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1 Genital Herpes: Clinical Update on Testing, Treatment and the Prevention of Transmission Gary A. Richwald, MD, MPH Clinical Virologist Former Director.

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Presentation on theme: "1 Genital Herpes: Clinical Update on Testing, Treatment and the Prevention of Transmission Gary A. Richwald, MD, MPH Clinical Virologist Former Director."— Presentation transcript:

1 1 Genital Herpes: Clinical Update on Testing, Treatment and the Prevention of Transmission Gary A. Richwald, MD, MPH Clinical Virologist Former Director and Chief Physician Los Angeles County Sexually Transmitted Disease Program Consultant, American Social Health Association Medical Advisor – LA/Orange County HELP Groups

2 2 The Herpesvirus Family Alphaherpesviruses Herpes simplex virus type 1 (HSV-1) Herpes simplex virus type 2 (HSV-2) Varicella-zoster virus (VZV) Betaherpesviruses Cytomegalovirus (CMV) Human herpesvirus 6 (HHV-6) Human herpesvirus 7 (HHV-7) Gammaherpesviruses Epstein-Barr virus (EBV) Human herpesvirus 8 (HHV-8)

3 3 The Herpesviruses

4 4 Genital Herpes is the Most Prevalent STI Genital Herpes (HSV-2) 45 million Chlamydia 2 million Hepatitis B 417,000 HIV 560,000 HPV 20 million Henry J. Kaiser Family Foundation. CDC Web site. Tracking the hidden epidemics: trends in STDs in the United States 2000:1-31. Xu, F. CDC. NHANES , Oral Presentation. IDSA, Boston Million New Genital Herpes (GH) Infections per Year in the US

5 5 Suburban Seroprevalence of HSV-2 Leone P. Sex Transm Dis 2004;31(5): Study Design: six US communities, six private medical practices in each community: Atlanta, Baltimore, Boston, Chicago, Dallas, and Denver Background: Many primary care providers believe genital herpes is not seen in their patient population Objective: Determine seroprevalence of HSV-2 in suburban practices 150 patients per practice, equal number of men and women Participation occurred as part of normal visit to office 75% Caucasian, 14% African-American, 4% Hispanic 45% household income >$60,000/year, 35% college grad Participation level very high

6 6 Suburban Seroprevalence of HSV-2 4.3% Less than 5% of year old patients report being told they have genital herpes Less than 5% of year old patients report being told they have genital herpes N=5,433 Patients (%) Patients acknowledge they have GH Leone P. Sex Transm Dis 2004;31(5):

7 7 Suburban Seroprevalence of HSV-2 9 Out of 10 Did Not Know They Had Genital Herpes 88% did NOT know they had GH 12% reported having GH Leone P. Sex Transm Dis. 2004;31(5): Patients (%) N=5,452 Patients seropositive for HSV-2 N=5,452 0% 10% 20% 30% 40% 25.5%

8 8 The Significance of Genital Herpes May cause physical and psychological concerns (1) HSV-2 infection increases the risk of HIV-1 infection by at least 2-fold, possibly as much as 4-fold (2) Impact on social health –89% expressed concern and anxiety about transmitting to a partner (3) Transmission of herpes to newborn during pregnancy or delivery –occurs in 1 per 3,200 live births (4) –may lead to serious complications such as seizures, blindness, psychomotor retardation, spasticity, learning disabilities, and death 2 1. CDC Sexually Transmitted Diseases Guidelines Wald A, Link K. J Infect Dis. 2002;185: Catotti DN et al. Sex Transm Dis. 1993;20: Brown Z et al. JAMA. 2003;289:

9 9 Herpes Simplex Virus 1 and 2 HSV-2 - Almost entirely genital; oral infections rare - >95 % of recurrent genital herpes - More frequent asymptomatic shedding than HSV-1 - Very low, if any, risk of HSV-1 acquisition HSV-1 - Mostly orolabial (cold sores, fever blisters) - Increasing proportion of cases of primary genital herpes, especially in younger sexually active patients - Shorter initial and recurrent outbreaks than HSV-2 - Infrequent recurrences and asymptomatic shedding - Continued risk for HSV-2 acquisition

10 10 Type-Specific Methods for Diagnosing Genital Herpes Swab symptomatic area to detect virus –Culture –Polymerase Chain Reaction (PCR) Draw blood to look for type-specific antibodies

11 11 Detection of Virus Using a Swab of Lesion/Infected Area Culture: if results are non type-specific, request lab to perform typing Not useful during intra-lesional period If Positive: –Patient likely has GH; false positives are very rare If Negative: –No detectable virus in that sample; does NOT mean patient doesn’t have GH –False negatives are very common, low sensitivity – often <50% for primary herpes, <30 % for recurrent herpes, especially when collected after day 3 of outbreak when viral load is low

