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Ribavirin for the treatment of Lassa fever: A systematic review and meta-analysis

Open AccessPublished:July 26, 2019DOI:https://doi.org/10.1016/j.ijid.2019.07.015

      Highlights

      • The quality of evidence for the use of ribavirin is very low, stemming largely from a single non-randomized clinical trial with historic controls and high risk of bias.
      • Based on this trial patients with severe Lassa fever seem to benefit from ribavirin treatment.
      • Treatment of mild Lassa fever may lead to an increase in mortality.
      • Re-assessment of ribavirin in the treatment of Lassa fever is urgently required.

      Abstract

      Objectives

      Lassa fever (LF) causes annual outbreaks in endemic regions with high mortality of symptomatic patients. Ribavirin is recommended as standard treatment for LF in national and international guidelines but the evidence base for this recommendation has been questioned recently.

      Methods

      We conducted a systematic review and included 6 studies providing efficacy data of ribavirin treatment for LF (PROSPERO protocol CRD42018103994).

      Results

      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).

      Conclusions

      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.

      Keywords

      Background

      Lassa fever (LF) is a zoonotic disease associated with acute and potentially fatal haemorrhagic disease caused by Lassa virus (LASV), a member of the Arenaviridae virus family. It is endemic in several West African countries and occurs sporadically as well as in annual outbreaks (
      • Fichet-Calvet E.
      • Rogers D.J.
      Risk maps of Lassa fever in West Africa.
      ). Although LASV can be transmitted between humans, the majority of cases is thought to be transmitted by contact with urine or faeces of the widespread commensal rodent Mastomys natalensis. Mastomys erythroleucu and Hylomyscus pamfi might also play a role in disease transmission (
      • Mari Saez A.
      • Cherif Haidara M.
      • Camara A.
      • Kourouma F.
      • Sage M.
      • Magassouba N.
      • et al.
      Rodent control to fight Lassa fever: evaluation and lessons learned from a 4-year study in Upper Guinea.
      ).
      LF is estimated to cause up to 300,000 cases and 5,000 deaths per year in endemic regions of West Africa (
      • Günther S.
      • Lenz O.
      Lassa virus.
      ). In 2018 and 2019, Nigeria experienced a large increase in the number of cases during the endemic peak season, which are thought to be at least in part a result of increased awareness and intensified case detection measures (
      • Kafetzopoulou L.E.
      • Pullan S.T.
      • Lemey P.
      • Suchard M.A.
      • Ehichioya D.U.
      • Pahlmann M.
      • et al.
      Metagenomic sequencing at the epicenter of the Nigeria 2018 Lassa fever outbreak.
      ). However, despite improved diagnostic capacities for early detection and treatment, the absolute numbers of deaths and the overall case fatality rate (CFR) remain unsatisfactorily high.
      Clinically, LF is difficult to distinguish from other febrile illnesses endemic in West Africa (
      • Mertens P.E.
      • Patton R.
      • Baum J.J.
      • Monath T.P.
      Clinical presentation of Lassa fever cases during the hospital epidemic at Zorzor, Liberia, March–April 1972.
      ). Symptoms include fever, pharyngitis, gastrointestinal complaints, and cough. In later stages bleeding, facial oedema, convulsions, pericardial effusions and coma are commonly observed (
      • Ehichioya D.U.
      • Asogun D.A.
      • Ehimuan J.
      • Okokhere P.O.
      • Pahlmann M.
      • Olschlager S.
      • et al.
      Hospital-based surveillance for Lassa fever in Edo State, Nigeria, 2005–2008.
      ,
      • Knobloch J.
      • McCormick J.B.
      • Webb P.A.
      • Dietrich M.
      • Schumacher H.H.
      • Dennis E.
      Clinical observations in 42 patients with Lassa fever.
      ,
      • Monson M.H.
      • Cole A.K.
      • Frame J.D.
      • Serwint J.R.
      • Alexander S.
      • Jahrling P.B.
      Pediatric Lassa fever: a review of 33 Liberian cases.
      ,
      • Troup J.M.
      • White H.A.
      • Fom A.L.
      • Carey D.E.
      An outbreak of Lassa fever on the Jos plateau, Nigeria, in January–February 1970. A preliminary report.
      ). Although the CFR among hospitalised patients may exceed 50% during outbreaks, most cases remain mild or even asymptomatic (
      • Fraser D.W.
      • Campbell C.C.
      • Monath T.P.
      • Goff P.A.
      • Gregg M.B.
      Lassa fever in the Eastern Province of Sierra Leone, 1970–1972. I. Epidemiologic studies.
