Ribavirin and supportive care
Evaluation of Ribavirin
The primary treatment for LF is ribavirin, in conjunction with supportive care. Ribavirin is an antiviral used to treat RNA viruses, such as hepatitis C. While ribavirin has not been licenced for Lassa fever and despite a small evidence base, ribavirin has been included in national and international Lassa fever treatment guidelines.
A recent systematic review found that “Besides retrospective case series, the evidence mostly relies on a single prospective clinical trial with critical risk of bias. In this trial, LF associated mortality is reduced for patients with elevated aspartate aminotransferase (AST) when treated with ribavirin (OR 0.41, 95% CI 0.23-0.73), while mortality is higher for patients without elevated AST (OR 2.37, 95% CI 1.07-5.25).” and that “Based on the available data, current treatment guidelines may therefore put patients with mild LF at increased risk of death. The role of ribavirin in the treatment of LF requires urgent reassessment.
It is thus clear that we need to examine carefully the evidence base for ribavirin dosing regimens. We are addressing this by
- Conducting systematic reviews of non-clinical and clinical studies
- Reanalysis of existing data
- Conducting prospective observational cohort studies to measure ribavirin levels in humans and the effects of LF and ribavirin on cardiovascular functions
Supportive care remains the mainstay of treatment for all viral haemorrhagic fevers (VHFs), including Lassa fever. However, supportive care guidelines are limited, there is wide variation in supportive care delivery, as well as a knowledge gap around the components of supportive care which contribute to disparities in survival rates.
There are currently two activities being undertaken within ISARIC around supportive care for VHFs:
- A systematic review which asks the question: What constitutes best supportive care for VHFs? This project explores Clinical Management Guidelines (CMGs), Standard Operating Procedures (SOPs) and trial protocols and compares consensus and ambiguity in the definition of best supportive care for VHF. The next phase of this project will look at how guidelines are implemented in clinical practice.
- As part of the WALC project <link to WALC below>, Work Package 2 is exploring ways of standardizing supportive care for clinical trials. This work is being conducted through a systematic review to identify general (non-VHF-specific) guidelines that could be implemented for a trial and a consultation with a number of research stakeholders to assess the implementability and applicability of these guidelines to Lassa fever.
A systematic review of non-clinical evidence for ribavirin in Lassa fever
The reviews of ribavirin in Lassa fever suggest that there is an urgent need to re-evaluate ribavirin’s effect on outcomes in Lassa fever in a placebo-controlled trial. However, before embarking on expensive and logistically complex trials, it is worth reviewing the non-clinical data for ribavirin in Lassa to help design and inform such trials. We have carried a systematic review of the non-clinical evidence for ribavirin in Lassa fever compromising five different domains of evidence: In-vitro data, animal data, mechanism of action data, animal pharmacokinetic (PK), and Human PK data. Our review highlights several critical issues with the non-clinical evidence base for ribavirin, both in terms of efficacy and safety, which, together with concerns regarding the clinical data in humans, add extra credence to the proposition that the routine use of ribavirin in Lassa fever should be reconsidered. This study is currently in submission.
Evidence of ribavirin treatment for Lassa fever: a systematic review of published and unpublished studies
Few studies have systematically appraised the evidence for the use of ribavirin in Lassa fever. We conducted a systematic review of published and unpublished literature retrieved from electronic databases and grey literature from inception to October 2020. We identified 11 studies of the comparative effectiveness of ribavirin and no ribavirin treatment on mortality. Although ribavirin was associated with decreased mortality, results of these studies were at critical risk of bias when appraised using the ROBINS-I tool. Important risks of bias related to missing data, immortal time bias and lack of control for confounders. Robust evidence supporting the use of ribavirin in Lassa fever is lacking. Robust clinical trials to elucidate the effectiveness of ribavirin for Lassa fever are needed. This study is currently under review.
Ribavirin is the only available Lassa fever–specific treatment and has been used routinely for over 25 years. However, intravenous ribavirin is not licensed for Lassa fever. Its mechanism of action is unclear, it is expensive and hard to source, and it has well-known toxicities. The rationale for using ribavirin in Lassa fever is primarily based on one clinical study by McCormick et al conducted in Sierra Leone in the late 1970s and early 1980s, which reported a 5% mortality with the use of intravenous ribavirin in patients with a serum aspartate aminotransferase (AST) level of ≥150 IU/L relative to a mortality of 60% in controls. Serious limitations to the comparisons presented include the use of historic controls, inclusion of pregnant women in the control group but their exclusion from the ribavirin group (case fatality is around 2-fold higher in pregnant women than nonpregnant patients), and post hoc merging of treatment groups. Despite this and the fact that the results only supported the use of ribavirin in nonpregnant adult patients with AST ≥150 IU/L, this study is the basis upon which ribavirin is now used in all patients with Lassa fever, including children, pregnant women, and people with normal liver function. It has been well known among Lassa specialists that the McCormick study reports a subset of a much larger dataset assembled by the Lassa treatment unit in Sierra Leone and that a report on the full dataset was commissioned by the United States Army Medical Research and Development Command. We obtained this report and the available dataset through a freedom of information request and derived aggregated datasets containing the number of deaths according to treatment groups and individual characteristics. Ribavirin reduced mortality only in patients with serum AST ≥150 IU/L, with less benefit (OR 0.48 [95% CI 0.30 to 0.78]) than reported by McCormick and colleagues. However, ribavirin appeared to increase mortality in patients with serum AST <150 IU/L (2.90 [1.42 to 5.95]). In fact, in our analysis, the only stratum in which ribavirin appeared protective (0.38 [0.21 to 0.70]) was serum AST >300 IU/L. In the reconstructed analyses, ribavirin was associated with overall increased mortality (2.12 [1.67, 2.68]), although this was attenuated after adjustment for AST (1.48 [1.05, 2.08]). These findings suggest that ribavirin treatment may harm Lassa fever patients with AST <150 IU/L, and that there is a compelling case to re-evaluate the role of ribavirin in the care of patients with Lassa fever.
Ribavirin pharmacokinetics and pharmacodynamics in Lassa fever patients: a prospective observational cohort study
We are currently carrying out a prospective study of ribavirin PK and PD in Lassa fever patients at Federal Medical Centre Owo (FMCO) in Nigeria in collaboration with FMCO and the Alliance for International Medical Action (ALIMA) and INSERM. We have recruited 50 patients into the study. The study will aim to delineate the PK of ribavirin in Lassa fever patients as well as give insights into correlations between ribavirin concentrations, viral load, hepatic function and inflammatory gene expression. Work is ongoing in developing the methodology for measuring ribavirin and ribavirin metabolite concentrations.
Cardiovascular function in Lassa fever patients: a prospective observational cohort study
Lassa fever is widely reported to be complicated by shock secondary to endothelial dysfunction and vascular leak in a significant proportion of patients, with this being the main pathway to death in some. However, the evidence for this being the case in humans is very weak. We therefore carried out a prospective study of cardiovascular function in Lassa fever at FMCO in Nigeria in collaboration with FMCO, ALIMA and INSERM. We have recruited 97 Lassa confirmed patients into the study and data analysis is ongoing. We used multiple different modalities to assess cardiovascular function, including electrocardiograms, lung ultrasound, bedside endothelial function testing, and non-invasive cardiac function measurements. The data for the study is currently being analysed.