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Travel Medicine and Infectious Disease 2021In 2018, tafenoquine was approved for malaria chemoprophylaxis. We evaluated all available data on the safety and efficacy of tafenoquine chemoprophylaxis. (Meta-Analysis)
Meta-Analysis
BACKGROUND
In 2018, tafenoquine was approved for malaria chemoprophylaxis. We evaluated all available data on the safety and efficacy of tafenoquine chemoprophylaxis.
METHODS
This systematic review followed the PRISMA guidelines and was registered on PROSPERO (CRD42019123839). We searched PubMed, Embase, Scopus, CINAHL and Cochrane databases. Two authors (JDM, PS) screened all papers.
RESULTS
We included 44 papers in the qualitative and 9 in the quantitative analyses. These 9 randomized, controlled trials included 2495 participants, aged 12-60 years with 27.3% women. Six studies were conducted in Plasmodium spp.-endemic regions; two were human infection studies. 200 mg weekly tafenoquine and higher dosages lead to a significant reduction of Plasmodium spp. infection compared to placebo and were comparable to 250 mg mefloquine weekly with a protective efficacy between 77.9 and 100% or a total risk ratio of 0.22 (95%-CI: 0.07-0.73; p = 0.013) in favour of tafenoquine. Adverse events (AE) were comparable in frequency and severity between tafenoquine and comparator arms. One study reported significantly more gastrointestinal events in tafenoquine users (p ≤ 0.001). Evidence of increased, reversible, asymptomatic vortex keratopathy in subjects with prolonged tafenoquine exposures was found. A single, serious event of decreased macular sensitivity occurred.
CONCLUSION
This systematic review and meta-analysis of trials of G6PD-normal adults show that weekly tafenoquine 200 mg is well tolerated and effective as malaria chemoprophylaxis focusing primarily on Plasmodium falciparum but also on Plasmodium vivax. Our safety analysis is limited by heterogenous methods of adverse events reporting. Further research is indicated on the use of tafenoquine in diverse traveller populations.
Topics: Adult; Aminoquinolines; Antimalarials; Chemoprevention; Female; Humans; Malaria; Male
PubMed: 33227500
DOI: 10.1016/j.tmaid.2020.101908 -
The Lancet. Infectious Diseases Feb 2024Primaquine radical cure is used to treat dormant liver-stage parasites and prevent relapsing Plasmodium vivax malaria but is limited by concerns of haemolysis. We... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Primaquine radical cure is used to treat dormant liver-stage parasites and prevent relapsing Plasmodium vivax malaria but is limited by concerns of haemolysis. We undertook a systematic review and individual patient data meta-analysis to investigate the haematological safety of different primaquine regimens for P vivax radical cure.
METHODS
For this systematic review and individual patient data meta-analysis, we searched MEDLINE, Web of Science, Embase, and Cochrane Central for prospective clinical studies of uncomplicated P vivax from endemic countries published between Jan 1, 2000, and June 8, 2023. We included studies if they had active follow-up of at least 28 days, if they included a treatment group with daily primaquine given over multiple days where primaquine was commenced within 3 days of schizontocidal treatment and was given alone or coadministered with chloroquine or one of four artemisinin-based combination therapies (ie, artemether-lumefantrine, artesunate-mefloquine, artesunate-amodiaquine, or dihydroartemisinin-piperaquine), and if they recorded haemoglobin or haematocrit concentrations on day 0. We excluded studies if they were on prevention, prophylaxis, or patients with severe malaria, or if data were extracted retrospectively from medical records outside of a planned trial. For the meta-analysis, we contacted the investigators of eligible trials to request individual patient data and we then pooled data that were made available by Aug 23, 2021. The main outcome was haemoglobin reduction of more than 25% to a concentration of less than 7 g/dL by day 14. Haemoglobin concentration changes between day 0 and days 2-3 and between day 0 and days 5-7 were assessed by mixed-effects linear regression for patients with glucose-6-phosphate dehydrogenase (G6PD) activity of (1) 30% or higher and (2) between 30% and less than 70%. The study was registered with PROSPERO, CRD42019154470 and CRD42022303680.
