Association between multivitamin supplementation and mortality among patients with Ebola virus disease: An international multisite cohort study.

INTRODUCTION: Micronutrient supplementation is recommended in Ebola Virus Disease (EVD) care; however, there is limited data on its therapeutic effects. METHODS: This retrospective cohort study included patients with EVD admitted to five Ebola Treatment Units (ETU) in Sierra Leone and Liberia during September 2014 to December 2015. A uniform protocol was used to guide ETU care, however, due to supply limitations, only a subset of patients received multivitamins. Data on demographics, clinical characteristics, and laboratory testing was collected. The outcome of interest was facility-based mortality and the primary predictor was multivitamin supplementation initiated within 48 h of admission. The multivitamin formulations included: thiamine, riboflavin, niacin and vitamins A, C, and D3. Propensity score models (PSM) were used to match patients based on covariates associated with multivitamin administration and mortality. Mortality between cases treated and untreated within 48 h of admission were compared using generalized estimating equations to calculate relative risk with bootstrap methods employed to assess statistical significance. RESULTS: There were 424 patients with EVD who had sufficient treatment data for analysis, of which 261 (61.6%) had daily multivitamins initiated within 48 h of admission. The mean age of the cohort was 30.5 years and 59.4% were female. In the propensity score matched analysis, mortality was 53.5% among patients receiving multivitamins and 66.2% among patients not receiving multivitamins, resulting in a relative risk for mortality of 0.81 (p = 0.03) for patients receiving multivitamins. CONCLUSION: Early multivitamin supplementation was associated with lower overall mortality. Further research on the impact of micronutrient supplementation in EVD is warranted.

Pharmacokinetics of TKM-130803 in Sierra Leonean patients with Ebola virus disease: plasma concentrations exceed target levels, with drug accumulation in the most severe patients.

BACKGROUND: TKM-130803 is a specific anti-EBOV therapeutic comprised of two small interfering RNAs (siRNA) siLpol-2 and siVP35-2. The pharmacokinetics (PK) of these siRNAs was defined in Ebola virus disease (EVD) patients, with reference to efficacy (ET) and toxicology thresholds (TT). The relationship between PK and patient survival was explored. METHODS: Pharmacokinetic (PK) and pharmacodynamic (PD) data were available for seven participants with EVD in Sierra Leone who received 0·3 mg/kg of TKM-130803 by intravenous infusion over 2 h daily for up to 7 days. Plasma concentration of siRNA was compared to survival at 14 days. PK data were fitted to two-compartment models then Monte Carlo simulated PK profiles were compared to ET (Cmax 0·04-0·57 ng/mL and mean concentration 1·43 ng/mL), and TT (3000 ng/mL). FINDINGS: Viral loads (VL) were not significantly different at treatment onset or during treatment (p = 0·1) in subjects who survived or died. siRNA was in quantitative excess of virus genomes throughout treatment, but the 95% percentile exceeded TT. The maximum AUC for which the 95% percentile remained under TT was a continuous infusion of 0·15 mg/kg/day. Plasma concentration of both siRNAs were higher in subjects who died compared to subjects who survived (p<0·025 both siRNAs). INTERPRETATION: TKM-130803 was circulating in molar excess of circulating virus; a level considered needed for efficacy. Given extremely high viral loads it seems likely that the patients died because they were physiologically beyond the point of no return. Subjects who died exhibited some indication of impaired drug clearance, justifying caution in dosing strategies for such patients. This analysis has given a useful insight into the pharmacokinetics of the siRNA in the disease state and illustrates the value of designing PKPD studies into future clinical trials in epidemic situations. FUNDING: This work was supported by the Wellcome Trust of Great Britain (grant number 106491/Z/14/Z and 097997/Z/11/A) and by the EU FP7 project PREPARE (602525). The PHE laboratory was funded by the UK Department for International Development. The funders had no role in trial design, data collection or analysis. The views expressed are those of the authors and not necessarily those of Public Health England, the Department of Health, or the EU. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201501000997429.

Association between multivitamin supplementation and mortality among patients with Ebola virus disease: an international multisite cohort study

Introduction: Micronutrient supplementation is recommended in Ebola Virus Disease (EVD) care; however, there is limited data on its therapeutic effects. Methods: This retrospective cohort study included patients with EVD admitted to five Ebola Treatment Units (ETU) in Sierra Leone and Liberia during September 2014 to December 2015. A uniform protocol was used to guide ETU care, however, due to supply limitations, only a subset of patients received multivitamins. Data on demographics, clinical characteristics, and laboratory testing was collected. The outcome of interest was facility based mortality and the primary predictor was multivitamin supplementation initiated within 48 h of admission. The multivitamin formulations included: thiamine, riboflavin, niacin and vitamins A, C, and D3. Propensity score models (PSM) were used to match patients based on covariates associated with multivitamin administration and mortality. Mortality between cases treated and untreated within 48 h of admission were compared using generalized estimating equations to calculate relative risk with bootstrap methods employed to assess statistical significance. Results: There were 424 patients with EVD who had sufficient treatment data for analysis, of which 261 (61.6%) had daily multivitamins initiated within 48 h of admission. The mean age of the cohort was 30.5 years and 59.4% were female. In the propensity score matched analysis, mortality was 53.5% among patients receiving multivitamins and 66.2% among patients not receiving multivitamins, resulting in a relative risk for mortality of 0.81 (p=0.03) for patients receiving multivitamins. Conclusion: Early multivitamin supplementation was associated with lower overall mortality. Further research on the impact of micronutrient supplementation in EVD is warranted

Vitamin A Supplementation Was Associated with Reduced Mortality in Patients with Ebola Virus Disease during the West African Outbreak.

BACKGROUND: Micronutrient supplementation is recommended in Ebola virus disease (EVD); however, there are limited data on therapeutic impacts of specific micronutrients. OBJECTIVE: To evaluate the association between vitamin A supplementation and mortality in EVD. METHODS: This retrospective cohort included patients with EVD admitted to 5 International Medical Corps Ebola Treatment Units (ETUs) in 2 countries during 2014-2015. Protocolized treatments with micronutrients were used at all ETUs: however, because of resource constraints, only a subset of patients received vitamin A. Standardized data on demographics, clinical characteristics, malaria status, and Ebola viral loads (cycle threshold values) were collected. The outcome of interest was mortality between cases treated with 200,000 IU of vitamin A on care days 1 and/or 2, and those not. Propensity scores based on the first 48 h of care were derived using covariates of age, ETU duration, malaria status, cycle threshold values, and clinical symptoms. Patients were matched 1:1 using nearest neighbors with replacement. Mortality between cases treated and not treated with vitamin A was compared using generalized estimating equations to calculate RR with associated 95% CI. RESULTS: There were 424 cases analyzed, of which 330 (77.8%) were treated with vitamin A. The mean age was 30.5 y and 40.3% were men. The most common symptoms were diarrhea (85.6%), anorexia (80.7%), and abdominal pain (76.9%). Mortality proportions among cases treated and not treated with vitamin A were 55.0% and 71.9%, respectively. In the propensity-matched analysis, mortality was significantly lower among cases receiving vitamin A (RR = 0.77, 95% CI: 0.59, 0.99; P = 0.041). In a subgroup analysis of patients treated with multivitamins already containing vitamin A, additional vitamin A supplementation did not impact mortality. CONCLUSION: Early vitamin A supplementation was associated with reduced mortality in patients with EVD, and should be further studied and considered for use in future epidemics.