A Randomized, Double-Blind Placebo Controlled Trial of Balapiravir, a Polymerase Inhibitor, in Adult Dengue Patients

Dengue is an acute illness caused by 1 of 4 single-stranded positive-sense RNA viruses and is the commonest arboviral infection of humans. In countries where dengue is endemic, the case burden strains already fragile healthcare systems and has an economic cost [1, 2]. There are currently no licensed vaccines for dengue (although late-stage trials are in progress), and mosquito vector control has been mostly unsuccessful or unsustainable. Clinically apparent dengue manifests with a spectrum of symptoms. High fever, erythema, headache, and myalgia are common symptoms, and laboratory findings of leukopenia and mild thrombocytopenia are typical. The critical phase occurs around the time of defervescence, typically on days 4–6 of illness, during which a transient capillary permeability syndrome manifests in some patients. In children particularly, capillary permeability can be significant enough to precipitate life-threatening circulatory shock, called dengue shock syndrome (DSS). Treatment is supportive, and the mortality rate for DSS in experienced hospital settings is <1% [2]. The magnitude of the early dengue virus (DENV) burden in patients with dengue has been associated with overall clinical outcome. For example, the early plasma viremia and/or NS1 antigenemia levels in pediatric dengue patients who develop clinically significant capillary permeability are higher than in patients without this complication [3–6]. The higher antigenic burden in these patients is believed to trigger a cascade of immunological events that promotes capillary permeability [7]. The association between high viral burdens in the first few days of illness and more severe outcomes has encouraged antiviral discovery efforts for dengue [8, 9], with the rationale that a reduction of the viral burden should result in a reduced incidence of severe complications and a lessening of symptoms and illness duration. Balapiravir is a prodrug of a nucleoside analogue (4′-azidocytidine) called R1479 and was developed for the treatment of chronic hepatitis C Virus (HCV) infection by Hoffmann-La Roche. [10–12]. Monotherapy twice per day for 14 days reduced plasma HCV levels in a dose- and time-dependent manner and was well-tolerated at doses up to 3000 mg in adult male patients [13]. However, the clinical development of balapiravir for HCV infection was stopped when clinical safety signals were detected in patients receiving extended courses (2–3 months) of balapiravir therapy in conjunction with pegylated interferon and ribavirin. Because HCV and DENV possess RNA-dependent RNA polymerases that share a similar overall architecture [14], we explored a new indication for balapiravir by testing the in vitro activity of R1479 against DENV. Subsequently, the safety, tolerability, and antiviral efficacy of balapirivir in adult dengue patients were investigated in a clinical trial.