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Wellcome Open Research 2017Antimalarial drugs affect the central nervous system, but it is difficult to differentiate the effect of these drugs from that of the malaria illness. We conducted a...
Antimalarial drugs affect the central nervous system, but it is difficult to differentiate the effect of these drugs from that of the malaria illness. We conducted a systematic review to determine the association between anti-malarial drugs and mental and neurological impairment in humans. We systematically searched online databases, including Medline/PubMed, PsychoInfo, and Embase, for articles published up to 14th July 2016. Pooled prevalence, heterogeneity and factors associated with prevalence of mental and neurological manifestations were determined using meta-analytic techniques. Of the 2,349 records identified in the initial search, 51 human studies met the eligibility criteria. The median pooled prevalence range of mental and neurological manifestations associated with antimalarial drugs ranged from 0.7% (dapsone) to 48.3% (minocycline) across all studies, while it ranged from 0.6% (pyrimethamine) to 42.7% (amodiaquine) during treatment of acute malaria, and 0.7% (primaquine/dapsone) to 55.0% (sulfadoxine) during prophylaxis. Pooled prevalence of mental and neurological manifestations across all studies was associated with an increased number of antimalarial drugs (prevalence ratio= 5.51 (95%CI, 1.05-29.04); P=0.045) in a meta-regression analysis. Headaches (15%) and dizziness (14%) were the most common mental and neurological manifestations across all studies. Of individual antimalarial drugs still on the market, mental and neurological manifestations were most common with the use of sulphadoxine (55%) for prophylaxis studies and amodiaquine (42.7%) for acute malaria studies. Mefloquine affected more domains of mental and neurological manifestations than any other antimalarial drug. Antimalarial drugs, particularly those used for prophylaxis, may be associated with mental and neurological manifestations, and the number of antimalarial drugs taken determines the association. Mental and neurological manifestations should be assessed following the use of antimalarial drugs.
PubMed: 28630942
DOI: 10.12688/wellcomeopenres.10658.2 -
Malaria Journal Apr 2017Naturally acquired immunity can reduce parasitaemia and potentially influence anti-malarial treatment outcomes; however, evidence for this in the current literature... (Review)
Review
BACKGROUND
Naturally acquired immunity can reduce parasitaemia and potentially influence anti-malarial treatment outcomes; however, evidence for this in the current literature provides conflicted results. The available evidence was synthesized to determine and quantify the association between host immunity and anti-malarial treatment failure.
METHODS
Four databases were searched to identify studies investigating malaria antibody levels in patients receiving anti-malarial treatment for symptomatic malaria with treatment failure recorded according to the World Health Organization classification. Odds ratios or hazard ratios were extracted or calculated to quantify the association between malarial antibody levels and treatment failure, and findings from different studies were visualized using forest plots.
RESULTS
Eight studies, including patients with falciparum malaria treated with mono- and combination therapy of artemisinin derivatives, sulfadoxine, pyrimethamine and chloroquine, were identified. Reported and calculated effect estimates varied greatly between studies, even those assessing the same antigens and treatments. An association between blood-stage IgG responses and treatment efficacy was observed. The greatest magnitudes of effect were observed for artemisinin [OR/HR (95% CI) range 0.02 (0.00, 0.45)-1.08 (0.57, 2.06)] and chloroquine [0.24 (0.04, 1.37)-0.32 (0.05, 1.96)] treatments, and larger magnitudes of effect were observed for variant surface antigen responses [0.02 (0.00, 0.45)-1.92 (0.94, 3.91)] when compared with merozoite specific responses [0.24 (0.04, 1.37)-2.83 (1.13, 7.09)].
CONCLUSIONS
Naturally acquired malarial immunity is associated with reduced anti-malarial treatment failure in malaria endemic populations. Anti-malarial IgG effects treatment outcome differently for different anti-malarial drugs and antigen targets, and had the greatest impact during treatment with the current first-line treatments, the artemisinins. This has implications for the assessment of the therapeutic efficacy of anti-malarials, particularly in the context of emerging artemisinin resistance.
