Antivirals for Avian Influenza Outbreaks

Transcription

1 Antivirals for Avian Influenza Outbreaks

2 Issues in Influenza Pandemic Preparedness 1. Surveillance for pandemic preparedness eg. H5N1 2. Public health intervention eg. efficacy, feasibility and impact of a broad range of public health measure 3. Antivirals eg. Early stage of pandemic :- availability, accessibility 4. Better Vaccine :- the most effective measure

3 Benefit of Antiviral Therapy in Influenza 1. Initiated within 3 day of illness will shorten the illness by d. 2. Decrease viral transmission 3. Prevent influenza-associated OM and antibiotic usage ( ~ 44% decrease in the incidence of OM compare with placebo.-pidj 2001;20:127.)

4 Classes of Antivirals for Avian Influenza

5 Classes of Antivirals Two classes Adamantanes Amantadine Rimantadine Neuraminidase inhibitors Oseltamivir (Tamiflu) Zanamivir (Relenza)

6 Influenza virus Type A, B, C segmented genome ss RNA (single stranded, negative sense) Neuraminidase Haemagglutinin N H

7 Adamantanes M2-ion channel blockers Effective only against influenza A Central nervous system and GI side effects

8 Adamantanes H5N1 virus isolates from humans show resistance to adamantanes 1 Resistance emerges readily during treatment Resistant variants readily transmissible human to human 1 Avian Influenza A (H5N1) Infection in Humans, NEJM Sept 29, 2005; 353:

9 Distribution of Amantadine-resistant H5N1 Avian Influenza Variants in Asia Resistance to the M2 ion channel-blocking Amantadine derivative Vietnam, Thailand resistance > 95% Indonesia resistance 6.3% China resistance 8.9% Leucine isoleucine at aa 26, Serine asparagine at aa 31. ( JID 2006; 193 : )

10 Neuraminidase (NA) inhibitors Active against influenza A and B Active against H5N1 and other avian influenza viruses Antiviral resistance occurs with oseltamivir treatment Oseltamivir is primary antiviral to be used for pandemic containment WHO has stockpile for rapid response

11 NA Inhibitors Different routes of administration Zanamivir is inhaled through mouth with special device Oseltamivir is orally administered capsule or suspension Mode of action Interfere with release of virus from host cells

12 NA inhibitors Mechanism of Action Oseltamivir/Zanamivir NAI prevent virus release and spread in respiratory tract

13 Antiviral Treatments, Regimens, and Side Effects

14 Antiviral Treatment Two recommended prescription drugs: Product Name: Oseltamivir: 1 1 year; Zanamivir 7 years Dosage: varies by age and weight Frequency: : varies depending upon drug Duration: varies depending upon drug Recommendation: begin treatment within 48 hours of illness onset

15 New Antivirals Oseltamivir Zanamivir

16 Oseltamivir Oral Formulations Capsules 75 mg each 10 capsules per box Manufacturer: Roche Brand name Tamiflu Tamiflu Store at room temperature ( C) Liquid suspension White powder to be mixed with 23 ml of drinking water Fruit flavored Refrigeration required Use within 10 days Oral dispenser included

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18 Oseltamivir Pharmacology Oseltamivir is pro-drug that is converted rapidly to active form in body Well-absorbed orally with over 80'% bioavailability of active form Absorption in critically ill? Plasma half-life life of active form averages hours twice daily dosing for treatment and once daily for prophylaxis Renal excretion dose reduction for renal failure (CrCl < 30 ml/mn mn) No important adverse drug interactions Probenicid delays excretion

19 Oseltamivir Treatment Doses Adults: 75 mg two times a day for 5 days Children > 1 year old (weight-based): <15 kg: 30 mg twice daily 15-<23 kg: 45 mg twice daily 23-<40 kg: 60 mg twice daily > 40 kg: 75 mg twice daily 5 day duration Not approved for children less than 1 year of age WHO Rapid Advice Guidelines on pharmacological management of humans infected with avian influenza A (H5N1) virus report dated May 2006

