Randomized, Placebo-controlled Trial of Nonpegylated and Pegylated Forms of Recombinant Human Alpha Interferon 2a for Suppression of Dengue Virus Viremia in Rhesus Monkeys

Overview

Journal Antimicrob Agents Chemother

Publisher American Society for Microbiology

Specialty Pharmacology

Date 2005 Oct 28

PMID 16251289

Citations 12

Authors

C Ajariyakhajorn

M P Mammen Jr

T P Endy

M Gettayacamin

A Nisalak

S Nimmannitya

D H Libraty

Affiliations

Soon will be listed here.

Abstract

Dengue fever and dengue hemorrhagic fever are caused by infection with any one of the four dengue viruses (DVs) and are significant public health burdens throughout the tropics. Higher viremia levels are associated with greater dengue disease severity. A therapeutic intervention to suppress viremia early in DV infection could potentially ameliorate severe disease. Recombinant alpha interferon 2a (rIFN-alpha-2a, Roferon-A) suppressed DV replication in human peripheral blood mononuclear cells in vitro. We therefore examined the effects of rIFN-alpha-2a and pegylated recombinant IFN-alpha-2a (PEG-rIFN-alpha-2a, PEGASYS) on DV serotype 2 (DV-2) viremia in rhesus monkeys. Flavivirus-naïve monkeys were inoculated with DV-2 and randomized to receive a single dose of rIFN-alpha-2a (10 million international units/m2) versus placebo or PEG-rIFN-alpha-2a (6 microg/kg) versus placebo 1 day after the onset of viremia. Serial daily viremia levels were measured, and convalescent-phase DV-2 neutralizing antibody titers were determined. Compared to placebo, a single injection of rIFN-alpha-2a temporarily suppressed DV-2 replication and delayed the time to peak viremia by a median of 3 days. However, measures of total viral burden were not different between the two groups. A single injection of PEG-rIFN-alpha-2a significantly lowered daily viremia levels and improved virus clearance, starting 48 h after administration. There were no significant differences in DV-2 neutralizing antibody titers between the treatment and placebo groups at 30 and 90 days postinfection. Based on their individual effects, future studies should investigate a combination of rIFN-alpha-2a and PEG-rIFN-alpha-2a for suppression of dengue virus viremia and as a potential therapeutic intervention.

Citing Articles

Zika antiviral chemotherapy: identification of drugs and promising starting points for drug discovery from an FDA-approved library.

Pascoalino B, Courtemanche G, Cordeiro M, Gil L, Freitas-Junior L F1000Res. 2016; 5:2523.

PMID: 27909576 PMC: 5112578. DOI: 10.12688/f1000research.9648.1.

Limited Effects of Type I Interferons on Kyasanur Forest Disease Virus in Cell Culture.

Cook B, Ranadheera C, Nikiforuk A, Cutts T, Kobasa D, Court D PLoS Negl Trop Dis. 2016; 10(8):e0004871.

PMID: 27479197 PMC: 4968803. DOI: 10.1371/journal.pntd.0004871.

Dengue therapeutics, chemoprophylaxis, and allied tools: state of the art and future directions.

Whitehorn J, Yacoub S, Anders K, Macareo L, Cassetti M, Nguyen Van V PLoS Negl Trop Dis. 2014; 8(8):e3025.

PMID: 25166493 PMC: 4148227. DOI: 10.1371/journal.pntd.0003025.

Endothelial cells in dengue hemorrhagic fever.

Srikiatkhachorn A, Kelley J Antiviral Res. 2014; 109:160-70.

PMID: 25025934 PMC: 4148486. DOI: 10.1016/j.antiviral.2014.07.005.

Targeting host factors to treat West Nile and dengue viral infections.

Krishnan M, Garcia-Blanco M Viruses. 2014; 6(2):683-708.

PMID: 24517970 PMC: 3939478. DOI: 10.3390/v6020683.

References

Stanley S, Ostrowski M, Justement J, Gantt K, Hedayati S, Mannix M . Effect of immunization with a common recall antigen on viral expression in patients infected with human immunodeficiency virus type 1. N Engl J Med. 1996; 334(19):1222-30. DOI: 10.1056/NEJM199605093341903. View

Wills R, SOIKE K . Pharmacokinetics of human recombinant interferon-alpha I after i.v. infusion and im injection in African green monkeys. J Interferon Res. 1988; 8(4):427-32. DOI: 10.1089/jir.1988.8.427. View

Koff W, Elm Jr J, Halstead S . Inhibition of dengue virus replication by amantadine hydrochloride. Antimicrob Agents Chemother. 1980; 18(1):125-9. PMC: 283951. DOI: 10.1128/AAC.18.1.125. View