FINDINGS
Of 226 identified studies, 18 studies with patient-level data from 5462 patients from 15 countries were included in the analysis. A haemoglobin reduction of more than 25% to a concentration of less than 7 g/dL occurred in one (0·1%) of 1208 patients treated without primaquine, none of 893 patients treated with a low daily dose of primaquine (<0·375 mg/kg per day), five (0·3%) of 1464 patients treated with an intermediate daily dose (0·375 mg/kg per day to <0·75 mg/kg per day), and six (0·5%) of 1269 patients treated with a high daily dose (≥0·75 mg/kg per day). The covariate-adjusted mean estimated haemoglobin changes at days 2-3 were -0·6 g/dL (95% CI -0·7 to -0·5), -0·7 g/dL (-0·8 to -0·5), -0·6 g/dL (-0·7 to -0·4), and -0·5 g/dL (-0·7 to -0·4), respectively. In 51 patients with G6PD activity between 30% and less than 70%, the adjusted mean haemoglobin concentration on days 2-3 decreased as G6PD activity decreased; two patients in this group who were treated with a high daily dose of primaquine had a reduction of more than 25% to a concentration of less than 7 g/dL. 17 of 18 included studies had a low or unclear risk of bias.
INTERPRETATION
Treatment of patients with G6PD activity of 30% or higher with 0·25-0·5 mg/kg per day primaquine regimens and patients with G6PD activity of 70% or higher with 0·25-1 mg/kg per day regimens were associated with similar risks of haemolysis to those in patients treated without primaquine, supporting the safe use of primaquine radical cure at these doses.
FUNDING
Australian National Health and Medical Research Council, Bill & Melinda Gates Foundation, and Medicines for Malaria Venture.
Topics: Humans; Antimalarials; Artemether, Lumefantrine Drug Combination; Artesunate; Australia; Hemoglobins; Hemolysis; Malaria, Vivax; Plasmodium vivax; Primaquine; Prospective Studies; Retrospective Studies
PubMed: 37748497
DOI: 10.1016/S1473-3099(23)00431-0 -
The Cochrane Database of Systematic... Jun 2022The World Health Organization (WHO) recommends artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria. Concerns about... (Review)
Review
BACKGROUND
The World Health Organization (WHO) recommends artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium 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, and the ISRCTN registry for ongoing or recently completed trials. The date of the last search was 27 October 2021.
SELECTION CRITERIA
For the efficacy analysis, we included randomized controlled trials (RCTs) of pyronaridine-artesunate for treating uncomplicated P falciparum malaria. For the safety analysis, we included RCTs that used pyronaridine alone or in combination with any other antimalarials. In addition to these analyses, we conducted a separate systematic review summarizing data on safety from non-randomized studies (NRS) of any patient receiving pyronaridine (NRS safety review). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data and assessed the certainty of the 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 RCTs. Seven RCTs were co-funded by Shin Poong Pharmaceuticals, and three were funded by government agencies. Efficacy analysis (RCTs) For the efficacy analysis, we identified five RCTs comprising 5711 participants. This included 4465 participants from 13 sites in Africa, and 1246 participants from five sites in Asia. The analysis included 541 children aged less than five years. Overall, pyronaridine-artesunate had a polymerase chain reaction (PCR)-adjusted treatment failure rate of less than 5%. We evaluated pyronaridine-artesunate versus the following. • Artemether-lumefantrine. Pyronaridine artesunate may perform better for PCR-adjusted failures at day 28 (RR 0.59, 95% confidence interval (CI) 0.26 to 1.31; 4 RCTs, 3068 participants, low-certainty evidence); for unadjusted failures at day 28 (RR 0.27, 95% CI 0.13 to 0.58; 4 RCTs, 3149 participants, low-certainty evidence); and for unadjusted failures at day 42 (RR 0.61, 95% CI 0.46 to 0.82; 4 RCTs, 3080 participants, low-certainty evidence). For PCR-adjusted failures at day 42, there may be little or no difference between groups (RR 0.86, 95% CI 0.49 to 1.51; 4 RCTs, 2575 participants, low-certainty evidence). • Artesunate-amodiaquine. Pyronaridine artesunate may perform better for