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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 -
PloS One 2019The WHO recommends artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated falciparum malaria. Hence, monitoring the efficacy of antimalarial... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The WHO recommends artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated falciparum malaria. Hence, monitoring the efficacy of antimalarial drugs is a key component of malaria control and elimination. The published randomized trials that assessed comparisons of ACTs for treating uncomplicated falciparum malaria reported conflicting results in treatment efficacy. A network meta-analysis is an extension of pairwise meta-analysis that can synthesize evidence simultaneously from both direct and indirect treatment comparisons. The objective was to synthesize evidence on the comparative efficacy of antimalarial drugs for treatment of uncomplicated falciparum malaria in Asian region.
METHODS
Relevant randomized trials that assessed efficacy of antimalarial drugs for patients having uncomplicated falciparum malaria in Asian region were searched in health-related databases. We evaluated the methodological quality of the included studies with the Cochrane risk of bias tool. Main outcome was treatment success at day 28 as determined by the absence of parasiteamia. We performed network meta-analysis of the interventions in the trials, and assessed the overall quality of evidence using the GRADE approach.
RESULTS
Seventeen randomized trials (n = 5043) were included in this network meta-analysis study. A network geometry was formed with 14 antimalarial treatment options such as artemether-lumefantrine (AL), artemisinin-piperaquine, artesunate-amodiaquine, artesunate-mefloquine (ASMQ), artesunate-chloroquine, artesunate-mefloquine home treatment, artesunate-mefloquine 2-day course, artesunate plus sulfadoxine-pyrimethamine, chloroquine, dihydroartemisinin-piperaquine (DHP), dihydroartemisinin-piperaquine home treatment, dihydroartemisinin-piperaquine 4-day course, dihydroartemisinin-piperaquine and added artesunate, sulfadoxine-pyrimethamine. A maximum number of trials included was DHP compared to ASMQ (n = 5). In general, DHP had better efficacy than AL at day 28 (DHP vs AL: OR 2.5, 95%CI:1.08-5.8). There is low certainty evidence due to limited number of studies and small trials.
DISCUSSION/ CONCLUSIONS
The findings suggest the superiority of DHP (3-day course) to AL and other comparator ACTs are with the overall low/very low quality of evidence judgements. Moreover, one drug regimen is better than another is only if current drug-resistance patterns are at play. For example, the AL might be better than DHP in areas where both artemisinin and piperaquine resistance patterns are prevalent. For substantiation, well-designed larger trials from endemic countries are needed. In the light of benefit versus harm concept, future analysis with safety information is recommended.
Topics: Antimalarials; Asia; Databases, Factual; Drug Resistance; Humans; Malaria, Falciparum; Randomized Controlled Trials as Topic
PubMed: 31856172
DOI: 10.1371/journal.pone.0225882 -
Transactions of the Royal Society of... Oct 2019Primaquine was the only licenced antimalarial hypnozoiticidal drug available until recently. Now there is a newly approved alternative: tafenoquine. This review explores...
Primaquine was the only licenced antimalarial hypnozoiticidal drug available until recently. Now there is a newly approved alternative: tafenoquine. This review explores the efficacy of tafenoquine as a primary and terminal prophylactic agent in malaria. Multiple databases (Cochrane Central Register of Controlled Trials [CENTRAL], MEDLINE [PubMed], Embase [Ovid], Scopus, CINAHL [EBSCOhost] and LILACS) were searched for clinical randomised controlled trials that had used tafenoquine for prophylaxis without language or time restrictions. The last date of searching was 13 August 2018. For primary prophylaxis, tafenoquine reduced episodes of malaria compared with placebo, at a dose range from 50 mg weekly to 400 mg monthly in three trials conducted in Ghana, Kenya and Thailand. Two trials compared tafenoquine vs mefloquine, but malaria episodes were too few to reach a conclusion. For terminal prophylaxis, evidence from two trials suggest that tafenoquine may have equal or better efficacy compared with primaquine. All trials excluded pregnant participants or those with G6PD deficiency. Tafenoquine is effective for both primary and terminal prophylaxis. If used for primary prophylaxis it may continue to offer protection against vivax relapses after exposure has ended (as terminal prophylaxis).
Topics: Aminoquinolines; Antimalarials; Humans; Malaria; Treatment Outcome
PubMed: 31225623
DOI: 10.1093/trstmh/trz052 -
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 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 -
The Lancet. Infectious Diseases Jan 2019A 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... (Meta-Analysis)
Meta-Analysis
BACKGROUND
A 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.