      ,
      • McCormick J.B.
      • Webb P.A.
      • Krebs J.W.
      • Johnson K.M.
      • Smith E.S.
      A prospective study of the epidemiology and ecology of Lassa fever.
      ,
      • Shaffer J.G.
      • Grant D.S.
      • Schieffelin J.S.
      • Boisen M.L.
      • Goba A.
      • Hartnett J.N.
      • et al.
      Lassa fever in post-conflict sierra leone.
      ). Underlying mechanisms for varying clinical courses of LF are unknown (
      • Khan S.H.
      • Goba A.
      • Chu M.
      • Roth C.
      • Healing T.
      • Marx A.
      • et al.
      New opportunities for field research on the pathogenesis and treatment of Lassa fever.
      ).
      In contrast to Ebola virus disease, there is currently no advanced vaccine candidate available (
      • Lukashevich I.S.
      • Paessler S.
      • de la Torre J.C.
      ). Treatment of LF is largely supportive and no antiviral drug has been approved by the United States Food and Drug Administration or the European Medicines Agency. Despite concerns regarding toxicity and lack of specificity, ribavirin (1-b-d-ribofuranosyl-1,2,4-triazole-3-carboxamide), a guanosine analogue that is active against a broad spectrum of DNA and RNA viruses has become an accepted off-label treatment for LF and is the recommended standard treatment for LF patients in national and international guidelines (
      • Bausch D.G.
      • Hadi C.M.
      • Khan S.H.
      • Lertora J.J.
      Review of the literature and proposed guidelines for the use of oral ribavirin as postexposure prophylaxis for Lassa fever.
      ,
      Nigeria centre for disease control. Viral haemorrhagic fevers preparedness and response plan.
      ,
      • World Health Organization
      Clinical management of patients with viral haemorrhagic fever: a pocket guide for front-line health workers: interim emergency guidance for country adaptation.
      ). These recommendations are however based largely on a single clinical trial, performed in Sierra Leone in 1986 by McCormick et al., which suggests a beneficial effect of ribavirin, especially when given within the first six days after onset of symptoms (
      • McCormick J.B.
      • King I.J.
      • Webb P.A.
      • Scribner C.L.
      • Craven R.B.
      • Johnson K.M.
      • et al.
      Lassa fever. Effective therapy with ribavirin.
      ). However, due to the non-specific nature of symptoms treatment initiation is often late and associated with adverse treatment outcome (
      • Shehu N.Y.
      • Gomerep S.S.
      • Isa S.E.
      • Iraoyah K.O.
      • Mafuka J.
      • Bitrus N.
      • et al.
      Lassa fever 2016 outbreak in plateau state, Nigeria-the changing epidemiology and clinical presentation.
      ). Furthermore, the mode of action of ribavirin in LF is still unclear. It efficiently suppresses the replication of LASV in vitro but showed only moderate efficacy in reducing viremia in vivo (
      • Bausch D.G.
      • Hadi C.M.
      • Khan S.H.
      • Lertora J.J.
      Review of the literature and proposed guidelines for the use of oral ribavirin as postexposure prophylaxis for Lassa fever.
      ,
      • Oestereich L.
      • Rieger T.
      • Lüdtke A.
      • Ruibal P.
      • Wurr S.
      • Pallasch E.
      • et al.
      Efficacy of favipiravir alone and in combination with ribavirin in a lethal, immunocompetent mouse model of Lassa fever.
      ). Instead, ribavirin was found to protect infected cells from cell-death, thereby significantly reducing the circulation of cell damage markers such as aspartate aminotransferase (AST) rather than suppressing viral transmission, viral production, or enhancing the host’s immune response in animal models (
      • Carrillo-Bustamante P.
      • Nguyen T.H.T.
      • Oestereich L.
      • Günther S.
      • Guedj J.
      • Graw F.
      Determining Ribavirin’s mechanism of action against Lassa virus infection.
      ). Particularly, a viral load “plateau” in mice was observed by Carrillo-Bustamante et al., which could be explained by the resulting longer survival of infected cells when treated with ribavirin, allowing for more viral production.
      Based on these data, the recommendation of ribavirin has been increasingly questioned by international experts and the World Health Organization (WHO) (
      • World Health Organization
      Efficacy trials of Lassa Therapeutics: endpoints, trial design, site selection.
      ). To address these concerns, additional data of the original prospective trial by McCormick et al. were released in March 2019 and a re-analysis was performed by independent experts. (

