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.

Figure 1.

Study enrollment and follow-up. The study enrolled 120 NS1-positive dengue patients who consented and were eligible to undergo screening against the inclusion and exclusion criteria; of these, 64 were eligible to continue into the study. The most common reasons for exclusion were low creatinine clearance rates (53.6% of excluded cases), hepatitis B surface antigen positivity (23.2%), and abnormal serum creatinine level (17.9%). All patients completed their dosage schedule of study drug.

Figure 2.

Viremia levels in balapiravir- and placebo-treated patients. Shown are serotype-stratified viremia levels, measured by reverse-transcription polymerase chain reaction, in 12-hour spaced plasma samples, in patients treated with placebo, low-dose balapiravir, or high-dose balapiravir. The colored lines in each graph represent smoothing lines derived from local polynomial regression fitting to data from each treatment arm. The gray background lines represent individual patient data. Abbreviations: DENV, dengue virus; R.arm, randomistation arm.

Figure 3.

Kaplan-Meier plot of NS1 antigenemia over time in balapiravir- and placebo-treated patients. Shown are the proportions of patients over time that tested NS1-positive in serial plasma samples collected daily from baseline (pretreatment) to study day 7, and again on study day 14. There was no significant difference in time to clearance of NS1 antigenemia between treatment groups. Abbreviation: R.arm, randomistation arm.