days of fever and higher pulse rates at presentation were predictors of poor outcome among patients with severe vivax malaria (P-value < 0.05).
CONCLUSIONS
Severe anemia was the most common major manifestation of P. vivax malaria guided by the WHO criterion. Severe anemia was found less frequently in patients with P. vivax than those with P. falciparum. Renal failure, jaundice, anuria/oliguria, and complication during treatment along with, mean days of fever and higher pulse rates at presentation might be predictors of poor outcome of patients with severe vivax malaria.
Topics: Adult; Anemia; Antimalarials; Anuria; Female; Fever; Heart Rate; Humans; Jaundice; Malaria, Falciparum; Malaria, Vivax; Male; Oliguria; Plasmodium falciparum; Plasmodium vivax; Prevalence; Renal Insufficiency; Risk Factors; Severity of Illness Index; Thrombocytopenia; Treatment Outcome; World Health Organization; Young Adult
PubMed: 32448216
DOI: 10.1186/s12879-020-05046-y -
PLoS Medicine May 2020The radical cure of Plasmodium vivax and P. ovale requires treatment with primaquine or tafenoquine to clear dormant liver stages. Either drug can induce haemolysis in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The radical cure of Plasmodium vivax and P. ovale requires treatment with primaquine or tafenoquine to clear dormant liver stages. Either drug can induce haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, necessitating screening. The reference diagnostic method for G6PD activity is ultraviolet (UV) spectrophotometry; however, a universal G6PD activity threshold above which these drugs can be safely administered is not yet defined. Our study aimed to quantify assay-based variation in G6PD spectrophotometry and to explore the diagnostic implications of applying a universal threshold.
METHODS AND FINDINGS
Individual-level data were pooled from studies that used G6PD spectrophotometry. Studies were identified via PubMed search (25 April 2018) and unpublished contributions from contacted authors (PROSPERO: CRD42019121414). Studies were excluded if they assessed only individuals with known haematological conditions, were family studies, or had insufficient details. Studies of malaria patients were included but analysed separately. Included studies were assessed for risk of bias using an adapted form of the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Repeatability and intra- and interlaboratory variability in G6PD activity measurements were compared between studies and pooled across the dataset. A universal threshold for G6PD deficiency was derived, and its diagnostic performance was compared to site-specific thresholds. Study participants (n = 15,811) were aged between 0 and 86 years, and 44.4% (7,083) were women. Median (range) activity of G6PD normal (G6PDn) control samples was 10.0 U/g Hb (6.3-14.0) for the Trinity assay and 8.3 U/g Hb (6.8-15.6) for the Randox assay. G6PD activity distributions varied significantly between studies. For the 13 studies that used the Trinity assay, the adjusted male median (AMM; a standardised metric of 100% G6PD activity) varied from 5.7 to 12.6 U/g Hb (p < 0.001). Assay precision varied between laboratories, as assessed by variance in control measurements (from 0.1 to 1.5 U/g Hb; p < 0.001) and study-wise mean coefficient of variation (CV) of replicate measures (from 1.6% to 14.9%; p < 0.001). A universal threshold of 100% G6PD activity was defined as 9.4 U/g Hb, yielding diagnostic thresholds of 6.6 U/g Hb (70% activity) and 2.8 U/g Hb (30% activity). These thresholds diagnosed individuals with less than 30% G6PD activity with study-wise sensitivity from 89% (95% CI: 81%-94%) to 100% (95% CI: 96%-100%) and specificity from 96% (95% CI: 89%-99%) to 100% (100%-100%). However, when considering intermediate deficiency (<70% G6PD activity), sensitivity fell to a minimum of 64% (95% CI: 52%-75%) and specificity to 35% (95% CI: 24%-46%). Our ability to identify underlying factors associated with study-level heterogeneity was limited by the lack of availability of covariate data and diverse study contexts and methodologies.
CONCLUSIONS
Our findings indicate that there is substantial variation in G6PD measurements by spectrophotometry between sites. This is likely due to variability in laboratory methods, with possible contribution of unmeasured population factors. While an assay-specific, universal quantitative threshold offers robust diagnosis at the 30% level, inter-study variability impedes performance of universal thresholds at the 70% level. Caution is advised in comparing findings based on absolute G6PD activity measurements across studies. Novel handheld quantitative G6PD diagnostics may allow greater standardisation in the future.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimalarials; Child; Child, Preschool; Female; Glucosephosphate Dehydrogenase; Glucosephosphate Dehydrogenase Deficiency; Humans; Infant; Infant, Newborn; Malaria; Male; Middle Aged; Spectrophotometry; Young Adult
PubMed: 32407380
DOI: 10.1371/journal.pmed.1003084 -
Malaria Research and Treatment 2019Malaria is a protozoan disease caused by the species. Among the five species. Among the five and malaria are by far the most predominant and widely Malaria is one... (Review)
Review
BACKGROUND
Malaria is a protozoan disease caused by the species. Among the five species. Among the five and malaria are by far the most predominant and widely Malaria is one of the leading causes of morbidity and mortality globally, particularly in the sub-Saharan countries including Ethiopia. It is also a major obstacle to socio-economic development in the country.