PCR-adjusted failures at day 28 (RR 0.55, 95% CI 0.11 to 2.77; 1 RCT, 1245 participants, low-certainty evidence); probably performs better for unadjusted failures at day 28 (RR 0.49, 95% CI 0.30 to 0.81; 1 RCT, 1257 participants, moderate-certainty evidence); may make little or no difference for PCR-adjusted failures at day 42 (RR 0.98, 95% CI 0.20 to 4.83; 1 RCT, 1091 participants, low-certainty evidence); and probably makes little or no difference for unadjusted failures at day 42 (RR 0.98, 95% CI 0.78 to 1.23; 1 RCT, 1235 participants, moderate-certainty evidence). • Mefloquine plus artesunate. Pyronaridine artesunate may perform better for PCR-adjusted failures at day 28 (RR 0.37, 95% CI 0.13 to 1.05; 1 RCT, 1117 participants, low-certainty evidence); probably performs better for unadjusted failures at day 28 (RR 0.36, 95% CI 0.17 to 0.78; 1 RCT, 1120 participants, moderate-certainty evidence); may make little or no difference for unadjusted failures at day 42 (RR 0.84, 95% CI 0.54 to 1.31; 1 RCT, 1059 participants, low-certainty evidence); but may lead to higher PCR-adjusted failures at day 42 (RR 1.80, 95% CI 0.90 to 3.57; 1 RCT, 1037 participants, low-certainty evidence). Safety analysis (RCTs) For the RCT safety analysis, we identified eight RCTs, one of which was delineated by study site, comparing pyronaridine-artesunate to other antimalarials. Pyronaridine-artesunate was associated with raised liver enzymes compared to other antimalarials: alanine aminotransferase (ALT) (RR 3.59, 95% CI 1.76 to 7.33; 8 RCTS, 6669 participants, high-certainty evidence) and aspartate transaminase (AST) (RR 2.22, 95% CI 1.12 to 4.41; 8 RCTs, 6669 participants, moderate-certainty evidence). No such effect was demonstrated with bilirubin (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. 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. NRS safety review A review on safety in NRS allowed us to increase the population within which safety was assessed. We included seven studies with 9546 participants: five single-arm observational studies, one cohort event monitoring study, and one dose-escalation study. All studies provided data on adverse event frequency, with a small number of participants experiencing serious adverse events and adverse effects related to pyronaridine: serious adverse events average 0.37%; drug-related 9.0%. In two studies reporting elevations in liver enzymes, small percentages of participants (2.4% and 14.1% respectively) experienced increases in either ALT, AST, or bilirubin on day 7; however, these were small increases that returned to normal by day 42. 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 abnormally raised ALT. The observational data did not signal an excess of clinically important adverse effects.
Topics: Antimalarials; Artemisinins; Artesunate; Bilirubin; Child; Drug Combinations; Humans; Malaria, Falciparum; Naphthyridines
PubMed: 35726133
DOI: 10.1002/14651858.CD006404.pub4 -
Pharmacological Research Aug 2019Malaria affects 200 million people worldwide. Today, the most successful treatments are artemisinin-based combination therapies (ACT). Resistance has already been...
Malaria affects 200 million people worldwide. Today, the most successful treatments are artemisinin-based combination therapies (ACT). Resistance has already been described for the elder anti-malarials chloroquine, sulfadoxine-pyrimethamine and mefloquine. Unfortunately, over the last few years there has also been an emerging resistance to the successfully used drug artemisinin, especially in African and Asian countries. A systematic PubMed literature research was conducted for studies published between January 2002 and December 2018. Despite ACTs continue to be first line treatment, the number of studies is rising reporting on artemisinin resistance mutations. Most publications reported on kelch13 mutations (45 studies), the second most frequent mutations were found in pfmdr1 (32 studies). PfATPase6 mutations have been mainly studied in Asian countries (4 of 6 studies). Bearing this in mind, there is a pressing need to further examine the role and spread of mutations conferring artemisinin resistance. A further decline of treatment efficacy could result in increased rates of malaria-related deaths.
