-
Clinical Microbiology and Infection :... Jul 2024Pneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection among people living with HIV (PWH), particularly among new and untreated cases. Several... (Meta-Analysis)
Meta-Analysis Comparative Study Review
Comparative efficacy and safety of Pneumocystis jirovecii pneumonia prophylaxis regimens for people living with HIV: a systematic review and network meta-analysis of randomized controlled trials.
BACKGROUND
Pneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection among people living with HIV (PWH), particularly among new and untreated cases. Several regimens are available for the prophylaxis of PCP, including trimethoprim-sulfamethoxazole (TMP-SMX), dapsone-based regimens (DBRs), aerosolized pentamidine (AP), and atovaquone.
OBJECTIVES
To compare the efficacy and safety of PCP prophylaxis regimens in PWH by network meta-analysis.
METHODS
DATA SOURCES: Embase, MEDLINE, and CENTRAL from inception to June 21, 2023.
STUDY ELIGIBILITY CRITERIA
Comparative randomized controlled trials (RCTs).
PARTICIPANTS
PWH.
INTERVENTIONS
Regimens for PCP prophylaxis either compared head-to-head or versus no treatment/placebo.
ASSESSMENT OF RISK OF BIAS
Cochrane risk-of-bias tool for RCTs 2.
METHODS OF DATA SYNTHESIS
Title or abstract and full-text screening and data extraction were performed in duplicate by two independent reviewers. Data on PCP incidence, all-cause mortality, and discontinuation due to toxicity were pooled and ranked by network meta-analysis. Subgroup analyses of primary versus secondary prophylaxis, by year, and by dosage were performed.
RESULTS
A total of 26 RCTs, comprising 55 treatment arms involving 7516 PWH were included. For the prevention of PCP, TMP-SMX was ranked the most favourable agent and was superior to DBRs (risk ratio [RR] = 0.54; 95% CI, 0.36-0.83) and AP (RR = 0.53; 95% CI, 0.36-0.77). TMP-SMX was also the only agent with a mortality benefit compared with no treatment/placebo (RR = 0.79; 95% CI, 0.64-0.98). However, TMP-SMX was also ranked as the most toxic agent with a greater risk of discontinuation than DBRs (RR = 1.25; 95% CI, 1.01-1.54) and AP (7.20; 95% CI, 5.37-9.66). No significant differences in PCP prevention or mortality were detected among the other regimens. The findings remained consistent within subgroups.
CONCLUSIONS
TMP-SMX is the most effective agent for PCP prophylaxis in PWH and the only agent to confer a mortality benefit; consequently, it should continue to be recommended as the first-line agent. Further studies are necessary to determine the optimal dosing of TMP-SMX to maximize efficacy and minimize toxicity.
Topics: Humans; Pneumonia, Pneumocystis; Randomized Controlled Trials as Topic; Network Meta-Analysis; Trimethoprim, Sulfamethoxazole Drug Combination; Pneumocystis carinii; HIV Infections; AIDS-Related Opportunistic Infections; Dapsone; Pentamidine; Atovaquone; Antifungal Agents; Treatment Outcome
PubMed: 38583518
DOI: 10.1016/j.cmi.2024.03.037 -
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 Journal of Antimicrobial... Mar 2018Atovaquone/proguanil, registered as Malarone®, is a fixed-dose combination recommended for first-line treatment of uncomplicated Plasmodium falciparum malaria in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Atovaquone/proguanil, registered as Malarone®, is a fixed-dose combination recommended for first-line treatment of uncomplicated Plasmodium falciparum malaria in non-endemic countries and its prevention in travellers. Mutations in the cytochrome bc1 complex are causally associated with atovaquone resistance.
METHODS
This systematic review assesses the clinical efficacy of atovaquone/proguanil treatment of uncomplicated malaria and examines the extent to which codon 268 mutation in cytochrome b influences treatment failure and recrudescence based on published information.
