Optimizing Therapy

1
Optimizing Therapy Pushing the Boundaries
in Herpes Management
Wednesday 10th October 2007, At the IHMF Annual
Meeting, Dubrovnik
2
Welcome and introduction
Richard J Whitley, MD The University of Alabama
at Birmingham
3
Objectives

• To openly discuss management strategies for
  recurrent HSV and VZV infections, recognising the
  difference in pathogenesis of each
• To consider alternative management options
  predicated on existing data or need for new
  clinical trials

4
Redefining therapeutic options in HSV
Lawrence R Stanberry, MD, PhD University of
Texas, Galveston, USA
5
Recurrent herpes simplex virus infections
Genitalis
Labialis
10 million recurrent episodes yearly in USA
100 million recurrent episodes yearly in USA
6
HSV Pathogenesis
Viral shedding ? lesion formation
Virus transmission to mucosal surface or abraded
epithelium
Anterograde transportto mucosal and cutaneous
sites
Establishment oflatent infection
Productive viral replication in sensory neurons
7
Biology of HSV latency and reactivation

• Reactivation results in multifocal inoculation of
  the epidermis
• Early events may produce prodromal symptoms
• Lesion development occurs early and quickly
• Rapid innate and acquired host responses
  terminates the acute phase of the lesion
• no growth of lesion area
• decline in lesion virus titer after 1224 hours
• crust formation after 4872 hours

8
Virus replication and crust formation occur in
first 48 hours in herpes simplex
Peak viral titer occurs in 1st 24 hrs
Prodrome, erythema and papule
Vesicle
Ulcer / soft crust
Hard crust
Dry flaking and residual swelling
Relative clinical severity
10
-1
0
1
2
3
4
5
6
7
8
Time (Days)
Adapted by P. Hoyle from Spruance et al. NEJM
197729769-75
9
Very short course high dose therapy

• Based on the natural history of recurrent HSV
  infections it is reasonable to speculate that
  early antiviral intervention will have the
  greatest therapeutic impact
• Herpes labialis
• Valacyclovir
• Famciclovir
• Genital herpes
• Famciclovir

10
Short-course valaciclovir for the treatment of
herpes simplex labialis

• 2000 mg valaciclovir bid for one day
• 2000 mg valaciclovir bid the first day and 1000
  mg valaciclovir bid the second day
• Matching placebo caplets for two days
• Patient-initiated at the beginning of a prodrome
• Two studies
• Primary efficacy variables
• Proportion of aborted lesions
• Episode duration

Spruance et al. AAC 2003471072-1080
11
Valaciclovir - herpes labialis study
Spruance et al. AAC 2003471072-1080
12
Valaciclovir - herpes labialis study
With one day treatment regimen patients
experienced a 1 to 1.1 day reduction in episode
duration (P 0.001) and a 0.6-0.8 day
reduction in healing time (Plt0.001)
Spruance et al. AAC 2003471072-1080
13
Valaciclovir - herpes labialis study

• One day high dose valaciclovir treatment regimen
• Reduced the episode duration by about 1d, or 15
• Reduced lesion healing time by 20
• Trend toward more aborted lesions (44 vs 37)
• Was just as effective as two days of treatment
• Treatment was well tolerated

Spruance et al. AAC 2003471072-1080
14
One day famciclovir for the treatment of herpes
simplex labialis

• Famciclovir 1500 mg single dose
• Famciclovir 750 mg bid for one day
• Matching placebo
• Patient-initiated within 1 hr of prodrome onset
• 1 multicenter study
• Primary efficacy variable
• Time to healing

