Modelling the Epidemic of Genital HSV Infection: What has and is Expected to Happen

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Modelling the Epidemic of Genital HSV Infection
What has and is Expected to Happen?

• S Blower (USA)

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Modelling the epidemic of genital HSV infection

• Dr. Sally Blower
• Department of Biomathematics
• David Geffen School of Medicine at UCLA

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Overview

• What transmission models have been developed?
• How would increased use of antivirals affect the
  genital HSV epidemic?
• episodic treatment ( drug resistance)
• suppressive treatment
• What recommendations can be made?
• treatment recommendations
• future modeling recommendations

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Topic 1

• What transmission models have been developed?

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What is a transmission model?

• It is a series of equations that are formulated
  based upon specific assumptions about the
  transmission dynamics of any specific pathogen
• realism versus simplicity
• Transmission models should be designed like
  clinical trials

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Utility of transmission models

• Explanatory to understand how epidemics evolve
• Quantifying uncertainty to make future
  predictions with errors
• Qualitative and quantitative predictions

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HSV2 in immunocompetents

• A series of models
• intrinsic dynamics (no treatment)
• dynamics with episodic treatment
• (no resistance)
• dynamics with episodic treatment
• ( resistance)

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How can models be analyzed?

• Mathematically (R0, equilibria)
• Computationally/Numerically
• Scenario Analysis
• Uncertainty Analysis (to predict the future with
  a certain degree of error)
• Sensitivity Analysis (to identify which
  parameters produce the most increase or decrease
  in the outcome variable of interest)

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The Basic Reproduction Number (Ro)

• Defined as the average number of secondary
  infectious cases of HSV2 that are produced when
  one infectious individual is introduced into a
  population where everyone is susceptible.
  if Ro gt1 EPIDEMIC
• if Ro lt1 ERADICATION

Macdonald G. The analysis of equilibrium in
malaria. Trop Dis Bull 49813-829,1952
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The Basic Reproduction Number HSV-2

• R0 b C D
• b transmission probability per sexual
  partnership
• C average number of new sex partners per year
• D average number of years that an HSV-2
  infected individual is infectious for during
  their sexual lifespan

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Why do we need uncertainty analysis?

• How else to deal with parameter estimation
  uncertainty?
• Use a probability distribution function (pdf)
• NOT a single value therefore parameter estimation
  uncertainty is translated into prediction
  estimation uncertainty.
• By using uncertainty analyses we can predict the
  future with a degree of uncertainty.

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Uncertainty Analysis LHS

• LHS is a type of stratified Monte Carlo sampling
  sampling technique that allows for the
  simultaneous variation of the values of all of
  the input parameters.
• Simulate the model many times after obtaining a
  good sample of the parameter hyperspace.
• LHS first proposed by McKay, Conover Beckman
  (1979) to aid in the analysis of nuclear reactor
  safety.

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Topic 2

• How would increased use of antivirals affect the
  genital HSV epidemic?
• episodic treatment ( resistance)
• suppressive treatment

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Episodic treatment ( resistance)

• At the epidemic-level treatment has opposing
  effects
• (i) treatment decreases drug-sensitive HSV-2
• (ii) treatment increases drug-resistant HSV-2

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Only 10 or less of cases are currently treated

• What would happen if episodic treatment rates
  increased substantially?

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Predicting the effect of antivirals

• What will be the beneficial epidemic-level
  effects?
• What will be the detrimental epidemic-level
  effects? (i.e. resistance)
• Blower, Porco Darby. Predicting preventing
  the emergence of antiviral drug resistance in
  HSV-2. Nature Medicine 1998 4664-5.

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Summary of results

• If treatment rates increase substantially
• (i) the prevalence of infection (drug sensitive)
  will
• decrease gradually slightly
• (ii) the prevalence of infectiousness (drug
  sensitive) will decrease quickly significantly
• (iii) the prevalence of drug resistance (DR) will
  increase very slowly over a period of decades but
  will remain low.
• Are the benefits gt costs?

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Treatment evaluation criterion

• TEC (t) average number of cases of
  drug-sensitive herpes averted at time t per
  prevalent case of drug-resistant herpes.

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HSV-2 generating theoretical drug resistance
(DR)(assume DR strains are both less infectious
reduced ability to reactivate)
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• Predicting the emergence of drug-resistant HSV-2
  new predictions
• Gershengorn, Darby Blower
• Even after 25 years of antivirals only expect 5
  out of 10,000 immunocompetent individuals to be
  shedding drug-resistant virus.

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Suppressive treatment

• White Garnett. Use of antiviral treatment is
  unlikely to have a major impact on the prevalence
  of HSV-2. 1999. Sex Trans Inf. 7549-54.
• Only looked at the impact on the prevalence of
  infection.
• Only allowed the newly infected to go on
  suppressive therapy.
• Could only go on therapy once.
• Finding see title.

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Suppressive treatment A Different View

• Blower, Gershengorn, Wang, Wald Corey. Treating
  core groups with chronic suppressive therapy the
  impact on HSV-2 epidemics. In prep.
• Examined the impact on the number of HSV-2
  infections prevented.
• Used biological core groups defined upon the
  number of recurrences a year.
• Could go on off therapy at any time. Both
  prevalent incident cases could receive chronic
  suppressive therapy (CST).

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Cumulative Percentage of HSV-2 Infections
Prevented
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of Population on HSV-2 CST(treating a few will
benefit many)
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Topic 3

• What treatment recommendations can be made?
• Increase treatment rates. This will be very
  beneficial at the epidemic-level AND will
  generate only very low levels of drug-resistant
  HSV-2.
• Increase CST and target core-groups. This will be
  very beneficial.
• Target new treatments therapeutic vaccines
  towards suppression of viral reactivation
• Decrease risky behavior!!!!!

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• What modeling recommendations can be made?
• Are models a good idea?
• Models are used to predict earthquakes, the
  weather, the economy.
• What else do we have? Guessing?
• Infectious diseases should become a predictive
  science

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• What modeling recommendations can be made?
• Develop simple models BEFORE developing complex
  models.
• All complex models should be tested against
  simple models.
• A variety of TECs should be defined evaluated.
  Clarify goals.

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• Models should be used as health policy tools (i)
  prediction (Uncertainty Analysis) (ii)
  prevention (Sensitivity Analysis). Be very wary
  of scenario analyses.
• Model the effects of HSV-2 on increasing the HIV
  epidemic. A few studies have shown that HSV can
  contribute to a substantial of HIV infections.
  Therefore will treating HSV decrease the HIV
  epidemic?
• Model the effects of HIV on increasing the HSV-2
  epidemic.