Pharmacokinetics of Ribavirin in the Treatment of Lassa Fever: An Observational Clinical Study at the Irrua Specialist Teaching Hospital, Edo State, Nigeria.

BACKGROUND: Lassa fever is endemic in large parts of West Africa. The recommended antiviral treatment is ribavirin. Two treatment regimens are currently endorsed in Nigeria: the "McCormick regimen" based on a study published in 1986 and the "Irrua regimen" constituting a simplified schedule developed at the Irrua Specialist Teaching Hospital, Nigeria. Evidence for the safety and efficacy of ribavirin in Lassa fever patients is poor and pharmacokinetic data for both regimens are lacking. METHODS: Polymerase chain reaction-confirmed Lassa fever patients with mild to moderate disease severity were invited to participate in this prospective, observational pharmacokinetic study. Pharmacokinetics of ribavirin, clinical, virologic, and clinical laboratory parameters were assessed. RESULTS: Using a population pharmacokinetic approach, plasma concentrations of ribavirin were best described by a 3-compartment model. Drug exposure was remarkably consistent between participants. Overall, drug clearance was 28.5% lower in female compared with male participants. Median (5th-95th percentile) time above half maximal inhibitory concentration (IC50) was 37.3% (16.9%-73.1%), 16.7% (8.2%-58.5%), and 9.6% (4.9%-38.4%) on days 1, 7, and 8, respectively. Clinical laboratory parameters indicated reduction of cell damage and development of hemolytic anemia in the course of the treatment period. CONCLUSIONS: This observational study characterizes the pharmacokinetics of ribavirin in the treatment of Lassa fever indicating consistent exposure across patients. Whereas only a short time interval of concentrations above the IC50 implies rather low antiviral efficacy in vivo, the prominent reduction of cell damage markers might point to indirect-potentially anti-inflammatory-effects of ribavirin. The role of ribavirin in the treatment of Lassa fever requires further scrutiny.

Psychiatric manifestations and associated risk factors among hospitalised patients with COVID-19 in Edo State, Nigeria: a cross-sectional study.

OBJECTIVE: To estimate the prevalence of depression and anxiety and identify associated risk factors in hospitalised persons with confirmed COVID-19 in Edo, Nigeria. DESIGN: A multicentre cross-sectional survey. SETTING: Patients with COVID-19 hospitalised at the three government-designated treatment and isolation centres in Edo State, Nigeria. PARTICIPANTS: The study was conducted from 15 April to 11 November 2020 among 489 patients with confirmed COVID-19 and in treatment and isolation centres in Edo State, Nigeria. The mean age of participants was 43.39 (SD=16.94) years. Male participants were 252 (51.5%) and female were 237 (48.5%). MAIN OUTCOME MEASURES: The nine-item Patient Health Questionnaire for depression, (total score: 0-27, depression ≥10), Generalized Anxiety Disorder-7 for anxiety (total score: 0-21, anxiety ≥10), and social demographic and clinical characteristics for associated risk factors. RESULTS: Of the 489 participants, 49.1% and 38.0% had depressive and anxiety symptoms, respectively. The prevalence rates of depression, anxiety and combination of both were 16.2%, 12.9% and 9.0%, respectively. Moderate-severe symptoms of COVID-19, ≥14 days in isolation, worrying about the outcome of infection and stigma increased the risk of having depression and anxiety. Additionally, being separated/divorced increased the risk of having depression and having comorbidity increased the risk of having anxiety. CONCLUSION: A substantial proportion of our participants experienced depression, anxiety and a combination of both especially in those who had the risk factors we identified. The findings underscore the need to address modifiable risk factors for psychiatric manifestations early in the course of the disease and integrate mental health interventions and psychosocial support into COVID-19 management guidelines.

Prospective observational study on the pharmacokinetic properties of the Irrua ribavirin regimen used in routine clinical practice in patients with Lassa fever in Nigeria.

INTRODUCTION: Lassa fever (LF) is a severe and often fatal systemic disease in humans and affects a large number of countries in West Africa. Treatment options are limited to supportive care and the broad-spectrum antiviral agent ribavirin. However, evidence for ribavirin efficacy in patients with LF is poor and pharmacokinetic (PK) data are not available.Irrua Specialist Teaching Hospital (ISTH) developed an intravenous ribavirin regimen different to the WHO recommendation. Apart from a lower total daily dose the drug is usually administered once per day which reduces the exposure of personnel to patients with LF. The aim of this study is to characterise the PK of the Irrua ribavirin regimen. METHODS AND ANALYSIS: This prospective, observational clinical study will assess PK properties of the Irrua ribavirin regimen on routinely ribavirin-treated patients with LF at ISTH, a referral hospital serving 19 local governmental areas in a LF endemic zone in Nigeria. Participants will be adults with PCR-confirmed LF. The primary objective is to describe classical PK parameters for ribavirin (maximum plasma drug concentration, time to maximum plasma drug concentration, area under the plasma drug concentration vs time curve, half-life time T1/2, volume of distribution). Blood samples will be collected at 0.5, 1, 3, 5, 8, 12 and 24 hours after doses on day 1, day 4 and day 10 of ribavirin treatment. Ribavirin plasma concentrations will be determined using liquid chromatography coupled to tandem mass spectrometry. ETHICS AND DISSEMINATION: The study will be conducted in compliance with the protocol, the Declaration of Helsinki, Good Clinical Practice (GCP) and the Nigerian National Code for Health Research Ethics. The protocol has received approval by the Health Research Ethics Committee of ISTH. Results will be made available to LF survivors, their caregivers, the funders, LF research society and other researchers. REGISTRATION DETAILS: ISRCTN11104750.