Topics: Antibodies, Protozoan; Antimalarials; Humans; Immunoglobulin G; Malaria, Falciparum; Plasmodium falciparum; Treatment Failure
PubMed: 28427418
DOI: 10.1186/s12936-017-1815-y -
Pathogens and Global Health Feb 2017Toxoplasmic encephalitis (TE) is caused by Toxoplasma gondii infection and can be a life-threatening disease in immunocompromised patients. This study evaluated the rate... (Meta-Analysis)
Meta-Analysis Review
Toxoplasmic encephalitis (TE) is caused by Toxoplasma gondii infection and can be a life-threatening disease in immunocompromised patients. This study evaluated the rate of relapse associated with pyrimethamine-based maintenance therapy (i.e. secondary prophylaxis) in patients with human immunodeficiency virus (HIV) or AIDs treated prior to and after the common use (i.e. 1996) of highly active antiretroviral therapy (HAART) (pre-HAART and post-HAART, respectively). PubMed, Google Scholar, and Cochrane databases were searched to 6 June 2016 using search terms: pyrimethamine, Daraprim, Fansidar, Metakelfin, Fansimef, 5-(4-chlorophenyl)-6-ethyl-2,4-pyrimidinediamine, encephalitis, cerebral, toxoplasmosis, toxoplasmic, and gondii. Single-arm cohort, retrospective, and randomized studies were included. Twenty-six studies with 1,596 patients were included in the analysis; twenty pre-HAART (n = 1,228) studies and six post-HAART (n = 368) were performed. Pooled proportions test for pyrimethamine-based therapy from pre-HAART studies indicated a relapse rate of 19.2% and 18.9% from the fixed-effects and random-effects models, respectively. The relapse rate in the post-HAART studies was 11.1% (fixed and random effects). Continuous therapy was suggestive of lower incidence of relapse compared with intermittent therapy in the pre-HAART era (range, 18.7 to 17.3% vs. 20.9 to 25.6%, respectively). These findings indicate that the likelihood of relapse associated with pyrimethamine-based therepy in patients with HIV and TE decreased after the introduction of HAART to approximately 11%. The findings have important implications as relapse may affect a patient's disease severity and prognosis, increase utilization of health care resources, and result in additional health care expenditure.
Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antiprotozoal Agents; Antiretroviral Therapy, Highly Active; Humans; Infectious Encephalitis; Pyrimethamine; Recurrence; Secondary Prevention; Toxoplasmosis, Cerebral
PubMed: 28090819
DOI: 10.1080/20477724.2016.1273597 -
Transactions of the Royal Society of... Nov 2016The present study is a systematic review of the literature on the efficacy and safety of the treatment of uncomplicated Plasmodium falciparum infections with... (Review)
Review
INTRODUCTION
The present study is a systematic review of the literature on the efficacy and safety of the treatment of uncomplicated Plasmodium falciparum infections with artesunate-mefloquine (ASMQ) compared to other artemisinin-based combination therapies (ACTs), designed to assist decision makers in Brazil.
METHODS
Twenty-four randomized controlled trials (RCTs) were selected in four electronic databases and in complementary sources. Meta-analyses were performed to evaluate the efficacy expressed by relative risks (RR) obtained from treatment failure confirmed by the PCR.
RESULTS
Due primarily to the presence of measurement bias in the selected studies, the quality of the evidence was considered predominantly moderate. Statistically significant associations were not observed when ASMQ was compared to artemether-lumefentrine and dihydroartemisinin-piperaquine. The results of studies performed in areas with a history of use of ASMQ, regardless of the intensity of transmission, were not statistically different from those presented in the meta-analyses. For comparisons with artesunate-amodiaquine and artesunate+sulfadoxine-pyrimethamine, the results were favourable to ASMQ. No deaths were attributed to ASMQ, severe adverse events were rare and some studies indicate a higher frequency of mild adverse events.
CONCLUSIONS
The use of ASMQ it is recommended to Brazil as first line treatment of uncomplicated P. falciparum infections.
