克流感抗藥性及替代療法 衛生署疾病管制局中區傳染病防治醫療網王任賢指揮官

Transcription

1 克流感抗藥性及替代療法 衛生署疾病管制局中區傳染病防治醫療網王任賢指揮官

2 Overview Neuraminidase Inhibitors Emergence of oseltamivir resistance in A(H1N1) in 2008 Resistance monitoring of pandemic H1N viruses Adamantanes Current levels of resistance in seasonal and pandemic viruses Summary

3 Overview Neuraminidase Inhibitors Emergence of oseltamivir resistance in A(H1N1) in 2008 Resistance monitoring of pandemic H1N viruses Adamantanes Current levels of resistance in seasonal and pandemic viruses Summary

4 Influenza antiviral drugs Neuraminidase (NA) inhibitors Inhibit neuraminidase Used since 1999 Zanamivir and Oseltamivir (Relenza and Tamiflu ) Effective for influenza A and B Large volumes stockpiled for pandemic use Prior to 2007, resistance was uncommon

5 Emergence of oseltamivir resistance European 2007/2008 influenza season Oseltamivir resistant isolates first detected in France, UK and Norway in late 2007 H274Y mutation in NA responsible for the resistance

6 Emergence of oseltamivir resistance European 2007/2008 influenza season Oseltamivir resistant isolates first detected in France, UK and Norway in late 2007 H274Y mutation in NA responsible for the resistance What impact does the H274Y have on resistance? Change in IC 50 Oseltamivir 1500-fold Zanamivir No change

7 Emergence of oseltamivir resistance European 2007/2008 influenza season Oseltamivir resistant isolates first detected in France, UK and Norway in late 2007 H274Y mutation in NA responsible for the resistance From untreated patients - low oseltamivir usage in Europe Oseltamivir prescriptions in 2007 No. of prescriptions (millions) Japan USA Europe Source : IMS Rx data Germany: 49 % France: 38 % Greece: 1 % Finland: 3 % Belgium: 7 % Austria: 2 % Other countries with negligible use

8 Emergence of oseltamivir resistance European 2007/2008 influenza season Oseltamivir resistant isolates first detected in France, UK and Norway in late 2007 H274Y mutation in NA responsible for the resistance From untreated patients - low oseltamivir usage in Europe Subsequent testing revealed spread of mutant throughout Europe

9 Emergence of oseltamivir resistance Meijer et. al., EID, 15 (4), 2009

10 Emergence of oseltamivir resistance European 2007/2008 influenza season Oseltamivir resistant isolates first detected in France, UK and Norway in late 2007 H274Y mutation in NA responsible for the resistance From untreated patients - low oseltamivir usage in Europe Subsequent testing revealed spread of mutant throughout Europe Variable resistance seen in different countries

11 Emergence of oseltamivir resistance Meijer et. al., EID, 15 (4), % Compared with < 1% resistance in previous seasons across all countries!! 47 % 67 %

12 Emergence of oseltamivir resistance European 2007/2008 influenza season Oseltamivir resistant isolates first detected in France, UK and Norway in late 2007 H274Y mutation in NA responsible for the resistance From untreated patients - low oseltamivir usage in Europe Subsequent testing revealed spread of mutant throughout Europe Variable resistance seen in different countries Fit oseltamivir resistant virus circulating not driven by drug usage USA 2007/2008 influenza season Oseltamivir resistant viruses being detected

13 16% 25%?

14 16% 25% WHO CC Melbourne received H1 viruses from these countries during 2008 season

15 % Resistance in A(H1N1) viruses in % (n=22) 44% (n=34) 6% (n=34) 0% (n=5) 91% (n=11) 100% (n=26) 30% (n=10) 86% (n=111) 100% (n=7) 75% (n=4)

16 Emergence of H274Y mutant viruses in different countries. Australia Oseltamivir resistant H274Y virus Oseltamivir sensitive virus Macau Malaysia New Caledonia New Zealand Philippines Singapore South Africa Taiwan Thailand Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct

17 Emergence of H274Y mutant viruses in different countries. Predominantly H274Y mutants Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Predominantly H274Y mutants Australia Macau Malaysia New Caledonia New Zealand Philippines Singapore South Africa Taiwan Thailand

