Individual risk of post-ivermectin serious adverse events in subjects infected with Loa loa.
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ABSTRACT: Background
Implementation of onchocerciasis elimination programmes has been delayed in Central Africa because of the risk of ivermectin-related serious adverse events (SAEs) in individuals with high Loa loa microfilarial densities (MFD). We developed the first statistical models enabling prediction of SAE risk in individuals with a given MFD.Methods
We used individual participant data from two trials conducted in loiasis-onchocerciasis co-endemic areas in Cameroon. among the 10 506 ivermectin-treated subjects included in the analysis, 38 (0·36%) developed an ivermectin-related SAE. To predict individual-level risk of SAE, we developed mixed multivariate logistic models including subjects' sex, age, pre-treatment L loa and Mansonella perstans MFDs, and study region.Findings
The models predicted that regardless of sex, about 1% of people with 20 000 L loa microfilariae per millilitre of blood (mf/mL), 10% of people with 50 000 mf/mL and about one third of those with 100 000 mf/mL will develop an SAE. For a given MFD, males have a three-fold higher risk of developing an SAE than females.Interpretation
By enabling the prediction of post-ivermectin SAE risk in communities with known distribution of L loa MFDs, our results can guide decisions on the choice of ivermectin-based treatment strategies. They also predict that 37 SAEs were prevented in 2015 by using a Test-and-Treat strategy in the Okola District of Cameroon.Funding
UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases; Institut de Recherche pour le Développement; Mectizan Donation Program; Bill & Melinda Gates Foundation.
SUBMITTER: Chesnais CB
PROVIDER: S-EPMC7700892 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundSevere adverse reactions have been observed in individuals with Loa loa infection treated with either diethylcarbamazine (DEC), the drug of choice for loiasis, or ivermectin (IVM), which is used in mass drug administration programs for control of onchocerciasis and lymphatic filariasis in Africa. In this study, posttreatment clinical and immunologic reactions were compared following single-dose therapy with DEC or IVM to assess whether these reactions have the same underlying pathophysiology.MethodsTwelve patients with loiasis and microfilarial counts <2000 mf/mL were randomized to receive single-dose DEC (8 mg/kg) or IVM (200 µg/kg). Clinical and laboratory assessments were performed at 4, 8, 24, 48, and 72 hours and 5, 7, 9, and 14 days posttreatment.ResultsPosttreatment adverse events were similar following DEC or IVM, but peaked earlier in subjects who received DEC, consistent with a trend toward more rapid and complete microfilarial clearance in the DEC group. After a transient rise (post-IVM) or fall (post-DEC) in the first 24 hours posttreatment, the eosinophil count rose significantly in both groups, peaking at day 5 in the DEC group and day 9 in the IVM group. Serum interleukin 5 levels and eosinophil activation, as assessed by surface expression of CD69 and serum levels of eosinophil granule proteins, were increased posttreatment in both groups.ConclusionsDespite differences in eosinophil and lymphocyte counts during the first 24 hours posttreatment, the overall pattern of hematologic and immunologic changes suggest that posttreatment reactions following DEC and IVM share a common pathophysiology.Clinical trials registrationNCT01593722.
| S-EPMC5850646 | biostudies-literature
Project description:The occurrence of Serious Adverse Experiences (SAEs) following Mectizan(R) treatment of onchocerciasis in Loa loa endemic areas has been increasingly reported over the past decade. These SAEs include a severely disabling, and potentially fatal, encephalopathy, which appears to correlate with a high load of L. loa microfilariae (> 30,000 mf/ml).Previous consultations organized by the Mectizan(R) Donation Program (MDP) in 1995 and 1999 have developed useful "case" definitions of encephalopathic SAEs following Mectizan(R) treatment and have summarized available evidence on its pathogenesis and optimal clinical management. At both meetings, the need for better understanding of the pathogenesis of the encephalopathy was emphasized, including the need for biological and autopsy specimens from the affected cases.Following a recommendation at the Joint Action Forum of the African Programme for Onchocerciasis Control in December 2001, the MDP, on behalf of the Mectizan(R) Expert Committee, organized a Scientific Working Group on L. loa associated SAEs following Mectizan(R) treatment in May 2002. The present report includes the background, new evidence, conclusions and recommendations from that Scientific Working Group. The following points