PubMed: 28039388
DOI: 10.1093/trstmh/trw077 -
Parasitology Research Feb 2017Plasmodium falciparum is responsible for the vast majority of the morbidity and mortality associated with malaria infection globally. Although a number of studies have... (Meta-Analysis)
Meta-Analysis Review
Plasmodium falciparum is responsible for the vast majority of the morbidity and mortality associated with malaria infection globally. Although a number of studies have reported the emergence of drug resistance in different therapies for P. falciparum infection, the degree of the drug resistance in different antimalarials is still unclear. This research investigated the risk of drug resistance in the therapies with different medications based on meta-analyses. Relevant original randomized control trials (RCTs) were searched in all available electronic databases. Pooled relative risks (RRs) with 95% confidence intervals (95% CIs) were used to evaluate the risk of drug resistance resulting from different treatments. Seventy-eight studies were included in the meta-analysis to compare drug resistance in the treatment of P. falciparum infections and yielded the following results: chloroquine (CQ) > sulfadoxine-pyrimethamine (SP) (RR = 3.67, p < 0.001 ), mefloquine (MQ) < SP (RR = 0.26, p < 0.001), artesunate + sulfadoxine-pyrimethamine (AS + SP) > artemether + lumefantrine (AL) (RR = 2.94, p < 0.001), dihydroartemisinin + piperaquine (DHA + PQ) < AL (RR = 0.7, p < 0.05), and non-artemisinin-based combination therapies (NACTs) > artemisinin-based combination therapies (ACTs) (RR = 1.93, p < 0.001); no significant difference was found in amodiaquine (AQ) vs. SP, AS + AQ vs. AS + SP, AS + AQ vs. AL, or AS + MQ vs. AL. These results presented a global view for the current status of antimalarial drug resistance and provided a guidance for choice of antimalarials for efficient treatment and prolonging the life span of the current effective antimalarial drugs.
Topics: Amodiaquine; Antimalarials; Artemisinins; Chloroquine; Drug Combinations; Drug Resistance; Drug Therapy, Combination; Humans; Malaria, Falciparum; Mefloquine; Plasmodium falciparum; Pyrimethamine; Quinolines; Risk; Sulfadoxine
PubMed: 28028628
DOI: 10.1007/s00436-016-5353-2 -
The Lancet. Infectious Diseases Feb 2017Intermittent preventive treatment (IPT) for malaria is used in infants, children, adults, and pregnant women. Dihydroartemisinin-piperaquine (DP) is an effective, well... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Intermittent preventive treatment (IPT) for malaria is used in infants, children, adults, and pregnant women. Dihydroartemisinin-piperaquine (DP) is an effective, well tolerated artemisinin-based combination therapy. The long half-life of piperaquine makes it attractive for IPT. We conducted a systematic review and meta-analysis to establish the efficacy and safety of repeated treatment with DP.
METHODS
Following PRISMA guidelines, we searched multiple databases on Sept 1, 2016, with the terms: "human" AND "dihydroartemisinin-piperaquine" OR "DHA-PPQ". Studies were eligible if they were randomised controlled trials (RCTs) or prospective cohort studies involving repeat exposures to standard 3-day courses of DP for either seasonal malaria chemoprevention, mass drug administration, or treatment of clinical malaria, conducted at any time and in any geographic location. Random-effects meta-analysis was used to generate pooled incidence rate ratios and relative risks, or risk differences.
FINDINGS
11 studies were included: two repeat treatment studies (one in children younger than 5 years and one in pregnant women), and nine IPT trials (five in children younger than 5 years, one in schoolchildren, one in adults, two in pregnant women). Comparator interventions included placebo, artemether-lumefantrine, sulfadoxine-pyrimethamine (SP), SP+amodiaquine, SP+piperaquine, SP+chloroquine, and co-trimoxazole. Of 14 628 participants, 3935 received multiple DP courses (2-18). Monthly IPT-DP was associated with an 84% reduction in the incidence of malaria parasitaemia measured by microscopy compared with placebo. Monthly IPT-DP was associated with fewer serious adverse events than placebo, daily co-trimoxazole, or monthly SP. Among 56 IPT-DP recipients (26 children, 30 pregnant women) with cardiac parameters, all QTc intervals were within normal limits, with no significant increase in QTc prolongation with increasing courses of DP.
INTERPRETATION
Monthly DP appears well tolerated and effective for IPT. Additional data are needed in pregnancy and to further explore the cardiac safety with monthly dosing.
FUNDING
Bill & Melinda Gates Foundation and NIH.
