Utility of Antivirals During a Pandemic: Uncertainties Persist
By Luciana Borio, M.D., July 30, 2008
Addendum (posted August 5, 2008)
During a pandemic, neuraminidase inhibitors will be the antivirals of choice. Based on their potential utility, the U.S. government has made substantial investments to ensure availability during a pandemic: 50 million treatment courses of the approved neuraminidase inhibitors, oseltamivir (Tamiflu), and zanamivir (Relenza), have been procured for the Strategic National Stockpile, and a $102.6 million contract was awarded in 2007 to BioCryst to advance clinical development of peramivir. Nonetheless, there remains great uncertainty about the usefulness of these drugs in a pandemic because access may be limited, resistance may develop, the dose and duration of treatment is uncertain, and numerous barriers may prevent the rapid administration necessary for optimal benefit.
The Promise of Zanamivir
Zanamivir is currently available only as an inhaler. Theoretically, an intravenous formulation would be beneficial because it could be used to treat more severely ill patients in a pandemic. Zanamivir is attractive because some viruses that have developed resistance to oseltamivir (H274Y variants) have retained susceptibility to zanamivir.1 Moreover, only one case of zanamivir resistance has been documented and that was in an immunocompromised child.2 There have been no reports of resistance in immunocompetent individuals.
Recent Study Results Limited, but Beneficial
Stittelaar and colleagues recently sought to evaluate the efficacy of i.v. zanamivir in preventing or treating H5N1 influenza A infection in cynomolgus macaques, an animal model* relevant to humans.3 To do so, they conducted two experiments on groups of six animals that were infected intratracheally with A/Hong Kong/156/97 (H5N1) virus. The first experiment assessed the efficacy of prophylactic i.v. zanamivir (2 or 10mg/kg) initiated 12 hours before infection and then given twice daily for 4 days. In the second experiment, the efficacy of a higher dose (20mg/kg) of prophylactic i.v. zanamivir, and the efficacy of treatment with i.v. zanamivir administered at 20mg/kg beginning 4 hours after challenge were examined. All animals were euthanized at 5 days post-infection for examination of gross and histological lung pathology. Results are summarized in the table below.
(log10 CCID50/g tissue)
In the first experiment, the higher prophylactic dose performed better than the lower dose or placebo, but there was significant variation observed between the animals in each group: only 3 of the 6 animals in the higher dose group had significantly reduced viral titers in their lungs. Evidence of pneumonia was also markedly reduced in the higher dose group: pneumonia was present in only 1 of 6 animals in the 10mg/kg group, compared with 4 of 6 in the 2mg/kg group and 3 of 6 in the placebo group.
In the second experiment, both prophylactically and therapeutically treated groups exhibited reduced lung viral titers as compared with placebo. However, the differences were not statistically significant. Evidence of frank pneumonia on gross pathology was virtually absent from the treated groups, whereas severe pneumonia was present in all of the control animals, often with adhesive fibrinous pleuritis. Histological changes of pneumonia were present in all of the animals that began treatment 4 hours post-challenge, however.
Of note, both control and treated animals shed virus from the pharynx after challenge, albeit at relatively low titers.
Study Conclusion: While this study may support a potential role for i.v. zanamivir in the therapeutic armamentarium against H5N1 influenza viruses, there was marked variability in the demonstrated efficacy among animals in each group, and the therapeutic benefit of zanamivir administered after flu challenge, to mimic treatment, was not statistically significant. This most likely reflects the small number of animals studied, but the authors also postulate variable infectivity of the H5N1 virus or genetic variation within the macaque population. Finally, the authors don’t indicate whether the pathology scoring was performed in a blinded fashion.
Last year BioCryst reported results from a Phase II study evaluating the efficacy of intramuscular peramivir for alleviating symptoms in patients with confirmed influenza infection: the improvement was not statistically significant. Given the lackluster study results, the potential for development of resistance, especially in the case of oseltamivir4, and as yet unresolved policies related to distribution, the most reasonable conclusion to be drawn right now is that additional investments to acquire antiviral stockpiles will have to be made under the shadow of uncertainty about the future benefit of these drugs.
*Note: The activity of zanamivir against H5N1 influenza A viruses has been shown previously in small animal models.2 However, because the respiratory tracts and drug metabolism in these animal models are inherently different from those of humans, the conclusions that can be drawn from the results of those studies are limited.
- Wetherall NT, Trivedi T, Zeller J, et al. Evaluation of neuraminidase enzyme assays using different substrates to measure susceptibility of influenza virus clinical isolates to neuraminidase inhibitors: report of the neuraminidase inhibitor susceptibility network. J Clin Microbiol. 2003;41(2):742-750.
- Gubareva LV, Matrosovich MN, Brenner MK, et al. Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis. 1998 Nov;178(5):1257-1262.
- Stittelaar KJ, Tisdale M, van Amerongen G, et al. Evaluation of intravenous zanamivir against experimental influenza A (H5N1) virus infection in the cynomolgus macaques. Antiviral Res. 2008; doi:10.1016/j.antiviral.2008.06.014. Accessed July 29, 2008.
- de Jong MD, Thanh TT, Khanh TH, et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med. 2005;353(25):2667-2672.
To our knowledge, it is the case that no therapeutic failures with zanamivir due to resistance have been reported in the literature. However, Dr. Henry Niman, one of our readers, pointed out that resistance testing and sequencing carried out during global surveillance of circulating seasonal influenza strains have detected the presence, albeit at a low level, of novel mutations in the neuraminidase gene that renders it resistant to zanamivir. These mutations include: Q136K, K150T, K143R. [Hurt AC and Barr IG. Novel Mutations in the ‘150-Cavity' of N1 Neuraminidase Confer Reduced Sensitivity to the Neuraminidase Inhibitors. Abstract O67. Options for the Control of Influenza VI Conference, June 17-23, 2007, Toronto, Canada]. The factors that lead to the emergence of resistance are still poorly understood and puzzling since resistant isolates have been retrieved from places where neuraminidase inhibitors are not widely used.
Although it is correct to assert that oseltamivir-resistant strains retain susceptibility to zanamivir, it is possible for neuraminidase inhibitors in general to lose their status as antivirals of choice in a pandemic if more widespread resistance emerges, regardless of whether or not they are widely used prior to a pandemic.
For more information, see: Sheu TG et al. Surveillance for neuraminidase inhibitor resistance among human influenza A and B viruses circulating worldwide in 2004-2008. Antimicrob Agents Chemother 2008;doi:10.1128/AAC.00555-08.
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