RESULTS
Data suggest that atovaquone/proguanil treatment efficacy is 89%-98% for P. falciparum malaria (from 27 studies including between 18 and 253 patients in each case) and 20%-26% for Plasmodium vivax malaria (from 1 study including 25 patients). The in vitro P. falciparum phenotype of atovaquone resistance is an IC50 value >28 nM. Case report analyses predict that recrudescence in a patient presenting with parasites carrying cytochrome b codon 268 mutation will occur on average at day 29 (95% CI: 22, 35), 19 (95% CI: 7, 30) days longer than if the mutation is absent.
CONCLUSIONS
Evidence suggests atovaquone/proguanil treatment for P. falciparum malaria is effective. Late treatment failure is likely to be associated with a codon 268 mutation in cytochrome b, though recent evidence from animal models suggests these mutations may not spread within the population. However, early treatment failure is likely to arise through alternative mechanisms, requiring further investigation.
Topics: Atovaquone; Drug Combinations; Drug Resistance, Multiple; Drug Therapy, Combination; Electron Transport Complex III; Humans; Malaria, Falciparum; Malaria, Vivax; Mutation; Plasmodium falciparum; Proguanil; Travel; Treatment Failure
PubMed: 29237012
DOI: 10.1093/jac/dkx431 -
Travel Medicine and Infectious Disease 2018We evaluated existing data on the prophylactic efficacy of atovaquone-proguanil (AP) in order to determine whether prophylaxis in travellers can be discontinued on the... (Review)
Review
BACKGROUND
We evaluated existing data on the prophylactic efficacy of atovaquone-proguanil (AP) in order to determine whether prophylaxis in travellers can be discontinued on the day of return from a malaria-endemic area instead of seven days after return as per currently recommended post-travel schedule.
METHODS
PubMed and Embase databases were searched to identify relevant studies. This PROSPERO-registered systematic review followed PRISMA guidelines. The search strategy included terms or synonyms relevant to AP combined with terms to identify articles relating to prophylactic use of AP and inhibitory and half-life properties of AP. Studies considered for inclusion were: randomized controlled trials, cohort studies, quasi-experimental studies, open-label trials, patient-control studies, cross-sectional studies; as well as case-series and non-clinical studies. Data on study design, characteristics of participants, interventions, and outcomes were extracted. Primary outcomes considered relevant were prophylactic efficacy and prolonged inhibitory activity and half-life properties of AP.
RESULTS
The initial search identified 1,482 publications, of which 40 were selected based on screening. Following full text review, 32 studies were included and categorized into two groups, namely studies in support of the current post-travel regimen (with a total of 2,866 subjects) and studies in support of an alternative regimen (with a total of 533 subjects).
CONCLUSION
There is limited direct and indirect evidence to suggest that an abbreviated post-travel regimen for AP may be effective. Proguanil, however, has a short half-life and is essential for the synergistic effect of the combination. Stopping AP early may result in mono-prophylaxis with atovaquone and possibly select for atovaquone-resistant parasites. Furthermore, the quality of the studies in support of the current post-travel regimen outweighs the quality of the studies in support of an alternative short, post-travel regimen, and the total sample size of the studies to support stopping AP early comprises a small percentage of the total sample size of the studies performed to establish the efficacy of the current AP regimen. Additional research is required - especially from studies evaluating impact on malaria parasitaemia and clinical illness and conducted among travellers in high malaria risk settings - before an abbreviated regimen can be recommended in current practice.
PROSPERO REGISTRATION NUMBER
CRD42017055244.
Topics: Antimalarials; Atovaquone; Drug Administration Schedule; Drug Combinations; Drug Synergism; Endemic Diseases; Humans; Malaria; Post-Exposure Prophylaxis; Proguanil; Travel; Travel-Related Illness
PubMed: 29242073
DOI: 10.1016/j.tmaid.2017.12.005 -
The Cochrane Database of Systematic... Oct 2017Mefloquine is one of four antimalarial agents commonly recommended for preventing malaria in travellers to malaria-endemic areas. Despite its high efficacy, there is... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Mefloquine is one of four antimalarial agents commonly recommended for preventing malaria in travellers to malaria-endemic areas. Despite its high efficacy, there is controversy about its psychological side effects.