represent a summary of the present status:1. Although there are more and better quality clinical and epidemiological data on L. loa, the pathogenesis of the Mectizan(R)-related L. loa encephalopathy remains obscure.2. Very limited progress has been made in research on the pathogenesis of encephalopathy, because of the lack of specimens from cases, and the lack of animal models.3. There has been no particular breakthrough in terms of the medical management of patients with L. loa encephalopathy; however, a favorable outcome usually results from prompt general nursing and nutritional care which remain the major interventions.The main recommendations for future actions are as follows:1. Validate and update the mapping of L. loa with a combination of remote sensing and RAPLOA techniques.2. Conduct an expert analysis of the apparent clustering of encephalopathic SAEs reported so far.3. Investigate a possible "pre-treatment" scheme with high-dose albendazole in L. loa endemic communities at high risk of encephalopathic SAEs if treated with Mectizan(R); this study will be conducted in collaboration with WHO/TDR.4. Establish a post of Loiasis Technical Advisor for research and operational support in Cameroon, to conduct population surveys and to facilitate better data collection from SAE cases, including postmortem studies as appropriate.5. Investigate the possibility of developing an animal model of L. loa encephalopathy; this activity would be linked to the above-mentioned research agenda in Cameroon.6. Investigate the best care model for encephalopathic SAEs, including identification of early warning signs and therapeutic interventions.7. Develop further models for health education messages needed for community compliance with Mectizan(R) treatment, and family support for SAE cases.8. Conduct research studies on the safety of combination therapy of Mectizan(R) and albendazole in areas co-endemic for L. loa and lymphatic filariasis (LF) with coordination from the relevant technical bodies that oversee these issues.The above recommendations will be implemented through a continuing collaboration between the interested parties represented at the Scientific Working Group, involved in onchocerciasis control and/or the Global Programme to Eliminate Lymphatic Filariasis.
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Project description: Not available
| S-EPMC1127542 | biostudies-literature
Project description:TOPIC:A comparison between ranibizumab and bevacizumab of the incidence of systemic serious adverse events (SAEs) among patients with neovascular age-related macular degeneration (nAMD) who participated in a large-scale randomized trial. Use of individual patient data, rather than aggregate data, allowed adjustment for strong predictors of SAEs. CLINICAL RELEVANCE:Relative safety of ranibizumab and bevacizumab is important in choosing an anti-VEGF drug for the hundreds of thousands of patients with nAMD treated each year worldwide. METHODS:Results of a Cochrane aggregate meta-analysis of the relative efficacy and safety of bevacizumab and ranibizumab that used searches of bibliographic databases and clinical trial registries as of March 14, 2014 and hand searching were reviewed to identify 6 large-scale, multicenter clinical trials. Individual patient data on SAEs, assigned drug and dosing regimen, and baseline prognostic factors were requested from the leaders of the 6 trials. A two-stage approach was used to estimate relative risks and 95% confidence intervals (CIs) from Cox proportional hazards models adjusting for baseline prognostic factors. The primary outcome measure was development of ?1 SAE; secondary outcome measures were death, arteriothrombotic events, events associated with systemic anti-VEGF therapy, and events not associated with systemic anti-VEGF therapy. RESULTS:Individual patient data were received from 5 trials to provide information on 3052 patients. There were no large imbalances between drug groups on baseline factors. The adjusted relative risk (95% CI) for bevacizumab relative to ranibizumab was 1.06 [(0.84, 1.35); p=0.61] for ?1 SAEs. For secondary outcomes, adjusted relative risks were 0.99 [ (0.69, 1.43); p=0.97] for death, 0.89 [ (0.62, 1.28); p=0.53] for arteriothrombotic events, 1.10 [ (0.81, 1.50); p=0.54] for events related to anti-VEGF treatment, and 1.11 [ (0.87, 1.40); p=0.40] for events not related to anti-VEGF treatment. CONCLUSION:Our findings support the absence of large differences in risk of systemic serious adverse events between these two anti-VEGF drugs; i.e., relative risks of ?1.5 are unlikely. Because additional head-to-head trials are unlikely, any further investigation of differential risk between anti-VEGF agents will only be achieved though post-marketing surveillance or through the interrogation of healthcare databases.
