Recurrent genital HSV infections: how brief can treatment be

1
Recurrent genital HSV infections how brief can
treatment be?

• Anna Wald
• University of Washington
• annawald_at_u.washington.edu

2
Acknowledgments

• Woody
• Peter Leone
• Fred Aoki
• Anders Strand
• Neil Bodsworth
• GSK
• Novartis

• Brad Bavaro
• Karen Mark
• Mike Remington
• Laura Olin
• Linda Drolette
• Amalia Magaret

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Background

• Almost all patients who experience an initial
  outbreak of genital HSV-2 will subsequently
  experience at least one recurrence many patients
  (38) will experience more than 6 recurrences
  per year1
• Traditional course of antiviral therapy for
  herpes recurrences has consisted of 5-day regimen
• However, viral replication ceases early in
  recurrences,2 indicating that shorter courses of
  antivirals may be effective

1 Benedetti J, et al. Ann Intern Med
1994121847-854. 2 Spruance SL, et al. N Engl J
Med. 1977 297(2)69-75 Spruance SL, et al. Oral
Surg Oral Med Oral Pathol 198458667-671.
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Spruance SL, Overall JC Jr, Kern ER, Krueger GG,
Pliam V, Miller W.The natural history of
recurrent herpes simplex labialis implications
for antiviral therapy. N Engl J Med.
197729769-75.

• Daily examination of 80 patients with recurrent
  herpes simplex labialis to define the course of
  the disease and to identify quantitative and
  objective measurements for use in monitoring the
  efficacy of antiviral chemotherapy.
• Pain, lesion size, mean virus titers from lesion
  swabs (10(5)plaque-forming units PFU) and
  frequency of virus-positive lesions (89)were
  maximal during the first 24 hours and decreased
  thereafter.
• Early application of antiviral therapy should
  theoretically be able to alter the course of this
  disease.

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Short course oral HSV therapy

• Spruance et al. AAC 20034710721080
• 1850 persons randomized
• 2 g of valacyclovir twice daily for 1 day (1-day
  treatment), 2 g of valacyclovir twice daily for 1
  day and then 1 g of valacyclovir twice daily for
  1 day (2-day treatment), or a matching placebo
• Median duration of the episode (primary endpoint)
  was reduced by 1.0 day (P 0.001) with 1-day
  treatment and 0.5 days (P0.009) with 2-day
  treatment compared to placebo.
• Spruance et al. J Am Acad Dermatol 20065547-53.
  
• 700 persons randomized
• famciclovir 1500 mg once vs. 750 mg twice vs.
  placebo
• Healing times in the famciclovir single-dose,
  famciclovir single-day, and placebo groups were
  4.4, 4.0, and 6.2 days, respectively (Plt0.001).

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Will short-course therapy for genital herpes also
work?

• Is a short course of antiviral therapies
  effective and safe for reducing the severity and
  duration of genital herpes recurrences?

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Will short-course therapy for genital herpes also
work?

• What is the profile of viral shedding subsequent
  to antiviral treatment?
• What is the effect on subsequent recurrence?
• Which patients are not good candidates for
  short-course therapies?

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Clinical trials of short-course antivirals for
genital herpes

• Valacyclovir for 3 days
• Acyclovir for 2 days
• Famciclovir for 2 days
• Famciclovir for 1 day
• Valacyclovir for 1 day

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Valacyclovir vs. Placebo in the Episodic
Treatment of Recurrent Genital Herpes, n987
Treated within 24 hours of symptom onset.
Results were replicated in a second trial.
Spruance SL, et al. Arch Intern Med.
19961561729-1735.
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Valacyclovir 3 Days vs 5 Days in the Episodic,
n1170
In otherwise healthy adults.
Leone et al, CID 2002
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Valacyclovir 500 mg bid for 3 days

• Efficacy comparable to 5 days
• No difference in time to lesion healing, length
  of episode or viral shedding
• Good tolerance, safe
• More convenient
• Duplicated in another study (Strand et al)
• FDA approved and frequently used in US

