What are our pharmacotherapeutic options for MERS-CoV?

Abstract

Since the initial description of Middle East Respiratory Syndrome-coronavirus (MERS-CoV), the disease has been associated with a high case-fatality rate. There is a lack of proven effective medications for therapy of MERS-CoV. The current knowledge of therapeutic options for MERS-CoV is based on the experience from SARS-CoV and from in vitro studies. In this article we review the different therapeutics available for MERS-CoV from SARS experience, in vitro and animal studies of this emerging disease.

Keywords::

• interferon
• MERS-CoV
• pegylated interferon
• ribavirin
• therapy

Since the emergence of the Middle East Respiratory Syndrome-coronavirus (MERS-CoV) in September 2012 to 9 January 2014, the disease affected a total of 178 patients with a mortality rate of 42% [1]. The pattern of the diseases seems to be different when looking at two time intervals [2]. These two intervals were the initial period that included Al-Hasa outbreak, from March to May 2013 and the second period was from June to September 2013. The second period was associated with lower intensive care unit admission (63 vs 33%), a lower mortality rate and lower case fatality rate (58 vs 27%) [2]. These findings are likely related to the identification of a significant number of asymptomatic and mildly symptomatic cases.

One of the challenges in the management of MERS-CoV is the lack of proven effective therapies. Two previous publications highlighted possible therapeutic options for MERS-CoV [3,4]. These possible therapeutic options were based on a literature review of therapies used for a phylogenetically related virus (severe acute respiratory syndrome [SARS]-coronavirus). Therapeutic agents for MERS-CoV could be classified as those blocking virus entry and spread, inhibiting virus replication, interfering with the host immune response and a combination therapy.

MERS-CoV neutralization could be accomplished by the use of convalescent plasma. Convalescent plasma scored a high level of recommendations as a therapy for MERS-CoV [3]. The availability of this approach depends on convalescent plasma from infected but recovered patients. The recommendation to use convalescent plasma is based on effectiveness of this agent in SARS-CoV patients. These studies included patients who received convalescent plasma in addition to corticosteroid and ribavirin. The studies were observational in design and the conclusions should be taken in this context. In a systematic review of the use of convalescent plasma in SARS-CoV, the effect of this modality was inconclusive as other factors may have played a role, such as patient comorbidities, extent of the disease or effect of other concomitant treatments [5]. The presence of MERS-CoV-specific antibodies was reported in two patients from Germany with a titer of 1:640 [6,7]. Whether convalescent plasma would be effective in the therapy of MERS-CoV is a question that remains to be answered.

Inhibition of MERS-CoV to cell receptors may show promise for therapy of this emerging virus. Dipeptidyl peptidase 4 (DPP4), also known as CD26, is a functional receptor for the newly discovered MERS-CoV [8]. The expression of DPP4 was found in primary human bronchiolar epithelial cell cultures and human bronchial lung tissue. In vitro, MERS-CoV infection could not be blocked by the DPP4 inhibitors, such as sitagliptin, vildagliptin or saxagliptin [8]. The development of inhibitors that target the binding site and receptors (DPP4) may prove to be of benefit for the therapy of MERS-CoV infection [9]. An in vitro study of MERS-CoV infection in ferrets showed that adenosine deaminase, a DPP4 binding protein, competed for virus binding and exhibited a natural antagonist for MERS-CoV infection [9]. For the search of an effective therapy, the domains of DPP4 (CD26) were required for the binding of MERS-CoV [8,10]. Anti-CD26 polycolnal antibody showed in vitro inhibitory effect of MERS-CoV infection [8]. A humanized anti-CD26 monoclonal antibody (mAb YS110), which recognizes six distinct epitopes of the CD26 molecule, had an inhibitory effect of infection with MERS-CoV [10].

Inhibitors of virus replication such as cylcophilin inhibitors were studied as possible therapy for MERS-CoV infection. Mycophenolic acid, an immunosuppressant agent that inhibits lymphocyte proliferation, prevents replication of viral RNA. In vitro studies showed that mycophenolic acid had low concentration required for 50% inhibition of enzyme activity and high selectivity index [11]. Mycophenolic acid showed strong inhibition of MERS-CoV in vitro [12]. Cyclosporine A inhibits cyclophilins by blocking the replication of all coronavirus genera, including SARS-CoV [13]. Cyclosporine A was also identified as an inhibitor of MERS-CoV replication in cell culture [14]. Although these agents showed in vitro activities, the question that needs to be addressed is the ability of these agents to give better therapeutic outcomes. One of the factors to achieve this goal is the dosage of these drugs and the achievable serum concentrations. An interesting finding is that therapeutic doses of mycophenolic acid and IFN-β1b achieve serum concentrations that are 60–300-times and 3–4-times higher than the in vitro anti-MERS-CoV activities [11].

CoVs express a 3′- to 5′-exoribonuclease in non-structural protein 14 [15]. In a recent study, ExoN was shown as a possible target for inhibition, and small-molecule inhibitors of ExoN activity may be potential pan-CoV therapeutics in combination with ribavirin [15]. These results require further clinical validation.