OBJECTIVES
To summarize the efficacy and safety of mefloquine used as prophylaxis for malaria in travellers.
SEARCH METHODS
We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published on the Cochrane Library; MEDLINE; Embase (OVID); TOXLINE (https://toxnet.nlm.nih.gov/newtoxnet/toxline.htm); and LILACS. We also searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; http://www.who.int/ictrp/en/) and ClinicalTrials.gov (https://clinicaltrials.gov/ct2/home) for trials in progress, using 'mefloquine', 'Lariam', and 'malaria' as search terms. The search date was 22 June 2017.
SELECTION CRITERIA
We included randomized controlled trials (for efficacy and safety) and non-randomized cohort studies (for safety). We compared prophylactic mefloquine with placebo, no treatment, or an alternative recommended antimalarial agent. Our study populations included all adults and children, including pregnant women.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed the eligibility and risk of bias of trials, extracted and analysed data. We compared dichotomous outcomes using risk ratios (RR) with 95% confidence intervals (CI). Prespecified adverse outcomes are included in 'Summary of findings' tables, with the best available estimate of the absolute frequency of each outcome in short-term international travellers. We assessed the certainty of the evidence using the GRADE approach.
MAIN RESULTS
We included 20 RCTs (11,470 participants); 35 cohort studies (198,493 participants); and four large retrospective analyses of health records (800,652 participants). Nine RCTs explicitly excluded participants with a psychiatric history, and 25 cohort studies stated that the choice of antimalarial agent was based on medical history and personal preference. Most RCTs and cohort studies collected data on self-reported or clinician-assessed symptoms, rather than formal medical diagnoses. Mefloquine efficacyOf 12 trials comparing mefloquine and placebo, none were performed in short-term international travellers, and most populations had a degree of immunity to malaria. The percentage of people developing a malaria episode in the control arm varied from 1% to 82% (median 22%) and 0% to 13% in the mefloquine group (median 1%).In four RCTs that directly compared mefloquine, atovaquone-proguanil and doxycycline in non-immune, short-term international travellers, only one clinical case of malaria occurred (4 trials, 1822 participants). Mefloquine safety versus atovaquone-proguanil Participants receiving mefloquine were more likely to discontinue their medication due to adverse effects than atovaquone-proguanil users (RR 2.86, 95% CI 1.53 to 5.31; 3 RCTs, 1438 participants; high-certainty evidence). There were few serious adverse effects reported with mefloquine (15/2651 travellers) and none with atovaquone-proguanil (940 travellers).One RCT and six cohort studies reported on our prespecified adverse effects. In the RCT with short-term travellers, mefloquine users were more likely to report abnormal dreams (RR 2.04, 95% CI 1.37 to 3.04, moderate-certainty evidence), insomnia (RR 4.42, 95% CI 2.56 to 7.64, moderate-certainty evidence), anxiety (RR 6.12, 95% CI 1.82 to 20.66, moderate-certainty evidence), and depressed mood during travel (RR 5.78, 95% CI 1.71 to 19.61, moderate-certainty evidence). The cohort studies in longer-term travellers were consistent with this finding but most had larger effect sizes. Mefloquine users were also more likely to report nausea (high-certainty evidence) and dizziness (high-certainty evidence).Based on the available evidence, our best estimates of absolute effect sizes for mefloquine versus atovaquone-proguanil are 6% versus 2% for discontinuation of the drug, 13% versus 3% for insomnia, 14% versus 7% for abnormal dreams, 6% versus 1% for anxiety, and 6% versus 1% for depressed mood. Mefloquine safety versus doxycyclineNo difference was found in numbers of serious adverse effects with mefloquine and doxycycline (low-certainty evidence) or numbers of discontinuations due to adverse effects (RR 1.08, 95% CI 0.41 to 2.87; 4 RCTs, 763 participants; low-certainty evidence).Six cohort studies in longer-term occupational travellers