Comment
Dengue control is in trouble. Since the severe form of dengue infection was described more than 50 years ago, this disease has spread to every corner of the tropics.1–3 In 2010, 4 billion people were at risk of infection with any of the four dengue viruses (DENV1–4), more than 390 million individuals were infected, and 96 million had overt disease.3 During a dengue infection, a small subset of individuals with circulating infection-enhancing dengue antibodies are at risk of an abrupt onset of acute vascular permeability accompanied by abnormalities in haemostasis, potentially leading to shock, severe bleeding, and death.4 This severe outcome typically occurs at the time of defervescence after several days of the symptoms of classic dengue fever. Additionally, dengue infections can have unfavourable outcomes in elderly individuals who have pre-existing chronic disorders. These clinical courses create a cruel diagnostic dilemma for physicians and have led to many efforts to identify clinical signs and symptoms premonitory of severe dengue.5 Meanwhile, despite the availability of many powerful insecticides, mosquito abatement efforts directed at the control or eradication of the dengue vector Aedes aegypti have conspicuously and universally failed.6 Because of the geographical expansion of dengue infections and failures in vector control, hopes have turned to vaccines, the development of which has been in progress since the 1970s. In a clinical trial of a live-attenuated tetravalent dengue vaccine in 4000 Thai children,7 overall efficacy was about 30%, with no protection against DENV2. Against this background of frustration, much expectation is now invested in dengue antivirals. Indeed, in 2002, Novartis established the Novartis Institute for Tropical Diseases in Singapore, where research is committed to the discovery of chemotherapeutics for dengue and tuberculosis. There is an opportunistic window for use of antivirals because dengue illnesses begin with the sudden onset of fever that prompts patients to seek medical intervention; the life-threatening vascular permeability occurs only 4–5 days later. Other groups in Singapore are also studying the efficacy of potential dengue antivirals. In The Lancet Infectious Diseases, Jenny Low and colleagues report the results of a trial of celgosivir.8 Unfortunately, the findings show that the drug should be added to the growing list
of potential antivirals (already containing chloroquine and balapiravir) that have little or no efficacy in dengue infection or disease expression when tested in people.8–10 Celgosivir is a 6-O butanoyl prodrug of the iminosugar castanospermine. Iminosugars can exert broad antiviral properties, disrupting virus morphogenesis through misfolding of glycosylated proteins, such as those encoded by the DENV genome.11 Preclinical studies of celgosivir in dengue infection11–13 had outstanding results. Celgosivir inhibited both DENV2 infection in a human monocyte cell line with and without infectionenhancing dengue antibodies, and growth of all four virus serotypes in continuous epithelial cells in vitro.11 Additionally, it prevented death in mice inoculated with lethal doses of mouse-adapted DENV2 in mice with and without infection-enhancing dengue antibodies.12–14 Low and colleagues used doses of celgosivir known to be effective in animals and used in previous large therapeutic trials of efficacy for hepatitis C and HIV infection.8 To be eligible for inclusion, a patient’s illness had to meet case definitions for dengue fever. 