Ribavirin, a nucleoside analog, has a wide spectrum of antiviral activity by inhibiting RNA replication. Ribavirin therapy for SARS was evaluated in seven studies [16–22]. There was an inconsistent mortality rate ranging from 5 to 43%. Two studies showed improvement of symptoms in 71.4 and 80% of patients [16,17]. In addition, a significant incidence of adverse events including hemolysis is reported with ribavirin [18]. Ribavirin in the SARS studies was used intravenously. In general, this formulation of therapy is not easily accessible and thus further limits the use of this agent as a therapeutic choice in the clinical setting.

Lopinavir and ritonavir are protease inhibitors. The use of lopinavir and ritonavir in addition to ribavirin improved clinical outcome and reduced death rate compared with ribavirin alone in SARS patients [23,24]. In vitro, HIV protease inhibitors, nelfinavir and lopinavir showed suboptimal 50% effective cytotoxic concentration against MERS-CoV [11].

Interfering with the host immune response is another way to develop therapeutic agents for MERS-CoV. From the SARS experience, in an open-label study, 22 patients with probable SARS were treated with corticosteroids (n = 13) or corticosteroids plus subcutaneous interferon alfacon-1 (n = 9) [25]. The interferon alfacon-1 treatment group had a shorter time to resolution of lung radiographic abnormalities, had better oxygen saturation, resolved their need for supplemental oxygen more rapidly, had less of an increase in creatine kinase levels and showed a trend toward more rapid resolution of lactate dehydrogenase levels compared with the group receiving corticosteroids alone [25].

The role of interferon therapy for MERS-CoV remains to be demonstrated in clinical settings. Recent publications showed that MERS-CoV results in an activation of IL-8 and an attenuated IFN-β response [26]. Experience from SARS-CoV showed that different regimens of interferon were used alone or in combination with ribavirin [4]. However, both IFN-α and IFN-λ inhibited MERS-CoV more effectively than SARS-CoV [27]. In vitro studies also showed that the addition of IFN-β had a significant antiviral effect on MERS-CoV resulting in a 3-log reduction of the virus to undetectable levels [28]. In another study comparing the susceptibility of MERS-CoV with different interferon products (IFN-α2b, IFN-γ, IFN-universal and IFN-α2a, IFN-β), IFN-β had the strongest inhibition of MERS-CoV in vitro [29]. Pegylated IFN-α was 50- to 100-times more effective in vitro for MERS-CoV than SARS-CoV [3]. The long half-life of pegylated IFN-α and the associated adverse effects calls for an extra-caution for the use of shorter-acting interferon [3].

A combination of antiviral therapy and an immune modulator is a modality that was used in SARS therapy. In vitro studies showed that ribavirin and interferon exhibit anti-MERS-CoV activity [11]. In vitro activity of interferon was further enhanced by the addition of ribavirin [30]. Recently, animal studies utilizing Rhesus Macaque monkeys infected with MERS-CoV were published [31–33]. Using intratracheal, ocular, oral and intranasal inoculation of MERS-CoV, Rhesus macaques developed a transient lower respiratory tract infection and had histopathologic changes of the disease and developed neutralizing antibodies [33]. From these studies, the pathogenesis of the disease revealed that MERS-CoV results in clinical disease, promotes virus shedding and replication in respiratory tissues, and that cytokines and chemokines peaked early in infection and decreased over time [33]. An earlier rhesus macaque model of MERS-CoV infection showed that both IFN-α2b and ribavirin combinations was effective in limiting MERS-CoV disease, clinically and radiographically [31]. In a recent observational study of five MERS-CoV patients treated with a combination of interferon and ribavirin, the median time from admission to therapy was 19 (range 10–22) days. In that study, none of the patients responded to the supportive or therapeutic interventions and all died of their illness [34]. It was concluded that critically ill patients with multiple comorbidities who were diagnosed late in the course of their illness may not benefit from combination antiviral therapy [34]. This observation was in sharp contrast to the animal model study described above in outcome and time of administration. In the animal model, the combination of ribavirin and interferon was given within 8 h of infection [31].

The development of new agents for the therapy of MERS-CoV or the use of pre-existing anti-viral medications is an important issue to tackle. The use of IFN-α2b, ribavirin, cyclophilin inhibitors and convalescent plasma from patients fully recovered from MERS-CoV infection need further clinical studies and prospective evaluation. The use of these therapeutic options should be evaluated in well-designed studies taking into account the characteristics of the patients and the clinical presentation. The use of any therapeutics for MERS-CoV should take into account the findings from in vitro, animal and limited experience from observational studies. The time of initiation of therapy for MERS-CoV is an important factor in predicting any meaningful response. The limited experience from an observational study of MERS-CoV showed that late therapy may be further complicated by the fact that the patients may have developed multiple complications to show any therapeutic effect. The sporadic cases and the presence of asymptomatic or mildly symptomatic MERS-CoV patients may further complicate the development of therapeutic options for the disease. The use of any of these agents should thus be considered in an appropriately planned evaluation of effectiveness [3].

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.