Genital Herpes Infections Clinical Guidelines and Consultation Linda Creegan, MS, FNP California STD/HIV Prevention Training Center Linda.creegan@ucsf.edu www.cdc.gov/std/treatment/ www.std.ca.gov Clinician Warmline 510-625-6000 CDC STDTreatment Guidelines App Available now, free Herpes: Most Prevalent STD in the US HPV 20 million Chlamydia 3 million Hepatitis B 1.25 million HIV 1.2 million Women are disproportionately affected by genital herpes Genital Herpes 50 million 1 in 5 women CDC MMWRApril 23, 2010 / 59(15);456-459 CDC www.cdc.gov. Satterwhite STD 2013; 40(3) 187-193 U.S. Census Bureau Web site. Available at: http://www.census.gov. 1 in 9 men HSV Types 1 & 2 HSV-1 Mostly orolabial (cold sores, fever blisters) 20-30% of genital herpes Pathogenesis PrimaryInfection Virus Recurrent Infection Virus HSV-2 Almost entirely genital; oral infection rare >95% of recurrent genital herpes Reactivated Virus Latent Virus Spinal Cord Corey L, et al. SexuallyTransmitted Diseases. 1999:285-312. Illustration by F.H. Netter. 2001 Icon Learning Systems 1
Classification of Genital Herpes Clinical Progression of Herpes Lesions First episode Primary infection: Naïve to both viruses then contracts one type or the other Non-primary first-episode infection: already has one type, then contracts the other Recurrent episode Subclinical shedding BakerDAand the ACOG Committee in Practice Bulletins Obstetrics. Int J Gynecol Obstet. 2000;68;165-174. Early Redness/ Swelling Thin-Walled Fluid- Filled Vesicles and Pustules Early Healing of Vesicles, Erosions, or Ulcers Crusting Scabbing Healed Skin Primary Genital Herpes Incubation period ~ 4 days (2-14 day range) Systemic symptoms in up to 80% Fever, headache, malaise, myalgia Local symptoms pain, itching, dysuria, discharge, inguinal adenopathy Multiple painful lesions develop bilaterally New lesions may appear for up to 10 days, with mean duration of lesions 18 days STD Atlas, 1997 Primary Herpes: Vulvar & Cervical ~70-90% HSV-2 primary episode have cervicitis; ~15-30%recurrent McGraw-Hill, Sexually Transmitted Disease, 3 rd ed. STD Atlas, 1997 Recurrent Genital Herpes Herpes Vesicles, Crusted lesions Milder clinical illness Less extensive distribution of lesions, typically unilateral Shorter duration of symptoms (5-10 d) Systemic symptom rare Prodrome common Complications rare Frequency variable May present as first clinical episode SFCC SFCC McGraw-Hill, Sexually Transmitted Disease, 3 rd ed. STD Atlas, 1997 2
Atypical Herpes Sores Atypical Herpes Sores in Women SFCC SFCC John 20 Y/O MSW with mod-severe dysuria x 5 days Sexual history recently started his first sexual relationship with a female partner unprotected vaginal and oral sex last week Denies discharge or lesions, otherwise feels well Went to another clinic 3 days prior Urine sent for GC/CT and C&S TMP-SMX for a UTI. He is on his third day of abx but notices no improvement John s Genital Exam Penis circumcised, no discharge, urethral meatus very tender to palpation 2 mm circular crusted lesion noted L distal shaft (patient unaware) No lymphadenopathy No scrotal swelling or testicular mass/pain Skin: no rash HSV as a Cause of Urethritis Genital herpes can present primarily with dysuria HSV-1 increasing as a cause of genital herpes Depending on population, proportion of genital herpes caused by HSV-1 ranges from 30-78% Direct test (culture or NAAT) can be taken at urethral meatus Wald, A STI 2006 Roberts et al, STD 2003 Symptomatic Genital Herpes: Tip of the Iceberg General U.S. seroprevalence 16.2%; MSM ~50% 50 million in U.S. infected; ~90% unrecognized MMWRApril 23, 21010; Xu, JAMA 2006; Photo:J. Hofmann 3
Viral Shedding Shedding more frequent with HSV-2 than HSV-1 The majority (>90%) of people with genital HSV-2 shed virus asymptomatically Shedding rates are highest in first years after infection HSV-2 In first 2 yrs shed 5-10% of days After 2 yrs shed 2% of days Shedding may occur from cervix, vulva, urethra, rectum, penis Most sexual transmission occurs during asymptomatic shedding Subclinical (Asymptomatic) Viral Shedding Subclinical shedding occurs at similar rates in HSV-2+ patients with a history of genital herpes as in those without 40 30 20 10 0 0 No reported history of genital herpes History of genital herpes >0 2.5 >2.5 5 >5 10 >10 % of days with subclinical viral shedding