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

Abstract

Background. Dengue is the most common arboviral infection of humans. There are currently no specific treatments for dengue. Balapiravir is a prodrug of a nucleoside analogue (called R1479) and an inhibitor of hepatitis C virus replication in vivo.Methods. We conducted in vitro experiments to determine the potency of balapiravir against dengue viruses and then an exploratory, dose-escalating, randomized placebo-controlled trial in adult male patients with dengue with <48 hours of fever.Results. The clinical and laboratory adverse event profile in patients receiving balapiravir at doses of 1500 mg (n = 10) or 3000 mg (n = 22) orally for 5 days was similar to that of patients receiving placebo (n = 32), indicating balapiravir was well tolerated. However, twice daily assessment of viremia and daily assessment of NS1 antigenemia indicated balapiravir did not measurably alter the kinetics of these virological markers, nor did it reduce the fever clearance time. The kinetics of plasma cytokine concentrations and the whole blood transcriptional profile were also not attenuated by balapiravir treatment.Conclusions. Although this trial, the first of its kind in dengue, does not support balapiravir as a candidate drug, it does establish a framework for antiviral treatment trials in dengue and provides the field with a clinically evaluated benchmark molecule.Clinical Trials Registration. NCT01096576.

18F-FDG as an inflammation biomarker for imaging dengue virus infection and treatment response

“…The use of the reduction of serum viremia as the primary laboratory endpoint for evaluating therapeutics against DF failed to show any significant efficacy, as recent clinical trials of repurposed drugs have demonstrated (10,(39)(40)(41)(42). Moreover, the potency of the tested drugs has been significantly questioned, since analysis showed an almost 4-log reduction in viral load during the acute phase for both the treated and untreated arms (10,(39)(40)(41)(42).…”

“…Moreover, the potency of the tested drugs has been significantly questioned, since analysis showed an almost 4-log reduction in viral load during the acute phase for both the treated and untreated arms (10,(39)(40)(41)(42). Viremia clearance is associated with the immune status of the patients and virus serotype (39,43).…”

Discovery of Dengue Virus NS4B Inhibitors

“…Most importantly, the current compound has provided an opportunity to answer two paramount questions for dengue therapeutics development: can an antiviral drug reduce viremia in dengue patients (infected with DENV-2 or -3), and, if so, will viremia reduction prevent patients from developing severe hemorrhagic fever and shock? Since compound 14a is not a prodrug and directly inhibits viral NS4B, it is expected to eliminate the complications of nucleoside inhibitors (which require host kinases to convert them to their triphosphate forms before being antiviral active), as evidenced by the efficacy failure of balapiravir in dengue patients (6,33).…”

Research on Dengue During World War II Revisited

“…The longer duration of fever in patients with primary dengue may make this group of patients more suitable for enrollment into therapeutic trials in which the duration of fever is a primary outcome. 33,34 The more rapid fever clearance in secondary infection may require a larger cohort of patients to observe a statistically significant reduction in fever duration. 35 This necessity not only increases cost but also the number of patients exposed to an investigational compound, and its safety profile remains to be fully determined.…”