Connie L. Celum, MD, MPH Professor University of Washington

1. Below the Belt and Above the Radar: Recognition and Management of Syphilis and Genital Herpes in HIV-Infected Persons Connie L. Celum, MD, MPHProfessorUniversity of Washington The International AIDS Society–USA

2. STDs in HIV-Infected Persons: Implications for clinical providers • Don’t ask, won’t tell - Importance of risk assessment to identify risk factors for & symptoms of STIs • Don’t look, won’t find - Importance of serologic screening, particularly for syphilis and HSV-2

3. Clinical Challenges: Syphilis & HIV • Most providers have little experience in diagnosing syphilis in the pre-AIDS era • Even in cities with syphilis outbreaks, most providers see few cases • Syphilis manifestations are protean, and easily misdiagnosed, particularly rash in HIV+ persons on HAART • Need to maintain high degree of clinical suspicion and routinely perform RPR serologies in asymptomatic persons

4. Chancres of Primary Syphilis

5. Healing Chancres, Darkfield negative

6. HIV & Syphilis: Challenges with the ‘3 R’s’-Recognize, Rx, Report- • Recognition can be more challenging - Atypical manifestations - Secondary syphilis rash often attributed to ARV side effects • Treatment generally same as for HIV-negative persons • Partner notification & contact tracing difficult with anonymous partners

7. GUD: Differential Diagnosis • STD pathogens: • Herpes simplex virus • Acute HIV • Syphilis • LGV • Chancroid • Granuloma Inguinale • Other causes: • Trauma • Psoriasis • Candidiasis • Reiter’s syndrome • Scabies • Fixed drug eruption • Contact dermatitis • Squamous cell CA • Behçet’s syndrome

8. Laboratory Testing for GUD • If available: • Darkfield microscopy • Stat RPR • Fluorescent darkfield for T. pallidum • VDRL/RPR • HSV culture • H. ducreyi culture (if indicated and available) • HIV • PCR not FDA approved

9. Case 1 • MSM seen in Oral Medicine, complaining of sore tongue • Thought to be HIV- by history (5 yrs since last HIV-negative test) • Found to be HIV positive with CD4 125

10. Case 1 • On 2nd visit at Urgent Care clinic, noted to have punched out lesion on palm • What is your differential diagnosis? • What testing should be done?

11. Case 1: Results of tests • VDRL 1:128, MHA-TP + (took 3 visits before syphilis was considered) • What treatment should be given? • Would you perform an LP?

12. Syphilis: Treatment2006 • Primary, secondary & early latent • BZN PCN (L-A) single dose IM 2.4 million units • Don’t use other PCN formulations! • Don’t use azithromycin • Doxycycline 100 mg PO bid x 14 days (inferior) • Ceftriaxone 1 g IV or IM daily x 8-10 days (alternative) • Late latent • BZN PCN IM 2.4 million units weekly x 3 doses (7.2 million u total) • Doxycycline 100 mg PO bid x 28 days (inferior) • Neurosyphilis • Aqueous PCN G 18-24 million units/day x 10-14 days • Procaine PCN G 2.4 million units/day PLUS probenecid 500 mg PO qid x 10-14 days • Ceftriaxone 2 g IV daily x 10-14 days (alternative) CDC STD Treatment Guidelines www.cdc.gov/std; Marra 2004; Winston 2005

13. Primary/Secondary SyphilisResponse to Treatment • No definitive criteria for cure or failure are established • Re-examine clinically and serologically at 6 and 12 months • Consider treatment failure if signs/symptoms persist or sustained 4x increase in non-treponemal test • Treatment failure: HIV test, CSF analysis; administer benzathine PCN weekly x 3 wks • Additional therapy not warranted in instances when titers don’t decline despite normal CSF & repeat therapy

14. HSV-2: “Primer” • Highly prevalent globally : • 22% of sexually active adults in United States • 60% of HIV-negative men who have sex with men (MSM) in Peru • 50% to 70% of HIV-negative women in southern Africa • >80% in HIV-infected men and women globally • Most common cause of genital ulcer disease (GUD) globally • Up to 90% of HSV-2-seropositive persons do not report prior GUD; but after counseling, most recognize genital herpes • Majority shed HSV-2 in the genital tract, even if previously unrecognized genital lesions  thus, are infectious