      Final Report Analysis of a Clinical Trial Ribavirin and the Treatment of Lassa Fever. report, 7 February 1992, SUBJECT: IND 16666 - Ribavirin (Virazole) (Serial No. 011); 1992. Available from: https://isaric.tghn.org/ribavirin-and-treatment-lassa-fever/final-report-analysis-clinical-trial-ribavirin-and-treatment-lassa-fever-7-february-1992/. [Accessed 10 May 2019].

      ,
      • Ludwig G.V.
      On behalf of Major General Holcomb.
      )
      Given the significant threat to public health in West Africa, the constant risk of spread from endemic regions and the absence of approved drugs or vaccines, the WHO has listed LF as a priority disease for urgent research and development (
      • Mehand M.S.
      • Al-Shorbaji F.
      • Millett P.
      • Murgue B.
      The WHO R&D Blueprint: 2018 review of emerging infectious diseases requiring urgent research and development efforts.
      ). The recently released revised results of the only clinical trial provide the opportunity to re-evaluate objectively the efficacy of ribavirin for the treatment of patients with LF in the context of other published evidence of ribavirin for LF. This systematic review contributes to LF research by summarizing all currently available evidence on the efficacy of ribavirin for the treatment of patients with LF by pooling all available studies.

      Methods

      Search strategy and selection criteria

      This study was performed as a systematic review and meta-analysis of all published and available evidence providing information on the efficacy of intravenous ribavirin for the treatment of LF. All randomised clinical trials, non-randomised studies, cohort studies, case-control studies, and case series with a minimum of 10 LF cases were considered for this systematic review. No restriction on the age of patients, publication date, language, or publication status was applied for the inclusion of respective studies. This systematic review was conducted following the PRISMA guidelines and the protocol was registered with PROSPERO (PRISMA checklist: Supplementary Fig. S1, PROSPERO protocol number: CRD42018103994). Articles were identified between February 2019 and March 2019 by electronic searches of PubMed, CINAHL, Science Citation Index Expanded, and Emerging Sources Citation Index, using “(lassa) NOT lassa[Author]” as search term and by checking bibliographies of included studies. Two investigators performed the literature search independently and discrepancies were resolved by discussion and consensus. Additionally, Conference Proceedings Citation Index-Science, ClinicalTrials.gov, and EU Clinical Trials Register were searched to identify currently ongoing and not yet published trials. Experts in the field were contacted to request information about grey literature. PROSPERO and the Cochrane Library were checked for similar systematic reviews.

