Lassa fever
Lassa fever is an acute viral haemorrhagic fever, which is endemic to parts of West Africa, including Nigeria, Sierra Leone, Guinea, and Liberia — though the regional risk of the virus likely extends further.
Surveillance of Lassa fever is challenging due to suboptimal availability of diagnostic tests (and no validated point-of-care pan-Lassa diagnostic test), need for capacity strengthening in laboratories and non-specific clinical presentation – making it particularly challenging to identify mild community cases, which it is estimated constitute approximately 80% of all infections. The true toll of Lassa fever infections could therefore be much higher than figures currently suggest – it is estimated that there are up to 500,000 new infections and 10,000 deaths per year across West Africa. The ‘Enable’ programme of the Coalition for Epidemic Preparedness Innovations (CEPI) is expected to provide useful information on the real incidence of LF in the region.
Symptoms of Lassa fever have often been described as non-specific and include fever, fatigue, muscle pains gastrointestinal symptoms and headache, making the disease difficult to discern from other illnesses. The estimated case fatality ratio varies widely. In hospitalised cases, the case fatality rate (CFR) has been reported between 24–27% overall and 34% for pregnant women, rising in the third trimester to 80% and 95% for the foetus. However, in a recent cohort study taking place in a research setting, the CFR for hospitalised cases was 13% for adults and 6% for children.
Ribavirin – although unlicensed – is the only treatment recommended for Lassa fever. This recommendation was based on a single clinical trial conducted in the 1980s, the results of which have since been re-evaluated and suggest potential harm in some cases. There is therefore an urgent need to re-evaluate ribavirin and investigate the novel therapeutic candidates that are currently progressing through the R&D pipeline and will likely be ready to undergo clinical testing in the near future.
ISARIC’s Response
We are committed to strengthening the evidence base for Lassa fever therapeutics and improving case management. Alongside a wide-range of partners and collaborators, we have conducted a number of activities to address these knowledge gaps, including:
- A systematic review of the clinical profile of Lassa fever patients
- Developing an efficient clinical design
- Identifying appropriate endpoints
- Trial site preparation
- Reassessment of ribavirin for Lassa fever treatment
- Developing a target product profile for Lassa fever therapies
- Creating a general roadmap and value proposition to develop, test, register and make new and better treatments available and affordable
Characterising disease
Historically, Lassa fever has been known to manifest in a number of general, non-specific symptoms, which make it difficult to discern from other illnesses and identify important patient outcomes that could be used as endpoints in clinical trials.
To synthesise the existing literature and better understand the presentation and evolution of Lassa fever over the course of illness and treatment, ISARIC researchers conducted a systematic review of published reports describing Lassa fever signs and symptoms and patient outcomes.
Our review corroborates the current characterisation of Lassa fever, but also highlights a broader range of other symptoms that characterise the illness, such as nervous system and musculoskeletal disorders that are not commonly included as indicators of Lassa fever. These findings, however, should be tempered by the lack of systematic assessment and reporting of presenting signs and symptoms, their evolution following treatment, and outcomes at discharge in the historic literature. It is therefore evident that a standardised set of data variables and outcome measures should be developed and incorporated into future trials and reported to accelerate collective knowledge.
Read our systematic review that identifies the clinical characteristics and outcomes of Lassa fever.
Improving Treatment
The primary treatment for Lassa fever is ribavirin in conjunction with supportive care. This recommendation is largely based on the results of a single prospective clinical trial that was conducted in the 1980s, which has since generated concern about its methods, analysis and safety when used to treat mild cases of Lassa fever. Although ribavirin is commonly used to treat Lassa fever, it is not licensed for this indication. No further clinical trials evaluating ribavirin or new therapeutics have been conducted in the subsequent 40 years.
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 the evidence base for ribavirin dosing regimens needs to be carefully examined. We have addressed 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
- A systematic review of supportive care guidelines
A systematic review of non-clinical evidence for ribavirin in Lassa fever
The existing 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.
Read more: A systematic review of pre-clinical studies and implications for human dosing
A systematic review of published and unpublished studies of ribavirin for the treatment of Lassa fever
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.
A reanalysis of ribavirin trial data
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.
Read more: Time to reconsider the role of ribavirin in 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 are currently being analysed.
Developing methodologies
With the input of a broad range of stakeholders coordinated through the West Africa Lassa fever Consortium (WALC), we have developed a roadmap for a regionally-owned, end-to-end approach towards developing, testing and making available therapies for Lassa fever, adopting a public health-driven portfolio approach to select and deliver the most promising options in an efficient way.
The project focused on understanding knowledge gaps, evaluating evidence for treatment, and generating the methodologies and tools on which future clinical trials can be built and treatments approved and made available and affordable to those in need. There were five key areas of investigation:
- Understanding the regulatory pathways to implement new trials and license treatments
- Designing an adaptive platform trial that could evaluate multiple therapeutics
- Evaluating capacity needs for potential trial sites
- Developing a Target Product Profile (TPP) for novel therapeutics
- Developing a value proposition to ensure new licensed products are made affordable and accessible to those who need them
Our partners
This work was supported by Wellcome.
Removing barriers
Value proposition
As one of the five work packages of the WALC project, we lay out a value proposition to realise the vision of an end-to-end framework for the development, manufacturing, and availability in Lassa fever-endemic countries of effective drugs for Lassa fever, for which a traditional economic business model will not work.
Such a framework must overcome operational challenges with clinical trials, maximize the chance of successfully delivering effective treatments in the fastest and most cost-effective way, mobilize adequate financing of R&D and equitable access.
This approach has four essential building blocks:
1) West African leadership;
2) A portfolio approach to drug development and clinical trials;
3) A clinical trial platform (infrastructure and capabilities) as the core asset, and
4) An end-to-end approach that links all partners along the value chain of drug development, testing, registration, production up to equitable access for patients.
Publications
Final Report – Analysis of a Clinical Trial: Ribavirin and The Treatment Of Lassa Fever
This is a copy of the Report Analysis of a Clinical Trial for Ribavirin and the Treatment of Lassa Fever. The data were collected by the US Centers for Disease Control under their IND 17186. Learn more
Clinical characterization of Lassa fever: a systematic review of clinical reports and research to inform clinical trial design
Research is urgently needed to reduce the morbidity and mortality of Lassa fever (LF), including clinical trials to test new therapies and to verify the efficacy and safety of the only current treatment recommendation, ribavirin, which has a weak clinical evidence base. To help establish a basis for the development of an adaptable, standardised clinical trial methodology, we conducted a systematic review to identify the clinical characteristics and outcomes of LF and describe how LF has ... Learn more
News
Time to reconsider the role of ribavirin in Lassa fever
Ribavirin is the only available Lassa fever–specific treatment and has been used routinely for over 25 years. However, 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.
Activities
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