reported our prespecified adverse effects; one RCT in military personnel and one cohort study in short-term travellers reported adverse events. Mefloquine users were more likely to report abnormal dreams (RR 10.49, 95% CI 3.79 to 29.10; 4 cohort studies, 2588 participants, very low-certainty evidence), insomnia (RR 4.14, 95% CI 1.19 to 14.44; 4 cohort studies, 3212 participants, very low-certainty evidence), anxiety (RR 18.04, 95% CI 9.32 to 34.93; 3 cohort studies, 2559 participants, very low-certainty evidence), and depressed mood (RR 11.43, 95% CI 5.21 to 25.07; 2 cohort studies, 2445 participants, very low-certainty evidence). The findings of the single cohort study reporting adverse events in short-term international travellers were consistent with this finding but the single RCT in military personnel did not demonstrate a difference between groups in frequencies of abnormal dreams or insomnia.Mefloquine users were less likely to report dyspepsia (RR 0.26, 95% CI 0.09 to 0.74; 5 cohort studies, 5104 participants, low certainty-evidence), photosensitivity (RR 0.08, 95% CI 0.05 to 0.11; 2 cohort studies, 1875 participants, very low-certainty evidence), vomiting (RR 0.18, 95% CI 0.12 to 0.27; 4 cohort studies, 5071 participants, very low-certainty evidence), and vaginal thrush (RR 0.10, 95% CI 0.06 to 0.16; 1 cohort study, 1761 participants, very low-certainty evidence).Based on the available evidence, our best estimates of absolute effect for mefloquine versus doxycyline were: 2% versus 2% for discontinuation, 12% versus 3% for insomnia, 31% versus 3% for abnormal dreams, 18% versus 1% for anxiety, 11% versus 1% for depressed mood, 4% versus 14% for dyspepsia, 2% versus 19% for photosensitivity, 1% versus 5% for vomiting, and 2% versus 16% for vaginal thrush.Additional analyses, including comparisons of mefloquine with chloroquine, added no new information. Subgroup analysis by study design, duration of travel, and military versus non-military participants, provided no conclusive findings.
AUTHORS' CONCLUSIONS
The absolute risk of malaria during short-term travel appears low with all three established antimalarial agents (mefloquine, doxycycline, and atovaquone-proguanil).The choice of antimalarial agent depends on how individual travellers assess the importance of specific adverse effects, pill burden, and cost. Some travellers will prefer mefloquine for its once-weekly regimen, but this should be balanced against the increased frequency of abnormal dreams, anxiety, insomnia, and depressed mood.
Topics: Adult; Antimalarials; Atovaquone; Child; Chloroquine; Doxycycline; Drug Combinations; Drug Resistance; Drug Therapy, Combination; Humans; Malaria, Falciparum; Mefloquine; Primaquine; Proguanil; Randomized Controlled Trials as Topic; Travel-Related Illness
PubMed: 29083100
DOI: 10.1002/14651858.CD006491.pub4 -
Travel Medicine and Infectious Disease 2019Malaria infection poses a significant risk in pregnancy, yet chemoprophylaxis for pregnant women is limited. A systematic review was conducted to evaluate the incidence...
BACKGROUND
Malaria infection poses a significant risk in pregnancy, yet chemoprophylaxis for pregnant women is limited. A systematic review was conducted to evaluate the incidence of adverse outcomes after atovaquone-proguanil (AP) exposure during pregnancy.
METHODS
Following PRISMA guidelines, the authors searched PubMed, MEDLINE, and the Malaria in Pregnancy Consortium Library to identify relevant literature including infant outcomes after exposure to atovaquone, proguanil, or AP in pregnancy. Two authors independently screened the titles, abstracts, and full texts, and extracted data into an EpiInfo database. Overall proportions and 95% confidence intervals of adverse outcomes were determined by pooling data across studies.
RESULTS
Of 455 records identified, 16 studies were included: ten AP studies and six proguanil studies. The overall proportions and 95% confidence intervals (CI) of adverse outcomes reported for the 446 women exposed to AP include miscarriage (8.08% CI: 5.07, 12.08%), stillbirth (1.05% CI: 0.03, 5.73%), early neonatal death (0% CI: 0, 7.4%), and congenital anomalies (2.56% CI: 1.28, 4.53%).