      Data extraction and analysis

      Data from included studies were extracted independently by the first two authors. Discussion of discrepancies and consultation of the last author led to a complete dataset for analysis. The variable extracted was CFR according to treatment with or without intravenous ribavirin. Risk of bias of individual studies was assessed using the ROBINS-I tool (
      • Sterne J.A.
      • Hernán M.A.
      • Reeves B.C.
      • Savović J.
      • Berkman N.D.
      • Viswanathan M.
      • et al.
      ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions.
      ). The certainty of evidence was determined using the GRADE approach and the GRADEpro GDT software (GRADEpro Guideline Development Tool, McMaster University, 2015) (
      • Schünemann H.
      • Jan B.
      • Gordon G.
      • Andrew O.
      Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach.
      ).
      Odds ratios (OR) with their 95% confidence intervals (CI) for dichotomous outcome measures were obtained using Mantel–Haenszel random effects models. Heterogeneity was assessed by visual inspection of forest plots and quantified by the statistic. Meta-analyses and forest plots were computed using the RevMan software (Review Manager Version 5.3, Copenhagen, 2014).

      Results

      We identified 2934 records from electronic literature search and two further references by contacting experts in the field (Figure 1). From these, we counted 1984 unique references after removing duplicates. We further removed 1746 references with results of in vitro or animal models only, reviews without patient data, or studies focussing on other diseases than LF by screening of titles. We screened abstracts of 238 records and considered 193 references to be irrelevant for our review (narrative reviews, editorials, studies covering fewer than ten clinical cases, no mortality rates reported according to intravenous ribavirin use). 45 full-text articles were considered for inclusion, of which we excluded 39 at the full-text screening stage because subjects were overlapping with other reports already included in the meta-analysis or of similar reasons as above (Supplementary Table S1). We included 6 studies in our systematic review and meta-analysis (Table 1, Supplementary Table S2).
      Figure 1
      Figure 1PRISMA Flow chart of study selection.
      Table 1Characteristics of studies included in the systematic review.
      StudyStudy typeCountryNumber of LF positive patientsCFR in %
      • Ajayi N.A.
      • Nwigwe C.G.
      • Azuogu B.N.
      • Onyire B.N.
      • Nwonwu E.U.
      • Ogbonnaya L.U.
      • et al.
      Containing a Lassa fever epidemic in a resource-limited setting: outbreak description and lessons learned from Abakaliki, Nigeria (January–March 2012).
      )
      Retrospective cohort studyNigeria1040
      • Asogun D.A.
      • Adomeh D.I.
      • Ehimuan J.
      • Odia I.
      • Hass M.
      • Gabriel M.
      • et al.
      Molecular diagnostics for Lassa fever at Irrua specialist teaching hospital, Nigeria: lessons learnt from two years of laboratory operation.
      )
      Retrospective cohort studyNigeria19831
      • Buba M.I.
      • Dalhat M.M.
      • Nguku P.M.
      • Waziri N.
      • Mohammad J.O.
      • Bomoi I.M.
      • et al.
      Mortality among confirmed Lassa fever cases during the 2015–2016 outbreak in Nigeria.
      )
      Retrospective cohort studyNigeria4760
      • Dahmane A.
      • van Griensven J.
      • Van Herp M.
      • Van den Bergh R.
      • Nzomukunda Y.
      • Prior J.
      • et al.
      Constraints in the diagnosis and treatment of Lassa Fever and the effect on mortality in hospitalized children and women with obstetric conditions in a rural district hospital in Sierra Leone.
      )
      Retrospective cohort studySierra Leone3661
      • Shaffer J.G.
      • Grant D.S.
      • Schieffelin J.S.
      • Boisen M.L.
      • Goba A.
      • Hartnett J.N.
      • et al.
      Lassa fever in post-conflict sierra leone.
      )
      Retrospective cohort studySierra Leone19069
      U.S. Centers for Disease Control and Sierra Leone Ministry of Health Studies, 1992Prospective clinical trialSierra Leone185318