12 12 PCR (Polymerase Chain Reaction): 3-4 times more sensitive than culture, most often not available outside of hospital and can be very expensive (5- 15 times the cost of culture) If Positive: –Patient likely has GH; false positives are very rare If Negative: –False negatives are rare –No virus in sample taken; patient could still have GH Detection of Virus Using a Swab of Lesion/Infected Area Ashley R. Laboratory Diagnosis of Viral Infections. 1999: Gupta R, et al. J Infect Dis. 2004; 190 (15): Wald A. J Clin Inv. 1997; 99(5): Wald A. J Infect Dis. 2003;188:

13 13 Detection of HSV-2 Antibody Using Type-Specific Serology Principal test: FDA-approved IgG type-specific antibody tests HerpeSelect ® ELISA HSV-2 or HSV-1 HerpeSelect ® Immunoblot for HSV-2 and HSV-1 biokit HSV-2 Rapid Test Much less commonly used TSST: Western blot First type-specific test, not FDA approved Not commercially available but can be sent to Univ. of Washington

14 14 HerpeSelect-2 and HerpeSelect-1 Type-Specific Tests

15 15 Genital Herpes: FDA-Approved Type-Specific Serologic Tests HerpeSelect TM 2 ELISA IgG HerpeSelect TM 1 ELISA IgG HerpeSelect TM Immunoblot 2 Immunoblot 1 *Based on comparison with the results of Western blot test. Percentages given for HerpeSelect, and Immunoblot, are for HSV-2 antibodies HerpeSelect TM is a trademark of Focus Diagnostics Adapted from Ashley RL. Sex Transm Infect. 2001;77: Ashley-Morrow R et al. Am J Clin Pathol; 2003;120 Sensitivity* Specificity* (%) (%) ` Type of Test Antibody tests become positive as early as three weeks, and by 16 weeks almost all tests of those infected are positive

16 16 Test Order Codes for HerpeSelect ® 1 and 2 IgG Type-Specific Antibodies Quest Diagnostics Runs only HerpeSelect IgG serology HSV-2 alone, HSV-1 alone, or the combination Order codes: –HerpeSelect HSV-1 ELISA: 3636X –HerpeSelect HSV-2 ELISA: 3640X –HSV-1 and HSV-2 combined: 6447X Labcorp Runs non-specific as well as type-specific HerpeSelect tests Order codes: –HerpeSelect HSV-1 ELISA: –HerpeSelect HSV-2 ELISA: –HSV-1 and HSV-2 combined: Mayo Clinic ∙ Runs only HerpeSelect IgG serology ∙ Order codes: requires ordering both tests together - HerpeSelect HSV-1 and HSV-2 ELISA: 84429

17 17 Is IgM Useful in Distinguishing New vs. Recurrent GH Infection? No! Do not order IgM antibodies to diagnose new vs. recurrent GH infection. Often laboratories automatically do IgM test Why aren’t IgM tests helpful in determining the recency of GH infection? - IgM tests are not type-specific – IgM could be from HSV-1 or HSV-2! - Each of the many episodes of viral reactivation can produce new IgM and IgG, making it difficult to interpret results as to acuity of infection. For example, some first infections can have no IgM (only IgG) and some recurrent infections can have IgM. Ashley RL. Herpes 1998;5:33–38.

18 18 Who Is a Candidate for HSV Serologic Testing? Patient with typical GH lesion; culture not done or negative Patient with recurrent clinical symptoms suggestive of GH, but without typical GH lesions Sexual partners of patients with GH Patient request to know infection status STD screening Prenatal screening Patient with HIV infection

19 19 Who Is a Candidate for HSV Serologic Testing? Persons with clinical evidence of HSV Patient has typical GH lesion; culture/PCR not done or negative Patient originally diagnosed with HSV by clinical exam only without culture/PCR Patient has recurrent clinical symptoms of lower genital tract inflammation not explained by another diagnosis (patient does not have typical GH lesions) Note: Helpful in making definitive diagnosis, eliminating misdiagnoses, differentiating between genital HSV-2 and HSV-1 which have different prognoses.

20 20 Who Is a Candidate for HSV Serologic Testing? Testing driven by patient risk-profile or request Patient with a previous or a current partner with GH Patient needs STD screening due to risk status Patient requests STD screening Patient requests HSV testing Patient is being evaluated for sexual assault Note: For patients in a relationship, HSV status will help determine if the patient or partner(s) would benefit from suppressive therapy to reduce transmission to uninfected partner(s).