Spruance et al. J Am Acad Dermatol 20065547-53
15
Famciclovir herpes labialis studyTime to
healing of primary vesicular lesions
1.0
0.9
0.8
0.7
0.6
Proportion of patients with healed lesions
0.5
0.4
0.3
Famciclovir 1500 mg, single dose
0.2
Famciclovir 750 mg bid, single day
0.1
Placebo
0.0
0
2
4
6
8
10
12
14
Time (Days)
With single dose treatment regimen patients
experienced a 1.8 day reduction in healing time
(Plt0.001) and a 2.5 day reduction in time to
normal skin (Plt0.001)
Modified intent-to-treat population
Spruance SL, et al. J Am Acad Dermatol 2006
16
Famciclovir herpes labialis study

• Single high dose famciclovir treatment regimen
• Reduced the time to healing of primary vesicular
  lesions by 1.8 days, or 30
• Reduced time to normal skin (episode duration)
  by 2.5 days, or 35
• No increase in aborted lesions was seen
• One dose was just as effective as two doses
• Treatment was well tolerated

Spruance SL, et al. J Am Acad Dermatol 2006
17
One day famciclovir for the treatment of
recurrent genital herpes

• Famciclovir 1000 mg BID for one day
• Matching placebo
• Patient-initiated at earliest symptom of
  recurrence and at lt6 hrs
• 1 multicenter study
• Primary efficacy variable
• Investigator-assessed time to healing of all
  non-aborted lesions

Aoki et al. Clin Infect Dis 2006425888-13
18
Famciclovir genital herpes study Time to
healing of non-aborted lesions
With single day treatment regimen patients
experienced a 1.8d reduction in healing time
(plt0.001) and an increase in PCR aborted lesions
from 5.3 of placebo recipients to 20.9 of
famciclovir recipients (plt0.001)
Aoki et al. Clin Infect Dis 2006425888-13
19
Famciclovir genital herpes study

• Single day famciclovir treatment regimen
• Reduced the time to healing of primary vesicular
  lesions by 1.8 days, or 30
• Increased proportion of PCR aborted lesions from
  5 to 21
• Treatment was well tolerated

20
What we know about patient-initiated high dose,
short course antiviral therapy for recurrent HSV
infections

• Clinical trials demonstrate that
  patient-initiated, high-dose, short course
  therapy is efficacious
• Significantly reduces the duration of the
  recurrent episodes of labialis and genital herpes
• Significantly more patients had aborted genital
  herpes episodes
• There was a trend towards aborted lesions in
  patients treated for labialis
• It is convenient and well tolerated
• Patients must have a supply of medication
  available to initiate therapy promptly

21
Points to consider

• How might these data change your management
  strategy for recurrent HSV infections?
• Duration of dosing?
• Number of days (1, 2, 3, 5, 7)
• Frequency of dosing?
• Number of doses per day
• Size of dose
• Timing from onset
• Lesions vs prodrome

22
Optimizing Therapy Pushing the Boundaries
in Herpes Management
Wednesday 10th October 2007, At the IHMF Annual
Meeting, Dubrovnik
23
Redefining therapeutic options in VZV
Robert W Johnson, MD Bristol, UK
24
Varicella Zoster Virus (VZV)

• Primary infection
• Varicella

• Persistence with clinical latency

• Reactivation
• Herpes zoster

25
Diagnosis

• Clinical diagnosis
• Up to 20 error rate
• Most common confusion
• HSV (cold sores, GH)
• Laboratory diagnosis
• Usually unnecessary
• PCR
• Culture

26
Who gets Herpes Zoster?

• Normal older adults
• Immunosenescence
• Immunocompromised individuals
• Malignancy and its treatment
• Lymphoma
• Chemotherapy, radiotherapy
• Immunocompromising disease
• HIV
• Therapeutic immune suppression
• Organ transplant
• Steroids etc
• Normal children and younger adults

