Controversies’ clarification regarding ribavirin efficacy in measles and coronaviruses: Comprehensive therapeutic approach strictly tailored to COVID-19 disease stages

ARTICLE HIGHLIGHTS

Research background

Ribavirin is a broad-spectrum nucleoside antiviral drug that despite it has been widely used clinically for almost five decades, evidence regarding its efficacy in viral infections remains conflicting. Ribavirin use has only been established in chronic hepatitis C virus infection, chronic hepatitis E virus infection in transplant recipients, respiratory syncytial virus in children, and some of the viral hemorrhagic fever viruses. Ribavirin was widely utilized alone, or in combination with other compounds in severe acute respiratory syndrome (SARS), Middle-East respiratory syndrome (MERS), and coronavirus disease 2019 (COVID-19) outbreaks. Despite the large amount of data however, the conclusions of all three coronaviruses studies concerning ribavirin efficacy have been contradictory. The present review article aims to clarify the underlying reasons for these discrepancies including possible study design inaccuracies and failures, misinterpretations of data, and to address these potential confounds. Moreover, the possible role of ribavirin in COVID-19 therapeutic schemes is thoroughly studied.

Research motivation

COVID-19 pandemic has emerged as a global health issue with the highest significance and is currently the number one priority for scientists worldwide. During the 2018 measles outbreak, we hospitalized a number of adult cases suffering measles pneumonitis and treated them with Ribavirin (RBV). Because of the lack of specific guidelines on severe measles disease treatment in adults, we reviewed the literature on RBV dosing regimens and outcomes in any infectious disease. The most amount of clinical data available was for SARS and MERS, where RBV was widely utilized. While preparing the measles/RBV study for publication, the new COVID-19 outbreak emerged, prompting us to focus heavily on COVID-19 treatment with RBV alone or in combination with other compounds.

Research objectives

To shed light in and clarify the confounding factors of ribavirin treatment studies regarding SARS, MERS, and COVID 19 and to propose a therapeutic scheme for COVID-19 that would be tailored to its distinct disease stages.

Research methods

A meticulous electronic search of PubMed database was performed covering a period of over five decades up to October 15, 2020 using the terms “ribavirin”, “treatment” in combination with “measles”, “SARS”, “MERS”, and “COVID-19”. All review articles referring to COVID-19 treatment were searched and studied, regardless of whether “ribavirin” was included in key words. In vitro, animal and clinical studies, reviews, and meta-analyses in English language only were considered for data extraction. The citations in each article were reviewed to locate additional references that were not retrieved during the initial search. Eligible to be included in the review were those studies referring to RBV treatment alone or in combination and/or those reporting on its dose regimens, adverse effects, or outcomes. The literature search was performed and described with respect to PRISMA guidelines.

Research results

A total of 32 severe acute respiratory syndrome-associated coronavirus studies, 18 Middle East respiratory syndrome coronavirus studies, and 17 severe acute respiratory syndrome-2 associated coronavirus studies were considered eligible to be included in this review. The burden of designing and conducting well-organized, double-blind, randomized controlled trials under the difficulties and pressures of an emerging pandemic is obvious. Hence, many of those studies succumbed to specific pitfalls that resulted in conflicting evidence regarding the clinical efficacy of ribavirin for coronaviruses infections. We detected six pitfalls that were carefully identified and described in this review and comprise: utilization of naturally ribavirin-resistant Vero cell lines in in vitro studies; study design inconsistent with the well-established clinical course of disease (i.e., antiviral administration late in the disease course or early use of corticosteroids); inappropriate pharmacology of applied treatments (i.e. dosing regimens, treatment duration); and misinterpretation of study results with misconceived generalizations. Considering all those studies with their pitfalls and mostly taking into account those with statistically significant outcomes, we concluded to a comprehensive treatment for COVID-19 documented by thorough, long-term investigation of ribavirin regimens in coronavirus infections which is strictly tailored to distinct disease stages.

Research conclusions

COVID-19 behaves like a bipolar disease being an asymptomatic or mild, self-limiting viral respiratory tract infection with the majority of patients recovering without sequelae on the one hand, and on the other it may progress to a severe pneumonitis with a deadly systematic auto-inflammatory disease component. Documented by accumulated data from the three coronaviruses studies and considering the six identified pitfalls to which most of the studies fall victim, the early antiviral treatment is crucial for reducing viral load, transmission, and preventing disease progression to severity. Interferon-β + Ribavirin + Lopinavir/ritonavir should be commenced as early as possible after disease onset resulting in an effective reduction of viral load and subsequent deterrence of disease progress, reduction of virus shedding, and thus reducing the risk of secondary transmission, therefore acting as a prophylaxis. This approach could target selected patients, as specific age groups (older than 50 years) present severe morbidity and mortality, as well as younger patients with well-recognized independent risk factors for severe illness and increased mortality. The remarkable advantage of this therapeutic regimen is that it can be applied on an outpatient basis with the patient at home in quarantine. On the other hand, corticosteroids and anti-interleukin monoclonal antibodies (tocilizumab or anakinra) should be used for severe pneumonitis and for systemic hyperinflammation syndrome with cytokine storm and possible occurrence of secondary hemophagocytic lymphohistiocytosis. Corticosteroids in COVID-19 comprise dexamethasone 6 mg/d as previously shown to reduce mortality; methylprednisolone 250 mg intravenously on day 1, 80 mg on days 2–5 and escalation of immunosuppressive treatment with a monoclonal antibody directed against the interleukin-6 receptor (tocilizumab) when respiratory status worsens; a third corticosteroid treatment proposal being the most tested and effective in SARS and MERS studies includes high-dose steroids with pulsed methylprednisolone at a dose of 0.5-1. 0 g/d for 2-3 d or for a total of 3 g. Finally, regarding measles pneumonitis, ribavirin seems an adequate treatment at a dose of 600 mg for 5-7 d, but in cases of hematological malignancies, or severely immunosuppressed patients, a longer regimen of 2-3 wk may be required.

Research perspectives

It is of paramount importance to confirm the efficacy of the early triple antiviral combination in reducing viral load, transmission, and preventing disease progress to severity by conducting Phase III randomized controlled trials, as this early triple antiviral combination efficacy has already been determined for COVID 19 in a Phase II clinical trial with statistically significant outcomes. It would be of great interest also to perform clinical studies to determine the impact of pulsed methylprednisolone on COVID 19 pneumonitis and/or on cytokine storm compared with the already approved approaches such as administration of dexamethasone 6 mg/ d. COVID 19 is the pinpoint of interest of all scientists worldwide.