WaldA, et al. N Engl J Med 2000;342:844 850 Interaction of HSV and HIV HSV-2 seropositive 2-3 times risk of acquiring HIV HSV-2 increases HIV genital shedding Suppressive treatment of HSV reduces genital and plasma levels of HIV Unfortunately Randomized trials of HSV-2 suppression with acyclovir to prevent HIV acquisition found no difference in acquisition of HIV Diagnostic Testing and Screening Celum, C et al, The Lancet, Vol 371:9630,2109-2119 HSV Diagnosis Clinical diagnosis is insensitive and nonspecific Direct virologic tests of lesion Cell Culture Nucleic acid amplification Type-specific serologic tests HSV Molcular-Based Tests BD ProbeTec HSV 1 & 2 Q x Assay Anogenital lesions in females and males >16 EraGen Multicode-RTx HSV 1 & 2 Anogenital lesions in females >17 BioHelix HSV Assay Oral/anogenital lesions females and males Indicates presence of HSV 1 or 2 Not type specific 4
Type-Specific Antibody Serologic Tests Based on the HSV-specific glycoprotein G2 (HSV-2) and glycoprotein G1 (HSV-1) Both laboratory-based assays and point-ofcare tests Type-Specific IgG-Based HSV Serology: Commercial Kits Sensitivity Specificity HerpeSelect-2 ELISA (Focus) 96-100 97-100 HerpeSelect Immunoblot (Focus) 97-100 98 Biokit HSV-2 (biokitusa ) 93-100 94-97 Cobas -HSV-2 (Roche) 93 98 Captia Select-HSV-2 (Trinity) 90-92 91-99 CDC 2010 STDTx Guidelines www.cdc.gov/std/treatment Cost varies; $20-$140 Western blot assay, consideredgold standard, available through University of Washington Sorting out recent from established infection using swab and blood tests Public Demand: I d like to be tested for everything, please Positive swab test for HSV 2, and negative antibody blood test for HSV 2 = recent infection Positive swab test and positive blood test = established infection (3 months or more) Patient s individual concern Symptoms? Contact? Just to know? Cost Counseling about test and results Public health vs. personal health issues Screening for HSV: Pros and Cons PRO Encourages behavioral change Informing partners Condoms Suppression therapy HIV transmission risk CON Cost: Who pays? No cure Psychosocial Harm of HSV-2 Serology? Systematic review examining psychosocial sequelae of HSV-2 serologic diagnosis in individuals without clinical history of herpes At least 1 post-test psychosocial assessment 9 studies met criteria (309 participants) 7/9 found no persistent negative impact 2/9-increased psychosocial distress, decreased sexual desirability Pre- to post-test perception of severity of an HSV-2 dx decreased. Ross K et al. STI 2011 epub ahead of print 5
David What does a positive serologic test mean? Does it mean David has HSV 2? 25 year-old male, requests blood test for herpes Female partner recently diagnosed with genital herpes Has never had blisters, sores, recurrent itch HSV 2 serology is ordered. One week later, result is positive. Does it tell how long he has had HSV 2? Does it tell whether he has had or will ever have symptoms? Counseling re: a Positive Serologic Test for HSV 2 Nature and chronicity of infection Transmission risks: both symptomatic and asymptomatic viral shedding Condoms partially protective No need for partner evaluation unless partner is symptomatic or wants testing Neonatal transmission risks Identification of prodrome Use of suppression therapy Herpes Serology: Recommendations Universal screening NOT recommended Beyond this, no firm consensus re: who to screen Type-specific HSV-2 serology tests may be useful: Recurrent/atypical symptoms w/ negative culture Clinical diagnosis without lab confirmation Patients with a partner with genital HSV HSV-2 serologic testing should be considered for persons presenting for an STD evaluation (especially for those persons with multiple sex partners), persons with HIV infection, and MSM at increased risk for HIV acquisition CDC 2014 DRAFTSTD Treatment Guidelines www.cdc.gov/std/treatment STD Screening Available On-line Google STD testing : multiple results Talk to a counselor by phone Find a lab Pay $200-600, depending on tests Results by phone in 24 hours, with written confirmation by mail Treatment and Suppression 6