METHODS
In 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.
FINDINGS
153 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; I=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.
INTERPRETATION
Our 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.
FUNDING
Australian National Health and Medical Research Council, Royal Australasian College of Physicians, Wellcome Trust, and Bill & Melinda Gates Foundation.
Topics: Adolescent; Adult; Antimalarials; Artemisinins; Child; Child, Preschool; Coinfection; Female; Humans; Malaria, Falciparum; Malaria, Vivax; Male; Parasitemia; Plasmodium falciparum; Plasmodium vivax; Quinolines; Risk; Treatment Outcome; Young Adult
PubMed: 30587297
DOI: 10.1016/S1473-3099(18)30596-6 -
BMC Infectious Diseases Dec 2018About 80% of all reported sickle cell disease (SCD) cases in children anually are recorded in Africa. Although malaria is considered a major cause of death in SCD... (Meta-Analysis)
Meta-Analysis
BACKGROUND
About 80% of all reported sickle cell disease (SCD) cases in children anually are recorded in Africa. Although malaria is considered a major cause of death in SCD children, there is limited data on the safety and effectiveness of the available antimalarial drugs used for prophylaxis. Also, previous systematic reviews have not provided quantitative measures of preventive effectiveness. The purpose of this research was to conduct a systematic review and meta-analysis of the available literature to determine the safety and effectiveness of antimalarial chemoprophylaxis used in SCD patients.
METHODS
We searched in PubMed, Medline, CINAHL, POPLine and Cochrane library, for the period spanning January 1990 to April 2018. We considered randomized or quasi-randomized controlled trials comparing any antimalarial chemoprophylaxis to, 1) other antimalarial chemoprophylaxis, 2) placebo or 3) no intervention, in SCD patients. Studies comparing at least two treatment arms, for a minimum duration of three months, with no restriction on the number of patients per arm were reviewed. The data were extracted and expressed as odds ratios. Direct pairwise comparisons were performed using fixed effect models and the heterogeneity assessed using the I-square.
RESULTS
Six qualified studies that highlighted the importance of antimalarial chemoprophylaxis in SCD children were identified. In total, seven different interventions (Chloroquine, Mefloquine, Mefloquine artesunate, Proguanil, Pyrimethamine, Sulfadoxine-pyrimethamine, Sulfadoxine-pyrimethamine amodiaquine) were evaluated in 912 children with SCD. Overall, the meta-analysis showed that antimalarial chemoprophylaxis provided protection against parasitemia and clinical malaria episodes in children with SCD. Nevertheless, the risk of hospitalization (OR = 0.72, 95% CI = 0.267-1.959; I = 0.0%), blood transfusion (OR = 0.83, 95% CI = 0.542-1.280; I = 29.733%), vaso-occlusive crisis (OR = 19, 95% CI = 1.713-2.792; I = 93.637%), and mortality (OR = 0.511, 95% CI = 0.189-1.384; I = 0.0%) did not differ between the intervention and placebo groups.
CONCLUSION
The data shows that antimalarial prophylaxis reduces the incidence of clinical malaria in children with SCD. However, there was no difference between the occurrence of adverse events in children who received placebo and those who received prophylaxis. This creates an urgent need to assess the efficacy of new antimalarial drug regimens as potential prophylactic agents in SCD patients.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO (CRD42016052514).
Topics: Africa; Anemia, Sickle Cell; Antimalarials; Chemoprevention; Child; Humans; Malaria; Network Meta-Analysis; Parasitemia; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 30541465
DOI: 10.1186/s12879-018-3556-0 -
The Cochrane Database of Systematic... Nov 2018The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine for malaria for all women who live in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine for malaria for all women who live in moderate to high malaria transmission areas in Africa. However, parasite resistance to sulfadoxine-pyrimethamine has been increasing steadily in some areas of the region. Moreover, HIV-infected women on cotrimoxazole prophylaxis cannot receive sulfadoxine-pyrimethamine because of potential drug interactions. Thus, there is an urgent need to identify alternative drugs for prevention of malaria in pregnancy. One such candidate is mefloquine.
OBJECTIVES
To assess the effects of mefloquine for preventing malaria in pregnant women, specifically, to evaluate:• the efficacy, safety, and tolerability of mefloquine for preventing malaria in pregnant women; and• the impact of HIV status, gravidity, and use of insecticide-treated nets on the effects of mefloquine.