24 patients experiencing primary or secondary infections with DENV1–3 received their first dose of celgosivir (400 mg) on the first or second day of a fever, and then received maintenance doses of 200 mg every 12 h for a total of nine doses. Mean virological log reduction was slightly higher in the celgosivir group than in the placebo group (–1·86, SD 1·07 vs –1·64, 0·75; difference –0·22, 90% CI –0·65 to 0·22, one-sided p=0·203), as was the area under the fever curve (54·95, SD 31·04 vs 40·72, 18·69; difference 14·20, 90% CI 2·16–26·25, one-sided p=0·973). However, time to clearance of serum NS1 was significantly shorter in the celgosivir group than the placebo group (log-rank p=0·026).8 This finding raises the question of whether celgosivir might indeed have some therapeutic effect against the more severe vascular permeability syndrome. The complex role that NS1 seems to have in dengue pathogenesis has been reviewed.15 NS1 itself could mediate some or all of the components of vascular permeability syndrome.16 Because few side-effects of oral celgosivir have been reported in people,8 a large trial might be necessary to test whether celgosivir reduces elements of the vascular permeability syndrome, with a design similar to that of a previous trial of corticosteroids given early in dengue infections in adults.17
www.thelancet.com/infection Published online May 28, 2014 http://dx.doi.org/10.1016/S1473-3099(14)70770-4
London School Of Hygiene And Tropical Medicine/SPL
Stumbles on the path to dengue control
Lancet Infect Dis 2014 Published Online May 28, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)70770-4 See Online/Articles http://dx.doi.org/10.1016/ S1473-3099(14)70730-3
1
Comment
Scott B Halstead
9
5824 Edson Lane, North Bethesda, MD 20852, USA [email protected]
10
I declare no competing interests. 1
2
3 4 5
6
7
8
2
Hammon WM, Rudnick A, Sather GE, Rogers KD, Morse LJ. New hemorrhagic fevers of children in the Philippines and Thailand. Trans Assoc Am Physicians 1960; 73: 140–55. Brady OJ, Gething PW, Bhatt S, et al. Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLoS Negl Trop Dis 2012; 6: e1760. Bhatt S, Gething PW, Brady OJ, et al. The global distribution and burden of dengue. Nature 2013; 496: 504–07. Halstead SB. Dengue. Lancet 2007; 370: 1644–52. Leo YS, Gan VC, Ng EL, et al. Utility of warning signs in guiding admission and predicting severe disease in adult dengue. BMC Infect Dis 2013; 13: 498. Gubler DJ. Epidemic dengue/dengue hemorrhagic fever as a public health, social and economic problem in the 21st century. Trends Microbiol 2002; 10: 100–03. Sabchareon A, Wallace D, Sirivichayakul C, et al. Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. Lancet 2012; 380: 1559–67. Low JG, Sung C, Wijaya L, et al. Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial. Lancet Infect Dis 2014; published online May 28. http://dx.doi.org/10.1016/S1473-3099(14)70730-3
11
12
13
14
15
16 17
Tricou V, Minh NN, Van TP, et al. A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults. PLoS Negl Trop Dis 2010; 4: e785. Nguyen NM, Tran CN, Phung LK, et al. A randomized, double-blind placebo controlled trial of balapiravir, a polymerase inhibitor, in adult dengue patients. J Infect Dis 2013; 207: 1442–50. Courageot MP, Frenkiel MP, Dos Santos CD, Deubel V, Despres P. Alpha-glucosidase inhibitors reduce dengue virus production by affecting the initial steps of virion morphogenesis in the endoplasmic reticulum. J Virol 2000; 74: 564–72. Rathore AP, Paradkar PN, Watanabe S, et al. Celgosivir treatment misfolds dengue virus NS1 protein, induces cellular pro-survival genes and protects against lethal challenge mouse model. Antiviral Res 2011; 92: 453–60. Schul W, Liu W, Xu HY, Flamand M, Vasudevan SG. A dengue fever viremia model in mice shows reduction in viral replication and suppression of the inflammatory response after treatment with antiviral drugs. J Infect Dis 2007; 195: 665–74. Watanabe S, Rathore AP, Sung C, et al. Dose- and schedule-dependent protective efficacy of celgosivir in a lethal mouse model for dengue virus infection informs dosing regimen for a proof of concept clinical trial. Antiviral Res 2012; 96: 32–35. Muller DA, Young PR. The flavivirus NS1 protein: molecular and structural biology, immunology, role in pathogenesis and application as a diagnostic biomarker. Antiviral Res 2013; 98: 192–208. Halstead SB. Identifying protective dengue vaccines: guide to mastering an empirical process. Vaccine 2013; 31: 4501–07. Tam DT, Ngoc TV, Tien NT, et al. Effects of short-course oral corticosteroid therapy in early dengue infection in Vietnamese patients: a randomized, placebo-controlled trial. Clin Infect Dis 2012; 55: 1216–24.