21 21 Pregnant women Patients prior to transplant or starting immunosuppressive therapy Patients with HIV infection Patients at risk for sexual acquisition of HIV infection Note: HSV-2 infected pregnant women should be offered a month of suppressive therapy prior to delivery. HSV-2 increases the risk of HIV transmission and HIV acquisition and can accelerate HIV progression. Who Is a Candidate for HSV Serologic Testing? Special populations

22 22 Corey L, Wald A. In: Sexually Transmitted Diseases. 1999: Wald A et al. NEJM. 1995;333: Mertz GJ et al Ann Intern Med. 1992;116: Asymptomatic Viral Shedding Asymptomatic viral shedding is the presence of HSV on the surface of the skin/mucosa in the absence of signs and symptoms Subclinical shedding may occur in the presence of symptoms such as itching or tingling without any apparent lesions The majority of people with genital HSV-2 shed virus asymptomatically; frequency of shedding is highest in first few years after acquisition Possible HSV-2 shedding sites can be described to patients as the area covered by “boxer shorts”

23 23 Gupta R, et al. J Infect Dis. 2004; 190 (15): Wald A et al. N Engl J Med. 1995;333: Corey L et al. N Engl J Med. 2004;350: Asymptomatic Viral Shedding is Common and Can Occur Frequently Most GH patients experience asymptomatic shedding* PCR has a ~3-4 times higher detection rate than culture * Shedding in the absence of lesions † Shedding rates can vary based upon time since diagnosis, frequency of recurrences, method of detection, frequency/site of sampling % of patients with ≥ 1 day % of days Asymptomatic sheddingvia culture † via PCR † 51-61% 2.0% - 6.6% 72-88% 7.8% - 27%

24 24 Adapted from Wald A et al. N Engl J Med. 1995;333: % of Asymptomatic Shedding* Episodes Occurred More Than 7 Days From a Lesion Examples + Viral shedding Lesions X *Shedding in the absence of lesions

25 25 Wald A et al. NEJM. 2000;342: No reported history of symptomatic GH Patients without a GH History Shed Asymptomatically* at a Similar Rate as Those with a History 32% No shedding 68% Shedding HSV-2+ patients with at least one shedding episode History of symptomatic GH 39% No shedding 61% Shedding *shedding in the absence of lesions as measured by culture In addition, both groups shed virus asymptomatically at a similar rate

26 26 Adapted from Mertz GJ et al. Ann Intern Med. 1992;116: % of Partners with HSV-2 Transmitted Genital Herpes to Their Susceptible Partners 14 of 144 acquired genital herpes: 3 of 79 susceptible males 11 of 65 susceptible females Study of 144 healthy couples discordant for genital herpes. Couples were followed for a median of 334 days:

27 27 Up to 70% of Transmission May Occur During Asymptomatic Viral Shedding Up to 30% Up to 70% Transmission during symptomatic outbreaks Transmission during asymptomatic viral shedding Adapted from Mertz GJ et al. Ann Intern Med. 1992;116: Results from a randomized, prospective study of 144 healthy couples discordant for genital herpes. Couples were followed for a median of 334 days, during which time 9.7% of partners became infected with genital herpes.

28 28 Common Manifestations of Genital Herpes “Classic” Presentation Painful vesiculopustular lesions Genital ulcers Perianal and anal ulcers Atypical Presentation Genital Itching Vulvar, scrotal or perianal fissures Cervicitis or proctitis Urethral or vaginal discharge Vulvar or perianal irritation Dysuria Penile or scrotal irritation Painless ulcers Asymptomatic Presentation Ashley RL, Wald A. Clin Microbiol Rev. 1999;12:1-8.

29 29 Commonly Misinterpreted Symptoms Men may misinterpret symptoms as 1 –Jock itch –Folliculitis –Hemorrhoids –Irritation from condom use, sex, tight clothing Women may misinterpret symptoms as 1 –UTI –Yeast infection –Hemorrhoids –Irritation from sex, condom use, or feminine products Have a high index of suspicion for GH in patients with recurrent genitourinary complaints Reference 1. Ashley RL and Wald A. Clin Microbiol Rev. 1999;12:1-8.