16. Effect of HIV on HSV-2 Alters clinical presentation & frequency of HSV-2 shedding Longer duration of lesions (CD4 <200)  HSV-2 acquisition & transmission Effect of HSV-2 on HIV  HIV acquisition  HIV levels in plasma & genital tract  HIV transmission HIV HSV-2 Interactions: HSV-2 and HIV Gray 2001 & 2003, Corey 2004, Wald 2002, Freeman 2004 & 2006

17. HSV-2 and HIV: Natural History • HSV-2 reactivation:  genital & plasma HIV levels in established HIV(Schacker 1998, 2002; Mole 2000) • HSV-2 & GUD:  HIV serum levels in early and chronic HIV infection(Gray, 2003) •  frequency of HSV-2 reactivation in HIV-positive persons (Corey 2004) • Mortality benefit in HIV-positive persons on acyclovir in pre-highly active antiretroviral therapy (HAART) era(Ioannidis 1998) • HAART:  symptomatic, not subclinical HSV-2 (Posavad 2004)

18. Summary: HSV-2 & HIV Interactions • HSV-2 is highly prevalent in HIV-infected persons • Strong epidemiologic & biologic data: HSV-2 increases HIV susceptibility & infectiousness • Large proof-of-concept study demonstrates reduction of HIV levels in plasma by 0.6 log10 & genital tract by 0.3 log10 • Complimentary HSV-2 suppression studies underway: acyclovir & HAART, ACV in GUD management, HIV acquisition & HIV transmission • HSV-2 provides a needed prevention strategy while developing HIV vaccine, microbicide & new interventions

19. Case 2 • Heterosexual male from east African, reports HIV- when immigrated 2 yrs ago • Complains of painful suprapubic lesion x 3 wks

20. Case 2: Results of testing • RPR negative • HSV-2 culture + • HIV+, CD4 40 • What treatment would you recommend?

21. 2002 CDC STD Treatment GuidelinesGenital Herpes in HIV+ First episode (same as HIV-) • Acyclovir 400 mg TID x 7-10 d • Acyclovir 200 mg 5x/d x 7-10 d • Famciclovir 250 mg TID x 7-10 d • Valacyclovir 1.0 g BID x 7-10 d Episodic Treatment of Recurrences • Acyclovir 400 mg TID x 5-10 d • Acyclovir 200 mg 5x/d x 5-10 d • Famciclovir 500 mg bid x 5-10 d • Valacyclovir 1 gm bid x 5-10 d Suppressive Treatment • Acyclovir 400-800 mg bid/tid • Famciclovir 500 mg bid • Valacyclovir 500 mg bid 2006: Add Acyclovir 800 mg PO TID for 2 days (only recommended for Immunocompetent persons)

22. What to do now re. HSV-2 in HIV+ persons? • HIV+ individuals should be offered HSV serological testing, where available • For HSV-2 + persons, counsel about clinical issues, ↑ infectiousness • If HSV-2 testing not available, counsel re high probability of infection, clinical manifestations • Test for HIV in persons with GUD in STI clinics • Include ACV in GUD management • Negotiate discounted pricing & increased availability of ACV • Consider suppressive antiviral therapy for HIV+ persons with symptomatic genital herpesor HSV-2 seropositive • CD4 >200 prior to HAART initiation • CD4 <200 not on HAART, or viremicon HAART

23. Myths about Genital Herpes to be Addressed in Counseling • Most presentations are severe, and thus you would know if you had HSV-2 infection • Herpes can only be spread during an active outbreak that the patient recognizes • Genital herpes always recurs in the same place and never scars • Herpes is self-limiting • Only those with severe and frequent outbreaks should receive suppressive therapy • Condoms don’t prevent HSV-2 transmission • Why bother with antivirals if they don’t “cure” HSV-2?

24. Implications for HIV Prevention • Majority of prevention effort has focused on HIV-negative persons • Enhanced counseling for MSM: Disclosure of HIV serostatus; where meet partners; use of crystal meth, poppers & sildenafil with sex • Need enhanced prevention efforts for HIV+ persons • Importance of knowledge of HIV serostatus • Effect of HAART on transmission? • HIV providers need to assess risk & counsel patients • Regular STD screening for sexually active HIV+ • New strategies for prevention are needed • HSV-2 suppression??