27
Age-related incidence of HZ and PHN
Rate per 1000 per year
11
10
9
Zoster
8
7
6
5
4
PHN
3
2
1
0
0
10
20
30
40
50
60
70
80
Age (years)
Hope-Simpson RE. J R Coll Gen Pract.1975
25571-575.
28
European population distribution by age
population pyramids
Age group
60
0-59
1950
2000
2050
Male
Female
80
Age
60
40
20
10
10
5
5
0
10
10
5
5
0
10
10
5
5
0
Percentage
Percentage
Percentage
Source UN World Population Ageing, 1959-2050
29
Historical increase in life expectancy (years)
18
Iron and Bronze-Age
About 2000 years agoRome
22
Middle AgesEngland
33
1687-1691Wroclaw
33.5
Before 1789Mass Wales
35.5
40.9
1836-1854England Wales
1900USA
49.2
1946USA
66.7
1985USA
74.7
2000USA
75.3
From Beatrix Grubeck-Loebenstein, Innsbruck,
Austria
30
Change

• Past, present and future
• Population demography
• Antiviral drugs
• Varicella vaccine
• Herpes zoster vaccine
• Management of HZ complications

31
Management of HZ

• Early and accurate recognition
• Prompt treatment with antivirals
• Preference for antiviral with good oral
  bioavailability and convenient dosing schedule
• Good analgesia including adjuvant drugs
• Recognition of PHN risk

32
What do antivirals achieve?

• Reduced acute pain
• Accelerated rash healing
• Reduced period of viral shedding
• Reduced duration of pain
• Effect on complications other than pain
• Excellent safety profile
• Reduction in overall burden of HZ

33
Do antivirals prevent PHN?

• It depends upon what you mean by PHN!
• Incidence of pain at 3 months and 6 months YES
• Incidence of pain at 1 year unknown but
  possibly not much
• Prevalence of PHN in the population YES but
  extent unknown

34
User-friendly antiviral prescription?

• Aciclovir 5 x daily inconvenient
• Valaciclovir TID - PHN duration
• Famciclovir TID - PHN duration
• Famciclovir 750mg once daily - Acute symptoms
• Brivudin once daily - PHN duration
• Valaciclovir 1.5g BID - equivalent to TID
• Would famciclovir once dailyalso reduce duration
  of PHN?

35
Famvir Dose proportionality of systemic
concentrations of penciclovir (Famvir dose
range 125 to 750 mg)
Mean SD plasma concentrations of penciclovir
following single oral administration of 125,
250, 500 and 750 mg famciclovir tablets to 20
healthy subjects
36
Famvir Dose proportionality of systemic
concentrations of penciclovir (Famvir dose
range 125 to 750 mg)
Mean SD plasma concentrations of penciclovir
following single oral administration of 125,
250, 500 and 750 mg famciclovir tablets to 20
healthy subjects


median range
37
Is 7 days treatment necessary?

• 21 days ACV no advantage over 7 days
• 10 days ACV no advantage over 7 days
• Would, say, 5 days be as effective?
• What about high doses of antiviral for shorter
  time periods (3 days or even single day)?
• Experience with HSV

38
Prevention of Herpes Zoster and PHN

• Reduction in number of susceptible individuals in
  population
• Varicella vaccine
• Increased VZV-specific CMI of seropositive
  individuals
• Relevance of exogenous boosting
• HZ vaccine

39
Burden of PHN patient and economy

• Patient suffering
• Loss of ability for self care
• (loss of ability to work)
• Financial implications for carers
• Primary care costs
• Specialist and hospital care costs

40
Cost of HZ 1st 6 months

• Societal and economic burden
• Prospective observational pilot study
• 70 patients had detailed follow-up
• Average overall cost 1st 6 months 524 (min 20,
  med 158, max 4218)
• Medical costs highest gt65
• Societal costs highest lt65

SUK study Scott F, Johnson R, Leedham-Green M,
Davies E, Edmunds WJ, Breuer J. Vaccine 2006
41
Cost of PHN

• UK
• Direct costs only
• Incidence estimates
• Clinical demographic characteristics
  Liverpool, UK
• PHN lifetime cost 770 / patient
• Annual UK cost of PHN 4.8 17.9 million

Davies L, Cossins L, Bowsher D, Drummond M.
Pharmacoeconomics1994
42
Other complications of HZ