Topics: Animals; Antimalarials; Artemisinins; Drug Resistance; Humans; Malaria; Mutation; Polymorphism, Genetic
PubMed: 31100335
DOI: 10.1016/j.phrs.2019.104275 -
The Cochrane Database of Systematic... Jan 2021The World Health Organization (WHO) in 2015 stated atovaquone-proguanil can be used in travellers, and is an option in malaria-endemic areas in combination with... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The World Health Organization (WHO) in 2015 stated atovaquone-proguanil can be used in travellers, and is an option in malaria-endemic areas in combination with artesunate, as an alternative treatment where first-line artemisinin-based combination therapy (ACT) is not available or effective. This review is an update of a Cochrane Review undertaken in 2005.
OBJECTIVES
To assess the efficacy and safety of atovaquone-proguanil (alone and in combination with artemisinin drugs) versus other antimalarial drugs for treating uncomplicated Plasmodium falciparum malaria in adults and children.
SEARCH METHODS
The date of the last trial search was 30 January 2020. Search locations for published trials included the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, and LILACS. To include recently published and unpublished trials, we also searched ClinicalTrials.gov, the metaRegister of Controlled Trials and the WHO International Clinical Trials Registry Platform Search Portal.
SELECTION CRITERIA
Randomized controlled trials (RCTs) reporting efficacy and safety data for atovaquone-proguanil or atovaquone-proguanil with a partner drug compared with at least one other antimalarial drug for treating uncomplicated Plasmodium falciparum infection.
DATA COLLECTION AND ANALYSIS
For this update, two review authors re-extracted data and assessed certainty of evidence. We meta-analyzed data to calculate risk ratios (RRs) with 95% confidence intervals (CI) for treatment failures between comparisons, and for safety outcomes between and across comparisons. Outcome measures include unadjusted treatment failures and polymerase chain reaction (PCR)-adjusted treatment failures. PCR adjustment differentiates new infection from recrudescent infection.
MAIN RESULTS
Seventeen RCTs met our inclusion criteria providing 4763 adults and children from Africa, South-America, and South-East Asia. Eight trials reported PCR-adjusted data to distinguish between new and recrudescent infection during the follow-up period. In this abstract, we report only the comparisons against the three WHO-recommended antimalarials which were included within these trials. There were two comparisons with artemether-lumefantrine, one trial from 2008 in Ethiopia with 60 participants had two failures with atovaquone-proguanil compared to none with artemether-lumefantrine (PCR-adjusted treatment failures at day 28). A second trial from 2012 in Colombia with 208 participants had one failure in each arm (PCR-adjusted treatment failures at day 42). There was only one comparison with artesunate-amodiaquine from a 2014 trial conducted in Cameroon. There were six failures with atovaquone-proguanil at day 28 and two with artesunate-amodiaquine (PCR-adjusted treatment failures at day 28: 9.4% with atovaquone-proguanil compared to 2.9% with artesunate-amodiaquine; RR 3.19, 95% CI 0.67 to 15.22; 1 RCT, 132 participants; low-certainty evidence), although there was a similar number of PCR-unadjusted treatment failures (9 (14.1%) with atovaquone-proguanil and 8 (11.8%) with artesunate-amodiaquine; RR 1.20, 95% CI 0.49 to 2.91; 1 RCT, 132 participants; low-certainty evidence). There were two comparisons with artesunate-mefloquine from a 2012 trial in Colombia and a 2002 trial in Thailand where there are high levels of multi-resistant malaria. There were similar numbers of PCR-adjusted treatment failures between groups at day 42 (2.7% with atovaquone-proguanil compared to 2.4% with artesunate-mefloquine; RR 1.15, 95% CI 0.57 to 2.34; 2 RCTs, 1168 participants; high-certainty evidence). There were also similar PCR-unadjusted treatment failures between groups (5.3% with atovaquone-proguanil compared to 6.6% with artesunate-mefloquine; RR 0.8, 95% CI 0.5 to 1.3; 1 RCT, 1063 participants; low-certainty evidence). When atovaquone-proguanil was combined with artesunate, there were fewer treatment failures with and without PCR-adjustment at day 28 (PCR-adjusted treatment failures at day 28: 2.16% with atovaquone-proguanil compared to no failures with artesunate-atovaquone-proguanil; RR 5.14, 95% CI 0.61 to 43.52; 2 RCTs, 375 participants, low-certainty evidence) and day 42 (PCR-adjusted treatment failures at day 42: 3.82% with atovaquone-proguanil compared to 2.05% with artesunate-atovaquone-proguanil (RR 1.84, 95% CI 0.95 to 3.56; 2 RCTs, 1258 participants, moderate-certainty evidence). In the 2002 trial in Thailand, there were fewer treatment failures in the artesunate-atovaquone-proguanil group compared to the atovaquone-proguanil group at day 42 with PCR-adjustment. Whilst there were some small differences in which adverse events were more frequent in the atovaquone-proguanil groups compared to comparator drugs, there were no recurrent associations to suggest that atovaquone-proguanil is strongly associated with any specific adverse event.