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Acyclovir 800 mg tid for 2 days vs. placebo

• Single site, IND study
• 87 people (54 women, 33 men) were observed
  through at least one recurrence
• 68 were followed for 2 episodes (32 ACV, 36 PLC)
• 19 were followed for 1 episode (8 ACV, 11 PLC)
• Each person received the same therapy for both
  recurrences
• Swabs for viral cultures were obtained twice daily

Wald et al, CID 2003
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Acyclovir 800 mg tid for 2 days vs. placebo
Acyclovir
Placebo
Wald et al, CID 2003
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Time-to-Negative Culture Lesion Healing
Wald et al, CID 2003
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Time-to- 2nd Recurrence
Wald et al, CID 2003
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Comparison of virologic outcomes
Wald et al, CID 2003
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High dose acyclovir for 2 days

• Effective in reducing lesion and episode duration
• Effective in reducing viral shedding
• Higher risk of aborted episodes
• No effect on time to next recurrence

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Famciclovir short course therapy study (FaST)

• Clinical trial with 800 pts and 1000
  recurrences
• Randomized to
• famciclovir 500 mg stat plus 250 mg bid for 2
  days
• Famciclovir 250 mg bid for 5 days

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Study Design 5 visits, 2 recurrences
1
2 3
4
5
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Probability of Lesions Being Present at 132 h
First recurrence per patient Recurrences ? ITT,
Evaluable PP Populations
Difference (Short Standard) -3 to -6 Upper
one-sided 97.5 CL 3 to 5
Within pre-specified limit of 10, the maximal
clinically acceptable difference
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Famciclovir short course therapy study (FaST)
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Single-day famciclovir therapy for recurrent
genital herpes

• Healthy adults with genital HSV-2 infection
• Famciclovir 1000 mg q12h 1 day vs placebo
• Double-blind, placebo-controlled trial
• At the earliest symptom of a recurrence and at
  lt6h
• PCR swab at beginning of the episode

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Proportion of patients with aborted lesions
PCR-Pos 5.3 20.9
294 lt0.001
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Time to healing of non-aborted lesions

• Median day
• Famciclovir 4.3
• Placebo 6.1,
• p lt 0.001

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Time to resolution of symptoms
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Famciclovir 1 day

• Effective in reducing lesion and episode duration
• Effective in increasing proportion of persons
  with aborted lesions
• Safe
• FDA approved in the US for therapy of genital
  herpes

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Open-label pilot study

• 1-day course of valacyclovir (2000 mg given by
  mouth b.i.d.) taken by participant at first sign
  of recurrence or prodrome
• 90 persons enrolled
• Participants maintained diaries of signs and
  symptoms for 14 days
• Collected swabs for culture until lesions healed
• Collected swabs for HSV DNA PCR for 14 days

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Outcomes Among Study Participants
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Outcomes Among Study Participants
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Proportion of Study Participants with Genital
Lesions, Positive Cultures, and Positive HSV PCR,
by Study Day
100
80
60
40
20
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Study day
Lesion
PCR
Culture
2nd lesion
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(No Transcript)
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Short course treatments for genital herpes
Corey et al, HERPES 2007
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Comparison among the regimens

• Each study population slightly different
• Cannot compare directly across population

• Ongoing study Efficacy and Safety of
  Famciclovir 1-Day Treatment Compared to 3-Day
  Treatment With Valacyclovir in Adults With
  Recurrent Genital Herpes

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Short-term regimens

• Effective and well tolerated
• High-dose loading may lead to aborted lesions
• Convenient for the patients/good adherence
• May be convenient for clinics
• May be less expensive
• No evidence of rebound in viral shedding or
  shortened time to next recurrence

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Limitations of short term episodic therapy

• No effect on infectiousness
• no sex during recurrences!
• No effect on natural history subsequent
  recurrences or asymptomatic shedding
• Not for use in immunocompromised/HIV patients
  may lead in resistance

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Patient management Optimizing episodic HSV Rx

• What is the goal of therapy?
• Self -initiation of therapy important
• Medication needs to be available to patient