18 Speed of H274Y global spread = prevalence of oseltamivirresistant A(H1N1) H274Y mutants in Oceania, South East Asia and South Africa From 0 to 100% in one year! Meijer et. al., EID, 15 (4), 2009

19 ..and now in 2009 Virtually 100% of seasonal A(H1N1) viruses are oseltamivir resistant Australia Thailand Singapore Philippines Fiji New Zealand Tahiti 97% (n=33) 100% (n=18) 100% (n=17) 100% (n=9) 100% (n=7) 100% (n=6) 100% (n=1)

20 Regional publication WHO CC and NIC collaboration It was great opportunity for an NIC / CC collaboration and co-publication 27 authors!!!

21 H274Y or H275Y? N1 amino acid sequence M N P N Q K N N A P N F H Y E H = Oseltamivir Sensitive Y = Oseltamivir Resistant Question: : If this is residue 275 why do people refer to the mutation as H274Y? Answer: : Because they are referring to the residue based on N2 numbering

22 H274Y or H275Y? N1 amino acid sequence M N P N Q K N N A P N F H Y E N2 amino acid sequence Equivalent Histidine residue M N P N Q K... G S A Q H V E

23 H274Y or H275Y? Traditionally N1 residues have been numbered based on the equivalent residue in the N2 neuraminidase However, either H274Y or H275Y are acceptable for reporting, publication, etc Important that: State which numbering system you are using eg H274Y (based on N2 numbering) Ensure that you are looking at the correct residue!!!

24 Overview Neuraminidase Inhibitors Emergence of oseltamivir resistance in A(H1N1) in 2008 Resistance monitoring of pandemic H1N viruses Adamantanes Current levels of resistance in seasonal and pandemic viruses Summary

25 Pandemic H1N As of 31 July, 162,000 cases confirmed Unprecedented volumes of oseltamivir (and zanamivir) used to treat infected patients and prophylax contacts Only eight reported cases of oseltamivir resistance Denmark, 4 x Japan, Canada, Hong Kong, Singapore All resistant viruses contained the H274Y mutation

26 Oseltamivir resistant cases Only eight reported cases of oseltamivir resistance Denmark, 4 x Japan, Canada, Singapore, Hong Kong Patients under Patient Patient did not oseltamivir received full receive prophylaxis oseltamivir oseltamivir dose Already infected? Of more concern if Suboptimal dose? resistant viruses are occurring in the absence No evidence of of drug selective transmission of resistant pressure virus to contacts

27 NA enzyme inhibition assay Neuraminidase enzyme inhibition assay (fluoresence( fluoresence- based) testing of cultured isolates April May June July Aug TOTAL New Zealand Australia Philippines Singapore Fiji TOTAL None of the isolates tested have demonstrated resistance to either oseltamivir or zanamivir

28 Genetic analysis Conventional sequencing Pyrosequencing Mutation detection H274Y Rapid: following PCR, can analyse 96 samples in less than one hour Dr Yi-Mo Deng, WHO CC, Melb None of the clinical specimens tested have contained the H274Y mutation

29 Overview Neuraminidase Inhibitors Emergence of oseltamivir resistance in A(H1N1) in 2008 Resistance monitoring of pandemic H1N viruses Adamantanes Current levels of resistance in seasonal and pandemic viruses Summary

30 Influenza antiviral drugs Adamantanes Inhibit M2 channel protein Used since 1967 Amantadine and rimantadine (Symmetrel and Flumadine )

31 Influenza antiviral drugs Adamantanes Inhibit M2 channel protein Used since 1967 Amantadine and rimantadine (Symmetrel and Flumadine ) Rapidly select for resistance Effective only for influenza A

32 Adamantane resistance Overall Australasia and South East Asia % adamanatne resistant A(H3N2) Sample date (Year)

33 Adamantane resistance Overall Australasia and South East Asia % adamanatne resistant A(H3N2) Sample date (Year) A(H1N1) pandemic 2009 A(H1N1) seasonal

34 Overview Neuraminidase Inhibitors Emergence of oseltamivir resistance in A(H1N1) in 2008 Resistance monitoring of pandemic H1N viruses Adamantanes Current levels of resistance in seasonal and pandemic viruses Summary

35 Summary Virtually 100% of current seasonal A(H1N1) viruses are oseltamivir ir resistant However the number of seasonal A(H1N1) viruses circulating has decreased significantly since the emergence of pandemic A(H1N1) Will the seasonal A(H1N1) continue to circulate?

