Effect of oseltamivir phosphate versus placebo on platelet recovery and plasma leakage in adults with dengue and thrombocytopenia; a phase 2, multicenter, double-blind, randomized trial

Abstract

Background Thrombocytopenia, bleeding and plasma leakage are major complications of dengue. Activation of endogenous sialidases with desialylation of platelets and endothelial cells may underlie these complications. We aimed to assess the effects of the neuraminidase inhibitor oseltamivir on platelet recovery and plasma leakage in dengue. Methods We performed a phase 2, double-blind, multicenter, randomized trial in adult dengue patients with thrombocytopenia (<70,000/μl) and a duration of illness ≤ 6 days. Oseltamivir phosphate 75mg BID or placebo were given for a maximum of five days. Primary outcomes were the time to platelet recovery (≥ 100,000/μl) or discharge from hospital and the course of measures of plasma leakage. Results A total of 70 patients were enrolled; the primary outcome could be assessed in 64 patients (31 oseltamivir; 33 placebo). Time to platelet count ≥100,000/μl (n = 55) or discharge (n = 9) were similar in the oseltamivir and placebo group (3.0 days [95% confidence interval, 2.7 to 3.3] vs. 2.9 days [2.5 to 3.3], P = 0.055). The kinetics of platelet count and parameters of plasma leakage (gall bladder thickness, hematocrit, plasma albumin, syndecan-1) were also similar between the groups. Discussion In this trial, adjunctive therapy with oseltamivir phosphate had no effect on platelet recovery or plasma leakage parameters. Trial registration ISRCTN35227717.

Dengue: Update on Clinically Relevant Therapeutic Strategies and Vaccines

“…Desialylation or removal of sialic acid on platelet membrane by endogenous neuraminidase, induced by binding of von Willebrand factor (VWN) to platelets, has been suggested as possible mechanism for increased platelet clearance in dengue patients [ 45 ]. Based on this, oseltamivir, a neuraminidase inhibitor that is commonly administered for influenza [ 45 ] was tested as a potential therapeutic for thrombocytopenia in a phase 2, TOTO trial (Treatment Of Thrombocytopenia with Oseltamivir in acute dengue virus infection: a randomized, placebo controlled, multicenter trial) conducted in Indonesia (ISRCTN35227717) [ 46 ]. Unfortunately, the drug was found to be ineffective for both platelet recovery and preventing plasma leakage in patients with acute dengue with moderate to severe thrombocytopenia.…”

“…Clinical trials for Vitamin C alone (SLCTR/2017/028) and in combination with Vitamin B1 (CTRI/2019/09/021244) are in progress Zinc Unclear mechanism Nil Randomized double-blind placebo-controlled trial ( n = 50) (TCTR20151110001) showed reduced hospitalization duration, but no improvement in other clinical or laboratorical outcomes [ 116 ] Treatment options without support for benefits Paracetamol Anti-pyretic Nil Randomized double-blind placebo-controlled trial ( n = 123) showed worse liver enzyme derangements in the treatment group, with no improvement in other clinical or laboratorical parameters. (NCT02833584) [ 20 •] Oseltamivir Neuraminidase inhibitor to block desialylation on platelet membrane One ex vivo study showed that oseltamivir reduced desialylation on platelets from healthy donors [ 45 ] Randomized double-blind placebo-controlled trial ( n = 70) did not show improvement in platelet recovery or plasma leakage parameters (ISRCTN35227717) [ 46 ] …”

“…Can act as an antioxidant Nil Randomized placebo-controlled trials showed faster platelet recovery (n = 66) [114] and reduced liver enzyme derangement (n = 127) (SLCTR/2015/012) [113] Vitamin D Unclear mechanism. Can increase calcium availability for immune cell activation Reduced viral replication and inflammatory cytokines production in vitro [120] Randomized clinical trial (n = 124) showed reduced relative risk for DHF (P, significance for trend was 0.0588) [115] Table One ex vivo study showed that oseltamivir reduced desialylation on platelets from healthy donors [45] Randomized double-blind placebo-controlled trial (n = 70) did not show improvement in platelet recovery or plasma leakage parameters (ISRCTN35227717) [46] most potential as dengue therapeutics and are in advanced stages of clinical testing. These have also been summarized in Table 1 and Fig.…”

Longitudinal proteomic profiling of the inflammatory response in dengue patients

“…This study used plasma samples from subjects in a phase 2, double-blind, multicenter, randomized placebo-controlled trial on the effect of oseltamivir phosphate on platelet recovery and plasma leakage in adults with dengue and thrombocytopenia (ISRCTN35227717) [8]. In brief, adult dengue patients (�16 years old) with fever (� 6 days), thrombocytopenia (< 70 x10 9 /L) and positive for rapid dengue virus (DENV) non-structural protein-1 (NS1) or IgM anti-DENV (PanBio, Diagnostics, Windsor, Australia) were enrolled in six different hospitals in Central and West Java, Indonesia, between January 2018 -July 2019.…”

“…A complete blood count was performed twice daily using a standardized hematology analyzer in each study center. Circulating albumin and syndecan-1 concentrations were determined as previously described [8].…”