AUTHORS' CONCLUSIONS
Atovaquone-proguanil was effective against uncomplicated P falciparum malaria, although in some instances treatment failure rates were between 5% and 10%. The addition of artesunate to atovaquone-proguanil may reduce treatment failure rates. Artesunate-atovaquone-proguanil and the development of parasite resistance may represent an area for further research.
Topics: Adult; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Atovaquone; Cameroon; Child; Colombia; Drug Combinations; Ethiopia; Humans; Malaria, Falciparum; Mefloquine; Proguanil; Randomized Controlled Trials as Topic; Thailand; Treatment Failure
PubMed: 33459345
DOI: 10.1002/14651858.CD004529.pub3 -
The Lancet. Infectious Diseases Aug 2020Malaria in pregnancy affects both the mother and the fetus. However, evidence supporting treatment guidelines for uncomplicated (including asymptomatic) falciparum... (Meta-Analysis)
Meta-Analysis
Efficacy and tolerability of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy: a systematic review and individual patient data meta-analysis.
BACKGROUND
Malaria in pregnancy affects both the mother and the fetus. However, evidence supporting treatment guidelines for uncomplicated (including asymptomatic) falciparum malaria in pregnant women is scarce and assessed in varied ways. We did a systematic literature review and individual patient data (IPD) meta-analysis to compare the efficacy and tolerability of different artemisinin-based or quinine-based treatments for malaria in pregnant women.
METHODS
We did a systematic review of interventional or observational cohort studies assessing the efficacy of artemisinin-based or quinine-based treatments in pregnancy. Seven databases (MEDLINE, Embase, Global Health, Cochrane Library, Scopus, Web of Science, and Literatura Latino Americana em Ciencias da Saude) and two clinical trial registries (International Clinical Trials Registry Platform and ClinicalTrials.gov) were searched. The final search was done on April 26, 2019. Studies that assessed PCR-corrected treatment efficacy in pregnancy with follow-up of 28 days or more were included. Investigators of identified studies were invited to share data from individual patients. The outcomes assessed included PCR-corrected efficacy, PCR-uncorrected efficacy, parasite clearance, fever clearance, gametocyte development, and acute adverse events. One-stage IPD meta-analysis using Cox and logistic regression with random-effects was done to estimate the risk factors associated with PCR-corrected treatment failure, using artemether-lumefantrine as the reference. This study is registered with PROSPERO, CRD42018104013.
FINDINGS
Of the 30 studies assessed, 19 were included, representing 92% of patients in the literature (4968 of 5360 episodes). Risk of PCR-corrected treatment failure was higher for the quinine monotherapy (n=244, adjusted hazard ratio [aHR] 6·11, 95% CI 2·57-14·54, p<0·0001) but lower for artesunate-amodiaquine (n=840, 0·27, 95% 0·14-0·52, p<0·0001), artesunate-mefloquine (n=1028, 0·56, 95% 0·34-0·94, p=0·03), and dihydroartemisinin-piperaquine (n=872, 0·35, 95% CI 0·18-0·68, p=0·002) than artemether-lumefantrine (n=1278) after adjustment for baseline asexual parasitaemia and parity. The risk of gametocyte carriage on day 7 was higher after quinine-based therapy than artemisinin-based treatment (adjusted odds ratio [OR] 7·38, 95% CI 2·29-23·82).