Genital Herpes Treatment 1st Clinical Recurrent Genital Herpes: Episode: Episodic Suppressive (mg for 7-10 days) (mg days) (mg, daily) Acyclovir 400 TID 400 TID x 5 d 400 BID 250 5x/day 800 BID x 5 d 800 TID x 2 d Famciclovir 250 TID 125 BID x 5 d 250 BID* 1000 BID x 1 d 500 mg PO x 1, then 250mg BID x 2 days Valacyclovir 1000 BID 500 BID x 3 d 500 QD 1000 QD x 5 d 1000 QD * Somewhatless effective forsuppression of shedding CDC 2010 STDTreatment Guidelines www.cdc.gov/std/treatment Episodic vs Suppressive Therapy Episodic therapy Decreases healing time by 2 days Decreases pain by 1 day Decreases viral shedding by 2 days Suppressive therapy Decreases frequency/severity of symptomatic recurrences Decreases subclinical viral shedding Decreases transmission Transmission of HSV-2 to Susceptible Partners is Reduced with Once-Daily Suppression 1484 heterosexual couples randomized to 500 mg of valacyclovir vs placebo once daily for 8 months Monthly serum samples collected from susceptible partners Valacyclovir group showed decreased transmission lower frequency of shedding fewer copies of HSV-2 DNA when shedding occurred Valacyclovir Group (N=743) Control Group (N=741) Considerations for Suppressive Therapy Frequency and severity recurrences Psychological and social impact of diagnosis and disease Patient willingness to take medication every day Patient desire to reduces shedding and transmission Corey et al, NEJM 2004; 350(1):11-20. How much drug is enough to completely suppress shedding? What about higher doses? Would that decrease the chance of shedding? Acyclovir 400 mg twice a day or Valacylovir 500 mg once a day Acyclovir 800mg three times a day Valcyclovir 1000 mg three times a day 7
Answer: None of them completely suppress shedding N=90 HSV+, HIV-negative participants, Swabs of genitals for PCR 4 times a day to look for shedding Regimens compared: No meds vs Acyclovir 400mg BID Valacyclovir 500 mg Daily vs Acyclovir 800mg TID Valacyclovir 500 mg Daily vs Valacyclovir 1 gm TID Bottomline: More drug is better Long-term suppressive therapy Continuous suppressive therapy appears safe Safety data for up to 6 years with continuous acyclovir, 1 year for valacyclovir and famciclovir Check-in once a year to discuss the need to continue. No laboratory monitoring is necessary in a healthy person Shedding happens even withhighest dose therapy. JohnstonC et al. Lancet2012 Fife KH et al. JID 1994 Karissa 26 year-old female, 3 year hx genital herpes with recurrences Getting married in 3 months Asks about taking herpes treatment to prevent outbreaks during the wedding and honeymoon Intermittent Suppression Treatment scenarios Reduce risk of episode on special occasions: wedding, vacation, final exam Reduce transmission risk: pregnancy, new sexual relationship To evaluate herpes symptoms or differentiate herpes symptoms from other symptoms Use suppressive therapy dosage indicated for each antiviral agent Initiate treatment ~ 5 days in advance of desired event Current HSV-2 Vaccine Research Therapeutic candidate (preliminary results: 2013) Novel T-cell vaccine, GEN-003, Genocea Biosciences Inc PI: Anna Wald, MD, University of Washington, Seattle Patients who received three doses had 50% reduction in the frequency of viral shedding Protective candidate (began in 2013) T-cell mediated, HSV529, Sanofi Pasteur PI:Lesia Dropulic, MD, NIAID s Laboratory of Infectious Diseases, Safety and the ability to generate an immune system response. Neonatal Herpes Infection Clinical disease manifests at 3-30 days of age Skin, eye or mucous membrane: low mortality, but recurrences possible CNS: 30% mortality, 50% serious sequelae Disseminated: 80% mortality, 10% serious sequelae Overall mortality ~ 20% 8
ACOG Recommendations Offer antivirals for primary outbreak* oral or IV if severe outbreak Offer suppressive therapy women 36 weeks with active recurrent genital HSV (level B) C-section for women with active symptoms or prodromal symptoms at delivery Offer suppressive therapy to reduce transmission in discordant couples + Genital Herpes: proposed updates for 2014 Treatment Guidelines NAATS are most sensitive and increasingly available Prevention: suppressive anti HSV therapy in HIV/HSV- 2 co-infected patients does not reduce risk of HIV transmission Discussion regarding counseling of HSV-1 genital infection New guidelines on management of asymptomatic neonates born to women with genital HSV lesions (Kimberlin, DW, Pediatrics, 2013) *ACOG practice bulletin No.82, June 2007 +ACOG practicebulletin No 57, Nov 2004 THANK YOU!!!! 9