SEARCH METHODS
We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, Latin American Caribbean Health Sciences Literature (LILACS), the Malaria in Pregnancy Library, and two trial registers up to 31 January 2018. In addition, we checked references and contacted study authors to identify additional studies, unpublished data, confidential reports, and raw data from published trials.
SELECTION CRITERIA
Randomized and quasi-randomized controlled trials comparing mefloquine IPT or mefloquine prophylaxis against placebo, no treatment, or an alternative drug regimen.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened all records identified by the search strategy, applied inclusion criteria, assessed risk of bias, and extracted data. We contacted trial authors to ask for additional information when required. Dichotomous outcomes were compared using risk ratios (RRs), count outcomes as incidence rate ratios (IRRs), and continuous outcomes using mean differences (MDs). We have presented all measures of effect with 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach for the following main outcomes of analysis: maternal peripheral parasitaemia at delivery, clinical malaria episodes during pregnancy, placental malaria, maternal anaemia at delivery, low birth weight, spontaneous abortions and stillbirths, dizziness, and vomiting.
MAIN RESULTS
Six trials conducted between 1987 and 2013 from Thailand (1), Benin (3), Gabon (1), Tanzania (1), Mozambique (2), and Kenya (1) that included 8192 pregnant women met our inclusion criteria.Two trials (with 6350 HIV-uninfected pregnant women) compared two IPTp doses of mefloquine with two IPTp doses of sulfadoxine-pyrimethamine. Two other trials involving 1363 HIV-infected women compared three IPTp doses of mefloquine plus cotrimoxazole with cotrimoxazole. One trial in 140 HIV-infected women compared three doses of IPTp-mefloquine with cotrimoxazole. Finally, one trial enrolling 339 of unknown HIV status compared mefloquine prophylaxis with placebo.Study participants included women of all gravidities and of all ages (four trials) or > 18 years (two trials). Gestational age at recruitment was > 20 weeks (one trial), between 16 and 28 weeks (three trials), or ≤ 28 weeks (two trials). Two of the six trials blinded participants and personnel, and only one had low risk of detection bias for safety outcomes.When compared with sulfadoxine-pyrimethamine, IPTp-mefloquine results in a 35% reduction in maternal peripheral parasitaemia at delivery (RR 0.65, 95% CI 0.48 to 0.86; 5455 participants, 2 studies; high-certainty evidence) but may have little or no effect on placental malaria infections (RR 1.04, 95% CI 0.58 to 1.86; 4668 participants, 2 studies; low-certainty evidence). Mefloquine results in little or no difference in the incidence of clinical malaria episodes during pregnancy (incidence rate ratio (IRR) 0.83, 95% CI 0.65 to 1.05, 2 studies; high-certainty evidence). Mefloquine decreased maternal anaemia at delivery (RR 0.84, 95% CI 0.76 to 0.94; 5469 participants, 2 studies; moderate-certainty evidence). Data show little or no difference in the proportions of low birth weight infants (RR 0.95, 95% CI 0.78 to 1.17; 5641 participants, 2 studies; high-certainty evidence) and in stillbirth and spontaneous abortion rates (RR 1.20, 95% CI 0.91 to 1.58; 6219 participants, 2 studies; I statistic = 0%; moderate-certainty evidence). IPTp-mefloquine increased drug-related vomiting (RR 4.76, 95% CI 4.13 to 5.49; 6272 participants, 2 studies; high-certainty evidence) and dizziness (RR 4.21, 95% CI 3.36 to 5.27; participants = 6272, 2 studies; moderate-certainty evidence).When compared with cotrimoxazole, IPTp-mefloquine plus cotrimoxazole probably results in a 48% reduction in maternal peripheral parasitaemia at delivery (RR 0.52, 95% CI 0.30 to 0.93; 989 participants, 2 studies; moderate-certainty evidence) and a 72% reduction in placental malaria (RR 0.28, 95% CI 0.14 to 0.57; 977 participants, 2 studies; moderate-certainty evidence) but has little or no effect on the incidence of clinical malaria episodes during pregnancy (IRR 0.76, 95% CI 0.33 to 1.76, 1 study; high-certainty evidence) and probably no effect on maternal anaemia at delivery (RR 0.94, 95% CI 0.73 to 1.20; 1197 participants, 2 studies; moderate-certainty evidence), low birth weight rates (RR 1.20, 95% CI 0.89 to 1.60; 1220 participants, 2 studies; moderate-certainty evidence), and rates of spontaneous abortion and stillbirth (RR 1.12, 95% CI 0.42 to 2.98; 1347 participants, 2 studies; very low-certainty evidence). Mefloquine was associated with higher risks of drug-related vomiting (RR 7.95, 95% CI 4.79 to 13.18; 1055 participants, one study; high-certainty evidence) and dizziness (RR 3.94, 95% CI 2.85 to 5.46; 1055 participants, 1 study; high-certainty evidence).
