Treatment of Dengue Failure of a Novel Agent
By Joseph F. John, Jr., MD, FACP, FIDSA, FSHEA
Associate Chief of Staff for Education, Ralph H. Johnson Veterans Administration Medical Center; Professor of Medicine, Medical University of South Carolina, Charleston
Dr. John reports no financial relationships in this field of study.
SYNOPSIS: There was no evidence of significant benefit from the administration of the antiviral agent, celgosivir, in the treatment of patients with dengue fever.
SOURCE: Low JG, 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 Inf Dis 2014;14:706-715.
Dengue is a miserable disease that occurs worldwide and has at times resulted in massive epidemics. Almost 400 million cases occur globally each year. There are no vaccines to prevent the disease and there is no proven therapy. Some antiviral chemotherapies have focused on inhibition of two genes, NS3 and NS5, that regulate polyprotein processing and RNA replication respectively. Celgosvir (sometimes called Bu-Cast and manufactured by Dalton Pharma Services, Toronto, Canada) is a 6-O butanoly prodrug of castanospermine, a compound that occurs naturally in the seeds of Castanospermum australe. It blocks the endoplasmic reticulum of all four serotypes of the virus.
This trial involved 50 subjects from among 69 who were screened. 18 (34%) had secondary dengue infection as evidenced by the presence of preexisting antibody to the virus.. Subjects were all from Singapore and received a loading dose of 400 mg and thereafter a dose of 200 mg every 12 hours. Subjects were admitted to a hospital for 5 days to participate in the study.
There was actually an international team running the study which had genomic and immunologic input. Statistical analysis was strong. A process called a finite mixture model was used to analyze the viral loads at day 2 and day 4. Clearance of the protein NS1 was also measured up through day 15. Use of drugs between day 1 and 5 was also measured.
The outcomes were disappointing for efficacy but the data generated by the study were most interestng. Viral loads and fever quantity were higher for the celgosivir than for placebo but the differences were not significant. Both for the treatment and placebo group, body temperature began above 38.0 degrees C for all subjects. By 90-96 hurs, almost all subjects had temperatures of 37 C. There were only about 5 severe events in both treatment and placebo groups. There was more diarrhea in the celgosvir group than in the placebo group. All patients recovered from their illness.
The results from this treatment study of dengue fever in Singapore showed that an antiviral medication, celgosivir, was well tolerated but resulted in no reduction in symptoms, hematological abnormalities nor in reduction of viral load. Patients were enrolled by point of care testing which did not detect all the secondary cases. The fact that 34% of cases were secondary was a potential confounding factor since recurrences of dengue are often more severe. Nevertheless, the fever curves and viral load reductions were so very similar that this particular confounding likely did not affect the outcomes.
As the authors point out the study was not powered to detect small changes in viral load so celgosivir may be worthy of further investigation, perhaps as combinational therapy or in increased dosage. This study was very useful to show that the serotype did not seem to influence the clinical course, hospitalization of patients may have resulted in a lack of fatality, and that this type of antiviral medication, an alpha-glucosidase inhibitor, could be well tolerated. The data were very useful also to show that fever reduction correlated with clearance of virus. There is a continued rationale, therefore, that antivirals aimed at reducing Dengue virus load may result in reduction of the disabling symptoms with this rampant mosquito-borne illness.