METHODS
Articles were searched from PubMed, Google Scholar, and Science Direct databases. The pooled prevalence estimates were analyzed using the DerSimonian-Laird random-effects model and the possible sources of heterogeneity were evaluated through subgroup analysis, metaregression, and sensitivity analysis. Publication bias was analyzed using funnel plots and Egger's test statistics. The data management and analysis were done using STATA 15.1 version software.
RESULTS
Among 922 studies initially identified, thirty-five full-text articles fulfilled the inclusion criteria and included in the study. The combined, and malaria are by far the most predominant and widely.
CONCLUSIONS
This systematic review and meta-analysis showed a high malaria prevalence in Ethiopia. Therefore, previous prevention and control measures should be revised and/or strengthened as appropriate and new strategies should be implemented. In addition, technical, financial and material support, and coordination of the regional capacity building and logistics should be adequately implemented.
PubMed: 32089818
DOI: 10.1155/2019/7065064 -
PLoS Medicine Oct 2019Artemisinin-based combination therapy (ACT) is recommended for uncomplicated Plasmodium vivax malaria in areas of emerging chloroquine resistance. We undertook a... (Comparative Study)
Comparative Study 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.
BACKGROUND
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.
METHODS AND FINDINGS
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.
CONCLUSIONS
In 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.
Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Humans; Malaria, Vivax; Plasmodium vivax; Primaquine; Quinolines; Recurrence; Risk; Treatment Outcome
PubMed: 31584960
DOI: 10.1371/journal.pmed.1002928 -
BMC Medicine Aug 2019Malaria causes a reduction in haemoglobin that is compounded by primaquine, particularly in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The aim of... (Meta-Analysis)
Meta-Analysis
The haematological consequences of Plasmodium vivax malaria after chloroquine treatment with and without primaquine: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis.
BACKGROUND
Malaria causes a reduction in haemoglobin that is compounded by primaquine, particularly in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The aim of this study was to determine the relative contributions to red cell loss of malaria and primaquine in patients with uncomplicated Plasmodium vivax.
METHODS
A systematic review identified P. vivax efficacy studies of chloroquine with or without primaquine published between January 2000 and March 2017. Individual patient data were pooled using standardised methodology, and the haematological response versus time was quantified using a multivariable linear mixed effects model with non-linear terms for time. Mean differences in haemoglobin between treatment groups at day of nadir and day 42 were estimated from this model.
RESULTS
In total, 3421 patients from 29 studies were included: 1692 (49.5%) with normal G6PD status, 1701 (49.7%) with unknown status and 28 (0.8%) deficient or borderline individuals. Of 1975 patients treated with chloroquine alone, the mean haemoglobin fell from 12.22 g/dL [95% CI 11.93, 12.50] on day 0 to a nadir of 11.64 g/dL [11.36, 11.93] on day 2, before rising to 12.88 g/dL [12.60, 13.17] on day 42. In comparison to chloroquine alone, the mean haemoglobin in 1446 patients treated with chloroquine plus primaquine was - 0.13 g/dL [- 0.27, 0.01] lower at day of nadir (p = 0.072), but 0.49 g/dL [0.28, 0.69] higher by day 42 (p < 0.001). On day 42, patients with recurrent parasitaemia had a mean haemoglobin concentration - 0.72 g/dL [- 0.90, - 0.54] lower than patients without recurrence (p < 0.001). Seven days after starting primaquine, G6PD normal patients had a 0.3% (1/389) risk of clinically significant haemolysis (fall in haemoglobin > 25% to < 7 g/dL) and a 1% (4/389) risk of a fall in haemoglobin > 5 g/dL.
CONCLUSIONS
Primaquine has the potential to reduce malaria-related anaemia at day 42 and beyond by preventing recurrent parasitaemia. Its widespread implementation will require accurate diagnosis of G6PD deficiency to reduce the risk of drug-induced haemolysis in vulnerable individuals.
