1. Slide #1 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. Below the Belt and Above the Radar: Recognition and Management of Syphilis and Genital Herpes in HIV-Infected Persons Connie L. Celum, MD, MPH Professor University of Washington The International AIDS Society–USA

2. Slide #2 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. 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 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. Slide #3 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. 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 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. Slide #4 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. Chancres of Primary Syphilis

5. Slide #5 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. Healing Chancres, Darkfield negative

6. Slide #6 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. 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 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. Slide #7 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. 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 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. Slide #8 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. 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 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. Slide #9 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. 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. Slide #10 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. Case 1 On 2 nd visit at Urgent Care clinic, noted to have punched out lesion on palm What is your differential diagnosis? What testing should be done? On 2 nd visit at Urgent Care clinic, noted to have punched out lesion on palm What is your differential diagnosis? What testing should be done?

11. Slide #11 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. 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? VDRL 1:128, MHA-TP + (took 3 visits before syphilis was considered) What treatment should be given? Would you perform an LP?

12. Slide #12 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. Syphilis: Treatment 2006 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) 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 2005www.cdc.gov/std

13. Slide #13 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. Primary/Secondary Syphilis Response 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 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. Slide #14 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. 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 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

15. Slide #15 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006.

16. Slide #16 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. Interactions: HSV-2 and HIV 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 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 HSV-2 HIV Gray 2001 & 2003, Corey 2004, Wald 2002, Freeman 2004 & 2006

17. Slide #17 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. 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) 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) HSV-2 and HIV: Natural History

18. Slide #18 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. 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 log 10 & genital tract by 0.3 log 10 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 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 log 10 & genital tract by 0.3 log 10 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. Slide #19 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. Case 2 Heterosexual male from east African, reports HIV- when immigrated 2 yrs ago Complains of painful suprapubic lesion x 3 wks Heterosexual male from east African, reports HIV- when immigrated 2 yrs ago Complains of painful suprapubic lesion x 3 wks

20. Slide #20 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. Case 2: Results of testing RPR negative HSV-2 culture + HIV+, CD4 40 What treatment would you recommend? RPR negative HSV-2 culture + HIV+, CD4 40 What treatment would you recommend?

21. Slide #21 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. 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 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 2002 CDC STD Treatment Guidelines Genital Herpes in HIV+ 2006: Add Acyclovir 800 mg PO TID for 2 days (only recommended for Immunocompetent persons)

22. Slide #22 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. 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 herpes or HSV-2 seropositive  CD4 >200 prior to HAART initiation  CD4 <200 not on HAART, or viremic on HAART  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 herpes or HSV-2 seropositive  CD4 >200 prior to HAART initiation  CD4 <200 not on HAART, or viremic on HAART

23. Slide #23 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. 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? 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. Slide #24 CL Celum, MD, MPH. Presented at RWCA Clinical Update, August 2006. 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??  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??