University of Alabama at Birmingham Jefferson County Depart. Of Health Back Again: Recurring Epidemics of Syphilis in the U.S. – A Syphilis Management Update Edward W. Hook III M. D. University of Alabama at Birmingham And Jefferson County Depart. Of Health Birmingham, Alabama

Treponema pallidum Morphology Spiral, 8-13x0.15 m Motility Corkscrew, Flexing Division Time 33 hours - 5 days In vitro Cultivation No (Culture)

Principles of STD Management Accurate Diagnosis Effective Therapy Dose Duration Compliance Concomitant Infections Management of Partners

SYPHILIS MANAGEMENT GOALS Resolution of clinical signs/symptoms Prevention of disease progression Prevention of transmission to others Prevention of HIV transmission/acquisition

EPIDEMIOLOGICAL CHARACTERISTICS OF SYPHILIS Rates highest during social upheaval War time Economic stress Most common in developing nations Disease most common in marginalized groups Lower socio-economic classes Racial / ethnic minorities Limited access to health care Commercial sex workers and drug users

Syphilis—Reported Cases by Stage of Infection, United States, 1941–2011 2011-Fig 36. SR

Primary and Secondary Syphilis—by Sex and Sexual Behavior, 33 Areas *32 states and Washington, DC reported sex of partner data for ³70% of cases of P&S syphilis for each year during 2007-2011. †MSM=men who have sex with men; MSW=men who have sex with women only. 2011-Fig 37. SR

Primary and Secondary Syphilis—Rates by Age and Sex, United States, 2011 2011-Fig 42. SR

Selected STD Rates, 2007 – U.S., Canada, U.K. and Sweden N. Gonorrhoeae 118.9 36.1 30.6 7.0 C. Trachomatis 370.2 224.4 200.3 458.4 Early (P, S & EL Syphilis) 7.4 3.7 4.3 2.6 CDC, STD Surveillance Public Health Agency of Canada, Reported cases of STI WHO 2009

SYPHILIS CONTROL CURRENTLY AVAILABLE TOOLS HAVE BEEN USED WITH SUCCESS THROUGHOUT MOST OF THE DEVELOPED WORLD

Features Favoring Syphilis Control No animal reservoir Reliable diagnostic tests Safe, effective curable and preventative therapy Relatively long, non-infectious incubation period Low or declining disease rates

National Plan for Syphilis Elimination Cross-Cutting Strategies Enhanced surveillance Strengthened community involvement and partnerships Intervention Strategies Rapid outbreak response Expanded clinical and laboratory services Enhanced health promotion Syphilis nearly non-existent in Europe. One of the reasons: Better access to care. Syphilis not reported from the vast majority of counties. Assume – as stated by Garnett/ others – improvements additional pressure from almost any source would be sufficient to push it over the edge. Basic philosophy – regarded it as a “sentinenl event” – some public health deficiency that could be improved by greater involvement of community groups, improving access to care. Etc.

Progress on Syphilis Elimination (1997-2001) Reduction 1997-2001 1997 1998 1999 2000 2001 P&S syphilis cases Congenital syphilis cases Counties responsible for 50% Black:White rate ratio 8,556 1,078 31 44:1 7,007 840 28 34:1 6,617 575 25 30:1 5,979 554 22 24:1 6,103 441 21 16:1 29% 60% 32% 63% In fact disparities were even greater earlier in the decade.

THE NEXT GREAT PLAGUE TO GO Thomas Parran’s 5-Point Program For Syphilis Control – 1936 Case Finding – Serologic Screening Programs Prompt Therapy Contact Identification, Testing, and Therapy Mandatory Serological Evaluations – Premarital and Early Pregnancy Public Education = Symptoms, Complications, Treatment

Principles of STD Management Accurate Diagnosis Effective Therapy Dose Duration Compliance Concomitant Infections Management of Partners

NATURAL HISTORY OF SYPHILIS 20-50% Exposure … 1° Latent 3 33% 25% 33% 2°

Parenthetical Comment: Rethinking Genital Herpes

Etiology of Genital Ulcers In 516 STD Clinic Patients 515 patients recruited from STD Clinics in 10 U.S Cities With High Syphilis Rates PCR Result Number (%) HSV 320 (62%) Syphilis 51 (10%) HSV and Syphilis 13 (3%) Chancroid 16 (3%) PCR Negative 116 (22%) Mertz K et al JID 1998: 178: 1795-9

Back To Syphilis

NATURAL HISTORY OF SYPHILIS 20-50% Exposure … 1° Latent 3 33% 25% 33% 2°

Secondary syphilis

NATURAL HISTORY OF SYPHILIS 20-50% Exposure … 1° Latent 3 33% 25% 33% 2°

Serologic Tests for Syphilis Nontreponemal Tests (VDRL, RPR) Antigen - cardiolipin-lecithin-cholesterol Quantitative Treponemal Tests (FTA-ABS, MHA-TP, EIAs) Treponemal Antigens Qualitative

Interpretation of Changing STS Titers Error of RPR VDRL Tests - + 1 dilution Meaningful change is 2 dilution (or 4-fold) change in titer e.g. 1:2  1:4 or 1:1, no meaningful change 1:2  1:8, meaningful change Quantitative RPR or VDRL test, results are not interchangeable Two dilution decline in titer indicates response to therapy however, failure to decline > 2 dilutions does not necessarily mean patient has failed treatment

SYPHILIS SERODIAGNOSIS: Why Use Confirmatory Tests? Imagine the results of false positive tests (BFPs) when 100,000 people without syphilis are tested. Assume BFP rates of 1.5% for the non-treponemal and 1% for treponemal tests used Screening Non-treponemal Test Treponemal Test 100,000 100,000 x .015 x 01 1500 1000 Confirmatory Testing Treponemal Test Non-treponemal Test 1,500 1,000 x .01 x 015 15 15