      Efficacy of ribavirin for the treatment of LF

      We identified five retrospective cohort studies with 372 participants (
      • Ajayi N.A.
      • Nwigwe C.G.
      • Azuogu B.N.
      • Onyire B.N.
      • Nwonwu E.U.
      • Ogbonnaya L.U.
      • et al.
      Containing a Lassa fever epidemic in a resource-limited setting: outbreak description and lessons learned from Abakaliki, Nigeria (January–March 2012).
      ,
      • Asogun D.A.
      • Adomeh D.I.
      • Ehimuan J.
      • Odia I.
      • Hass M.
      • Gabriel M.
      • et al.
      Molecular diagnostics for Lassa fever at Irrua specialist teaching hospital, Nigeria: lessons learnt from two years of laboratory operation.
      ,
      • Buba M.I.
      • Dalhat M.M.
      • Nguku P.M.
      • Waziri N.
      • Mohammad J.O.
      • Bomoi I.M.
      • et al.
      Mortality among confirmed Lassa fever cases during the 2015–2016 outbreak in Nigeria.
      ,
      • Dahmane A.
      • van Griensven J.
      • Van Herp M.
      • Van den Bergh R.
      • Nzomukunda Y.
      • Prior J.
      • et al.
      Constraints in the diagnosis and treatment of Lassa Fever and the effect on mortality in hospitalized children and women with obstetric conditions in a rural district hospital in Sierra Leone.
      ,
      • Shaffer J.G.
      • Schieffelin J.S.
      • Grant D.S.
      • Goba A.
      • Momoh M.
      • Kanneh L.
      • et al.
      Data set on Lassa fever in post-conflict Sierra Leone.
      ) and one prospective clinical trial with 894 participants meeting our inclusion criteria (

      Final Report Analysis of a Clinical Trial Ribavirin and the Treatment of Lassa Fever. report, 7 February 1992, SUBJECT: IND 16666 - Ribavirin (Virazole) (Serial No. 011); 1992. Available from: https://isaric.tghn.org/ribavirin-and-treatment-lassa-fever/final-report-analysis-clinical-trial-ribavirin-and-treatment-lassa-fever-7-february-1992/. [Accessed 10 May 2019].

      ). Doses of intravenous ribavirin treatment varied slightly between studies (Supplementary Table S3). The length of follow-up was not specified but most studies relied upon discharge from hospital as the primary endpoint.
      In the pooled analysis of the included retrospective studies, 104 fatalities occurred in 272 individuals receiving parenteral ribavirin versus 83 deaths in 100 patients not receiving ribavirin (Figure 2). Despite the presence of a moderate heterogeneity, the synthesis demonstrates that patients who died were more often not treated with ribavirin (OR 0.13, 95% CI 0.04–0.40,  = 55%). However, patients in all studies were retrospectively allocated into analysis groups based on whether ribavirin treatment was initiated or not. This procedure included late presenting patients dying before treatment with ribavirin could be initiated, leading to a critical risk for bias of these reports by overestimating the treatment effect of ribavirin and therefore to a very low certainty of evidence (Supplementary Tables S4 and S5).
      Figure 2
      Figure 2Forest plot of retrospective cohort studies evaluating the efficacy of intravenous ribavirin versus no ribavirin on the outcome mortality in patients with Lassa fever.
      Only one prospective clinical trial was identified evaluating the efficacy of ribavirin for the treatment of LF. The original publication of this trial by McCormick et al. provided results of patients with elevated transaminases only (
      • McCormick J.B.
      • King I.J.
      • Webb P.A.
      • Scribner C.L.
      • Craven R.B.
      • Johnson K.M.
      • et al.
      Lassa fever. Effective therapy with ribavirin.
      ). Instead of randomizing patients to treatment or control arm, the authors made use of data from a historic cohort as control group and pooled data from treatment groups that were judged not having an effect in retrospect. It remains unclear how participants were selected and allocated in the respective groups for analysis. Furthermore, randomization of participants in the treatment arm to distinct treatment options was unreliable. During the course of the clinical trial, important deviations from the study protocol occurred: distinct treatment groups were joined and patients with normal AST level were recruited to a lower extent apparently following an interim analysis. Because of these shortcomings of the original report, an extended version of the study data was recently made publicly available covering outcomes of all study participants from the original prospective clinical trial (