Topics: Antimalarials; Artemisinins; Drug Combinations; Drug Therapy, Combination; Humans; Malaria; Pyrimethamine; Quinolines; Randomized Controlled Trials as Topic; Sulfadoxine
PubMed: 27865890
DOI: 10.1016/S1473-3099(16)30378-4 -
HIV Medicine Feb 2017The objective of this study was to perform a systematic review and meta-analysis of the literature to evaluate the efficacy and safety of therapies for cerebral... (Meta-Analysis)
Meta-Analysis Review
A systematic review and meta-analysis of the relative efficacy and safety of treatment regimens for HIV-associated cerebral toxoplasmosis: is trimethoprim-sulfamethoxazole a real option?
OBJECTIVES
The objective of this study was to perform a systematic review and meta-analysis of the literature to evaluate the efficacy and safety of therapies for cerebral toxoplasmosis in HIV-infected adults. The pyrimethamine plus sulfadiazine (P-S) combination is considered the mainstay therapy for cerebral toxoplasmosis and pyrimethamine plus clindamycin (P-C) is the most common alternative treatment. Although trimethoprim-sulfamethoxazole (TMP-SMX) has potential advantages, its use is infrequent.
METHODS
We searched PubMed and four other databases to identify randomized controlled trials (RCTs) and cohort studies. Two independent reviewers searched the databases, identified studies and extracted data. Risk ratios (RRs) were pooled across studies using random-effects models.
RESULTS
Nine studies were included (five RCTs, three retrospective cohort studies and one prospective cohort study). In comparison to P-S, treatment with P-C or TMP-SMX was associated with similar rates of partial or complete clinical response [P-C: RR 0.87; 95% confidence interval (CI) 0.70-1.08; TMP-SMX: RR 0.97; 95% CI 0.78-1.21], radiological response (P-C: RR 0.92; 95% CI 0.82-1.03), skin rash (P-C: RR 0.81; 95% CI 0.56-1.17; TMP-SMX: RR 0.17; 95% CI 0.02-1.29), gastrointestinal impairment (P-C: RR 5.16; 95% CI 0.66-40.11), and drug discontinuation because of adverse events (P-C: RR 0.32; 95% CI 0.07-1.47). Liver impairment was more frequent with P-S than P-C (P-C vs. P-S: RR 0.48; 95% CI 0.24-0.97).
CONCLUSIONS
The current evidence fails to identify a superior regimen in terms of relative efficacy or safety for the treatment of HIV-associated cerebral toxoplasmosis. Use of TMP-SMX as preferred treatment may be consistent with the available evidence and other real-world considerations. Larger comparative studies are needed.
Topics: Adult; Antiprotozoal Agents; Clindamycin; Cohort Studies; Female; HIV Infections; Humans; Male; Middle Aged; Pyrimethamine; Randomized Controlled Trials as Topic; Sulfadiazine; Toxoplasmosis, Cerebral; Trimethoprim, Sulfamethoxazole Drug Combination
PubMed: 27353303
DOI: 10.1111/hiv.12402 -
The Cochrane Database of Systematic... May 2016Acute toxoplasma retinochoroiditis causes transient symptoms of ocular discomfort and may lead to permanent visual loss. Antibiotic treatment aims primarily to reduce... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Acute toxoplasma retinochoroiditis causes transient symptoms of ocular discomfort and may lead to permanent visual loss. Antibiotic treatment aims primarily to reduce the risk of permanent visual loss, recurrent retinochoroiditis, and the severity and duration of acute symptoms. There is uncertainty about the effectiveness of antibiotic treatment.
OBJECTIVES
To compare the effects of antibiotic treatment versus placebo or no treatment for toxoplasma retinochoroiditis.
SEARCH METHODS
We searched CENTRAL (which contains the Cochrane Eyes and Vision group Trials Register) (2016, Issue 1), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to February 2016), EMBASE (January 1980 to February 2016), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to February 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 22 February 2016. We searched the reference lists of identified articles and contacted pharmaceutical companies for unpublished trials.
SELECTION CRITERIA
We included randomised controlled trials that compared any antibiotic treatment against placebo or no treatment. We excluded trials that included immunocompromised participants. We considered any antibiotic treatment known to be active against Toxoplasma gondii. Antibiotic treatment could be given in any dose orally, by intramuscular injection, by intravenous infusion, or by intravitreal injection.