INTERPRETATION
Efficacy and tolerability of artemisinin-based combination therapies (ACTs) in pregnant women are better than quinine. The lower efficacy of artemether-lumefantrine compared with other ACTs might require dose optimisation.
FUNDING
The Bill & Melinda Gates Foundation, ExxonMobil Foundation, and the University of Oxford Clarendon Fund.
Topics: Amodiaquine; Anti-Bacterial Agents; Antimalarials; Artemisinins; Artesunate; Atovaquone; Clindamycin; Drug Combinations; Drug Therapy, Combination; Female; Humans; Malaria, Falciparum; Mefloquine; Pregnancy; Pregnancy Complications, Parasitic; Proguanil; Pyrimethamine; Quinine; Quinolines; Sulfadoxine
PubMed: 32530424
DOI: 10.1016/S1473-3099(20)30064-5 -
BMC Medicine Jun 2020Malaria in pregnancy, including asymptomatic infection, has a detrimental impact on foetal development. Individual patient data (IPD) meta-analysis was conducted to... (Meta-Analysis)
Meta-Analysis
Pregnancy outcomes and risk of placental malaria after artemisinin-based and quinine-based treatment for uncomplicated falciparum malaria in pregnancy: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis.
BACKGROUND
Malaria in pregnancy, including asymptomatic infection, has a detrimental impact on foetal development. Individual patient data (IPD) meta-analysis was conducted to compare the association between antimalarial treatments and adverse pregnancy outcomes, including placental malaria, accompanied with the gestational age at diagnosis of uncomplicated falciparum malaria infection.
METHODS
A systematic review and one-stage IPD meta-analysis of studies assessing the efficacy of artemisinin-based and quinine-based treatments for patent microscopic uncomplicated falciparum malaria infection (hereinafter uncomplicated falciparum malaria) in pregnancy was conducted. The risks of stillbirth (pregnancy loss at ≥ 28.0 weeks of gestation), moderate to late preterm birth (PTB, live birth between 32.0 and < 37.0 weeks), small for gestational age (SGA, birthweight of < 10th percentile), and placental malaria (defined as deposition of malaria pigment in the placenta with or without parasites) after different treatments of uncomplicated falciparum malaria were assessed by mixed-effects logistic regression, using artemether-lumefantrine, the most used antimalarial, as the reference standard. Registration PROSPERO: CRD42018104013.
RESULTS
Of the 22 eligible studies (n = 5015), IPD from16 studies were shared, representing 95.0% (n = 4765) of the women enrolled in literature. Malaria treatment in this pooled analysis mostly occurred in the second (68.4%, 3064/4501) or third trimester (31.6%, 1421/4501), with gestational age confirmed by ultrasound in 91.5% (4120/4503). Quinine (n = 184) and five commonly used artemisinin-based combination therapies (ACTs) were included: artemether-lumefantrine (n = 1087), artesunate-amodiaquine (n = 775), artesunate-mefloquine (n = 965), and dihydroartemisinin-piperaquine (n = 837). The overall pooled proportion of stillbirth was 1.1% (84/4361), PTB 10.0% (619/4131), SGA 32.3% (1007/3707), and placental malaria 80.1% (2543/3035), and there were no significant differences of considered outcomes by ACT. Higher parasitaemia before treatment was associated with a higher risk of SGA (adjusted odds ratio [aOR] 1.14 per 10-fold increase, 95% confidence interval [CI] 1.03 to 1.26, p = 0.009) and deposition of malaria pigment in the placenta (aOR 1.67 per 10-fold increase, 95% CI 1.42 to 1.96, p < 0.001).
CONCLUSIONS
The risks of stillbirth, PTB, SGA, and placental malaria were not different between the commonly used ACTs. The risk of SGA was high among pregnant women infected with falciparum malaria despite treatment with highly effective drugs. Reduction of malaria-associated adverse birth outcomes requires effective prevention in pregnant women.