30 30 Ashley RL, Wald A. Clin Microbiol Rev. 1999;12:1-8. Merck Manual Genital Herpes Signs and Symptoms Are Attributed to Many Other Conditions Consider a differential diagnosis of genital herpes for patients with recurrent symptoms Undiagnosed Patients Often Attribute Their Genital Herpes Symptoms to Other Conditions Itching Burning Redness Discharge Pain with urination Urinary frequency and urgency UTIVaginitisYeast Genital Herpes Possible Overlapping Symptoms Patient Reported Conditions Actual Diagnosis

31 31 First Episode Treatment –Acyclovir 400 mg three times a day for 7-10 days − Valacyclovir (Valtrex) 1000 mg twice a day for 7-10 days − Famciclovir (Famvir) 250 mg three times a day for 7-10 days CDC Sexually Transmitted Diseases Guidelines

32 32 Episodic Therapy –Acyclovir 400 mg TID for five days − Valtrex 500 mg BID for three to five days − Famvir 125 mg BID for five days CDC Sexually Transmitted Diseases Guidelines

33 33 Suppressive Therapy –Acyclovir 400 mg BID daily –Valtrex 500 mg QD daily for people with 9 or fewer outbreaks per year –Valtrex 500 mg BID or 1000 QD for people with 10 or more outbreaks per year –Famvir 250 mg BID CDC Sexually Transmitted Diseases Guidelines

34 34 Long Term Suppression – Safety Issues Safety data available for up to 20 years of constant use (JID, Oct, 2002, Tyring) No safety labs need to be drawn (such as LFT, kidney functions) Drug holidays not needed

35 35 HSV Resistance is Rare Isolation of resistant isolates is <<1% in immunocompetent patients Only a few documented cases of clinical resistance No detectable increase in resistance since introduction in 1981 No documented cases of transmission of resistant virus Most resistant strains are deficient in viral thymidine kinase (TK-): these are less virulent than wild-type virus in animal models) Recent published model of antiviral resistance predicts that after 25 years of high antiviral use, only 5 of 10,000 immunocompetent patients will be shedding drug-resistant virus Kost RG et al. NEJM. 1993;329: Collins P, Ellis MN. J Med Virol. 1993;1(suppl 1): Mouly F et al. Dermatology. 1995;190:177.Corey L, Wald A. In: Sexually Transmitted Diseases. 1999: Bacon T et al. Clin Microbiol Rev. 2003;16: Gershengorn HB et al. BMC Inf Dis.2003;3:1

36 36 Corey L et al. NEJM. 2004;350: HSV-2 Transmission Study Design Immunocompetent, heterosexual partners, age ≥18, in a stable monogamous relationship Source partner suitable for suppressive therapy, history of 9 or fewer episodes/year Source partners randomized to valacyclovir 500 mg once daily or placebo for 8 months Susceptible partner monitored for acquisition of HSV Source PartnerSusceptible Partner HSV-2HSV-2 SeropositiveSeronegative Couples (N=1484)

37 % with Clinical Disease Placebo Valacyclovir 500 mg once daily 2.2% (16/741) 0.5% (4/743) P=0.011 RR: 0.25 (95% CI: 0.08,0.74) 75% reduction Proportion of Susceptible Partners with Symptomatic Genital Herpes Corey L et al. NEJM. 2004;350:11-20.

38 PlaceboValacyclovir 500 mg once daily 3.6% 1.9% % with HSV-2 Infection 48% reduction P=0.054 RR: 0.52 (95% CI: 0.27,0.97) (27/741) (14/743) Proportion of Susceptible Partners with Overall Acquisition of HSV-2 Infection Corey L et al. NEJM. 2004;350:11-20.

39 39 Patients Infected <2 Years were More Likely to Infect Their Partner Placebo Valacyclovir Corey L et al. NEJM. 2004;350: Duration of Infection

40 40 Patients in Current Relationship for <1 Year were Also More Likely to Infect Their Partner Placebo Valacyclovir Duration of Relationship Corey L et al. NEJM. 2004;350:11-20.

41 41 HSV-2 Shedding Substudy Conducted in a subset of subjects enrolled in the main study 89 source partners from 3 US sites Participated for ~ 60 days Daily genital swabs for HSV-2 by PCR Additional swab of lesion if present

42 42 PlaceboValacyclovirP (N=50)(N=39)Value % of days with 10.8%2.9%<0.001 total shedding* (mean) HSV DNA copies/mL4.21.7<0.001 on all days (mean log 10 ) 64% fewer days of asymptomatic shedding † in the valacyclovir treatment group vs placebo (2.8% vs 7.8%, P<0.001) * Symptomatic and asymptomatic † Shedding in the absence of lesions Corey L et al, NEJM 2004;350:11-20 Source Partners Using Valacyclovir Shed on 73% Fewer Days Than Those on Placebo

