Treating MERS-CoV during an outbreak
Authors: Christopher M Coleman, Matthew B Frieman
Journal: The Lancet Infectious Diseases (2014)

When a new virus emerges, health-care systems face major challenges, not least of which is deciding which treatments to use. The drug development process, from novel compound screening to final approval, can take more than 10 years to complete and cost hundreds of millions of dollars. By contrast, viruses can emerge rapidly, spread widely, and pose a substantial, immediate threat to public health. For example, Middle East respiratory syndrome coronavirus (MERS-CoV) was first reported in November, 2012, and, as of September, 2014, cases have been reported in 21 countries, with 837 confirmed cases and 319 deaths. Approved drugs can be repurposed for use against various viral infections to shorten the time taken from virus emergence to treatment availability. We, and others, have screened libraries of drugs for anti-MERS-CoV activity in vitro;1de Wilde AH Jochmans D Posthuma CC et al.Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture.Antimicrob Agents Chemother. 2014; 58: 4875-4884Crossref PubMed Scopus (581) Google Scholar, 2Dyall J Coleman CM Hart BJ et al.Repurposing of clinically developed drugs for treatment of middle East respiratory syndrome coronavirus infection.Antimicrob Agents Chemother. 2014; 58: 4885-4893Crossref PubMed Scopus (515) Google Scholar however, the absence of pathological small animal models makes the screening of many drugs in vivo challenging. The major benefit to the screening of preapproved drugs is that these drugs are not required to undergo extensive safety testing to be used in human beings, since they are already deemed safe for human use. In The Lancet Infectious Diseases, Ali Omrani and colleagues3Omrani AS Saad MM Baig K et al.Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study.Lancet Infect Dis. 2014; (published online Sept 30.)http://dx.doi.org/10.1016/S1473-3099(14)70920-XPubMed Google Scholar report the results of their retrospective cohort study on the use of the preapproved drugs ribavirin and interferon alfa-2a for the treatment of MERS-CoV. Ribavirin is a synthetic analogue of the ribonucleoside guanosine. Ribavirin contains a carboxamide group on the guanine nucleotide, allowing ribavirin to be incorporated into RNA in place of either adenosine or guanosine and pair equally well with uracil or cytosine. Therefore, ribavirin is thought to introduce hypermutation into RNA replication products by random incorporation of uracil and cytosine. Ribavirin has been shown to have some efficacy for treatment of respiratory syncytial virus4Turner TL Kopp BT Paul G Landgrave LC Hayes Jr, D Thompson R Respiratory syncytial virus: current and emerging treatment options.Clinicoecon Outcomes Res. 2014; 6: 217-225Crossref PubMed Google Scholar and haemorrhagic fever viruses—eg, hantavirus5Jonsson CB Hooper J Mertz G Treatment of hantavirus pulmonary syndrome.Antiviral Res. 2008; 78: 162-169Crossref PubMed Scopus (113) Google Scholar and Lassa fever virus.6Khan SH Goba A Chu M et al.New opportunities for field research on the pathogenesis and treatment of Lassa fever.Antiviral Res. 2008; 78: 103-115Crossref PubMed Scopus (151) Google Scholar Interferon alfa-2a is a type I interferon, an innate immune cytokine involved in the antiviral innate immune response. Type I interferons have been identified as potential treatments for a range of viruses, and pegylated interferon alfa-2a is used in combination with ribavirin to treat hepatitis C virus infection.7Ascione A De Luca M Tartaglione MT et al.Peginterferon alfa-2a plus ribavirin is more effective than peginterferon alfa-2b plus ribavirin for treating chronic hepatitis C virus infection.Gastroenterology. 2010; 138: 116-122Summary Full Text Full Text PDF PubMed Scopus (160) Google Scholar Omrani and colleagues present data from the first clinical use of ribavirin and pegylated interferon alfa-2a in patients with MERS-CoV. They show that treatment with ribavirin and pegylated interferon alfa-2a significantly improves survival 14 days after diagnosis of MERS-CoV infection (p=0·004). They note enhanced survival 28 days after diagnosis in patients who received ribavirin and pegylated interferon alfa-2a, but this enhanced survival was not statistically significant (p=0·054). The investigators acknowledge that the sample size in the study was small (44 patients; 20 who received treatment and 24 control patients) and a small sample might affect the statistics in a complex population. Therefore, the data for 28 days after diagnosis have value as a guideline and might be statistically significant in a larger sample of patients. Despite the small number of patients, this study is the largest clinical test of ribavirin and interferon alfa-2a combination therapy, with previous studies presenting only five8Al-Tawfiq JA Momattin H Dib J Memish ZA Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study.Int J Infect Dis. 2014; 20: 42-46Summary Full Text Full Text PDF PubMed Scopus (264) Google Scholar and two9Khalid M Al Rabiah F Khan B Al Mobeireek A Butt TS Al Mutairy E Ribavirin and interferon (IFN)-alpha-2b as primary and preventive treatment for Middle East respiratory syndrome coronavirus (MERS-CoV): a preliminary report of two cases.Antivir Ther. 2014; (published online May 15.)https://doi.org/10.3851/IMP2792Crossref PubMed Scopus (65) Google Scholar patients. This study takes advantage of the relatively large number of patients with MERS-CoV being treated at the Prince Sultan Military Medical City, Saudi Arabia, to make some important initial observations on the use of ribavirin and pegylated interferon alfa-2a combination therapy. In any outbreak situation, time to treatment is crucial, and the number of patients needed to undertake large-scale clinical trials might be too small while the pathogen is still rare. By contrast, the initial stages of an outbreak are often the most important for stopping the spread of the pathogen, therefore smaller studies such as this have a very important role as a guide for future clinical trials. Overall, this study provides important guidance on the use of combination therapy and approved drugs in the treatment of the continuing MERS-CoV outbreak. We declare no competing interests. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort studyIn patients with severe MERS-CoV infection, ribavirin and interferon alfa-2a therapy is associated with significantly improved survival at 14 days, but not at 28 days. Further assessment in appropriately designed randomised trials is recommended. Full-Text PDF