Jonas M . Interferon-alpha for viral hepatitis. J Pediatr Gastroenterol Nutr. 1996; 23(2):93-106. DOI: 10.1097/00005176-199608000-00001. View

Eckels K, Dubois D, Putnak R, Vaughn D, Innis B, Henchal E . Modification of dengue virus strains by passage in primary dog kidney cells: preparation of candidate vaccines and immunization of monkeys. Am J Trop Med Hyg. 2004; 69(6 Suppl):12-6. DOI: 10.4269/ajtmh.2003.69.12. View

Wills R, SPIEGEL H, SOIKE K . Pharmacokinetics of recombinant alpha A interferon following I.V. infusion and bolus, I.M., and P.O. administrations to African green monkeys. J Interferon Res. 1984; 4(3):399-409. DOI: 10.1089/jir.1984.4.399. View

De Clercq E, Naesens L, De Bolle L, Schols D, Zhang Y, Neyts J . Antiviral agents active against human herpesviruses HHV-6, HHV-7 and HHV-8. Rev Med Virol. 2001; 11(6):381-95. DOI: 10.1002/rmv.336. View

Lanciotti R, Calisher C, Gubler D, Chang G, Vorndam A . Rapid detection and typing of dengue viruses from clinical samples by using reverse transcriptase-polymerase chain reaction. J Clin Microbiol. 1992; 30(3):545-51. PMC: 265106. DOI: 10.1128/jcm.30.3.545-551.1992. View

Henchal E, Putnak J . The dengue viruses. Clin Microbiol Rev. 1990; 3(4):376-96. PMC: 358169. DOI: 10.1128/CMR.3.4.376. View

10.

Diamond M, Roberts T, Edgil D, Lu B, Ernst J, Harris E . Modulation of Dengue virus infection in human cells by alpha, beta, and gamma interferons. J Virol. 2000; 74(11):4957-66. PMC: 110847. DOI: 10.1128/jvi.74.11.4957-4966.2000. View

11.

Guzman M, Kouri G . Dengue diagnosis, advances and challenges. Int J Infect Dis. 2004; 8(2):69-80. DOI: 10.1016/j.ijid.2003.03.003. View

12.

Diamond M, Zachariah M, Harris E . Mycophenolic acid inhibits dengue virus infection by preventing replication of viral RNA. Virology. 2002; 304(2):211-21. DOI: 10.1006/viro.2002.1685. View

13.

Firpi R, Nelson D, Davis G . Lack of antiviral effect of a short course of mycophenolate mofetil in patients with chronic hepatitis C virus infection. Liver Transpl. 2003; 9(1):57-61. DOI: 10.1053/jlts.2003.50003. View

14.

Haria M, Benfield P . Interferon-alpha-2a. A review of its pharmacological properties and therapeutic use in the management of viral hepatitis. Drugs. 1995; 50(5):873-96. DOI: 10.2165/00003495-199550050-00007. View

15.

Libraty D, Endy T, Houng H, Green S, Kalayanarooj S, Suntayakorn S . Differing influences of virus burden and immune activation on disease severity in secondary dengue-3 virus infections. J Infect Dis. 2002; 185(9):1213-21. DOI: 10.1086/340365. View

16.

Huggins J . Prospects for treatment of viral hemorrhagic fevers with ribavirin, a broad-spectrum antiviral drug. Rev Infect Dis. 1989; 11 Suppl 4:S750-61. DOI: 10.1093/clinids/11.supplement_4.s750. View

17.

Zeuzem S, Feinman S, Rasenack J, Heathcote E, Lai M, Gane E . Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med. 2000; 343(23):1666-72. DOI: 10.1056/NEJM200012073432301. View

18.

Endy T, Nisalak A, Chunsuttitwat S, Vaughn D, Green S, Ennis F . Relationship of preexisting dengue virus (DV) neutralizing antibody levels to viremia and severity of disease in a prospective cohort study of DV infection in Thailand. J Infect Dis. 2004; 189(6):990-1000. DOI: 10.1086/382280. View

19.

Vaughn D, Green S, Kalayanarooj S, Innis B, Nimmannitya S, Suntayakorn S . Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. J Infect Dis. 1999; 181(1):2-9. DOI: 10.1086/315215. View

20.

Takeda M, Pekosz A, Shuck K, Pinto L, Lamb R . Influenza a virus M2 ion channel activity is essential for efficient replication in tissue culture. J Virol. 2002; 76(3):1391-9. PMC: 135863. DOI: 10.1128/jvi.76.3.1391-1399.2002. View