20 Zanamivir Formulation Oral inhalation 4 blister packs with two 5 mg powder mixture of zanamivir and lactose 5 rotadisks and 1 diskhaler Manufacturer: GlaxoSmithKline Brand name Relenza Relenza Store at controlled room temperature 25 C Proper use of Diskhaler is essential

21 Zanamivir Treatment Doses Dry powder inhalation >7 7 yr old 2 inhalations twice daily for 5 days Not recommended for patients with underlying airway disease

22 H5N1 Treatment with Oseltamivir Active against H5N1 viruses in the laboratory and in experimental animals No proof for effectiveness in human H5N1 disease Some evidence of better outcome Optimal dose and duration of treatment are uncertain Use oseltamivir dosing for seasonal influenza per WHO recommendations

23 Limitation of Antiviral Agents 1. effective within 48 hr. of onset 2. decreased duration of symptoms by 1-2 d. 3. decreased viral population (data from human influenza) (no data for avian influenza) (Red Book 2003 : 384-5)

24 Use of Oseltamivir to Prevent Influenza Oseltamivir administered daily for six weeks by the oral route is safe and effective (~ 75-92%) for the prevention of influenza. (Frederick HC. N Engl J Med 1999; 341:1336.)

25 NAI Chemoprophylaxis Doses* Oseltamivir >13 yrs old Oseltamivir 1-12 year old Zanamivir > 5 yrs old 1 capsule (75 mg) once a day < 15 kg: 30 mg once a day 15-<23 kg: 45 mg once a day 23-<40 kg: 60 mg once a day > 40 kg: 75 mg once a day 2 inhalations once a day *Duration of prophylaxis depends on epidemiologic setting. Post-exposure use is typically for 7-10 days.

26 Warnings and Side Effects Oseltamivir Warnings Dosage reductions required for renally impaired patients Zanamivir Not recommended for patients with underlying airway disease or allergies to lactose Side effects Nausea, vomiting, stomach pain* Throat pain/discomfort, cough *Avoid ingestion on empty stomach (fasting). Take with food or snack to reduce risk of GI upset.

27 Serious Adverse Events* Oseltamivir Allergic reactions Skin rash (sometimes severe) Facial swelling Dizziness Hepatitis Zanamivir Bronchospasm, sometimes severe or life-threatening *A causal relationship to NAI exposure has not been established for many of these

28 NAI Contraindications and Precautions Pregnant or breastfeeding mothers No recognized birth defects in pre-clinical testing No human clinical studies demonstrating safety or efficacy Use if benefit outweighs risk Liver disease Safety and efficacy not yet evaluated Kidney disease Decrease oseltamivir dose based on creatinine clearance

29 Question? What are the possibilities when someone develops fever while taking oseltamivir prophylaxis?

30 Antivirals at Different Stages within a Pandemic

31 WHO Pandemic Phases Phase Period Level of Risk 1 Interpandemic period Low risk of human cases 2 New virus in animals, no human cases Higher risk of human cases 3 Pandemic alert No or very limited human-tohuman transmission 4 New virus causes human cases 5 New virus causes human cases Evidence of increased humanto-human transmission Evidence of significant human-to-human transmission 6 Pandemic Efficient and sustained human-to-human transmission

32 Recommendations for Antivirals at Different Phases of Pandemic Period No or limited human-tohuman transmission (P 3) Increased or significant human-to-human transmission (P 4-5 ) Efficient and sustained human-to-human transmission (P 6 ) Recommendation Drugs are being used to treat patients and prevent infection in close contacts (i.e. family and healthcare workers) Drugs administered to entire community where clusters occur might prevent improved transmission or international spread Drugs are used as the only influenza-specific medical intervention for reducing morbidity and mortality

33 Different Uses of Antivirals Use Treatment Contacts Containment Recommendation Administered w/in 48 hours if possible Oseltamivir or Zanamivir Determine feasibility If outbreak occurs during influenza season, healthcare workers should be vaccinated Determination of clusters Evaluate effectiveness Provision for prophylaxis for entire affected community