| S-EPMC5640431 | biostudies-literature
Project description:BackgroundCystic fibrosis (CF) is an autosomal recessive disease characterized by chronic sinopulmonary symptoms and chronic gastrointestinal symptoms that begins in infancy. Children with CF are increasingly being included in clinical trials. In order to fully evaluate the impact of new therapies in future clinical trials, an understanding of baseline adverse event (AE) rates in children with CF is needed. To address this, we determined the rates of common AEs in pediatric patients with CF who participated in two clinical trials.MethodsWe reviewed AEs for placebo recipients in the AZ0004 study and inhaled tobramycin recipients in the Early Pseudomonas Infection Control (EPIC) clinical trial. AEs were categorized based on Medical Dictionary for Regulatory Activities (MedDRA) coding classifications and pooled into common, batched AE descriptors. AE rates were estimated from negative binomial models according to age groups, severity of lung disease, and season.ResultsA total of 433 children had 8,266 total AEs reported, or 18.1 (95% CI 17.0, 19.2) AEs per person per year. Respiratory AEs were the most commonly reported AEs, with a rate of 7.6 events per person-year. The total SAE rate was 0.33 per person per-year. Cough was the most commonly reported respiratory AE, with 61% of subjects reporting at least one episode of cough within 4 months. The rate ratio of any AE was higher in Spring, Fall, and Winter, compared with Summer.ConclusionsAEs occur commonly in pediatric CF clinical trial participants. Season of enrollment could affect AE rates.
| S-EPMC8448791 | biostudies-literature
Project description:BackgroundThere have been postmarketing reports of adverse cardiovascular events associated with the use of varenicline, a widely used smoking cessation drug. We conducted a systematic review and meta-analysis of randomized controlled trials to ascertain the serious adverse cardiovascular effects of varenicline compared with placebo among tobacco users.MethodsWe searched MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, websites of regulatory authorities and registries of clinical trials, with no date or language restrictions, through September 2010 (updated March 2011) for published and unpublished studies. We selected double-blind randomized controlled trials of at least one week's duration involving smokers or people who used smokeless tobacco that reported on cardiovascular events (ischemia, arrhythmia, congestive heart failure, sudden death or cardiovascular-related death) as serious adverse events asociated with the use of varenicline.ResultsWe analyzed data from 14 double-blind randomized controlled trials involving 8216 participants. The trials ranged in duration from 7 to 52 weeks. Varenicline was associated with a significantly increased risk of serious adverse cardiovascular events compared with placebo (1.06% [52/4908] in varenicline group v. 0.82% [27/3308] in placebo group; Peto odds ratio [OR] 1.72, 95% confidence interval [CI] 1.09-2.71; I(2) = 0%). The results of various sensitivity analyses were consistent with those of the main analysis, and a funnel plot showed no publication bias. There were too few deaths to allow meaningful comparisons of mortality.InterpretationOur meta-analysis raises safety concerns about the potential for an increased risk of serious adverse cardiovascular events associated with the use of varenicline among tobacco users.
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Project description:To examine the risk of treatment emergent, cardiovascular serious adverse events associated with varenicline use for tobacco cessation.Meta-analysis comparing study effects using four summary estimates.Medline, Cochrane Library, online clinical trials registries, and reference lists of identified articles.We included randomised controlled trials of current tobacco users of adult age comparing use of varenicline with an inactive control and reporting adverse events. We defined treatment emergent, cardiovascular serious adverse events as occurring during drug treatment or within 30 days of discontinuation, and included any ischaemic or arrhythmic adverse cardiovascular event (myocardial infarction, unstable angina, coronary revascularisation, coronary artery disease, arrhythmias, transient ischaemic attacks, stroke, sudden death or cardiovascular related death, or congestive heart failure).We identified 22 trials; all were double blinded and placebo controlled; two included participants with active cardiovascular disease and 11 enrolled participants with a history of cardiovascular disease. Rates of treatment emergent, cardiovascular serious adverse events were 0.63% (34/5431) in the varenicline groups and 0.47% (18/3801) in the placebo groups. The summary estimate for the risk difference, 0.27% (95% confidence interval -0.10 to 0.63; P = 0.15), based on all 22 trials, was neither clinically nor statistically significant. For comparison, the relative risk (1.40, 0.82 to 2.39; P = 0.22), Mantel-Haenszel odds ratio (1.41, 0.82 to 2.42; P = 0.22), and Peto odds ratio (1.58, 0.90 to 2.76; P = 0.11), all based on 14 trials with at least one event, also indicated a non-significant difference between varenicline and placebo groups.This meta--analysis--which included all trials published to date, focused on events occurring during drug exposure, and analysed findings using four summary estimates-found no significant increase in cardiovascular serious adverse events associated with varenicline use. For rare outcomes, summary estimates based on absolute effects are recommended and estimates based on the Peto odds ratio should be avoided.