www.thelancet.com/infection Published online May 28, 2014 http://dx.doi.org/10.1016/S1473-3099(14)70770-4
Dengue control is in trouble. Since the severe form of dengue infection was described more than 50 years ago, this disease has spread to every corner of the tropics.1–3 In 2010, 4 billion people were at risk of infection with any of the four dengue viruses (DENV1–4), more than 390 million individuals were infected, and 96 million had overt disease.3 During a dengue infection, a small subset of individuals with circulating infection-enhancing dengue antibodies are at risk of an abrupt onset of acute vascular permeability accompanied by abnormalities in haemostasis, potentially leading to shock, severe bleeding, and death.4 This severe outcome typically occurs at the time of defervescence after several days of the symptoms of classic dengue fever. Additionally, dengue infections can have unfavourable outcomes in elderly individuals who have pre-existing chronic disorders. These clinical courses create a cruel diagnostic dilemma for physicians and have led to many efforts to identify clinical signs and symptoms premonitory of severe dengue.5 Meanwhile, despite the availability of many powerful insecticides, mosquito abatement efforts directed at the control or eradication of the dengue vector Aedes aegypti have conspicuously and universally failed.6 Because of the geographical expansion of dengue infections and failures in vector control, hopes have turned to vaccines, the development of which has been in progress since the 1970s. In a clinical trial of a live-attenuated tetravalent dengue vaccine in 4000 Thai children,7 overall efficacy was about 30%, with no protection against DENV2. Against this background of frustration, much expectation is now invested in dengue antivirals. Indeed, in 2002, Novartis established the Novartis Institute for Tropical Diseases in Singapore, where research is committed to the discovery of chemotherapeutics for dengue and tuberculosis. There is an opportunistic window for use of antivirals because dengue illnesses begin with the sudden onset of fever that prompts patients to seek medical intervention; the life-threatening vascular permeability occurs only 4–5 days later. Other groups in Singapore are also studying the efficacy of potential dengue antivirals. In The Lancet Infectious Diseases, Jenny Low and colleagues report the results of a trial of celgosivir.8 Unfortunately, the findings show that the drug should be added to the growing list
of potential antivirals (already containing chloroquine and balapiravir) that have little or no efficacy in dengue infection or disease expression when tested in people.8–10 Celgosivir is a 6-O butanoyl prodrug of the iminosugar castanospermine. Iminosugars can exert broad antiviral properties, disrupting virus morphogenesis through misfolding of glycosylated proteins, such as those encoded by the DENV genome.11 Preclinical studies of celgosivir in dengue infection11–13 had outstanding results. Celgosivir inhibited both DENV2 infection in a human monocyte cell line with and without infectionenhancing dengue antibodies, and growth of all four virus serotypes in continuous epithelial cells in vitro.11 Additionally, it prevented death in mice inoculated with lethal doses of mouse-adapted DENV2 in mice with and without infection-enhancing dengue antibodies.12–14 Low and colleagues used doses of celgosivir known to be effective in animals and used in previous large therapeutic trials of efficacy for hepatitis C and HIV infection.8 To be eligible for inclusion, a patient’s illness had to meet case definitions for dengue fever. 