DATA COLLECTION AND ANALYSIS
The primary outcomes for this review were visual acuity at least three months after treatment and risk of recurrent retinochoroiditis. Secondary outcomes were improvement in symptoms and signs of intraocular inflammation, size of lesion, and adverse events. We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
Four trials that randomised a total of 268 participants met the inclusion criteria. In all four studies antibiotic was administered orally.One study conducted in Brazil in both adults and children compared trimethoprim-sulfamexacocol over 20 months to no treatment and was judged to be at high risk of performance, detection, and attrition bias. The other three studies compared antibiotic treatment to placebo. We judged these three studies to be at a mixture of low or unclear risk of bias due to poor reporting. One study conducted in the US in adults studied pyrimethamine-trisulfapyrimidine for eight weeks; one study conducted in the UK in children and adults evaluated pyrimethamine for four weeks; and one study conducted in Brazil in adults investigated trimethoprim-sulfamethoxazole for 12 months. In the last study, all participants had active retinochoroiditis and were treated with antibiotics for 45 days prior to randomisation to trimethoprim-sulfamethoxazole versus placebo.Only the study in Brazil of trimethoprim-sulfamethoxazole over 12 months, in participants with healed lesions, reported the effect of treatment on visual acuity. People treated with antibiotics may have a similar change in visual acuity compared with people treated with placebo at one year (mean difference -1.00 letters, 95% confidence interval (CI) -7.93 to 5.93 letters; 93 participants; low-quality evidence).Treatment with antibiotics probably reduces the risk of recurrent retinochoroiditis compared with placebo (risk ratio (RR) 0.26, 95% CI 0.11 to 0.63; 227 participants; 3 studies; I(2) = 0%; moderate-quality evidence); similar results were seen for acute and chronic retinochoroiditis.The UK study of pyrimethamine for four weeks reported an improvement in intraocular inflammation in treated compared with control participants (RR 1.76, 95% CI 0.98 to 3.19; 29 participants; low-quality evidence). The study in Brazil of trimethoprim-sulfamethoxazole for 12 months stated that the severity of inflammation was higher in the comparator group when compared to the antibiotic-treated group but did not provide further details. In the US study of pyrimethamine-trisulfapyrimidine for eight weeks intraocular inflammation had almost completely resolved by eight weeks in all participants, however in this study all participants received steroid treatment.Two studies (UK and US studies) reported an increased risk of adverse events in treated participants. These were a fall in haemoglobin, leucocyte, and platelet count, nausea, loss of appetite, rash, and arthralgia.
AUTHORS' CONCLUSIONS
Treatment with antibiotics probably reduces the risk of recurrent toxoplasma retinochoroiditis, but there is currently no good evidence that this leads to better visual outcomes. However, absence of evidence of effect is not the same as evidence of no effect. Further trials of people with acute and chronic toxoplasma retinochoroiditis affecting any part of the retina are required to determine the effects of antibiotic treatment on visual outcomes.
Topics: Administration, Oral; Adult; Anti-Bacterial Agents; Child; Chorioretinitis; Drug Combinations; Humans; Pyrimethamine; Randomized Controlled Trials as Topic; Recurrence; Secondary Prevention; Sulfadiazine; Sulfamerazine; Sulfamethazine; Toxoplasmosis, Ocular; Trimethoprim, Sulfamethoxazole Drug Combination; Visual Acuity; Watchful Waiting
PubMed: 27198629
DOI: 10.1002/14651858.CD002218.pub2 -
The Cochrane Database of Systematic... Mar 2016Malaria causes ill health and death in Africa. Treating illness promptly with artemisinin-based combination therapy (ACT) is likely to cure people and avoid the disease... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Malaria causes ill health and death in Africa. Treating illness promptly with artemisinin-based combination therapy (ACT) is likely to cure people and avoid the disease progressing to more severe forms and death. In many countries, ACT use remains low. Part of the problem is that most people seek treatment from the retail sector where ACTs are expensive; this expense is a barrier to their use.The Global Fund and other international organisations are subsidising the cost of ACTs for private retail providers to improve access to ACTs. The subsidy was initially organised through a stand-alone initiative, called the Affordable Medicines Facility-malaria (AMFm), but has since been integrated into the Global Fund core grant management and financial processes.