36 Summary Virtually 100% of current seasonal A(H1N1) viruses are oseltamivir ir resistant However the number of seasonal A(H1N1) viruses circulating has decreased significantly since the emergence of pandemic A(H1N1) Will the seasonal A(H1N1) continue to circulate? Influenza specimens analysed from Victoria, Australia, by VIDRL 20 July 27 July 3 August 10 August A(H1N1) pandemic A(H3N2) A(H1N1) Influenza B Data kindly provided by Dr Chris Birch, VIDRL, Melbourne

37 Summary Virtually 100% of current seasonal A(H1N1) viruses are oseltamivir ir resistant However the number of seasonal A(H1N1) viruses circulating has decreased significantly since the emergence of pandemic A(H1N1) Will the seasonal A(H1N1) continue to circulate? Large volumes of NA inhibitors have been used to treat pandemic A(H1N1) infections Encouragingly only a few cases of resistance have been detected with no evidence of further transmission Pandemic A(H1N1) and seasonal A(H3N2) are all resistant to adamantanes Continued monitoring of pandemic A(H1N1) viruses is essential, particularly in patients under treatment and their contacts

38 替代療法

39 替代療法之選項 自我健康管理 其他 NA inhibitor Vaccination

40 自我健康管理

41 Pandemic (H1N1) 2009 fatal cases WPR Total death 136 Clinical course (n=27) 9 days-medium interval from onset of symptoms to death (range 4-14) 5 days-medium interval from onset of symptoms to hospitalization (range 2-8) 3 days-medium interval from hospitalization to death (range 2-9)

42 北京朝陽醫院 1054 ph1n1 輕症案例 潛伏期 2.2 天 發燒 2-3 天 咳嗽 4-6 天 Viral shedding 6-7 天 Pneumonia 6% 潛伏期 發燒 咳嗽 Viral shedding 均同於無肺炎者

43

44 ph1n1 之轉診時機 流感病患若有症狀後第三日仍高燒不退就是 impending 重症 應給予照胸部 X 光 鼻咽採檢 及投與克流感 個人適當之自我健康管理可減少克流感之使用, 進而減低抗藥性之產生

45 Oseltamivir and viral shedding by RT-PCR 1023/1054 mild ph1n1 cases Viral shedding days Mean=6.4 days 0 No <24 h h >48 Onset to oseltamivir

46 Case fatality rate by time from symptom onset to treatment with oseltamivir Deceasesd (%) Untreated Treated 0 to 2 3 to 4 5 to 6 7 to 8 9 to Treatment status and time from symptom onset to treatment (days)

47 Risk of death: oseltamivir treatment vs no antiviral to 2 3 to 4 5 to 6 7 to 8 9 to Risk of death Time from symptom onset to treatment (days)

48 Oseltamivir treatment of ph1n1, Vietnam, May-June 2009 Number (%) Virus Positive on Hospital Day RT- PCR (n=44) 44 (100%) 25 (57%) 21 (48%) 8 (18%) 8 (18%) 0 Culture (n=13) 10/11 (91%) 6/11 (55%) 4/13 (31%) 6/13 (46%) 2/7 (27%) NR R van Doorn et al. ProMED 8 July 2009, 8 August 2009

49 其他 NA inhibitors

50 NA Inhibitor Resistance Profiles NA mutation NA type /subtype Susceptibility in the NAI assay (fold ) Oselt Zana Peram A E119V A/N2 R (>50) S (1) S (1) S (1) R292K A/N2 R (>1000) S (4-25) R (40-80) S (8) H274Y A/N1 R (>700) S (1) R (40-100) S (3) R152K B R (>30-750) R (10-100) R (>400) R (150) Peram: Peramivir (BCX-1812) Mishin et al. AAC 49:4516, 2006; Wetherall et al. AAC 41:742, 2003

51 Relenza Indications (In Most European Countries) Relenza is indicated for the treatment of influenza A and B virus in adults and children 5 years of age Relenza is indicated for post-exposure prophylaxis of influenza A and B in adults and children 5 years of age following contact with a clinically diagnosed case in a household In exceptional circumstances, Relenza may be considered for seasonal prophylaxis during a community outbreak (e.g., mismatch between vaccine and circulating strain, and a pandemic) Relenza SPC. GlaxoSmithKline; 2006.