| S-EPMC3344735 | biostudies-other
Project description:ObjectiveTo assess the association between the use of sodium glucose cotransporter 2 (SGLT2) inhibitors and seven serious adverse events of current concern.DesignRegister based cohort study.SettingSweden and Denmark from July 2013 to December 2016.ParticipantsA propensity score matched cohort of 17?213 new users of SGLT2 inhibitors (dapagliflozin, 61%; empagliflozin, 38%; canagliflozin, 1%) and 17?213 new users of the active comparator, glucagon-like peptide 1 (GLP1) receptor agonists.Main outcome measuresThe primary outcomes were lower limb amputation, bone fracture, diabetic ketoacidosis, acute kidney injury, serious urinary tract infection, venous thromboembolism, and acute pancreatitis, as identified from hospital records. Hazard ratios and 95% confidence intervals were estimated by using Cox proportional hazards models.ResultsUse of SGLT2 inhibitors, as compared with GLP1 receptor agonists, was associated with an increased risk of lower limb amputation (incidence rate 2.7 v 1.1 events per 1000 person years, hazard ratio 2.32, 95% confidence interval 1.37 to 3.91) and diabetic ketoacidosis (1.3 v 0.6, 2.14, 1.01 to 4.52) but not with bone fracture (15.4 v 13.9, 1.11, 0.93 to 1.33), acute kidney injury (2.3 v 3.2, 0.69, 0.45 to 1.05), serious urinary tract infection (5.4 v 6.0, 0.89, 0.67 to 1.19), venous thromboembolism (4.2 v 4.1, 0.99, 0.71 to 1.38) or acute pancreatitis (1.3 v 1.2, 1.16, 0.64 to 2.12).ConclusionsIn this analysis of nationwide registers from two countries, use of SGLT2 inhibitors, as compared with GLP1 receptor agonists, was associated with an increased risk of lower limb amputation and diabetic ketoacidosis, but not with other serious adverse events of current concern.
| S-EPMC6233755 | biostudies-literature
Project description:IntroductionAdministration of ivermectin (IVM) as part of mass drug administration (MDA) campaigns for onchocerciasis and/or lymphatic filariasis (LF) has been suspended in areas co-endemic for Loa loa due to severe post-treatment adverse events (SAEs) associated with high-burden of infection (>30,000 mf/ml). One simple approach for preventing SAEs is to identify and exclude individuals at risk from MDA. Here, we describe a repurposed hand-held automated cell counter (Scepter 2.0; HHAC) as a rapid, point-of-care method for quantifying microfilariae (mf) in the blood of infected individuals.Methodology/principal findingsThe quantification of microfilarial levels in blood of naturally infected humans, experimentally infected baboons, or mf-spiked human blood was tested using a microfluidic-based automated counter and compared to traditional calibrated thick-smears. We demonstrate that mf can be quantified in 20 µl of whole blood following lysis with 10% saponin within a minute of obtaining blood. There was a highly significant concordance between the counts obtained by the HHAC and those by microscopy for mf densities of >5,000 (p<0.0001, r(c) = 0.97) or >30,000 per ml (p<0.0001, r(c) = 0.90). Preliminary proof of concept field studies in Cameroon with 20 µl of blood from L. loa infected humans (n = 22) and baboons (n = 4) also demonstrated a significantly high concordance (p<0.0001, r(c) = 0.89) with calibrated thick blood smears counts.Conclusions/significanceA repurposed HHAC is a portable, sensitive, rapid, point-of-care and quantitative tool to identify individuals with high levels of L. loa mf that put them at risk for SAEs following MDA. In addition, it provides ease of data storage and accessibility.
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Project description:This study aimed to test the hypothesis that the risk of major adverse cardiovascular events (MACE) is similar for subjects with asymptomatic mild and moderate carotid artery stenosis (CAS). We enrolled a total of 453 subjects with asymptomatic CAS (30-69%) detected on baseline screening Doppler ultrasound (DUS) examination between January 2008 and December 2010. The follow-up DUS findings and MACE occurrence (fatal or nonfatal myocardial infarction or stroke and all-cause mortality) were compared between subjects with mild (30-49%) and moderate (50-69%) CAS during the 8-year follow-up period. There was no significant difference in the occurrence of MACE between subjects with mild (n = 289) and moderate (n = 164) CAS (13.8% vs. 15.9%, respectively; p = 0.56), although there was a nonsignificant trend toward an increased risk of major ipsilateral stroke in subjects with moderate CAS (1.4% vs. 4.3%; p = 0.06). Multivariate regression analysis indicated that worsening CAS was independently associated with MACE occurrence (hazard ratio [HR], 4.40; 95% confidence interval [CI], 2.65-7.27; p < 0.01), whereas an increased serum high-density lipoprotein cholesterol level was correlated with a decreased risk of MACE (HR, 0.42; 95% CI, 0.23-0.75; p < 0.01). The cumulative risk of MACE in subjects with asymptomatic mild CAS is similar to that in subjects with asymptomatic moderate CAS.
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