Topics: Adult; Antimalarials; Artemisinins; Female; Humans; Malaria, Falciparum; Placenta; Pregnancy; Pregnancy Outcome; Quinine; Young Adult
PubMed: 32482173
DOI: 10.1186/s12916-020-01592-z -
Frontiers in Pharmacology 2021The WHO recommends Artemisinin-based combination therapy (ACTs) as the first-line treatment for malaria. This meta-analysis aims to analyze the effects of artemisinin... (Review)
Review
The Effect of Artemisinin-Based Drugs vs Non-artemisinin-based Drugs on Gametophyte Carrying in the Body After the Treatment of Uncomplicated Falciparum Malaria: A Systematic Review and Meta-analysis.
The WHO recommends Artemisinin-based combination therapy (ACTs) as the first-line treatment for malaria. This meta-analysis aims to analyze the effects of artemisinin and its derivatives as well as non-artemisinin drugs on the gametophytes in the host during the treatment of falciparum malaria. Fourteen studies were included in this analysis, and the artemisinin combination drugs involved were: artemether-lumefantrine (AL), artemisinin (AST), artemether-benflumetol (AB), dihydroartemisinin-piperaquine + trimethoprim + primaquine (CV8), amodiaquine + sulfadoxine-pyrimethamine (ASP), pyronaridine-phosphate + dihydroartemisinin (PP-DHA), dihydroartemisinin (DHA), and mefloquine + artesunate (MA), with 1702 patients. The control intervention measures involved the following: sulfadoxine-pyrimethamine (SP), mefloquine (MQ), atovaquone-proguanil (AT-PG), chloroquine + sulfadoxine-pyrimethamine (C-SP), quinine (Q), pyronaridine-phosphate (PP), pyronaridine (PN), and mefloquine + primaquine (MP), with 833 patients. The effect of ACTs was more obvious (OR = 0.37, 95%CI: 0.22-0.62, < 0.05). In the control group of second malaria attacks, the difference between the two groups was not statistically significant (RD = 1.16, 95%CI: 0.81-1.66, < 0.05); there was no significant difference in treatment failure during follow-up (RD = -0.01, 95%CI: 0.04-0.03, < 0.05). There were also very few serious adverse events in both groups. ACTs showed good therapeutic effects in preventing gametocythemia but did not control the recrudescence rate and overall cure, which indicated the effectiveness of the combination of antimalarial drugs. Further research is required to explore which compatibility method is most conducive to the development of clinical malaria control.
PubMed: 35069184
DOI: 10.3389/fphar.2021.707498 -
Transactions of the Royal Society of... Feb 2024To provide a continuous update on the safety and efficacy of artesunate-mefloquine (ASMQ) compared with other artemisinin combination therapy (ACT) schemes used in the... (Meta-Analysis)
Meta-Analysis
To provide a continuous update on the safety and efficacy of artesunate-mefloquine (ASMQ) compared with other artemisinin combination therapy (ACT) schemes used in the treatment of uncomplicated malaria caused by Plasmodium falciparum, this study updated and expanded the results of the systematic literature review published in 2016. Only randomised controlled clinical trials published from 1 January 2001 to 12 June 2023 from five databases were included in this study. The results related to efficacy, expressed through RR, were summarized in meta-analyses, performed according to the compared ACTs and with the intention-to-treat and per-protocol analyses. The results related to safety were synthesized in a descriptive manner. Thirty-two studies were included, of which 24 had been analysed in the 2016 review and eight new ones were added. Although the methodological quality of most studies was considered moderate, the body of evidence gathered indicates that ASMQ continues to be safe and effective for the treatment of uncomplicated infections caused by P. falciparum compared with other ACTs. However, the inclusion of two new studies, which identified failure rates exceeding 10%, suggests a possible reduction in the efficacy of ASMQ in the analysed locations. The incidence of serious adverse effects, such as seizure, encephalopathy and cardiac arrhythmia, was infrequent in both the ASMQ group and the comparison groups. After including new evidence, ASMQ is still recommended as a first-line treatment of uncomplicated malaria caused by P. falciparum, although local aspects need to be considered.
