# Presentation: 662079

## Pandemic Influenza Planning: Antiviral Strategies  

- Ben Schwartz, MD
- National Vaccine Program Office, DHHS

- “The pandemic influenza clock is ticking.
-   We just don’t know what time it is.”
- 				*Ed Marcuse, ACIP Member*

- Drug Use Strategy:
- Prophylaxis versus Treatment

## Potential Antiviral Drug Strategies

- Post-exposure prophylaxis (10 days)
- Duration of community outbreak (6-8 wks)
- Duration of pandemic wave (3-4 mo)
- Treatment (5 days)

## Criteria for Evaluating Antiviral Strategies

- Effectiveness
- Preventing adverse health outcomes
- Direct impacts
- Indirect impacts
- Maintaining essential services (medical care and other)
- Efficiency
- Outcome per quantity of antiviral drugs
- Prevention or cost-effectiveness
- Feasibility - ability to effectively implement
- Acceptability

## Summary of Influenza Antiviral Prophylaxis & Treatment Impacts

- Prophylaxis with NIs and adamantanes (if strain is susceptible) is highly effective in preventing clinical illness
- PEP has been implemented successfully in nursing homes to abort influenza outbreaks
- Treatment within 48 hrs of symptom onset
- Reduces complications and hospitalization
- Shortens illness duration
- Impacts are greater if treatment is started earlier

## Direct and Indirect Effects of Targeted Antiviral Prophylaxis 

- Mathematical simulation model of influenza spread in a structured population calibrated to age specific attack rates from the 1957 pandemic
- Targeted antiviral prophylaxis intervention
- Treatment of cases and “mixing groups” (households, day-care centers, play groups, schools)
- Prophylaxis provided 1 day after symptoms in case
- TAP duration from 1-8 weeks

- Longini, Am J Epi 2004

## Direct and Indirect Effects of Targeted Antiviral Prophylaxis 

| Intervention | Cases/103 | Deaths/103 | EPP* |
| --- | --- | --- | --- |
| None | 334 | 0.58 |  |
| 80% TAP |  |  |  |
|    1 wk | 212 | 0.33 |   6 |
|    2 wks | 150 | 0.23 | 28 |
|    4 wks |   71 | 0.11 | 61 |
|    6 wks |   36 | 0.06 | 75 |
|    8 wks |   23 | 0.04 | 79 |

- *EPP = Epidemic prevention potential, where illness attack rate <2.5%

- Longini, Am J Epi 2004

## Direct and Indirect Effects of Targeted Antiviral Prophylaxis

- 80% TAP required for effectiveness
- Antiviral drug use for 4-8 weeks TAP
- Treat 222-321 people/1000 population
- Require 692-775 antiviral drug courses/1000 population (198-224 million courses for the U.S. population)
- TAP must be started <3 days for EPP effect

- Longini, Am J Epi 2004

## Prophylaxis vs Treatment in Occupational Settings: Maintaining Critical Functions

- Limitations of a treatment strategy
- Time lost from work due to illness
- Absenteeism due to fear of becoming infected
- Risk of transmission before symptom onset or after return to work if still shedding virus
- Acceptability to workforce – ability to assure drug availability and to implement treatment early
- Importance of treatment limitations is likely related to pandemic severity

## Fold Increase in Antiviral Drug Use: Prophylaxis vs Treatment

| 
Illness
attack rate | Ratio Prophylaxis:Treatment  |  |
| --- | --- | --- |
|  | 40 days
(~6-weeks) | 8-weeks |
| 15% | 26.7:1 | 37.3:1 |
| 25% | 16.0:1 | 22.4:1 |
| 35% | 11.4:1 | 16.0:1 |

## Number of Antiviral Drug Courses for Prophylaxis vs Treatment

| Group | Population | Number of courses |  |
| --- | --- | --- | --- |
|  |  | Prophylaxis* | Therapy** |
| HCWs | 12.4 m | 69.4 m | 4.3 m |
| Hospital – patient care | 3 m | 16.8 m | 1.1 m |
| Public safety | 2.3 m | 12.9 m | 0.8 m |