43 43 Revised ACOG Guideline Summary of Recommendations for Suppressive Therapy Use in GYN Patients (Level A): “Women with frequent recurrences should be offered suppressive therapy.” “For couples in which one partner has HSV-2 infection, suppressive antiviral therapy should be recommended for the partner with HSV-2 to reduce the rate of transmission.” ACOG Practice Bulletin No. 57 November 2004 ACOG Practice Bulletin No. 57, Vol 104, Nov. 2004,

44 44 VALTREX ® (valacyclovir HCl): Dosage for Suppression of Genital Herpes In immunocompetent adults, the recommended dosage of VALTREX for chronic suppressive therapy of recurrent genital herpes is 1 g once daily with an alternative dose of 500 mg once daily for patients with 9 or fewer recurrences The safety and efficacy beyond one year has not been established Most commonly occurring adverse events with suppressive therapy include: –headache (35% - 1 g, 38% mg, 34% - placebo) –nausea (11%, 11%, 8%) –abdominal pain (11%, 9%, 6%)

45 45 Important Safety Information WARNING: Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), in some cases resulting in death, has occurred in patients with advanced HIV disease and also in allogeneic bone marrow transplant and renal transplant recipients participating in clinical trials of VALTREX ® (valacyclovir HCl) at doses of 8 g per day

46 46 Important Safety Information (cont) Precautions: The safety and efficacy of VALTREX ® (valacyclovir HCl) for reduction in the risk of transmission of genital herpes has not been established in nonheterosexual patients, patients with multiple sexual partners, or patients with more than 9 episodes per year The safety and efficacy of VALTREX for reduction in the risk of transmission of genital herpes has only been evaluated for 8 months

47 47 Important Safety Information (cont) Precautions: When VALTREX ® (valacyclovir HCl) is used to reduce the risk of transmission of genital herpes, patients should be counseled to use safer sex practices with suppressive therapy (see current CDC Sexually Transmitted Diseases Treatment Guidelines) VALTREX has not been shown to reduce the risk of transmission of sexually transmitted infections other than HSV-2 There is no cure for genital herpes. Even with treatment, it may be possible to spread genital herpes to others

48 48 Dosage of VALTREX ® (valacyclovir HCl) for Patients with Renal Impairment Genital herpes Suppressive 1 gram everyNo500 mg every500 mg every therapy 24 hours reduction 24 hours 24 hours Suppressive 500 mg everyNo500 mg every500 mg every therapy 24 hours reduction 48 hours 48 hours Normal dosage regimen (creatinine Indications clearance  50) <10 Creatinine clearance (mL/min)  Dosage adjustment recommended for patients with varying degrees of renal dysfunction

49 49 ACOG Practice Bulletin Women with primary HSV during pregnancy should treat this episode with antiviral therapy Cesarean delivery should be performed on women with first episode HSV or recurrent HSV who have active genital lesions or prodrome at delivery For women at or beyond 36 weeks gestation with a first episode of HSV occurring during pregnancy, antiviral therapy should be considered For HSV seropositive women at or beyond 36 weeks gestation and at risk of recurrent HSV, antiviral therapy may be considered, although such therapy may not reduce the likelihood of cesarean delivery In women with no active lesions or prodromal symptoms during labor, cesarean delivery should not be performed on the basis of a history of recurrent HSV disease.

50 50 All pregnant women screened at weeks gestation HSV-2 Seropositive Condoms Abstinence Suppression (partner) Avoid oral-genital contact Condoms Abstinence Suppression (partner) Exam for lesions in labor Education Suppression (patient) Avoid if possible – AROM – Scalp electrodes – Vacuum extractors – Forceps HSV-1 Seropositive Partner HSV-2 Seropositive HSV Seronegative Partner HSV-1 Seropositive

51 51 Interactions between HSV and HIV HSV-2 increases risk of HIV acquisition HSV-2 increases risk of HIV transmission HIV alters the natural history of HSV-2 HSV-2 accelerates HIV progression

52 52 Initial infection - Valacyclovir 1.0 g PO bid for 10 days - Famciclovir 250 mg PO tid for 10 days* - Acyclovir 400 mg PO tid* (or 200 mg PO 5 times daily) for 10 days Episodic therapy for recurrence - Valacyclovir 500 mg PO bid for 3 days - Famciclovir 125 mg PO bid for 5 days - Acyclovir 400 mg PO tid (or 200 mg PO 5 times daily) for 5 days Suppressive therapy - Valacyclovir 500 mg PO daily † - Famciclovir 250 mg PO bid - Acyclovir 400 mg PO bid Treatment Regimens † Use 1.0g when >10 episodes per year * These are out-of-label regimens, listed by the CDC in the 2002 STD Guidelines for the Treatment of STDs

53 53 Gary Richwald, MD, MPH


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