Topics: Humans; Mefloquine; Artesunate; Antimalarials; Drug Therapy, Combination; Malaria, Falciparum; Malaria; Plasmodium falciparum
PubMed: 37772768
DOI: 10.1093/trstmh/trad069 -
The Lancet. Infectious Diseases Feb 2024Primaquine is used to eliminate Plasmodium vivax hypnozoites, but its optimal dosing regimen remains unclear. We undertook a systematic review and individual patient... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Primaquine is used to eliminate Plasmodium vivax hypnozoites, but its optimal dosing regimen remains unclear. We undertook a systematic review and individual patient data meta-analysis to investigate the efficacy and tolerability of different primaquine dosing regimens to prevent P vivax recurrence.
METHODS
For this systematic review and individual patient data meta-analysis, we searched MEDLINE, Web of Science, Embase, and Cochrane Central for prospective clinical studies of uncomplicated P vivax from endemic countries published between Jan 1, 2000, and June 8, 2023. We included studies if they had active follow-up of at least 28 days, and if they included a treatment group with daily primaquine given over multiple days, where primaquine was commenced within 7 days of schizontocidal treatment and was given alone or coadministered with chloroquine or one of four artemisinin-based combination therapies (ie, artemether-lumefantrine, artesunate-mefloquine, artesunate-amodiaquine, or dihydroartemisinin-piperaquine). We excluded studies if they were on prevention, prophylaxis, or patients with severe malaria, or if data were extracted retrospectively from medical records outside of a planned trial. For the meta-analysis, we contacted the investigators of eligible trials to request individual patient data and we then pooled data that were made available by Aug 23, 2021. We assessed the effects of total dose and duration of primaquine regimens on the rate of first P vivax recurrence between day 7 and day 180 by Cox's proportional hazards regression (efficacy analysis). The effect of primaquine daily dose on gastrointestinal symptoms on days 5-7 was assessed by modified Poisson regression (tolerability analysis). The study was registered with PROSPERO, CRD42019154470.
FINDINGS
Of 226 identified studies, 23 studies with patient-level data from 6879 patients from 16 countries were included in the efficacy analysis. At day 180, the risk of recurrence was 51·0% (95% CI 48·2-53·9) in 1470 patients treated without primaquine, 19·3% (16·9-21·9) in 2569 patients treated with a low total dose of primaquine (approximately 3·5 mg/kg), and 8·1% (7·0-9·4) in 2811 patients treated with a high total dose of primaquine (approximately 7 mg/kg), regardless of primaquine treatment duration. Compared with treatment without primaquine, the rate of P vivax recurrence was lower after treatment with low-dose primaquine (adjusted hazard ratio 0·21, 95% CI 0·17-0·27; p<0·0001) and high-dose primaquine (0·10, 0·08-0·12; p<0·0001). High-dose primaquine had greater efficacy than low-dose primaquine in regions with high and low relapse periodicity (ie, the time from initial infection to vivax relapse). 16 studies with patient-level data from 5609 patients from ten countries were included in the tolerability analysis. Gastrointestinal symptoms on days 5-7 were reported by 4·0% (95% CI 0·0-8·7) of 893 patients treated without primaquine, 6·2% (0·5-12·0) of 737 patients treated with a low daily dose of primaquine (approximately 0·25 mg/kg per day), 5·9% (1·8-10·1) of 1123 patients treated with an intermediate daily dose (approximately 0·5 mg/kg per day) and 10·9% (5·7-16·1) of 1178 patients treated with a high daily dose (approximately 1 mg/kg per day). 20 of 23 studies included in the efficacy analysis and 15 of 16 in the tolerability analysis had a low or unclear risk of bias.
INTERPRETATION
Increasing the total dose of primaquine from 3·5 mg/kg to 7 mg/kg can reduce P vivax recurrences by more than 50% in most endemic regions, with a small associated increase in gastrointestinal symptoms.
FUNDING
Australian National Health and Medical Research Council, Bill & Melinda Gates Foundation, and Medicines for Malaria Venture.
Topics: Humans; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artesunate; Malaria; Malaria, Vivax; Plasmodium vivax; Primaquine; Prospective Studies; Recurrence; Retrospective Studies
PubMed: 37748496
DOI: 10.1016/S1473-3099(23)00430-9