• Cutaneous
• Visceral
• Neurological
• Ocular

43
Management of complications

• It seems logical to include antiviral drugs in
  the therapy of most complications but evidence is
  lacking for many
• Evidence exists for use of antivirals to manage
  ocular complications and facial nerve palsies

44
Lifetime changes in immune status
VZV T cells
Varicella exposure
Silent reactivation?
Zoster vaccination
Zoster threshold
Herpes zoster
Varicella
Age
Arvin A, NEJM 20053522266-7
45
HZ vaccine The Shingles Prevention Study

• A Vaccine to Prevent Herpes Zoster and
  Postherpetic Neuralgia in Older Adults
• MN Oxman, MJ Levin, GR Johnson, KE Schmader, SE
  Straus, LD Gelb, et al.
• NEJM 20053522271-84 .

46
Efficacy of HZ on burden of illness (BOI)
Vaccine efficacy on HZ incidence
BOI score
Placebo
EFFICACY 61.1 (95 CI 51.169.1)
10
Vaccine
5.7
plt0.001
8
6
2.2
4
2
plt0.001 versus placebo
0

• HZ BOI Incidence x severity x duration of HZ
  associated pain
• Similar HZ Vaccine Efficacy when results
  stratified according to sex or age

M.N. Oxman et al, N Engl J Med, 2005 Jun 2 352
(22) 2271-84
47
Efficacy on HZ
HZ case definition PCR or culture or CEC
Vaccine efficacy on HZ incidence
Incidence of HZ/1000 Pt-yr
Placebo
Vaccine
EFFICACY 51.3 (95 CI 44.2 57.6)
15
11.12
plt0.001
10
5.42
5
plt0.001 versus placebo
0
HZ vaccine efficacy greater among 60-69 year old
subjects than subjects gt70 years (64 versus 38,
plt0.001)
M.N. Oxman et al, N Engl J Med, 2005 Jun 2 352
(22) 2271-84
48
Efficacy on PHN incidence
PHN presence of pain (score 3 on 0-10 scale)
beyond 90 days after HZ rash onset
Vaccine efficacy on PHN incidence
Incidence of PHN/1000 Pt-yr
Placebo
Vaccine
EFFICACY 66.5 (95 CI 47.5 79.2)
1.5
plt0.001
1.38
1
0.46
0.5
plt0.001 versus placebo
0
Cases of PHN HZ vaccine group 27 versus Placebo
group 80 Similar HZ vaccine efficacy when
results stratified according to age or sex
M.N. Oxman et al, N Engl J Med, 2005 Jun 2 352
(22) 2271-84
49
ZOSTAVAX efficacy by age
HZ
Ages 60-69
PHN
Ages gt69
95 CI
BOI
0
20
40
60
80
100
Vaccine efficacy ()
50
Other contenders for prevention of PHN

• Oral steroids
• Epidural steroids
• Somatic / sympathetic nerve blocks
• Effective pain relief including early use of
  strong opioid and adjuvant drugs

51
Management plan for VZV
Children
Vaccination
Adults
Vaccination
Herpes Zoster
Antiviral drugs Early neuropathic pain
treatment(e.g., Amitriptyline/Gabapentin)
Postherpetic Neuralgia
Postherpetic Neuralgia
Anti-depressants (e.g. Amitripyline)
Anti-convulsants (Gabapentin, Pregabalin)
Topicals (Lidocaine Capsaicin)
Opioids(Tramadol, Oxycodone,Morphine)
52
Points to consider

• Duration of dosing?
• Number of days (1, 3, 5, 7)
• Frequency of dosing?
• Number of doses per day
• Size of dose
• Timing from onset
• Lesions vs prodrome
• Are new clinical trials in zoster necessary?

53
Panel discussion
Can the new HSV management paradigms be applied
in VZV management?
54
Concluding remarks
Richard J Whitley, MD The University of Alabama
at Birmingham
55
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