      Final Report Analysis of a Clinical Trial Ribavirin and the Treatment of Lassa Fever. report, 7 February 1992, SUBJECT: IND 16666 - Ribavirin (Virazole) (Serial No. 011); 1992. Available from: https://isaric.tghn.org/ribavirin-and-treatment-lassa-fever/final-report-analysis-clinical-trial-ribavirin-and-treatment-lassa-fever-7-february-1992/. [Accessed 10 May 2019].

      ). Subgroup analysis according to AST level of this newly released data demonstrates that mortality was reduced for patients of this trial presenting with elevated AST level when treated with ribavirin versus not being treated with ribavirin (OR 0.41, 95% CI 0.23–0.73). However, ORs for mortality were higher in LF patients without elevated transaminases at presentation when receiving ribavirin versus not being treated with ribavirin (OR 2.37, 95% CI 1.07–5.25, Figure 3). However, despite the provided additional results, this extended data version of the original trial has critical risk of bias due to missing data, misclassifications of participants to non-LF patients, and unreliable randomization and treatment allocation procedures (Supplementary Tables S4 and S5).
      Figure 3
      Figure 3Forest plot of a prospective clinical trial evaluating the efficacy of intravenous ribavirin versus no ribavirin according to AST level on the outcome mortality in patients with Lassa fever.

      Discussion

      This systematic review reveals two main findings. First, although LF was discovered 50 years ago and despite the high local burden and the constant risk of spread to non-endemic regions, treatment options are still very limited. International guidelines recommending therapy with ribavirin are based largely on evidence stemming from the original report of a single prospective clinical trial and a few available retrospective cohort studies. As shown in the assessment of this study, this report suffers from serious limitations. The clinical trial was apparently not conducted following the original study protocol as criteria for recruitment into the trial were modified following interim analysis. Importantly, this study was not a properly randomized controlled clinical trial as the comparator group was constituted retrospectively combining treatment groups with heterogeneous baseline characteristics and groups with different interventions. Notably, the comparator group was not recruited at the same time as the active treatment group but was rather a historic control. This opens the risk for bias due to improvement of supportive care during the study, which is known to be associated with an improved survival of patients with LF. In summary the assessment of the only prospective clinical trial reveals evidence of very low certainty due to critical limitations in the conduct, analysis and reporting of the clinical trial. Likewise, retrospective studies included in this review were assessed as having critical risk of bias. This limitation stems on the one hand from their retrospective study design and from methodological limitations in the analysis of the patient data by not taking into account the preferential allocation of severely ill and late presenting patients into the comparator group when death occurs prior to ribavirin treatment initiation. In analogy to other viral diseases such as Crimean–Congo hemorrhagic fever or influenza, late treatment initiation may not have a measurable impact on disease outcome, underlining the importance of early treatment initiation in viral infections in general. In agreement with a recent WHO expert meeting, this analysis therefore concludes that current international and national treatment guidelines recommending ribavirin treatment for all patients with LF lacks solid evidence (
      • World Health Organization
      Efficacy trials of Lassa Therapeutics: endpoints, trial design, site selection.
      ).
      Second, the recently released additional data and re-analysis of the prospective trial data unravel some new and highly important aspects on ribavirin treatment of patients with LF. Whereas ribavirin therapy was associated with a reduced mortality in LF patients with high levels of AST in this trial, patients with normal levels of transaminases had higher ORs for a fatal disease outcome when treated with intravenous ribavirin compared to patients receiving supportive therapy only (

      Final Report Analysis of a Clinical Trial Ribavirin and the Treatment of Lassa Fever. report, 7 February 1992, SUBJECT: IND 16666 - Ribavirin (Virazole) (Serial No. 011); 1992. Available from: https://isaric.tghn.org/ribavirin-and-treatment-lassa-fever/final-report-analysis-clinical-trial-ribavirin-and-treatment-lassa-fever-7-february-1992/. [Accessed 10 May 2019].