PITFALLS ENCOUNTERED IN SYPHILIS SERODIAGNOSIS AND FOLLOW-UP Biologic False Positives False Negative or Delayed STS Reactivity Delayed or Partial Response to Therapy Interpretation of Test Results in Pregnant Patients Interpretation of Test Results in Patients with Prior Syphilis

EIA Serologic Tests for Syphilis EIA= Enzyme Immuno- Assay Pro’s Cloned Treponemal Antigens Easy to do in large numbers. Inexpensive Con’s Limited data on specificity Positives need quantitative test to assess response to therapy and perhaps for confirmation

EIA (ELISA) Serologic Tests for Syphilis Suggested Evaluation of Positive Tests Clinical Evaluation and Record Search. Significance of positive test unknown in persons with prior syphilis. Confirm result with RPR/VDRL. If positive, use for monitoring response to therapy. If negative- ?? Possible longstanding infection vs.. false positive. Clinical evaluation/correlation required

HIV/STD Potential Interactions STDs as markers for HIV risk STDs as risk factors for HIV/acquisition transmission Alterations of clinical +/or laboratory manifestations of STDs due to coexistent HIV infection Decreases susceptibility to STD therapy due to coexistent HIV infection Acceleration of HIV natural history due to coexistent or intercurrent STDs

Syphilis Therapy: Goals Cure of disease: improvement of clinical signs and symptoms; prevention of disease progression Prevention of disease transmission Reduction of risk for HIV acquisition

NATURAL HISTORY OF SYPHILIS 20-50% Exposure … 1° Latent 3 33% 25% 33% 2°

Recommend Treatment For Gonorrhea and Syphilis, 1935 - 2006 Gonorrhea Syphilis Sulfonilamide Penicillin Penicillin Ampicillin Tetracycline Spectinomycin Ceftriaxone Fluoroquinolones Cefixime

2010 CDC STD TREATMENT GUIDELINES Early Syphilis Recommended Benzathine Penicillin G, 2.4 Mu IM Penicillin Allergy Doxycyline 100 mg PO, BID x 14d Limited Data Ceftriaxone 1.0 g IM or IV x 8-10d Azithromycin 2.0g PO

SYPHILIS THERAPY: RESPONSE TO THERAPY Primary or Secondary Syphilis – Fourfold (2 dilution) or greater decline in RPR or VDRL titers by time of 3 month follow-up Early Latent Syphilis – Fourfold (2 dilution) or greater decline in RPR or VDRL titers by time of 6 month follow-up

MANIFESTATIONS OF SYPHILIS TREATMENT FAILURE Clinical Relapse (Recurrent or New Signs) Serologic Failure Relapse following initial response Serologic progression despite therapy Serologic non-response N.B. Treatment failure must be differentiated from reinfection

TREATMENT OF EARLY SYPHILIS IN HIV-INFECTED AND UNINFECTED PERSONS Proportion of Subjects with RPR Decline <2 Dilutions 3 Mo. 6 Mo. 12 Mo. Treatment Group Usual 25% (175) 24% (157) 18% (137) Enhanced 29% (189) 19% (172) 17% (144) Rolfs et al, NEJM

2010 STD TREATMENT GUIDELINES Syphilis in Pregnant Patients Serological Screening for All Women in Early Pregnancy; Repeat Screening at 28-32 Weeks and at Delivery in High Risk Patients or High Prevalence Communities Treat as Recommended for Non-Pregnant Patients No Infant Should Leave the Hospital Without Maternal Serologic Status having Been Determined at Least Once During Pregnancy

HIV/STD Potential Interactions STDs as markers for HIV risk STDs as risk factors for HIV/acquisition transmission Alterations of clinical +/or laboratory manifestations of STDs due to coexistent HIV infection Decreases susceptibility to STD therapy due to coexistent HIV infection

TREATMENT OF EARLY SYPHILIS IN HIV-INFECTED AND UNINFECTED PERSONS Proportion of Subjects with RPR Decline <2 Dilutions 3 Mo. 6 Mo. 12 Mo. Treatment Group Usual 25% (175) 24% (157) 18% (137) Enhanced 29% (189) 19% (172) 17% (144) HIV-Status Positive 38% (76)* 28% (69) 21% (61) Negative 24% (287) 19% (259) 16% (219) *P < 0.05 Rolfs et al, NEJM

2010 STD TREATMENT GUIDELINES Syphilis in HIV Infected Patients Treat as Recommended for Patients Without HIV Infection Closer Follow-up (3, 6, 9, 12, and 24 mos)

2010 STD TREATMENT GUIDELINES Early vs. Late Latent Syphilis Early Latent Syphilis Documented Seroconversion Past Year Unequivocal history of 1°, 2° syphilis symptoms, past year Sex partner with 1°, 2°, or EL syphilis, past year Late Latent Syphilis All others (STD Titers Do Not Differentiate Early vs. Late Latent Syphilis)

2010 CDC STD TREATMENT GUIDELINES Late Latent and Tertiary Syphilis Benzathine Penicillin G 2.4 Mu IM weekly x 3 Penicillin Allergy Doxycycline 100 mg PO, BID x 28

Syphilis Therapy: Response To Therapy Late Latent or Tertiary Syphilis Other Than Neurosyphilis – Follow-up at 6 and 12 months. If titers increase fourfold, if an initially high (> 1:32) fails to decrease, or if signs or symptoms progress or develop, re-evaluate for neurosyphilis and re-treat.

Latent Syphilis: Response To Therapy

SYPHILIS MANAGEMENT GOALS Resolution of clinical signs/symptoms Prevention of disease progression Prevention of transmission to others Prevention of HIV transmission/acquisition