OBJECTIVES
To assess the effect of programmes that include ACT price subsidies for private retailers on ACT use, availability, price and market share.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 1, The Cochrane Library, including the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register); MEDLINE (OvidSP), EMBASE (OvidSP), CINAHL (EbscoHost), EconLit (ProQuest), Global Health (OvidSP), Regional Indexes (Global Health Library, WHO), LILACS (Global Health Library, WHO), Science Citation Index and Social Sciences Citation Index (ISI Web of Science) and Health Management (ProQuest). All databases were searched February 2015, except for Health Management which was searched November 2013, without any date, language or publication status restrictions. We also searched the International Clinical Trials Registry Platform (ICTRP; WHO), ClinicalTrials.gov (NIH) and various grey literature sources. We also conducted a cited reference search for all included studies in ISI Web of Knowledge, checked references of identified articles and contacted authors to identify additional studies.
SELECTION CRITERIA
Randomised trials, non-randomised trials, controlled before-after studies and interrupted-time-series studies that compared the effects of ACT price subsidies for private retailers to no subsidies or alternative ACT financing mechanisms were eligible for inclusion. Two authors independently screened and selected studies for inclusion.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data, assessed study risk of bias and confidence in effect estimates (certainty of evidence) using Grading of Recommendations, Assessment, Development and Evaluation (GRADE).
MAIN RESULTS
We included four trials (two cluster-randomised trials reported in three articles and two non-randomised cluster trials). Three trials assessed retail sector ACT subsidies combined with supportive interventions (retail outlet provider training, community awareness and mass media campaigns). One trial assessed vouchers provided to households to purchase subsidised ACTs. Price subsidies ranged from 80% to 95%. One trial enrolled children under five years of age; the other three trials studied people of all age groups. The studies were done in rural districts in East Africa (Kenya, Uganda and Tanzania).In this East Africa setting, these ACT subsidy programmes increased the percentage of children under five years of age receiving ACTs on the day, or following day, of fever onset by 25 percentage points (95% confidence interval (CI) 14.1 to 35.9 percentage points; 1 study, high certainty evidence). This suggests that in practice, among febrile children under five years of age with an ACT usage rate of 5% without a subsidy, subsidy programmes would increase usage by between 19% and 41% over a one year period.The ACT subsidy programmes increased the percentage of retail outlets stocking ACTs for children under five years of age by 31.9 percentage points (95% CI 26.3 to 37.5 percentage points; 1 study, high certainty evidence). Effects on ACT stocking for patients of any age is unknown because the certainty of evidence was very low.The ACT subsidy programmes decreased the median cost of ACTs for children under five years of age by US$ 0.84 (median cost per ACT course without subsidy: US$ 1.08 versus with subsidy: US$ 0.24; 1 study, high certainty evidence).The ACT subsidy programmes increased the market share of ACTs for children under five years of age by between 23.6 and 63.0 percentage points (1 study, high certainty evidence).The ACT subsidy programmes decreased the use of older antimalarial drugs (such as amodiaquine and sulphadoxine-pyrimethamine) among children under five years of age by 10.4 percentage points (95% CI 3.9 to 16.9 percentage points; 1 study, high certainty evidence).None of the three studies of ACT subsidies reported the number of patients treated who had confirmed malaria.Vouchers increased the likelihood that an illness is treated with an ACT by 16 to 23 percentage points; however, vouchers were associated with a high rate of over-treatment of malaria (only 56% of patients taking ACTs from the drug shop tested positive for malaria under the 92% subsidy; 1 study, high certainty evidence).
AUTHORS' CONCLUSIONS
Programmes that include substantive subsidies for private sector retailers combined with training of providers and social marketing improved use and availability of ACTs for children under five years of age with suspected malaria in research studies from three countries in East Africa. These programmes also reduced prices of ACTs, improved market share of ACTs and reduced the use of older antimalarial drugs among febrile children under five years of age. The research evaluates drug delivery but does not assess whether the patients had confirmed (parasite-diagnosed) malaria. None of the included studies assessed patient outcomes; it is therefore not known whether the effects seen in the studies would translate to an impact on health.
Topics: Africa, Eastern; Antimalarials; Artemisinins; Child, Preschool; Drug Costs; Financial Support; Humans; Infant; Malaria; Private Sector; Program Evaluation; Randomized Controlled Trials as Topic
PubMed: 26954551
DOI: 10.1002/14651858.CD009926.pub2 -
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