34 Prioritizing Antivirals in the Event of an Outbreak

35 Cost and Use of Antivirals Product Usage Cost Oseltamivir (75 mg.) Zanamivir (5 mg. disk) Treatment and chemoprophylaxis of influenza A in patients > 1 year Treatment of influenza A in patients > 7 years and prevention of influenza A in persons >5 years. $32 (per pack of 10 capsules) $ (per pack of 5 disks)

36 Potential Antiviral Priority Groups Hospitalized patients with influenza HCWs with direct patient contact Highest risk outpatients Pandemic health responders, public safety & key government decision makers Other high risk outpatients Outbreak response (e.g., PEP in nursing homes) Prophylaxis HCWs in ER, ICU, EMS, dialysis Pandemic societal responders & other HCWs Other outpatients Prophylaxis for highest risk outpatients Prophylaxis for other HCWs w/ patient contact

37 Level of Risk High Moderate Risk Groups for Antivirals Prophylaxis Description Household or close family contacts of a suspected or confirmed case Unprotected individuals in contact with animals infected with H5N1 Healthcare personnel in close contact with suspect/confirmed case Low Personnel who properly used PPE during contact with patient or animals Personnel involved in culling noninfected animals as a control measure

38 When NAI are Available Level of Risk High Moderate Low Description Oseltamivir for 7-10 days after exposure Zanamivir as alternative Oseltamivir for 7-10 days after exposure Zanamivir as alternative Oseltamivir or Zanamivir should not be used NOTE: Amantadine or rimantadine SHOULD NOT be administered as chemoprophylaxis

39 When NAI are NOT Available Level of Risk High Moderate Low Description Amantadine or Rimantadine if local surveillance shows virus susceptibility Same as high risk Amantadine or Rimantadine should not be used NOTE: Amantadine or rimantadine SHOULD NOT be used for pregnant women. Amantadine SHOULD NOT be used elderly with impaired renal function

40 Distribution of Antivirals

41 Steps for Distributing & Dispensing Antivirals Planning - Estimating the size and needs of priority groups and developing a plan Assessing - antiviral stocks available Activating - plans for the transport, receipt, storage, security, tracking, and delivery

42 Planning Considerations for Distributing Antivirals 1. Leadership roles 2. Human resource needs 3. Site of drug distribution: household, clinic, other facility (eg( eg,, school) 4. Clinic layout and specifications 5. Crowd management inside/outside of the facility 6. Security of drug supplies 7. Communication, advertising

43 Assessing Antiviral Supplies WHO antiviral stockpile 3 million oseltamivir courses by May 2006 Reserved for containment of pandemic virus Assess local supplies Pharmacies Manufacturing companies Hospitals or private doctors

44 Antiviral Agents Stockpiling for Pandemic Influenza Treatment :-: ~ 25% of total population (20-40%) Prophylaxis :-: additional courses for 1. public safety officers 2. HCW s in direct contact with patients

45 Activating the Plan Questions to address when activating the plan: What sites are available for a mass clinic event? What is the mechanism for receiving antivirals and transporting to locations where supplies are needed? Who is responsible for making the request? What are the implications for monitoring?

46 Avian / Pandemic Flu Clinical Trial Feasibility in Thailand SEA Influenza Clinical Research Network (Thailand, Indonesia, Vietnam, Oxford University US-NIH,Wellcome Trust- UK, WHO) Ongoing research on Oseltamivir High VS Standard dose in Severe Flu and Avian Flu Future research on new antivirus agent eg. Peramivir and other new Avian/Pande.vaccine

47 Summary Oseltamivir and Zanamivir are recommended antivirals for treatment and prophylaxis of AI when available Amantadine and Rimantadine can be used when surveillance shows low resistance to these drugs Use of antivirals depends upon the phase, use, cost, availability, and risk. All must be considered when distributing antivirals.

48 Thank you