52 Relenza Delivered Direct to the Respiratory Tract and Acts Rapidly Drug levels in the lung following inhalation (ng/ml; induced sputum) 1 Immediate ~6,900 (> 1,000-fold IC 50 ) 6 hours 1,366 (> 670-fold IC 50 ) 12 hours 304 (> 300-fold IC 50 ) 24 hours 47 (> 50-fold IC 50 ) Relenza begins to work within 10 seconds 2 1. Cass et al. 1999; Peng et al. 2000; 2. Moscona A. NEJM 2005; 353:

53 Relenza Reduces Duration of Illness and Complications in High-Risk Patients Pooled analysis of 750 patients at high risk of influenza complications* Median time to alleviation of symptoms (compared to placebo)1.5 days earlier (p=0.003) Incidence of complications requiring antibiotics reduced by 28% compared with placebo (p=0.028) in patients with confirmed influenza High-risk patients defined as elderly ( 65 years of age) patients with or without underlying medical conditions, patients with chronic respiratory disease (asthma or COPD), or significant cardiovascular disease (excluding those with hypertension only). GlaxoSmithKline, Data on file.

54 Relenza Has Unsurpassed Efficacy in the Prophylaxis of Influenza Infection Study design Study Setting Nr. subjects Post-exposure prophylaxis Hayden et al NEJM 2000; 343; Household contacts Protective efficacy vs placebo 337 families 79% Post-exposure prophylaxis Monto et al JID 2002; 186: Household contacts 487 families 81% Seasonal prophylaxis Seasonal prophylaxis Monto et al JAMA 1999; 282:31-35 LaForce et al Clin Ther 2007; 29(8): Healthy adults (University) 1,107 67% High risk 3,363 83%

55 Relenza Has Excellent Efficacy in Post-Exposure Prophylaxis Monto Study N = 487 households with suspected case of influenza Incidence of households with 1 family member diagnosed with symptomatic, laboratory-confirmed influenza Relenza n = 10/245 (4.1%) P<.001 Placebo n = 46/242 (19%) Number Of Families 81% protective efficacy rate vs placebo Monto AS et al. J Infect Dis 2002;186:

56 Relenza Has Activity Against H5N1 and Oseltamivir-Resistant H5N1 Intranasal zanamivir protects mice against lethal challenge with influenza A/HK/156/97 (H5N1) 1 Reduced viral replication in lungs Reduced mortality and morbidity Prevented viral spread to the brain 2 Clinical isolate of oseltamivir-resistant H5N1 (H274Y) from treated child in Vietnam Susceptible to treatment with Relenza in the ferret 3 A further oseltamivir-resistant strain (294S) has been isolated from two patients who died from H5N1 in Egypt in December 2006 The oseltamivir-resistant strain in Egypt was shown susceptible to Relenza 4 1. Gubareva et al. JID 1998; 178: ; 2. Leneva et al. AAC 2001; 45: ; 3. Le et al. Nature 2005; 437:1108; 4. WHO warns of Tamiflu resistance 19 th January Available from: ACCESSED 12 th November 2007.

57 Selected Investigational Anti-Influenza Agents in Clinical Development Agent Target Sponsor Route Development phase Zanamivir NA gsk IV Phase 2 Peramivir NA Biocryst, Shionogi Laninamivir (CS-8958) Favipiravir (T-705) NA Biota, Daiichi- Sankyo IV Phase 3 Inhaled Phase 3 Polymerase Toyama Oral Phase 2-3 DAS181 HA receptor Nexbio Inhaled Phase 1