AUTHORS' CONCLUSIONS
Mefloquine was more efficacious than sulfadoxine-pyrimethamine in HIV-uninfected women or daily cotrimoxazole prophylaxis in HIV-infected pregnant women for prevention of malaria infection and was associated with lower risk of maternal anaemia, no adverse effects on pregnancy outcomes (such as stillbirths and abortions), and no effects on low birth weight and prematurity. However, the high proportion of mefloquine-related adverse events constitutes an important barrier to its effectiveness for malaria preventive treatment in pregnant women.
Topics: Anemia; Antimalarials; Drug Combinations; Drug Therapy, Combination; Female; HIV Seronegativity; Humans; Malaria; Mefloquine; Parasitemia; Placenta Diseases; Pregnancy; Pregnancy Complications; Pregnancy Complications, Infectious; Pyrimethamine; Randomized Controlled Trials as Topic; Stillbirth; Sulfadoxine; Trimethoprim, Sulfamethoxazole Drug Combination; Vomiting
PubMed: 30480761
DOI: 10.1002/14651858.CD011444.pub3 -
BMC Medicine Nov 2018Several quinoline and structurally related antimalarial drugs are associated with cardiovascular side effects, particularly hypotension and electrocardiographic QT...
BACKGROUND
Several quinoline and structurally related antimalarial drugs are associated with cardiovascular side effects, particularly hypotension and electrocardiographic QT interval prolongation. A prolonged QT interval is a sensitive but not specific risk marker for the development of Torsade de Pointes-a potentially lethal polymorphic ventricular tachyarrhythmia. The increasing use of quinoline and structurally related antimalarials in mass treatments to eliminate malaria rapidly highlights the need to review their cardiovascular safety profiles.
METHODS
The primary objective of this systematic review was to describe the documented clinical and electrocardiographic cardiovascular side effects of quinine, mefloquine, lumefantrine, piperaquine, halofantrine, chloroquine, sulfadoxine-pyrimethamine, amodiaquine, and primaquine. Trials in healthy subjects or patients with Plasmodium falciparum or P. vivax infection were included if at least two ECGs were conducted during the trial. All trial designs were included except case reports and pooled analyses. Secondary outcomes were the methods adopted by trials for measuring and reporting the QT interval.
RESULTS
Data from trials published between 1982 and July 2016 were included. A total of 177 trials met the inclusion criteria. 35,448 participants received quinoline antimalarials in these trials, of which 18,436 participants underwent ECG evaluation. Subjects with co-medication use or comorbidities including cardiovascular disease were excluded from the majority of trials. Dihydroartemisinin-piperaquine was the drug most studied (5083 participants). Despite enormous use over the past 60 years, only 1076, 452, and 150 patients had ECG recordings reported in studies of chloroquine, amodiaquine, and primaquine respectively. Transiently high concentrations of quinine, quinidine, and chloroquine following parenteral administration have all been associated with hypotension, but there were no documented reports of death or syncope attributable to a cardiovascular cause, nor of electrocardiographic recordings of ventricular arrhythmia in these trials. The large volume of missing outcome information and the heterogeneity of ECG interval reporting and measurement methodology did not allow pooled quantitative analysis of QT interval changes.
CONCLUSIONS
No serious cardiac adverse effects were recorded in malaria clinical trials of 35,548 participants who received quinoline and structurally related antimalarials with close follow-up including 18,436 individuals who underwent ECG evaluation. While these findings provide further evidence of the rarity of serious cardiovascular events after treatment with these drugs, they also underscore the need for continued strengthening of pharmacovigilance systems for robust detection of rare drug adverse events in real-world populations. A standardised approach to measurement and reporting of ECG data in malaria trials is also needed.
TRIAL REGISTRATION
PROSPERO CRD42016036678.
Topics: Adult; Antimalarials; Cardiotoxicity; Female; Humans; Malaria, Falciparum; Male; Quinolines; Young Adult
PubMed: 30400791
DOI: 10.1186/s12916-018-1188-2