TRIAL REGISTRATION
This trial was registered with PROSPERO: CRD42016053312. The date of the first registration was 23 December 2016.
Topics: Adult; Anemia, Hemolytic; Antimalarials; Chloroquine; Female; Glucosephosphate Dehydrogenase Deficiency; Hemolysis; Humans; Malaria, Vivax; Male; Middle Aged; Plasmodium vivax; Primaquine
PubMed: 31366382
DOI: 10.1186/s12916-019-1386-6 -
The Cochrane Database of Systematic... Jul 2019Malaria caused by Plasmodium vivax requires treatment of the blood-stage infection and treatment of the hypnozoites that develop in the liver. This is a challenge to...
BACKGROUND
Malaria caused by Plasmodium vivax requires treatment of the blood-stage infection and treatment of the hypnozoites that develop in the liver. This is a challenge to effective case management of P vivax malaria, as well as being a more general substantial impediment to malaria control. The World Health Organization (WHO) recommends a 14-day drug course with primaquine, an 8-aminoquinoline, at 0.25 mg/kg/day in most of the world (standard course), or 0.5 mg/kg/day in East Asia and Oceania (high-standard course). This long treatment course can be difficult to complete, and primaquine can cause dangerous haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, meaning that physicians may be reluctant to prescribe in areas where G6PD testing is not available. This Cochrane Review evaluated whether more patient-friendly alternative regimens are as efficacious as the standard regimen for radical cure ofP vivax malaria.
OBJECTIVES
To assess the efficacy and safety of alternative primaquine regimens for radical cure of P vivax malaria compared to the standard or high-standard 14 days of primaquine (0.25 or 0.5 mg/kg/day), as well as comparison of these two WHO-recommended regimens.
SEARCH METHODS
We searched the Cochrane Infectious Diseases Group (CIDG) Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (PubMed); Embase (Ovid); and LILACS (BIREME) up to 17 December 2018. We also searched the WHO International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov, and checked the reference lists of all studies identified by the above methods.
SELECTION CRITERIA
Randomized controlled trials (RCTs) of adults and children with P vivax malaria using any regimen of either chloroquine or an artemisinin-based combination therapy (ACT) plus primaquine with either higher daily doses for 14 days, shorter regimens with the same total dose, or using weekly dosing regimens; compared with the usual standard regimens recommended by the WHO (0.25 or 0.5 mg/kg/day for 14 days), or a comparison of these two WHO-recommended regimens.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trial eligibility and quality, and extracted data. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous data. We grouped efficacy data according to length of follow-up. We analysed safety data where this information was included.
MAIN RESULTS
High-standard 14-day course versus standard 14-day courseTwo RCTs compared the high-standard 14-day regimen with the standard 14-day regimen. People with G6PD deficiency and pregnant or lactating women were excluded. We do not know if there is any difference in P vivax recurrences at 6 months with 0.5 mg/kg/day primaquine therapy for 14 days compared to 0.25 mg/kg/day primaquine therapy for 14 days (with chloroquine: RR 0.82, 95% CI 0.47 to 1.43, 639 participants, very low-certainty evidence; with chloroquine or an ACT: RR 1.11, 95% CI 0.17 to 7.09, 38 participants, very low-certainty evidence). No serious adverse events were reported. We do not know whether there is a difference in adverse events with the higher dosage (very low-certainty evidence).0.5 mg/kg/day primaquine for 7 days versus standard 14-day courseFive RCTs compared 0.5 mg/kg/day primaquine for 7 days with the standard 14-day course. There may be little or no difference in P vivax recurrences at 6 to 7 months when using the same total dose (0.5 mg/kg/day to 210 mg) over 7 days as compared to 14 days (RR 0.96, 95% CI 0.66 to 1.39; 1211 participants; low-certainty evidence). No serious adverse events were reported. There may be little or no difference in the number of adverse events known to occur with primaquine between the primaquine shorter regimen as compared to the longer regimen (RR 1.06, 95% CI 0.64 to 1.76; 1154 participants; low-certainty evidence). We do not know whether there is any difference in the frequency of anaemia or discontinuation of treatment between groups (very low-certainty evidence). Three trials excluded people with G6PD deficiency, and two did not provide this information. Pregnant and lactating women were either excluded or no details were provided regarding their inclusion or exclusion.0.75 mg/kg primaquine/week for 8 weeks versus high-standard course One RCT compared weekly primaquine with the high-standard 14-day course. G6PD-deficient patients were not randomized but were included in the weekly primaquine group. Only one G6PD-deficient participant was detected during the trial. We do not know whether weekly primaquine increases or decreases recurrences of P vivax compared to the 14-day regimen at 11 months' follow-up (RR 3.18, 95% CI 0.37 to 27.6; 122 participants; very low-certainty evidence). No serious adverse events and no episodes of anaemia were reported.Three other RCTs evaluated different alternative regimens and doses of primaquine, but one of these RCTs did not have results available, and two used regimens that have not been widely used and the evidence was of very low certainty.
