1. NEW DEVELOPMENTS IN THE MANAGEMENT OF GENITAL HERPES Elaine Rosenblatt NP Clinical Associate Professor School of Nursing July 14, 2004

2. OBJECTIVES 1. Understand the range of presentations for genital herpes. 2. Review new testing and treatment options for genital herpes. 3. Discuss the importance of asymptomatic viral shedding in the transmission and prevention of genital herpes I have no disclosures to report.

3. Case 1—Testing and Treatment Options A 26 year old woman is seen in your practice with c/o of a mildly painful “sore” on her vulva. She hasn’t had a similar problem in the past and has no known history of genital herpes. The sore has been present for about 10 days and she‘s been treating the area with vaseline. What testing and treatment options are available?

4. Case 2—Viral Shedding JW is a 21 year old male diagnosed with herpes type 1 about two years ago. He went on suppressive therapy with valacyclovir when he became involved with his present partner. His partner has now gotten tested with type specific serology and is positive for type 1. JW comes in to your clinic and asks you if he need to continue on valacyclovir. What advice can you give him?

5. Epidemiology of Genital Herpes One of the 3 most common STIs, increased 30% from late 70s to early 90s 25% of US population by age 35 HSV-2: 80-90%, HSV-1: 10-20% (majority of infections in some regions) Most cases subclinical Transmission primarily from subclinical infection, and higher from men to women Complications: neonatal transmission, enhanced HIV transmission, psychosocial issues Sores

16. Genital Ulcer Disease with Inguinal Lymphadenopathy DiseaseCauseUlcer TypeAdenopathy Type HerpesHSV-1 or HSV-2Small, painful when scraped, soft Firm, tender when palpated SyphilisTreponema pallidium Painless, hard, indurated Firm, nontender, rubbery ChancroidHaemophilus ducreyi Painful, soft or indurated, purulent Fluctuant, tender, overlying erythema LGVChlamydia trachomatis Usually absentFluctuant, tender DonovanosisCalymmato- bacterium granulomatis Painless, chronic, spreading No adenopathy

17. MOST COMMON TESTS FOR DIAGNOSING GENITAL HERPES Isolation of virus in culture Polymerase Chain Reaction (PCR): DNA amplification method Serology for antibody detection –IgG detection –Glycoprotein G (gG) tests—allows for typing. –Western Blot—allows for typing

19. Type of HSV Infection, Clinical Symptoms, and Antibody at Time of Presentation Infection TypeLesions/ Symptoms Type-Specific Antibody At Time of Presentation HSV-1 Type-Specific Antibody At Time of Presentation HSV-2 First Episode Primary (type 1 or 2) +/Severe, Bilateral - - First Episode Nonprimary Type 2 +/Moderate + - Symptomatic Recurrence Type 2 +/Mild +/- + Infection Type 2+/Mild, Unilateral +/- +

20. HerpeSelect Immunoblot Kit Antibodies detected: HSV-1 or HSV-2 Sensitivity: 97% - 100% accurate Specificity: 98% accurate HRC recommended window period: 12 to 16 weeks after exposure Collection method: blood draw (sent to local lab) Result time: ~ 1-2 weeks Can be used during pregnancy: Yes Cost of test: $80 - $160

21. POCit Rapid Test Antibodies detected: HSV-2 only Sensitivity: 93% -100% Specificity: 94% - 97% HRC recommended window period: 12 to 16 weeks after exposure Collection method: finger prick blood draw Result time: less than 10 minutes Can be used during pregnancy: not FDA approved Cost of test: $50 - $100

22. HerpeSelect ELISA Kits Antibodies detected: HSV-1 and HSV-2 Sensitivity: 96% - 100% accurate Specificity: 97% - 100% accurate HRC recommended window period: 12 to 16 weeks after exposure Collection method: blood draw (sent to local lab) Result time: ~ 1-2 weeks Can be used during pregnancy: Yes Cost of test: $40 - $80

24. Challenging the Paradigm Current treatment by many clinicians is to treat Initial Presentation “Wait & See” for recurrence rate for management strategy Reliance on episodic therapy to address lesions Suppressive therapy if >6 recurrences/year Most new HSV infections are due to transmission from asymptomatic partners… 1.6 million new cases per year in the USA.

25. Corey L, Wald A. In: Sexually Transmitted Diseases. 1999:285-312. Wald A et al. N Engl J Med. 1995;333:770-775. Mert GJ et al Ann Intern Med. 1992;116:197-202. Asymptomatic Viral Shedding Asymptomatic viral shedding is the presence of HSV in the absence of signs and symptoms Many clinicians use the terms asymptomatic and subclinical HSV shedding interchangeably, although subclinical shedding may occur in the presence of symptoms such as itching or tingling without any apparent lesions

26. Subclinical Viral Shedding Subclinical HSV shedding: no lesions consistent with genital herpes but not necessarily “without symptoms” The majority of people with genital HSV-2 shed virus asymptomatically at some time Highest rate of shedding and recurrences in the first year postinfection Mertz et al 1992 study showed that up to 70% of transmission may occur during periods of asymptomatic shedding

27. Corey L, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med. 2004;350:11-20 Can suppressive therapy with valacyclovir reduce the risk of transmission of genital herpes in immunocompetent heterosexual monogamous couples discordant for HSV-2?