CONCLUSIONS
The limited available data suggest that outcomes following AP exposure during pregnancy are similar to expected rates in similar populations. AP may be a promising option for pregnant women, but further data are needed on its safety in pregnancy.
Topics: Abortion, Spontaneous; Antimalarials; Atovaquone; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Infant, Newborn; Malaria; Malaria, Falciparum; Pregnancy; Pregnancy Complications, Parasitic; Proguanil; Stillbirth; Travel
PubMed: 30654041
DOI: 10.1016/j.tmaid.2019.01.008 -
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 -
Travel Medicine and Infectious Disease 2022Atovaquone/proguanil (AP) is a highly effective malaria chemoprophylaxis combination. According to current guidelines, AP is taken once daily during, and continued for... (Review)
Review
Discontinuing atovaquone/proguanil prophylaxis ad-hoc post-exposure and during-travel dose-sparing prophylactic regimens against P. falciparum malaria: An update with pointers for future research.
BACKGROUND
Atovaquone/proguanil (AP) is a highly effective malaria chemoprophylaxis combination. According to current guidelines, AP is taken once daily during, and continued for seven days post exposure. A systematic review by Savelkoel et al. summarised data up to 2017 on abbreviated AP regimens, and concluded that discontinuing AP upon return may be effective, although the available data was insufficient to modify current recommendations. The same applies to other studies evaluating during-travel dose-sparing regimens.
METHODS
A literature search in Pubmed and Embase was performed including search terms related to AP prophylaxis and pharmacokinetics to search for recent studies on abbreviated AP regimens published since 2017.
RESULTS
Since the 2017 review, no new studies assessing discontinuing AP ad-hoc post-exposure prophylaxis have been published. Two new studies were identified assessing other abbreviated AP regimens; one investigated a twice-weekly AP regimen in 32 travellers, and one a three-day AP course in therapeutic dose (1000/400 mg) prior to exposure in 215 travellers. No malaria cases were detected in the study participants adhering to these regimens.
CONCLUSIONS
Further research would be needed if the research question is considered of sufficient importance to facilitate evidence-based decision-making to modify current guidelines, as efficacy studies in travellers are fraught with confounders. We recommend human challenge trials to study abbreviated AP regimens pertaining to malaria chemoprophylaxis as they allow for rational, subject number, time- and cost-saving trial designs.
Topics: Antimalarials; Atovaquone; Drug Combinations; Humans; Malaria; Malaria, Falciparum; Proguanil; Travel
PubMed: 35661741
DOI: 10.1016/j.tmaid.2022.102365 -
Malaria Journal Feb 2016Pregnancy has been reported to alter the pharmacokinetic properties of anti-malarial drugs, including the different components of artemisinin-based combination therapy... (Review)
Review
BACKGROUND
Pregnancy has been reported to alter the pharmacokinetic properties of anti-malarial drugs, including the different components of artemisinin-based combination therapy (ACT). However, small sample sizes make it difficult to draw strong conclusions based on individual pharmacokinetic studies. The aim of this review is to summarize the evidence of the influence of pregnancy on the pharmacokinetic properties of different artemisinin-based combinations.
METHODS
A PROSPERO-registered systematic review to identify clinical trials that investigated the influence of pregnancy on the pharmacokinetic properties of different forms of ACT was conducted, following PRISMA guidelines. Without language restrictions, Medline/PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, LILACS, Biosis Previews and the African Index Medicus were searched for studies published up to November 2015. The following components of ACT that are currently recommend by the World Health Organization as first-line treatment of malaria in pregnancy were reviewed: artemisinin, artesunate, dihydroartemisinin, lumefantrine, amodiaquine, mefloquine, sulfadoxine, pyrimethamine, piperaquine, atovaquone and proguanil.