AUTHORS' CONCLUSIONS
Although limited data were available, the analysis did not detect a difference in recurrence between the 7-day regimen and the standard 14-day regimen of 0.5 mg/kg/day primaquine, and no serious adverse events were reported in G6PD-normal participants taking 0.5 mg/kg/day of primaquine. This shorter regimen may be useful in G6PD-normal patients if there are treatment adherence concerns. Further large high-quality RCTs are needed, such as the IMPROV trial, with more standardised comparison regimens and longer follow-up to help resolve uncertainties.
Topics: Antimalarials; Drug Administration Schedule; Humans; Malaria, Vivax; Primaquine; Primary Prevention; Randomized Controlled Trials as Topic; Recurrence
PubMed: 31274189
DOI: 10.1002/14651858.CD012656.pub2 -
Revista Latino-americana de Enfermagem Mar 2019systematic review with a meta-analysis of the prevalence of malaria relapse. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
systematic review with a meta-analysis of the prevalence of malaria relapse.
METHOD
it consisted in a search for cross-sectional studies, carried out in three databases, without application of filters. A total of 1,924 articles were identified, selected based on eligibility criteria. The selection was made in pairs from the reading of the titles, abstracts and text. The meta-analysis was performed with a statistical program.
RESULTS
a sample of 1,308 patients with malaria, ranging from 70 to 586 patients in the study. Relapse was estimated at 0.47%, with a 95% confidence interval and 99.04% of squared i. In the included studies, the prevalence of relapse ranged from 17.00% to 92.85%. The result of the meta-analysis is considered relevant, despite the heterogeneity.
CONCLUSION
relapse is a phenomenon that can contribute to the maintenance of the endemicity of malaria in the world and to introduce it in non-affected areas. In addition, there is the need for advancement in the production of knowledge regarding this disease, to qualify the research methods on prevalence.
Topics: Brazil; Humans; Malaria; Malaria, Vivax; Observational Studies as Topic; Plasmodium vivax; Prevalence; Recurrence
PubMed: 30916225
DOI: 10.1590/1518-8345.2619.3111 -
The Cochrane Database of Systematic... Jan 2019The World Health Organization (WHO) recommends artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum (P falciparum) malaria.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The World Health Organization (WHO) recommends artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum (P falciparum) malaria. Concerns about artemisinin resistance have led to global initiatives to develop new partner drugs to protect artemisinin derivatives in ACT. Pyronaridine-artesunate is a novel ACT.
OBJECTIVES
To evaluate the efficacy of pyronaridine-artesunate compared to alternative ACTs for treating people with uncomplicated P falciparum malaria, and to evaluate the safety of pyronaridine-artesunate and other pyronaridine treatments compared to alternative treatments.
SEARCH METHODS
We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE; Embase; and LILACS. We also searched ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform Search Portal, and the International Standard Randomized Controlled Trial Number (ISRCTN) registry for ongoing or recently completed trials. The date of the last search was 8 May 2018.
SELECTION CRITERIA
Efficacy analysis: randomized controlled trials (RCTs) of pyronaridine-artesunate for treating uncomplicated P falciparum malaria.Safety analysis: RCTs of pyronaridine-artesunate or pyronaridine for treating P falciparum or P vivax malaria.
DATA COLLECTION AND ANALYSIS
For this update, two review authors independently re-extracted all data and assessed certainty of evidence. We meta-analysed data to calculate risk ratios (RRs) for treatment failures between comparisons, and for safety outcomes between and across comparisons.
