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Influenza pandemic the use of antivirals Aura Timen, MD, PhD 1 20 januari 2011 Content 1. 2. 3. 4. 2 20 januari 2011 the viruses the disease seasonal flu/pandemic use of antivirals Influenza: the viruses Oseltamivir: neuraminidase inhibitor Neuraminidase: 9 subtypes : N1, N2…N9 Hemagglutinine: 16 subtypes: H1, H2,…H16 3 Influenza A © 1998 American Museum of Natural History Pandemie | 20 januari 2011 •Usually Seasonal influenza: clinical picture •Acute onset •Fever (>38ºC) •Sore throat •Dry cough •Chills Copyright a.j.jacobi •Muscle pain •Severe disease, complications •Dyspnea •Chest pain •Hemoptysis •Prolonged or recurrent fever •Altered mental status 4 Pandemie | 20 januari 2011 4 5 BRON: NIVEL Pandemie | 20 januari 2011 New virus: combination of genes from 4 viruses ~ 1998 PB2,PA: Triple reassortant ~ 1968 ~ 1998 PB1: ~ 1918 HA, NP, NS: ~ 1979 NA, MA: Classical swine Eurasian swine A/California/4/2009 PB2 PB1 PA HA NP Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team*, New England Journal of Medicine, 2009 6 Pandemie | 20 januari 2011 NA MA NS Pandemics of influenza H2N2 H2N2 H1N1 H1N1 H3N8 1895 1905 1889 Russian influenza H2N2 1915 1925 1900 Old Hong Kong influenza H3N8 1955 1918 Spanish influenza H1N1 1965 1957 Asian influenza H2N2 1975 1985 2005 2010 2009 Novel influenza H1N1v H9* 1999 H5 1997 2003 H7 1980 1955 1995 1968 Hong Kong influenza H3N2 Recorded new avian influenzas 7 H1N1v H3N2 1965 1975 1985 1996 1995 2002 2005 Pandemie | 20 januari 2011 Reproduced and adapted (2009) with permission of Dr Masato Tashiro, Director, Center for Influenza Virus Research, National Institute of Infectious Diseases (NIID), Japan. BRON: ECDC 2015 Some of the 'known unknowns' in the 20th century pandemics ● ● ● ● ● Three pandemics (1918, 1957, 1968) Different shapes and waves Differences in effective reproductive number Different groups affected Different levels of severity including case fatality ratio ● Imply different approaches to mitigation •New virus •Efficient person-toperson transmission •Significant disease •No previous immunity Worldwide spread 8 Pandemie | 20 januari 2011 Age-specific clinical attack rate in previous pandemics 60% 1957 Kansas City 1957 S Wales 1957 SE London 1968 Kansas City % with clinical disease 50% 1918 New York State 1918 Manchester 1918 Leicester 1918 Warrington & Wigan 40% 30% 20% 10% 0% 0 20 40 60 80 Age (midpoint of age class) 9 With thanks to Peter Grove, Department of Health, London, UK Pandemie | 20 januari 2011 ECDC Differing attack rates determined by serology: serological attack rate observed in the UK 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 0-9 10-19 1969 (first wave) 10 Courtesy of the Health Protection Agency, UK 20-29 30-39 40-49 50-59 60-69 1970 (second wave) Pandemie | 20 januari 2011 70-79 1957 ECDC Different age-specific excess deaths in pandemics 4000 Excess deaths 3500 3000 2500 2000 1500 1000 Excess deaths, second wave, 1918 epidemic 500 0 <1 1-2 2-5 5-10 10-15 15-20 20-25 25-35 35-45 45-55 55-65 65-75 75+ Age group 16000 Excess deaths 14000 12000 10000 8000 6000 Excess deaths second wave 1969 pandemic, England and Wales 4000 2000 0 0-4 5-9 10-14 15-19 20-24 25-34 35-44 45-54 55-64 65-74 75+ Age group 11 Source: Department of Health, UK Pandemie | 20 januari 2011 ECDC Numbers affected in seasonal influenza epidemics and pandemics (overall clinical attack rate in previous pandemics) 45% clinical attack rate (%) 40% 35% 30% 25% 20% 15% 10% 5% 0% 12 Seasonal influenza 1918 New York State 1918 Leicester 1918 Warrington and Wigan 1957 SE London 1968 Kansas City Pandemie | 20 januari 2011 ECDC Seasonal influenza compared to pandemic — proportions of types of cases Deaths Requiring hospitalisation Deaths Requiring hospitalisation Clinical symptoms Asymptomatic Seasonal influenza 13 Clinical symptoms Asymptomatic Pandemic Pandemie | 20 januari 2011 14 Pandemie | 20 januari 2011 15 Pandemie | 20 januari 2011 16 Pandemie | 20 januari 2011 17 Pandemie | 20 januari 2011 www.who.int 18 Pandemie | 20 januari 2011 FASE 6 19 www.who.int Pandemie | 20 januari 2011 Oseltamivir stockpile: 5.000.000 courses (assumption clinical AR = 30%) Gezondheidsraad, publicatienr. 2005/05 Treatment 2 dd 75 mg/5 days Prophylaxis 1 dd 75 mg/ 7 days 20 Pandemie | 20 januari 2011 v/d Wijngaard et al. NTVG 21 Pandemie | 20 januari 2011 Notification rules change AH1N1 is comparable with seasonal flu Laboratory confirmed cases of Novel Influenza A (H1N1), date of onset April 29 to August 14 (N=1564) All countries with significant local transmission in the case definition Import Transmission in the Netherlands US included in the case definition 22 Routine contact tracing stops Pandemie | 20 januari 2011 v/d Wijngaard et al. ● ● ● ● ● ● Ned Tijdschr Geneeskd. 2009;153:A1053NTVG jaar 2005 2006 2007 2008 2009 (tot 1 juli) oseltamivir 14 158 8 805 1 048 608 9 069 zanamivir 353 92 58 46 92 Aantal verstrekkingen van oseltamivir en zanamivir per jaar via openbare apotheken in Nederland, in de periode 2005-2009 (bron: Stichting Farmaceutische Kengetallen) 1000 kuren door GGD’s 23 Pandemie | 20 januari 2011 Antivirals ● Containment: PHS – April 28-June 29: treatment of patients and prophylaxis in household contacts (in NL: 126 patients) – June 30-August 15: treatment of patients (in NL: > 1000 patients) ● Mitigation: GP’s, hospitals – August 15 – February 2010: treatment of patients from risk groups or with severe disease 24 Pandemie | 20 januari 2011 Tamifluverstrekking aan apotheken, ziekenhuizen en apotheekhoudende huisartsen (1 = 30 kuren) 160 140 Hoeveelheid kuren 120 100 80 60 40 20 33 34 35 36 37 38 39 40 41 42 43 Week 25 Pandemie | 20 januari 2011 44 45 Antivirale middelen (aug – dec) 26 • Zeer beperkt voorgeschreven • Oseltamivir en indicatie: 72% Pandemie | 20 januari 2011 Conclusions ● ● ● ● 27 Incidents trigger an increase in consumption Prescribing behavior of GP’s and PHS is according to the guidelines Proper communication about indications Restricted demand from the public Pandemie | 20 januari 2011 Influenza A (H1N1) 2009 pandemic in the Netherlands ● 2193 patients admitted to hospital (50% with co-morbidity) ● 63 notified deaths (90% with co-morbidity) 28 Pandemie | 20 januari 2011 Leeftijdsverdeling van patiënten met ziekenhuisopname IC opname Sterfte 29 BRON: CIb Pandemie | 20 januari 2011 Where do we stand now? 30 Pandemie | 20 januari 2011