-   *Assumes 8-week prophylaxis
- **Assumes 35% attack rate

## Expert Panel on Antiviral Drug Impacts for Pandemic Influenza

- Panelists: Fred Hayden, Arnold Monto, Janet Englund, Keiji Fukuda
- Objectives
- Consider parameters for pandemic influenza
- Estimate parameters where study data are lacking
- Delphi methodology
- Identified parameters of interest (stratified by age and risk status)
- Obtained initial estimates (and range)
- Explanation of outliers
- Opportunity for revision

## Delphi Panel Estimates of Influenza Antiviral Drug Treatment Impacts

| Parameter | Neuraminidase inhibitors | Adamantanes |
| --- | --- | --- |
| Decrease in LRI | 19-38% | 14-20% |
| Decrease in hosp. | 28-44% |   9-21% |
| Decrease in mortality | 20-40% | 12-15% |

- Range of estimates based on treatment group and how
- soon therapy is begun after symptom onset (within 48 h)

## Antiviral Modeling Methods 

- Illness, hospitalization, and mortality estimates based on 1957/1968 pandemic strains
- Modeling uses multiple simulation (Monte Carlo) methods
- In each simulation, a parameter value is randomly selected within a range defined by expert estimates
- Likelihood of selecting a value in that range is based on a distribution defined by the convergence of expert estimates

## Agreement by Delphi Panelists

- Convergence rule definition:
- If CR=

## Estimated Impacts of Antivirals onMortality in an Influenza Pandemic

## Prevention Effectiveness: Treatment vs Prophylaxis in High-Risk Groups

- 80%T 20% P

- 100% Prophylaxis

- Assumes targeting to most ill 50%

## Impact of Targeting Therapy to Those with Death/Hospitalization as Outcome

**Percentage of outpatients (end outcome) treated**

**65+ yr HR**

**0-19 yr HR**

**20-64 yr HR**

## Implementation Issues

- Outbreak prophylaxis
- Deliver at occupational sites; partial vs full course
- Post-exposure prophylaxis
- Requires rapid identification of contacts & prophylaxis
- Treatment
- Delivery site will be the point of care
- Hospitals will be a critical delivery node
- Through occupational health for employees
- At admission for seriously ill patients
- In Emergency Department for high-risk outpatients
- Delivery sites unclear for other occupational groups

## Comparison of Antiviral Drug Use Strategy Attributes

| 
Criterion | 
Treatment | Prophylaxis |  |
| --- | --- | --- | --- |
|  |  | Post-expos | 6-8 wks |
| Prevent death | ++ | +++ | ++++ |
| Maintain services | +(+) | +++ | ++++ |
| Efficiency | ++++ | ++ | + |
| Cost effectiveness | ++++ | ++ | + |
| Ability to implement | ++ | + | ++++ |
| Acceptability | +++ | +++ | ++ |

## Potential Mix of Antiviral Strategies

- PEP – use when exposures are uncommon, and populations well defined and limited size
- Persons in institutions (LTCF, prisons)
- Outbreak prophylaxis – use in extremely high risk, high exposure, or critical function populations of small size
- BMT patients
- ER docs
- Nuclear power plant operators? CT surgeons?
- Treatment – use in all other settings

## Is There a Role for Adamantanes for Prophylaxis in the SNS?

- Pro
- Readily available – may be a partial stopgap until NIs acquired
- Inexpensive – extends capacity for drug intervention
- Used for prophylaxis can reserve NIs for treatment
- Con
- Pandemic strain may be resistant (as is Asian H5N1)
- Resistance would rapidly develop as drug is used for therapy in the private sector
- May provide decision-makers with a false sense of having addressed the issue and could decrease NI stockpiling

- Defining Target Groups for
- Antiviral Drug Interventions

## Target Groups for Antiviral Drug Interventions

- Priority groups are not defined in the draft pandemic plan
- Establish priorities based on pandemic response goals
- Draft report developed by an HHS/DoD/VA working group proposes priority groups for antiviral drugs
- Represents conclusions from the working group and not HHS or its agencies