MAIN RESULTS
We included 10 relevant studies. Seven studies were co-funded by Shin Poong Pharmaceuticals which manufactures the drug. Three studies were funded by government agencies.For efficacy analysis we identified five RCTs with 5711 participants. This included 4465 participants from 13 sites in Africa, and 1246 participants from five sites in Asia. It included 541 children aged less than five years.For polymerase chain reaction (PCR)-adjusted failures at day 28, pyronaridine-artesunate may have fewer failures compared to artemether-lumefantrine (RR 0.59, 95% confidence interval (CI) 0.26 to 1.31; 4 RCTs, 3068 participants, low-certainty evidence), artesunate-amodiaquine (RR 0.55, 95% CI 0.11 to 2.77; 1 RCT, 1245 participants, low-certainty evidence), and mefloquine plus artesunate (RR 0.37, 95% CI 0.13 to 1.05; 1 RCT, 1117 participants, low-certainty evidence).For unadjusted failures at day 28, pyronaridine-artesunate may have fewer failures compared to artemether-lumefantrine (RR 0.27, 95% CI 0.13 to 0.58; 4 RCTs, 3149 participants, low-certainty evidence), and probably has fewer failures compared to artesunate-amodiaquine (RR 0.49, 95% CI 0.30 to 0.81; 1 RCT, 1257 participants, moderate-certainty evidence) and mefloquine plus artesunate (RR 0.36, 95% CI 0.17 to 0.78; 1 RCT, 1120 participants, moderate-certainty evidence).For PCR-adjusted failures at day 42, pyronaridine-artesunate may make little or no difference compared to artemether-lumefantrine (RR 0.86, 95% CI 0.49 to 1.51; 4 RCTs, 2575 participants, low-certainty evidence) and artesunate-amodiaquine (RR 0.98, 95% CI 0.20 to 4.83; 1 RCT, 1091 participants, low-certainty evidence), but may have higher failures than mefloquine plus artesunate (RR 1.80, 95% CI 0.90 to 3.57; 1 RCT, 1037 participants, low-certainty evidence). Overall, pyronaridine-artesunate had a PCR-adjusted treatment failure rate of less than 5%.For unadjusted failures at day 42, pyronaridine-artesunate may have fewer failures compared to artemether-lumefantrine (RR 0.61, 95% CI 0.46 to 0.82; 4 RCTs, 3080 participants, low-certainty evidence), may make little or no difference compared to mefloquine plus artesunate (RR 0.84, 95% CI 0.54 to 1.31; 1 RCT, 1059 participants, low-certainty evidence), and probably makes little or no difference compared to artesunate-amodiaquine (RR 0.98, 95% CI 0.78 to 1.23; 1 RCT, 1235 participants, moderate-certainty evidence).For the safety analysis of severe adverse events and liver function, we identified eight RCTs with 6614 participants comparing pyronaridine-artesunate to other antimalarials, four of which were not in the previous version of this review. A further two RCTs, comparing pyronaridine alone to other treatments, contributed to the synthesis of all adverse events.Raised alanine aminotransferase (ALT) greater than five times the upper limit of normal (> 5 x ULN) is more frequent with pyronaridine-artesunate compared to other antimalarials (RR 3.34, 95% CI 1.63 to 6.84; 8 RCTS, 6581 participants, high-certainty evidence). There is probably little or no difference for raised bilirubin > 2.5 x ULN between pyronaridine-artesunate and other antimalarials (RR 1.03, 95% CI 0.49 to 2.18; 7 RCTs, 6384 participants, moderate-certainty evidence). There was one reported case in which raised ALT occurred with raised bilirubin, meeting criteria for moderate drug-induced liver injury. No study reported severe drug-induced liver injury. Electrocardiograph (ECG) abnormalities were less common with pyronaridine-artesunate compared to other antimalarials. We identified no other safety concerns.
AUTHORS' CONCLUSIONS
Pyronaridine-artesunate was efficacious against uncomplicated P falciparum malaria, achieved a PCR-adjusted treatment failure rate of less than 5% at days 28 and 42, and may be at least as good as, or better than other marketed ACTs.Pyronaridine-artesunate increases the risk of episodes of raised ALT > 5 x ULN. This meets criteria for mild drug-induced liver injury. On one instance this was linked to raised bilirubin, indicating moderate drug-induced liver injury. No episodes of severe drug-induced liver injury were reported. The findings of this review cannot fully inform a risk-benefit assessment for an unselected population. Readers should remain aware of this uncertainty when considering use of pyronaridine-artesunate in patients with known or suspected pre-existing liver dysfunction, and when co-administering with other medications which may cause liver dysfunction.
Topics: Adult; Amodiaquine; Antimalarials; Artemisinins; Artesunate; Child; Drug Combinations; Drug Therapy, Combination; Humans; Liver; Lumefantrine; Malaria, Falciparum; Mefloquine; Naphthyridines; Randomized Controlled Trials as Topic
PubMed: 30620055
DOI: 10.1002/14651858.CD006404.pub3