Efficacy of Topical Drug Therapy for

Monkey B Virus Exposure

R Eberle

Center for Veterinary Health SciencesOklahoma State University

Stillwater, OK

• Macacine herpesvirus 1• Naturally occurring in genus Macaca• Symptoms similar to HSV in humans• Serious disease is rare in natural host

Monkey B Virus

Monkey B Virus:

Zoonotic Infections

• First isolation from human case in 1932

• About 50 documented human cases total

• Infection usually acquired from macaques via bites or scratches

• ~80% fatal if untreated, ~20% with immediate drug therapy

• Was a “Select Agent” – govt controlled

research (now removed from list)

• All drugs were developed to treat HSV, not BV

• Immediate post-exposure prophylactic treatment is oral ACV or oral ValACV

• If any clinical symptoms are evident treatment is i.v. ACV or i.v. GCV

• If CNS signs evident treatment is i.v. GCV

• There is no scientific evidence that these represent optimal treatment regimens

Current Treatment for Zoonotic BV Infections

Comparative Drug Efficacy – In vitro

Drug EC50

ACV 23.3 ± 4.3AraA (Tox) 5.7 ± 1.6BUdR >200BVDU >200CDV 12.4 ± 2.1EDU 14.2 ± 5.8HBPG >200GCV 18.4 ± 3.6IUdR (Tox) 1.3 ± 0.5PCV 11.3 ± 1.4PFA >100TFT (Tox) 1.3 ± 0.2

BV Mouse Model

• 10-12 gm female Balb/c• Shave flank• Scarify skin• Apply 105 PFU BV (~10 LD50)• Observe 2x/day, 14-21 days• Drugs given over 7 day course Systemic = inject i,p. Topical = transdermal PLO gel

BV Mouse Model: Neurological Scoring & Clinical Signs of

Infection Score Clinical Neurological Signs

1 Abnormal tail-lift reflex (curling of ipsilateral foot/leg)

2 Paresis of ipsilateral hind leg, still alert & active3 Paralysis of ipsilateral hind leg, still alert & active4 Bilateral hind limb paralysis, scruffy coat, not very

active5 Immobile, tremors, dead or requiring euthanasia

Normal Abnormal

Systemic Efficacy ACV, PCV & EDU

Start drugs day -1 for 7 days; i.p. injection 2x/day

Perc

en

t S

urv

ival

Days Post-Infection 0 7 14

100

90

80

70

60

50

40

30

20

10

0

CDV (mg/kg/day)100, 50, 25, 12.5, 6.2, 3.1,1.6

0 7 14

GCV (mg/kg/day)200, 100, 50, 25

100

90

80

70

60

50

40

30

20

10

0

Systemic Efficacy GCV & CDV

Start drugs day -1, i.p. injection 2x/day

Neurological Symptoms GCV & CDV

Start drugs day -1 for 7 days; i.p. injection 2x/day

100

80

60

40

20

0

Effect of Delaying Start of Drug Therapy

-1 0 1 2 3 4 5

Perc

en

t S

urv

ival

CDV (25 mg/kg/day)

GCV (100 mg/kg/day)

Virus in DRG

Virus in Spinal Cord

Start of Drug Regimen (DPI)

• ACV, EDU & PCV not effective

• GCV & CDV effective• Only when treatment started before virus gets into CNS

• CDV more effective than GCV• CDV effective dose ~10 fold lower than GCV

• High CDV doses can prevents development of clinical

neurological signs

Conclusions

Implications

• To be effective treatment must start before virus invades CNS

• Best to prevent virus from reaching CNS

• Most effective drugs are also toxic• Cannot use drugs most effective against BV

• GCV & CDV are also toxic, so treatments are in-patient

• Use of less effective drugs may be bad• Ineffective inhibition may allow virus to replicate

& invade nervous system• Infection becomes harder to treat effectively once neurological symptoms become evident

Possible Alternative Approach:

Topical Drug Treatment?• Some toxic drugs can be used topically

• Patients can self-medicate• Lower cost (out-patient) • Easy to administer, likely high patient compliance

• Can initiate treatment soon after exposure• Early peripheral treatment may stop virus from accessing the nervous system

5% GCV 5% CDV

0

1

2

3

0

1

2

3

0 7 14 21 0 7 14 21

Neu

rolo

gic

al S

core

Days PI Days PI

3 hr PI 6 hr PI 24 hr PI Treatment started at:

Trial Topical Drug Treatment

Veh ACV PCV GCV CDV TFT RRI IUdR EDU Abrv

100

80

60

40

20

0

% S

urv

ival

All drugs at 3%

Start treatment at 4 hr PI

3x/day for 7 days

Screening of Drugs for

Topical Efficacy

100

80

60

40

20

0 0 7 14

Days Post-Infection

100

80

60

40

20

0 0 7 14

Days Post-Infection

100

80

60

40

20

0 0 7 14

Days Post-Infection

5%3%1%0.3%0.1%Vehicle

RRI

CDV GCV

Comparative Drug Efficacy: Survival

Start drug treatments at 24 hr PI

3x/day for 7 days

0

1

2

3

4

5 0 7 14

Days Post-Infection

0

1

2

3

4

5 0 7 14

Days Post-Infection

0

1

2

3

4

5 0 7 14

Days Post-Infection

5%3%1%0.3%0.1%Vehicle

RRI

CDV GCV

Comparative Drug Efficacy: Neurological Signs

Start drug treatments at 24 hr PI

3x/day for 7 days

Future Experiments

• Dual drug regimens:

GCV + RRI

CDV + RRI

• Dual drug efficacy once BV is in CNS

• Temporal efficacy of CDV suppression of BV replication in the skin

Acknowledgements

Funding: Dolphin Fdn, ACLAM Fdn

Collaborators/Personnel:

Dr Lara Maxwell Dr George Wright Darla Black Vet Pharmacol CEO GLSynthesis Lab Manager

Questions?