      ,
      • Ludwig G.V.
      On behalf of Major General Holcomb.
      ). This finding contradicts current treatment recommendations and medical practice in endemic regions encouraging the use of ribavirin even for mild cases (
      • Okokhere P.
      • Colubri A.
      • Azubike C.
      • Iruolagbe C.
      • Osazuwa O.
      • Tabrizi S.
      • et al.
      Clinical and laboratory predictors of Lassa fever outcome in a dedicated treatment facility in Nigeria: a retrospective, observational cohort study.
      ). A potentially harmful effect of ribavirin in LF patients without elevated AST levels is pathophysiologically conceivable as ribavirin apparently has little antiviral properties and may be associated with higher viraemia, which may be disadvantageous in mild cases of LF (
      • Carrillo-Bustamante P.
      • Nguyen T.H.T.
      • Oestereich L.
      • Günther S.
      • Guedj J.
      • Graw F.
      Determining Ribavirin’s mechanism of action against Lassa virus infection.
      ,
      • Oestereich L.
      • Rieger T.
      • Lüdtke A.
      • Ruibal P.
      • Wurr S.
      • Pallasch E.
      • et al.
      Efficacy of favipiravir alone and in combination with ribavirin in a lethal, immunocompetent mouse model of Lassa fever.
      ). This practice ultimately might in part contribute to the unsatisfactorily high CFR of LF despite improved diagnostic and treatment infrastructure.
      At the same time this finding raises important concerns for the role of ribavirin as post-exposure prophylaxis for LF. In this indication the risk benefit analysis may rather suggest withholding ribavirin based on the current evidence from mild LF cases. Future research should focus on the question of whether potentially harmful effects of ribavirin in patients without severe cell damage are caused by direct toxic effects, or by an increase in viral load due to enhanced survival of virus producing cells (
      • Carrillo-Bustamante P.
      • Nguyen T.H.T.
      • Oestereich L.
      • Günther S.
      • Guedj J.
      • Graw F.
      Determining Ribavirin’s mechanism of action against Lassa virus infection.
      ,
      • Gowen B.B.
      • Smee D.F.
      • Wong M.H.
      • Hall J.O.
      • Jung K.H.
      • Bailey K.W.
      • et al.
      Treatment of late stage disease in a model of arenaviral hemorrhagic fever: T-705 efficacy and reduced toxicity suggests an alternative to ribavirin.
      ). Randomised controlled trials are required to investigate the efficacy of ribavirin in different subgroups and indications and answer the question whether lower doses of ribavirin or shorter treatment durations could have similar properties of cell protection with at the same time a lower risk of unfavourable effects (
      • Khan S.H.
      • Goba A.
      • Chu M.
      • Roth C.
      • Healing T.
      • Marx A.
      • et al.
      New opportunities for field research on the pathogenesis and treatment of Lassa fever.
      ).
      In conclusion, the efficacy of ribavirin for treating Lassa fever is uncertain because of critical risk of bias in underlying studies. Recently released data from a prospective trial, originally published in 1986, suggest a beneficial effect in patients with severe forms of LF and a potentially harmful effect in patients with mild forms of the disease. Re-assessment of the benefit of ribavirin in the treatment of LF seems urgently required.

      Role of the funding source

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Conflict of interest statement

      All authors declare no conflict of interests.

      Acknowledgements

      The authors are thankful to the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) for obtaining the revised data of the prospective clinical trial “Final Report Analysis of a Clinical Trial Ribavirin and the Treatment of Lassa Fever” through a request under the U.S. Freedom of Information Act and making them publicly available.

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