58 Summary of Recent Antiviral Clinical Trials Uncomplicated seasonal influenza Peramivir: single IV dose (300 or 600 mg) superior to placebo and comparable to 5 days of oseltamivir in adults Laninamivir (CS-8958): single inhaled doses of 20 mg or 40 mg comparable to 5 days of oseltamivir in adults and children Favipiravir (T-705): higher oral doses comparable to 5 days of oseltamivir in adults Hospitalized adults Peramivir: multiple IV doses comparable to oseltamivir in hospitalzed adults (phase 2)

59 Investigational Anti-Influenza Agents Neuraminidase (NA) inhibitors Peramivir (IV/IM), A (oral) Long-acting NA inhibitors (LANI) R (topical), Flunet (topical) Conjugated sialidase Fludase (topical) HA inhibitors- cyanovirin-n, sialyl-glycopolymer Polymerase inhibitors sirna; ribavirin (aerosol/iv/po); T-705; viramidine Protease inhibitors- aprotinin

60 (Peramivir)

61 IV Zanamivir in Experimental Influenza A/H1N1 NW Viral Titer Symptom Score Calfee et al. AAC 43:1616, 1999

62 Antiviral combination If virus M2 inhibitor susceptible, then synergistic interaction in vitro and survival in mice when combined with oseltamivir or ribavirin If virus M2 inhibitor resistant, no benefit to use in combination with oseltamivir or ribavirin In mice the oral combination of T-705 and oseltamivir showed dose-related additive to synergistic survival benefits for H1N1, H3N2, and H5N1 virus

63 Vaccination

64 流感疫苗 流感疫苗注射無法防止感染流感, 但由於能產生全身性抗體, 可以降低流感之死亡率 季節性流感死亡多出現在老人, 故施打對象為老人 ; 新流感死亡多出現在年輕人, 故施打對象為年輕人 孩童因為流感病毒排出時間長於成人, 為了減低病毒之擴散, 亦為流感疫苗優先施打之對象 流感疫苗由於呶到病毒到疫苗施打時間相當短, 因此國際上普遍接受不做大型臨床試驗, 而以小型臨床試驗證實安全無豫後即可上市

65 國光疫苗 vs 諾華疫苗 國光疫苗 (AdimFlu) 抗原 15 mcg 無佐劑 諾華疫苗 (Forcetria) 抗原 7.5 mcg 有佐劑 (MF59)

66 國光疫苗 vs 諾華疫苗 : 歲之抗體反應 國光疫苗 諾華疫苗 抗 HA 抗體 Seroprotective rate (day 22) Total N=120 Seronegative at baseline N=98 Total N=132 Seronegative at baseline N= % 92.9% 96% 98% GMR (day 22 to day1) Seroconversion or significant increase 93.3% 92.9% 88% 98%

67 國光疫苗 vs 諾華疫苗 : 60 歲以上之抗體反應 國光疫苗 諾華疫苗 抗 HA 抗體 Seroprotective rate (day 22) Total N=53 Seronegative at baseline N=33 Total N=122 Seronegative at baseline N= % 81.8% 72% 56% GMR (day 22 to day1) Seroconversion or significant increase 71.7% 81.8% 43% 56%

68 國光疫苗 vs 諾華疫苗 : 18 歲以下之抗體反應 3 weeks after 1 st 國光疫苗 vaccination (n/n), (1-3 y: 7.5 mcg, >3 % y: 15 mcg) 1-<3 years 21/ % 3-<6 years 32/ % 6-<10 years 17/ % 10-<18 years 28/ % 諾華疫苗 (all 7.5 mcg with adjuvant) 29 Jan, Dec, Dec, Dec, 2009

69 國光疫苗 vs 諾華疫苗 : 不良反應 Event 國光疫苗 N=292 (15 mcg=177, 30 mcg=115) 諾華疫苗 N=254 (7.5 mcg with adjuvant) Redness 14.7% Very common (10-100%) Swelling 16.4% Very common (10-100%) Fever (>38.3) 0.7% Common (1-10%) Muscle aches/myalgia 17.5% Very common (10-100%) Headache 13.4% Very common (10-100%) Nausea 4.8% Common (1-10%)

70 結論 克流感必須節約使用, 防止今年冬天抗藥性病毒株出現大流行 瑞樂沙在今年可以開始試用, 明年之後全面引進取代克流感 流感疫苗一定要施打, 施打率最好能迫近 100% 請相信國光疫苗之品質

71 懇請賜教