New animal data published in Antimicrobial Agents and Chemotherapy show that the oral antiviral drug Tamiflu® (oseltamivir) is effective against two currently circulating strains of H5N1 avian influenza viruses, preventing death if treatment is initiated within 24 hours of virus exposure[i]. Conclusions drawn from the study data add to the growing bank of evidence showing oseltamivir is effective against H5N1 avian influenza strains[ii], and adds further support to the important role that oseltamivir will play in the event of a pandemic.
"The results of this study confirm that oseltamivir can prevent mortality caused by infection with H5N1 avian influenza viruses", commented Dr. Elena Govorkova, St. Jude Children's Research Hospital, lead investigator of the study. "There was also no emergence of oseltamivir-resistant variants when the drug is administered at optimal dosages."
The laboratory study evaluated the administration of 5 mg/kg/day (equivalent to half of the recommended dose of 75 mg/kg in humans) of oseltamivir for five days, administered either four hours or twenty-four hours post-infection with either the highly pathogenic A/Vietnam/1023/04 (H5N1) virus strain, or the less pathogenic A/Turkey/15/06 (H5N1) virus strain. Administration of oseltamivir within four hours resulted in 100% survival following inoculation of the virus.1
When treatment was delayed until 24 hours after virus inoculation, treatment with the higher dose of 25 mg/kg/day was required against the Vietnam H5N1 strain and the higher dose of 10 mg/kg/day against the less pathogenic Turkey H5N1 strain.1 This was associated with 100% survival against both strains and markedly reduced the severity of disease, weight loss and fever.1
The research also examined whether oseltamivir treatment affects immune responses for subsequent infections, and showed that exposure to oseltamivir resulted in an immune response that offered complete protection from re-infection.1 Furthermore, no resistance to the drug was detected during the study.1
"The course of H5N1 infection in ferrets is very similar to that in humans," said Robert Webster, a member of the Infectious Diseases department, holder of the Rose Marie Thomas Chair at St. Jude, and senior author of the report. "This model lets us study infection with a variety of H5N1 viruses," he added. "Since not all human cases of H5N1 infection are fatal, it is useful to evaluate drugs against viruses of different pathogenicity."
According to the World Health Organization (WHO), human cases of avian influenza A (H5N1) infection have remained rare and sporadic, but the disease can be very severe and the case fatality is high[iii]. The H5N1 influenza viruses isolated in Southeast Asia and Turkey induce a severe infection in humans, which results in deaths of more than 50% of those infected. The WHO has confirmed 282 human infections (March 27th, 2007) which has resulted in 169 deaths[iv].
This study provides further insights into this highly pathogenic virus, confirming both its efficiency at replicating and its virulence. Virologists expect that the H5N1 avian influenza virus must mutate before it becomes efficient in human-to-human transmission. Oseltamivir is designed to be active against all clinically relevant influenza viruses[v], including the H5N1 virus, and has previously been shown to be effective in cell culture and in animals infected with the H5N1 virus isolated from humans[vi].
The WHO strongly recommends oseltamivir for the treatment of patients with confirmed or strongly suspected human infection with the H5N1 virus. This guidance was based on discussions from an international multidisciplinary panel of experts in March 2006 to develop rapid advice for the pharmacological management of patients with H5N1 infection by using innovative guideline development methods based on the best available evidence. The panel considered the benefits, harm, burden and cost of intervention in several patient and exposure groups when developing the recommendations. The recommendations and pharmacological guidelines for the prophylaxis and treatment of patients with avian influenza have been published in the January 2007 issue of The Lancet Infectious Diseases[vii].