24 patients experiencing primary or secondary infections with DENV1–3 received their first dose of celgosivir (400 mg) on the first or second day of a fever, and then received maintenance doses of 200 mg every 12 h for a total of nine doses. Mean virological log reduction was slightly higher in the celgosivir group than in the placebo group (–1·86, SD 1·07 vs –1·64, 0·75; difference –0·22, 90% CI –0·65 to 0·22, one-sided p=0·203), as was the area under the fever curve (54·95, SD 31·04 vs 40·72, 18·69; difference 14·20, 90% CI 2·16–26·25, one-sided p=0·973). However, time to clearance of serum NS1 was significantly shorter in the celgosivir group than the placebo group (log-rank p=0·026).8 This finding raises the question of whether celgosivir might indeed have some therapeutic effect against the more severe vascular permeability syndrome. The complex role that NS1 seems to have in dengue pathogenesis has been reviewed.15 NS1 itself could mediate some or all of the components of vascular permeability syndrome.16 Because few side-effects of oral celgosivir have been reported in people,8 a large trial might be necessary to test whether celgosivir reduces elements of the vascular permeability syndrome, with a design similar to that of a previous trial of corticosteroids given early in dengue infections in adults.17
www.thelancet.com/infection Published online May 28, 2014 http://dx.doi.org/10.1016/S1473-3099(14)70770-4
London School Of Hygiene And Tropical Medicine/SPL
Stumbles on the path to dengue control
Lancet Infect Dis 2014 Published Online May 28, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)70770-4 See Online/Articles http://dx.doi.org/10.1016/ S1473-3099(14)70730-3
1
Comment
Scott B Halstead
9
5824 Edson Lane, North Bethesda, MD 20852, USA [email protected]
10
I declare no competing interests. 1
2
3 4 5
6
7
8
2
Hammon WM, Rudnick A, Sather GE, Rogers KD, Morse LJ. New hemorrhagic fevers of children in the Philippines and Thailand. Trans Assoc Am Physicians 1960; 73: 140–55. Brady OJ, Gething PW, Bhatt S, et al. Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLoS Negl Trop Dis 2012; 6: e1760. Bhatt S, Gething PW, Brady OJ, et al. The global distribution and burden of dengue. Nature 2013; 496: 504–07. Halstead SB. Dengue. Lancet 2007; 370: 1644–52. Leo YS, Gan VC, Ng EL, et al. Utility of warning signs in guiding admission and predicting severe disease in adult dengue. BMC Infect Dis 2013; 13: 498. Gubler DJ. Epidemic dengue/dengue hemorrhagic fever as a public health, social and economic problem in the 21st century. Trends Microbiol 2002; 10: 100–03. Sabchareon A, Wallace D, Sirivichayakul C, et al. Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. Lancet 2012; 380: 1559–67. Low JG, Sung C, Wijaya L, et al. Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial. Lancet Infect Dis 2014; published online May 28. http://dx.doi.org/10.1016/S1473-3099(14)70730-3
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12
13
14
15
16 17
Tricou V, Minh NN, Van TP, et al. A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults. PLoS Negl Trop Dis 2010; 4: e785. Nguyen NM, Tran CN, Phung LK, et al. A randomized, double-blind placebo controlled trial of balapiravir, a polymerase inhibitor, in adult dengue patients. J Infect Dis 2013; 207: 1442–50. Courageot MP, Frenkiel MP, Dos Santos CD, Deubel V, Despres P. Alpha-glucosidase inhibitors reduce dengue virus production by affecting the initial steps of virion morphogenesis in the endoplasmic reticulum. J Virol 2000; 74: 564–72. Rathore AP, Paradkar PN, Watanabe S, et al. Celgosivir treatment misfolds dengue virus NS1 protein, induces cellular pro-survival genes and protects against lethal challenge mouse model. Antiviral Res 2011; 92: 453–60. Schul W, Liu W, Xu HY, Flamand M, Vasudevan SG. A dengue fever viremia model in mice shows reduction in viral replication and suppression of the inflammatory response after treatment with antiviral drugs. J Infect Dis 2007; 195: 665–74. Watanabe S, Rathore AP, Sung C, et al. Dose- and schedule-dependent protective efficacy of celgosivir in a lethal mouse model for dengue virus infection informs dosing regimen for a proof of concept clinical trial. Antiviral Res 2012; 96: 32–35. Muller DA, Young PR. The flavivirus NS1 protein: molecular and structural biology, immunology, role in pathogenesis and application as a diagnostic biomarker. Antiviral Res 2013; 98: 192–208. Halstead SB. Identifying protective dengue vaccines: guide to mastering an empirical process. Vaccine 2013; 31: 4501–07. Tam DT, Ngoc TV, Tien NT, et al. Effects of short-course oral corticosteroid therapy in early dengue infection in Vietnamese patients: a randomized, placebo-controlled trial. Clin Infect Dis 2012; 55: 1216–24.
www.thelancet.com/infection Published online May 28, 2014 http://dx.doi.org/10.1016/S1473-3099(14)70770-4
