Efficacy of sofosbuvir as treatment for yellow fever: protocol for a randomised controlled trial in Brazil (SOFFA study)

Abstract

IntroductionAn ongoing outbreak of yellow fever (YF) has been reported in Brazil with 1261 confirmed cases and 409 deaths since July 2017. To date, there is no specific treatment available for YF. Recently published papers describing in vitro and animal models suggest a potential effect of antiviral drugs (approved for the treatment of hepatitis virus) against flaviviruses, including YF. The primary aim of this study is to analyse the effect of sofosbuvir on viral kinetics and clinical outcomes among patients presenting with YF. This is a multicentre open-label randomised controlled trial with 1:1 individual allocation, stratified by severity and by recruiting centre.Methods and analysisAdults with suspected or confirmed YF infection and symptoms lasting up to 15 days are screened. Eligible and consenting patients are randomised to receive oral sofosbuvir 400 mg daily for 10 days or to receive standard clinical care. Viral kinetics are measured daily and the reduction in YF plasma viral load from the sample at inclusion to 72 hours after randomisation will be compared between active and control groups. Clinical outcomes include severity meeting criteria for intensive care support, liver transplantation, in-hospital mortality and mortality within 60 days.Ethics and disseminationEthics approval was obtained at the participating sites and at the national research ethics committee (CAAE 82673018.6.1001.0068). The trial has been submitted for ethical approval at additional potential recruiting centres. Results of the study will be published in journals and presented at scientific meetings.Trial registrationBrazilian Clinical Trials Registry (RBR-93dp9n).

Atazanavir, Alone or in Combination with Ritonavir, Inhibits SARS-CoV-2 Replication and Proinflammatory Cytokine Production

“…This approach proved feasible for combating the Zika, yellow fever and chikungunya outbreaks experienced in Brazil over the past 5 years, when our group demonstrated that sofosbuvir, a blockbuster drug against hepatitis C, could represent a compassionate countermeasure against these diseases (25)(26)(27)(28)(29).…”

“…Preclinical data on the susceptibility of an emerging virus to clinically approved drugs can allow for the rapid mobilization of resources toward clinical trials ( 8 ). This approach proved feasible for combating the Zika, yellow fever, and chikungunya outbreaks experienced in Brazil over the past 5 years, when our group demonstrated that sofosbuvir, a blockbuster drug against hepatitis C, could represent a compassionate countermeasure against these diseases ( 25 – 29 ).…”

Thein vitroantiviral activity of the anti-hepatitis C virus (HCV) drugs daclatasvir and sofosbuvir against SARS-CoV-2

“…To rapidly respond to unfolding pandemics, the cataloguing of preclinical data on susceptibility of SARS-CoV-2 to approved drugs is of paramount importance, and provides opportunities for rational selection of promising products for evaluation in clinical trials [37]. The investigators used this approach during ZIKV, YFV, and CHIKV outbreak in Brazil, and demonstrated susceptibility of these viruses to SFV [13–16,38]. SFV and DCV are considered safe and well tolerated anti-HCV therapies that are orally bioavailable.…”

AT-752, a double prodrug of a guanosine nucleotide analog, inhibits yellow fever virus in a hamster model

“…Despite many attempts to develop an effective treatment for yellow fever, including other nucleoside analogs [3,10,11,14], no compound has successfully demonstrated efficacy against the disease in human testing. Sofosbuvir, a clinically approved drug against hepatitis C virus (HCV), has recently been shown to inhibit YFV in vitro and in vivo [2,8], and a clinical trial in Brazil to test its efficacy in humans infected with YFV is currently underway [16]. AT-752 has also been shown to be a potent inhibitor of HCV [12], as is its congener AT-527 which forms the same active triphosphate, and was up to 58-fold more potent than sofosbuvir against HCV clinical isolates [13].…”