## Potential Target Groups for Antiviral Drugs and Population Size

| Group | Population | Source |
| --- | --- | --- |
| Front line hosp HCW | 2.5 M | 50% hosp HCW |
| Admitted patients | 1-11.8 M | Extrapolation from 1918, 1957, 1968 |
| Front line outpt HCW | 3 M | 50% outpatient HCW |
| Public safety workers | 2.3 M | Police, fire, and corrections workers |
| Key decision makers | 75,000 | Assume 1,000/state and 25,000 federal |
| Essential community service | 3 M | Assume 1,000/million |
| High risk outpatients | 83 M | Based on ACIP recs |
| LTCF residents | 3.1 M | Based on NH and assisted living facilities |
| Other HCWs | 5 M | Remaining HCWs |

## Treatment at Hospital Admission:Potential Population Size by Pandemic Severity

|  | Low estimate
(1957 & 68 based) | High estimate
(1918 based) |
| --- | --- | --- |
| Deaths |     104-243,000 | 952,000-2.2 m |
| Hospitalizations |     360-839,000 | 4.1-9.6 m |
| Total | 0.46-1.1 m | 5.1-11.8 m |

- Source: Meltzer, CDC, unpublished data

## Cumulative Antiviral Courses for Proposed Groups by Pandemic Severity

## Conclusions: Antiviral Drug Strategies in the Context of Uncertainty

- Key uncertainties
- Pandemic severity
- Epidemiology and risk groups for severe illness
- Absenteeism with a treatment strategy
- Impacts of absenteeism on critical societal functions
- Impacts of treatment at >48 hrs after symptom onset
- Ability to deliver therapy early after symptom onset
- Ability to target therapy to outpatients more likely to progress to severe illness
- Amount of antiviral drug that will be available

## Chemoprophylaxis of Epidemic Influenza

| Strategy | Efficacy (vs placebo or no drug) |  |  |
| --- | --- | --- | --- |
|  | AM/RM | ZNV | OSEL |
| Outbreak (6-8 wks)
  Non-immunized adults
  Immunized NH elderly | 
85-91%
58-75% | 
84%
? | 
84%
92% |
| Post-exposure (10-14 d)
  Households
  Nursing homes | 
3-100%
Variable | 
82%
Yes | 
73-89%
Yes |

- Source: Hayden

## Influenza A Nursing Home Outbreak, Ontario 2005

## Oseltamivir PEP in a Nursing Home, Ontario, 2000

- Bowles, JAGS 2002

## Oseltamivir and Risk of Pneumonia and Hospitalization: Results of a Retrospective Cohort Study 

| Outcome | Exposed
 | Unexposed | Adj. Hazard Ratio (95% CI) |
| --- | --- | --- | --- |
| Age 1-12
  Pneumonia
  Hosp. | (n=586)
4 (0.7%)
1 (0.2%) | (n=17,886)
453 (2.5%)
120 (0.7%) | 
0.34 (0.13, 0.90)
0.29 (0.04, 2.07) |
| Age 13-59
  Pneumonia
  Hosp. | (n=10,649)
138 (1.3%)
  99 (0.9%) | (n=41,007)
885 (2.1%)
510 (1.2%) | 
0.81 (0.68, 0.97)
0.75 (0.60, 0.93) |
| Age 60+
  Pneumonia
  Hosp. | (n=463)
8 (1.7%)
10 (2.2%) | (n=3,298)
290 (8.8%)
163 (4.9%) | 
0.41 (0.20, 0.82)
0.55 (0.29, 1.05) |

- Nordstrom, ICAAC, 2004

## Impact of Time from Symptom Onset 

- Aoki et al. J Antimicrob Chemo 51:123, 2003

- Impact of Time from Symptom Onset
- on Oseltamivir Treatment Outcomes

## Impact of Oseltamivir on Durations of Illness and of Fever

- Predicted illness duration (until relief of all symptoms) if treated at _<_6 hrs = 91-99 hrs
- 90% of patients had a fever or <37.8 within 36 hours of their first oseltamivir dose
- Early therapy had greatest impact on duration of fever (“acceleration factor” 1.12 vs 1.05 for duration of symptoms)

- Aoki et al. J Antimicrob Chemo 51:123, 2003