A Randomized, Double-Blind Placebo Controlled Trial of Balapiravir, a Polymerase Inhibitor, in Adult Dengue Patients
Nguyet Minh Nguyen,Chau Nguyen Bich Tran,Lam Khanh Phung,Kien Thi Hue Duong,Huy Le Anh Huynh,Jeremy Farrar,Quyen Nguyen,Hien Tinh Tran,Chau Van Vinh Nguyen,Laura Merson,Long T. Hoang,Martin L. Hibberd,Pauline P. K. Aw,Andreas Wilm,Niranjan Nagarajan,Dung Thi Nguyen,Mai Phuong Pham,Truong Thanh Nguyen,Hassan Javanbakht,Klaus Klumpp,Janet Hammond,Rosemary Petric,Marcel Wolbers,Chinh Nguyen,Cameron P. Simmons +24 more
TLDR
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 d Dengue and provides the field with a clinically evaluated benchmark molecule.Abstract:
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.read more
Citations
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Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses
Timothy P. Sheahan,Amy C. Sims,Rachel L. Graham,Vineet D. Menachery,Lisa E. Gralinski,James Brett Case,Sarah R. Leist,Krzysztof Pyrc,Joy Y. Feng,Iva Trantcheva,Roy Bannister,Yeojin Park,Darius Babusis,Michael O. Clarke,Richard L. Mackman,Jamie E. Spahn,Christopher A. Palmiotti,Dustin Siegel,Adrian S. Ray,Tomas Cihlar,Robert Jordan,Mark R. Denison,Ralph S. Baric +22 more
TL;DR: Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses in vitro and in vivo and may prove effective against endemic MERS-CoV in the Middle East, circulating human CoV, and, possibly most importantly, emerging CoV of the future.
Journal ArticleDOI
LoFreq: a sequence-quality aware, ultra-sensitive variant caller for uncovering cell-population heterogeneity from high-throughput sequencing datasets
Andreas Wilm,Pauline Poh Kim Aw,Denis Bertrand,Grace Hui Ting Yeo,Swee Hoe Ong,Chang Hua Wong,Chiea Chuen Khor,Rosemary Petric,Martin L. Hibberd,Niranjan Nagarajan +9 more
TL;DR: It is shown that LoFreq has near-perfect specificity, with significantly improved sensitivity compared with existing methods and can efficiently analyze deep Illumina sequencing datasets without resorting to approximations or heuristics.
Journal ArticleDOI
Ten years of dengue drug discovery: Progress and prospects
Siew Pheng Lim,Qing Yin Wang,Christian G. Noble,Yen Liang Chen,Hongping Dong,Bin Zou,Fumiaki Yokokawa,Shahul Nilar,Paul Smith,David Beer,Julien Lescar,Pei Yong Shi +11 more
TL;DR: The knowledge accumulated during the past decade has provided a better rationale for ongoing dengue drug discovery and it is optimistic that this continuous, concerted effort will lead to an effective d Dengue therapy.
Journal ArticleDOI
Therapeutic Potential of Spirooxindoles as Antiviral Agents.
TL;DR: This review highlights recent advances in the development of biologically active spirooxindoles for their antiviral potential, primarily focusing on the structure-activity relationships (SARs) and modes of action, as well as future directions to achieve more potent analogues toward a viable antiviral therapy.
Journal ArticleDOI
Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond
TL;DR: Infections with flaviviruses, such as dengue, West Nile virus and the recently re-emerging Zika virus, are an increasing and probably lasting global risk, and broad-spectrum activity is particularly desirable to prepare for the next flaviviral epidemic.
References
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Journal ArticleDOI
Dengue Viremia Titer, Antibody Response Pattern, and Virus Serotype Correlate with Disease Severity
David W. Vaughn,Sharone Green,Siripen Kalayanarooj,Bruce L. Innis,Suchitra Nimmannitya,Saroj Suntayakorn,Timothy P. Endy,Boonyos Raengsakulrach,Alan L. Rothman,Francis A. Ennis,Ananda Nisalak +10 more
TL;DR: Higher peak titers were associated with increased disease severity for the 31 patients with a peak titer identified, and increased dengue disease severity correlated with high viremia titer, secondary d Dengue virus infection, and DEN-2 virus type.
Journal ArticleDOI
High circulating levels of the dengue virus nonstructural protein NS1 early in dengue illness correlate with the development of dengue hemorrhagic fever
Daniel H. Libraty,Paul R. Young,Darren Pickering,Timothy P. Endy,Siripen Kalayanarooj,Sharone Green,David W. Vaughn,Ananda Nisalak,Francis A. Ennis,Alan L. Rothman +9 more
TL;DR: In this paper, the secreted dengue virus nonstructural protein NS1 (sNS1) was measured daily in 32 children with Dengue-2 virus infections participating in a prospective, hospital-based study.
Journal ArticleDOI
Differing Influences of Virus Burden and Immune Activation on Disease Severity in Secondary Dengue-3 Virus Infections
Daniel H. Libraty,Timothy P. Endy,Huo-Shu H. Houng,Sharone Green,Siripen Kalayanarooj,Saroj Suntayakorn,Wanya Chansiriwongs,David W. Vaughn,Ananda Nisalak,Francis A. Ennis,Alan L. Rothman +10 more
TL;DR: Quantitative differences in virus burden and host immune responses, and the timing of type 1 cytokine responses, have differing influences on the severity of disease manifestations during secondary dengue-3 virus infections.
Journal ArticleDOI
Crystal Structure of the Dengue Virus RNA-Dependent RNA Polymerase Catalytic Domain at 1.85-Angstrom Resolution
Thai Leong Yap,T. Xu,Yen Liang Chen,Hélène Malet,Marie-Pierre Egloff,Bruno Canard,Subhash G. Vasudevan,Julien Lescar,Julien Lescar +8 more
TL;DR: The structure of the NS5 nuclear localization sequences, previously thought to fold into a separate domain, form an integral part of the polymerase subdomains and reveals the presence of two zinc ion binding motifs, which should inform and accelerate the structure-based design of antiviral compounds against dengue virus.
Journal ArticleDOI
Cost of dengue cases in eight countries in the Americas and Asia: a prospective study.
Jose A. Suaya,Donald S. Shepard,João Bosco Siqueira,Celina Maria Turchi Martelli,Lucy Chai See Lum,Lian Huat Tan,Sukhontha Kongsin,Sukhum Jiamton,Fàtima Garrido,Romeo Montoya,Blas Armién,Rekol Huy,Leticia Castillo,Mariana Caram,Binod K. Sah,Rana Sughayyar,Karen R. Tyo,Scott B. Halstead +17 more
TL;DR: The first multicountry estimates of the direct and indirect costs of dengue cases in eight American and Asian countries using a common protocol are presented, showing that Dengue imposes substantial costs on both the health sector and the overall economy.
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