TREATING MEXICAN (NOVEL) INFLUENZA IN AN IMMUNOCOMPROMISED PATIENT

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Charity Freeman
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1 TREATING MEXICAN (NOVEL) INFLUENZA IN AN IMMUNOCOMPROMISED PATIENT

Zanamivir (carbons coloured grey) No conformational change required to

Oseltamivir (carbons coloured yellow) with selected carbon atoms numbered

from: Collins PJ, Haire LH, Lin YP, et al.

4 Zanamivir (carbons coloured grey) No conformational change required to allow binding Sialic acid Natural Substrate (carbons coloured blue), Oseltamivir (carbons coloured yellow) with selected carbon atoms numbered Conformational change of active site required to allow binding Reproduced from: Collins PJ, Haire LH, Lin YP, et al. Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants. Nature 2008; 453:

5 What is antiviral resistance? Neuraminidase inhibitors - Relenza (zanamavir) and Tamiflu (oseltamivir) work by.

The pattern of OS resistance depends on the N subtype.

6 Mechanism of resistance to oseltamivir The neuraminidase active site changes shape to create a pocket for oseltamivir Amino acids changes can lead ro reduction in binding oseltamivir. The pattern of OS resistance depends on the N subtype. For N1 the change occurs at H275Y, does not confer cross resistance to zanamivir. Reproduced from Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med 2005;353: , with permission.

7 Influenza mutants resistant to NAI`s Gubareva et al. Lancet 2000; Bantia et al. Antiviral Res 2000; Carr et al. Antiviral Res 2000 Mutation Drug Reduction (fold) in NA sensitivity Reduction (fold) in animal infectivity In vitro/ clinical Virus Glu119Gly Zanamivir >100 4 in vitro A/H1N9 Glu119Ala Zanamivir >100 in vitro A/H4N2 Glu119Asp Zanamivir >1000 in vitro B Glu119Val Oseltamivir ~20 > clinical A/H3N2 Arg292Lys Oseltamivir ~ > both A/H3N2 Arg292Lys Zanamivir ~10-30 ~400 Arg292Lys RWJ ~10-20 Arg152Lys Zanamivir >1000 ~60 His274Tyr Oseltamivir >400 >1000 in vitro in vitro clinical both A/H4N2 A/H2N2 B A/H1N1

8 H5N1 treatment effects of oseltamivir. M. de Jong et al., NEJM 2005

9 Antiviral resistance: summary Antivirals Influenza Viruses H1N1 H3N2 B Pandemic H1N1/09 Adamantanes Susceptible Resistant Resistant Resistant Oseltamivir Resistant Susceptible Susceptible Susceptible Zanamivir Susceptible Susceptible Susceptible Susceptible

10 Pattern of OS Resistance Incidents of resistance by month Number of cases June 09 July 09 August 09 September 09 October 09 November 09 December 09 January 10 Month

11 Incidence of oseltamivir resistance to p- H1N1 by country Incidents of resistance by country Countries where cases reported Yemen Vietnam USA UK Thailand Taiwan Taipei Switzerland Spain Singapore Portugal Netherlands Korea Japan Italy Israel Hong Kong Germany France Denmark China Canada Australia number of cases

12 Incidence of oseltamivir-resistant viruses by patient and intervention characteristics Incidents of resistance by key characteristics 80 Number of cases PEP Immunocompromised Treatment No Exposure Tamiflu Exposure confirmed Characteristic PEP = post-exposure prophylaxis

13 TM European Summary of Product Characteristics (SmPC) Overview (Please refer to full SmPC for further informati September 2009 Please note: Local approval is required before use. 1

14 Therapeutic Indication and Dosage Indication Treatment Influenza A & B in adults and children (> 5 years) who present with symptoms typical of influenza when influenza is circulating in the community. Prophylaxis Post-exposure prophylaxis of Influenza A and B in adults and children (> 5 years) following contact with a clinically diagnosed case in a household. Seasonal prophylaxis of Influenza A and B during community outbreak in exceptional circumstances. Dosage Two inhalations (2 x 5 mg) twice daily for five days, providing a total daily inhaled dose of 20 mg. Treatment should begin as soon as possible, within 48 hours after onset of symptoms for adults, and within 36 hours after onset of symptoms for children. Post-exposure Prophylaxis Two inhalations (2 x 5 mg) once daily for 10 days. Therapy should begin as soon as possible and within 36 hours of exposure to an infected person. Seasonal prophylaxis Two inhalations (2 x 5 mg) once daily for up to 28 days. No dose modification is required in patients with impaired renal or hepatic function or in elderly patients. 5

16 The patient was given zanamivir 20 mg per day inhalation and oseltamivir 2dd 75 mg po.

17 Genotypic assay

18 Genotypic assay

19 Oseltamivir sensitivity

20 Zanamivir sensitivity

21 Two days later the patient required mechanical ventilation for progressive respiratory failure and intravenous zanamivir (600 mg per day on compassionate use basis ) was started along with continued oseltamivir p.o 2 x 75mg.

24 Patient casus

25 Discussion & Conclusion During prolonged infection with an OS resistant virus combination therapy did result in a disappearance of the OS resistant virus. Combination therapy did not lead inhibition of viral replication of clearance of the virus Pharmacological issues are most probably limiting the efficacy of zanamivir (i.v) in immuno compromised patients Additional anti-influenza drugs are urgently needed given the ease of spread od OS resistant viruses and the limited efficacy of zanamivir ( iv)) in immuno compromised patients.

26 Acknowledgements University Medical Center Groningen Heleen Aardema,, Jaap Tulleke, Ries Van den Biggelaar,, Bert Wolters,, Corine de Jager, Bert Niesters, Annelies Riezebos-Brilman. Erasmus Medical Center Rotterdam Erhard van der Vries, Martin Schutten, Thijs Beersma, Annemiek van de Eijk, Ab Osterhaus

Situation Update Pandemic (H1N1) August 2009

Situation Update Pandemic (H1N1) 2009 31 August 2009 Timeline pandemic (H1N1) 2009 April 12: an outbreak of influenza-like illness in Veracruz, Mexico reported to WHO April 15-17: two cases of the new