Effect of antiviral use on the emergence of resistance to nucleoside analogs in Herpes Simplex Virus, Type 1

Marc Lipsitch, Bruce Levin, Rustom Antia, Jeffry Leary, Teresa Bacon

Herpes Simplex Virus, Type 1

• Cause of recurrent herpes labialis (RHL =“cold sores”)

• More severe diseases– Respiratory and neurologic infections– Neonatal herpes– Disseminated disease in immunocompromised

patients

Impetus for work

• Topical antiviral Penciclovir, available Rx in US

• Sponsor wished to obtain OTC license • FDA had denied OTC Acyclovir for

genital herpes– Concerns about resistance, precedent

• Penciclovir sponsor requested resistance risk analysis

HSV-1 Transmission

• Primary asymptomatic or symptomatic infection, latency and reactivation

• Infection can be detected serologically• Reactivation (cold sores) associated with heavy

viral shedding• 1-5% shedding among asymptomatic carriers• Little direct evidence of when transmission

occurs

HSV-1 Treatment and Resistance• Nucleoside analog family

– acyclovir (prodrug valacyclovir)– penciclovir (prodrug famciclovir)

• Prevents viral DNA replication• Does not cure latently infected cells• Resistance readily selected in vitro and in

immunocompromised patients• Resistance arises rarely in immunocompetent during

treatment virulence (usually), transmissibility (probably)

Resistance to nucleoside analogs in HSV-1

• Presently about 0.3% in immunocompetent, 3-10% in immunocompromised

• No evidence of increasing trend since acyclovir was introduced in early 1980s

• QUESTION: How would levels of resistance change following a substantial increase in nucleoside analog use?

• Research was sponsored by the manufacturer of topical penciclovir, which wished to apply for OTC status for the treatment of RHL

Cold SoresUntreated

death

Susceptiblebirth

Seropositive:Sensitive

Seropositive:Resistant

Asymptomatic

C.S.Treated

Asymptomatic

Cold Sores

Basic Model for Transmission of Resistance

Force ofinfection

Force ofinfection

Complex Model

I’S

S’

I’R

I’D

Immunocompetent Immunocompromised

IS

S

infection

IR

birthID

infection

secondaryinfection

Acquiredresistance

Transmission of Resistance: Key Assumptions and Parameters

• Up to 30% of cold sore sufferers use topical PCV.• Topical PCV reduces transmission of sensitive HSV-

1.• Individuals infectious when symptomatic, and

possibly when asymptomatic.• Resistance transmissibility 0-50%.• PCV treatment does not cause “acquired resistance.” • Total or partial immunity to HSV-1 superinfection

Acyclovir Resistance in HSV-1: Model Predictions

(No acquired resistance)

0.0%

0.2%

0.4%

0.6%

0.8%

1.0%

0 10 20 30 40 50

Time (years)

Pre

vale

nce

of

infe

ctio

n

wit

h r

esis

tan

t H

SV

-1

70

278

Acquired Resistance

• Approximately 1800 immunocompetent patients with multiple viral samples in clinical trials of nucleoside analogs (HSV-1 and HSV-2, oral and topical, several different compounds).

• No evidence of acquired resistance– 0/1800 95%CI (0, 0.0017) (0, 1/625)– Biological limitations of the assay

• Biological barriers • 4 possible case reports in immunocompetent

Model with Acquired Resistance

No acquired resistance

P(AR) = 1/625 treated episodes

P(AR) = 1/6250 treated episodes

P(AR) = 1/2500 treated episodes

0.0%

0.2%

0.4%

0.6%

0.8%

1.0%

0 10 20 30 40 50

Time (years)

Pre

vale

nce

of

infe

ctio

n

wit

h r

esis

tan

t H

SV

-1

70

2780.0%

0.2%

0.4%

0.6%

0.8%

1.0%

0 10 20 30 40 50

Time (years)

Pre

vale

nce

of

infe

ctio

nw

ith

res

ista

nt

HS

V-1

3460

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

0 10 20 30 40 50

Time (years)

Pre

vale

nce

of

infe

ctio

nw

ith

res

ista

nt

HS

V-1

5 7

0.0%

0.2%

0.4%

0.6%

0.8%

1.0%

0 10 20 30 40 50

Time (years)

Pre

vale

nce

of

infe

ctio

n

wit

h r

esis

tan

t H

SV

-1

1726

Conclusions: HSV-1

• Very slow increase in prevalence of resistance from transmission alone

• Acquired resistance necessary for noticeable buildup of resistance, but the necessary rate of acquired resistance is extremely low (0.1% >>0)

• Moderate fitness cost of resistance can also markedly reduce rate of increase, even of acquired resistance

• Doubling times range from years to centuries• Similar to predictions for HSV-2 (Blower et al.)

Conclusions

• Emergence rate a key determinant of outcome– Small, hard to measure

• Risk of resistance relatively low vs. other bug-drug combinations

• FDA advisory group recommended against approval– Antivirals adcom vs. OTC adcom

Lessons of the example

• Dynamic models required to estimate population process over time

• Both direct and indirect effects important

• Identified surprising locus of uncertainty

• Risk is only one side of the equation

What the model couldn’t do

• Calculate the probability of rare events (deterministic)

• Account for heterogeneities of resistant strains• Be “validated” rigorously

– Model predicted resistance would be low now– It is– So?

• These problems not unique to dynamical approach