28. Study Population-Couples N=1484 Source partner was HSV-2 seropositive and the susceptible partner was HSV-2 seronegative. Immunocompetent, heterosexual partners, age  18, in a stable monogamous relationship Source partner suitable for suppressive therapy, history of 9 or fewer episodes/year Susceptible partner monitored for acquisition of HSV

29. Corey L et al. N Engl J Med. 2004;350:11-20. Study Design International, randomized, double-blind, placebo-controlled study Source partners randomized to valacyclovir 500 mg once daily or placebo for 8 months Susceptible partners evaluated monthly for genital herpes At each monthly visit, couples counseled to practice safer sex, including use of condoms

30. Corey L et al. N Engl J Med. 2004;350:11-20. Primary Endpoint Proportion of susceptible partners with clinical evidence (symptomatic acquisition) of a first episode of genital HSV-2 –clinical signs or symptoms confirmed by HSV-2 seroconversion, culture, or PCR

31. Corey L et al. N Engl J Med. 2004;350:11-20. Data on file, GlaxoSmithKline. Secondary Endpoints Proportion of susceptible partners with overall acquisition of genital HSV-2 –confirmed primary endpoint and/or HSV-2 seroconversion Time to clinical (symptomatic) acquisition of HSV-2 Time to overall acquisition of HSV-2 Proportion of source partners recurrence free

32. RESULTS The results of the study’s primary endpoint demonstrated a 75% reduction in the risk of transmission of symptomatic genital herpes among the valacyclovir group when compared to the placebo group (from 2.2% to 0.5% P 0.01)

33. RESULTS One of the study’s secondary endpoint demonstrated a 48% reduction in risk of overall acquisition in susceptible partners among the valacyclovir group when compared to the placebo group (Placebo: 27/741 (3.6%), Valacyclovir (500 mg once daily): 14/743 (1.9%): P=0.054) HSV-2 shedding substudy demonstrated that the valacyclovir group had significantly fewer days of total and asymptomatic viral shedding when compared to the placebo group

34. Considerations for Choosing Suppressive Treatment Recurrences seriously impacting job performance and/pr relationships/social interactions/activities Frequent recurrences Severe recurrences (regardless of frequency) Anxiety associated with recurrences, concerns about communicability Patient choice and willingness to take daily medication

35. HERPES Asymptomatic transmission control is the goal Most transmission due to asymptomatic shedding: patients can be infectious without lesions Pts especially infectious early in disease Shedding may be significantly decreased with suppressive therapy Patients fear transmission more than recurrences (pain, discomfort) Many patients prefer the suppression option when educated on the treatment options

36. Case 1 A 26 yo woman is seen in your practice with c/o of a mildly painful “sore” on her vulva. She hasn’t had a similar problem in the past and has no known hx of genital herpes. The sore has been present for about 10 days and she‘s been treating the area with vaseline. Exam shows a shallow ulcer 1 cm in diameter with a glandular base. The lesion is mildly tender to touch. Shotty inguinal lymphadenopathy is present and is mildly tender.

37. Case 1 cont. Differential diagnosis: Herpes Syphilis Chancroid Abrasion Infected folliculitis What tests would you order?

38. Case 1 cont. Tests: Herpes Culture or PCR Consider Serology, since lesion resolving Darkfield Exam / VDRL & FTA Chancroid Culture if appropriate

39. Case 1 cont If herpes culture came back positive, how would you explain such a mild outbreak for a “first case of Herpes”. Answer: first episode non primary

40. Case 1 cont What treatment would you offer at Day 10? Day 10 - symptomatic What treatment would you offer at Day 3? Acyclovir 200 mg 5x a day or 400 mg TID for 7 - 10 days Or - Valacyclovir 1 gm bid x 10 days Or - Famciclovir 250 mg tid for 7-10 days Plus symptomatic treatment

41. Case 1 cont. Is long term treatment appropriate? Answer: discuss pros and cons with patient, especially in light of asymptomatic viral shedding and recurrences. Offer patient appropriate teaching.

42. Case 2 JW is a 21 yo male diagnosed with herpes type 1 about 2 years ago. He went on suppressive therapy with valacyclovir when he became involved with his present partner. His partner has now gotten tested with type specific serology and is positive for type 1. JW comes in to your clinic and asks you if he needs to continue on valacyclovir. What advice can you give him?

43. Case 2 cont. They no longer need to worry about transmission in between outbreaks. Therefore he can stop suppressive therapy (his original concern was transmission issues, not recurrences) and start episodic treatment of outbreaks (valacyclovir 500 mg bid for 3-5 days at the onset of sx or appropriate doses of acyclovir or famacyclovir.) Type 1 has few recurrences, but if he does have a problem with recurrences, he can go back on suppressive therapy.

44. Herpes Testing Type-specific serology is not useful in which of the following clinical situations: –A. Establishing the diagnosis of genital herpes in a patient with a highly suspicious clinical history –B. When culture results are positive for HSV –C. As part of a general STI work-up for a low risk patient –D. Predicting recurrences by distinguishing between HSV-2 and HSV- 1 infection

45. Patient Counseling Have a handout listing patient resources, information about the disease Be certain the patient is aware of symptomatic and asymptomatic transmissibility and ways to prevent communicability, treatment options (symptomatic as well as episodic and suppressive therapy), recurrences and pregnancy issues Discuss emotional impact/relationship issues Remind patients they’re not alone: 1 in 4 adults in infected with HSV-2

47. Episodic Treatment Rx recurrences with: acyclovir 400 mg TID x 5 days famciclovir 125 mg po bid x 5 days valacyclovir 500 mg bid x 3-5 days valacyclovir 1 gm daily x 5 days

48. Suppressive Treatment Document recurrence rate, severity and frequencies before starting suppressive Rx for 1 – 2 years of –Acyclovir 400 mg BID –Famciclovir 250 mg bid or –Valacyclovir 1gm daily, if less recurrences try 500 mg qd Or consider suppressive Rx for 1st 3 -12 mos after dx of primary: studies support increased viral shedding during that time