RESULTS
The literature search identified 121 reports, 27 original studies were included. 829 pregnant women were included in the analysis. Comparison of the available studies showed lower maximum concentrations (Cmax) and exposure (AUC) of dihydroartemisinin, the active metabolite of all artemisinin derivatives, after oral administration of artemether, artesunate and dihydroartemisinin in pregnant women. Low day 7 concentrations were commonly seen in lumefantrine studies, indicating a low exposure and possibly reduced efficacy. The influence of pregnancy on amodiaquine and piperaquine seemed not to be clinically relevant. Sulfadoxine plasma concentration was significantly reduced and clearance rates were higher in pregnancy, while pyrimethamine and mefloquine need more research as no general conclusion can be drawn based on the available evidence. For atovaquone, the available data showed a lower maximum concentration and exposure. Finally, the maximum concentration of cycloguanil, the active metabolite of proguanil, was significantly lower, possibly compromising the efficacy.
CONCLUSION
These findings suggest that reassessment of the dose of the artemisinin derivate and some components of ACT are necessary to ensure the highest possible efficacy of malaria treatment in pregnant women. However, for most components of ACT, data were insufficient and extensive research with larger sample sizes will be necessary to identify the exact influences of pregnancy on the pharmacokinetic properties of different artemisinin-based combinations. In addition, different clinical studies used diverse study designs with various reported relevant outcomes. Future pharmacokinetic studies could benefit from more uniform designs, in order to increase quality, robustness and effectiveness.
STUDY REGISTRATION
CRD42015023756 (PROSPERO).
Topics: Antimalarials; Artemisinins; Drug Combinations; Female; Humans; Malaria; Plasmodium falciparum; Plasmodium ovale; Plasmodium vivax; Pregnancy
PubMed: 26891915
DOI: 10.1186/s12936-016-1160-6 -
Journal of Travel Medicine Feb 2021Nearly a year into the COVID-19 pandemic, we still lack effective anti-SARS-CoV-2 drugs with substantial impact on mortality rates except for dexamethasone. As the...
BACKGROUND
Nearly a year into the COVID-19 pandemic, we still lack effective anti-SARS-CoV-2 drugs with substantial impact on mortality rates except for dexamethasone. As the search for effective antiviral agents continues, we aimed to review data on the potential of repurposing antiparasitic drugs against viruses in general, with an emphasis on coronaviruses.
METHODS
We performed a review by screening in vitro and in vivo studies that assessed the antiviral activity of several antiparasitic agents: chloroquine, hydroxychloroquine (HCQ), mefloquine, artemisinins, ivermectin, nitazoxanide (NTZ), niclosamide, atovaquone and albendazole.
RESULTS
For HCQ and chloroquine we found ample in vitro evidence of antiviral activity. Cohort studies that assessed the use of HCQ for COVID-19 reported conflicting results, but randomized controlled trials (RCTs) demonstrated no effect on mortality rates and no substantial clinical benefits of HCQ used either for prevention or treatment of COVID-19. We found two clinical studies of artemisinins and two studies of NTZ for treatment of viruses other than COVID-19, all of which showed mixed results. Ivermectin was evaluated in one RCT and few observational studies, demonstrating conflicting results. As the level of evidence of these data is low, the efficacy of ivermectin against COVID-19 remains to be proven. For chloroquine, HCQ, mefloquine, artemisinins, ivermectin, NTZ and niclosamide, we found in vitro studies showing some effects against a wide array of viruses. We found no relevant studies for atovaquone and albendazole.
CONCLUSIONS
As the search for an effective drug active against SARS-CoV-2 continues, we argue that pre-clinical research of possible antiviral effects of compounds that could have antiviral activity should be conducted. Clinical studies should be conducted when sufficient in vitro evidence exists, and drugs should be introduced into widespread clinical use only after being rigorously tested in RCTs. Such a search may prove beneficial in this pandemic or in outbreaks yet to come.
Topics: Animals; Antiparasitic Agents; COVID-19; Drug Repositioning; Humans; Hydroxychloroquine; Ivermectin; Pandemics; Randomized Controlled Trials as Topic; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33480414
DOI: 10.1093/jtm/taab005