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Home , Syphilis

Syphilis and : Clinical Problem Solving

Edward W. Hook III M.D. Departments of Medicine, Epidemiology, and Univ. of at Birmingham Birmingham, Alabama Edward W. Hook, III, M.D.

Grant/Research NIH, CDC, WHO, Becton Support: Dickinson, Cepheid, Hologic/Gen-Probe, Roche Molecular,

Consultant: None

Speakers Bureau: None

Treponema pallidum

Morphology Spiral, 8-13x0.15 µm

Motility Corkscrew, Flexing

Division Time 33 hours - 5 days

In vitro Cultivation No (Culture) NATURAL HISTORY OF

20-50%

Exposure … 1° 2° Latent 3° 33% 25% 33% Syphilis — Rates of Reported Cases by Stage of , United States, 1941–2015

NOTE: Data collection for syphilis began in 1941; however, syphilis became nationally notifiable in 1944. Refer to the National Surveillance System (NNDSS) website for more information: https://wwwn.cdc.gov/nndss/conditions/syphilis/. Primary and Secondary Syphilis — Rates of Reported Cases by Sex and Male-to-Female Rate Ratios, United States, 1990–2015 Primary and Secondary Syphilis — Reported Cases by Sex, Sexual Behavior, and HIV Status, 31 States*, 2015

* 31 states were able to classify ≥70% of reported cases of primary and secondary syphilis as MSW †, MSM †, or women and ≥70% of cases as HIV-positive or HIV-negative during 2015. † MSM = men who have sex with men; MSW = men who have sex with women only. Three Decades of Hot Topics in Syphilis Management 1990’s – Neurological involvement in early syphilis

1990’s – Changes in the clinical manifestations of syphilis in persons with HIV

1990’s – Treatment of early syphilis in persons with HIV

2015 - Ocular Syphilis

Ocular Syphilis

Described predominantly in persons with early, relatively recently acquired infection

Described in persons with and without HIV

Described in persons with and without CNS involvement

Responses described to benzathine penillin therapy Ocular Syphilis How Hard Are We Looking For Subtle Ocular Syphilis?

Visual changes are gradual and thus difficult for patients to detect.

Possible increased frequency of retinal detachment

Has the changed? Ocular Syphilis

2012-13 - Ocular or otologic symptoms in 3.5-8% of interviewed syphilis cases (Dombrowski wt al, Sex Trans Dis. 42, 702-3, 2015)

1931 - Iritis noted in 4.5% (111/2413) patients with early syphilis (Moore JE, Am J Opthal, 110-116, 2015)

1932 – Ocular syphilis noted in 2.8% (91/3244) early syphilis patients (Stokes et al, Modern Clinical Syphilology, 1945) Case 1

A 40 YO male presents following notification that his recently tested tested positive for syphilis. He is a local businessman, unmarried, states he has been involved in a monogomous relationship for the past two years. He was treated with levofloxacin for a urinary tract infection by a colleague 6 months ago.

On further history, that sex partner is a male who works as a flight attendant. To the patient’s knowledge, neither has been tested for other STIs since their relationship began.

The laboratory reports the positive was an EIA test for syphilis. Your next step should be: Case 1 continued…

1. Order an TPHA test

2.Order an RPR test

3.Initiate treatment with benzathine G, 2.4 Mu

4.Request that the patient’s partner present for evaluation

5.Screen for and at all recent sites of sexual exposure

6.Test for HIV Case 1 continued…

1. Order an TPHA test

2.Order an RPR test

3.Initiate treatment with benzathine penicillin G, 2.4 Mu

4.Request that the patient’s partner present for evaluation

5.Screen for gonorrhea and chlamydia at all recent sites of sexual exposure

6.Test for HIV CDC-Recommended Algorithm for Reverse Sequence Syphilis Screening

CDC. MMWR 2011; 60 (5): 133-137 Reasons for Serological Testing For Syphilis

Screening

Diagnostic Testing

Monitoring Outcomes of Therapy Serologic Tests for Syphilis

Nontreponemal Tests (VDRL, RPR) Antigen - -lecithin-cholesterol Quantitative, declining over time and with treatment

Treponemal Tests (FTA-ABS, MHA-TP, TPPA, EIAs) Treponemal Antigens Qualitative with lifelong positivity EIA Serologic Tests for Syphilis EIA= Enzyme Immunoassay

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 Reasons For EIA+/RPR- Test Results

Past (treated) Syphilis

Chronic Untreated Syphilis

Very Early Syphilis

False Positive Reasons for Serological Testing For Syphilis

Screening

Diagnostic Testing

Monitoring Outcomes of Therapy Case 1 continued…

RPR is positive at a 1:16 dilution, HIV is negative, urine and rectal specimens are positive for C. trachomatis. The patient is treated with 2.4 Mu of benzathine penicillin and 1.0g of azithromycin for chlamydia. As follow-up, he should:

1. Have repeat syphilis testing in three months

2. Have repeat HIV testing in three months

3. Have repeat testing for chlamydia at 3 months

4. All of the above Case 1 continued…

Three months later the patient returns for follow-up. Gonorrhea, chlamydia, and HIV tests are negative. The RPR is positive at a 1:8 dilution. Based on his test results, the patient is:

1. A treatment failure and should now be re-treated with 2.4 Mu of benzathine penicillin G for three weeks.

2. Successfully treated and can be followed routinely

3. Serofast 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 Meaningful Change in STS Titers- +/- 2 Dilutions

1:1 1:2 1:4 1:8 1:16

1:32 1:64 1:128 1:256 1:512

• Two tube or fourfold dilution decrease • 16/4 = 2 Response To Early Syphilis Therapy at 3 Months Following Benzathine Penicillin G or Azithromycin Treatment (n=470)

Serological Cure 78.5% (369) Serofast 20.4% (96) Serological Failure 1.1% (5)

Hook et al, JID 2010; 201: 1729-35 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 1997; 44: 307-14. Factors Associated With Serological Response To Therapy

Younger Age Earlier Stage of Disease (1o>2o>EL) Jarisch-Herxheimer Reaction Higher Baseline Titer (within stage)

Not Associated – Gender, Race, Prior syphilis,

Sena et al CID 2011; 53: 1092-9 Case 2

A 54 YO man is diagnosed with syphilis of unknown duration based on an RPR reactive at a 1:4 dilution and a reactive treponemal IgG assay. There are no signs of syphilis and no prior serological tests for syphilis. Physical examination is normal. Patient has been reliable with follow-up appointments and medication adherence. CD4 is 480/mm3, VL in non-detectable

Planned therapy with benzathine penicillin, 2.4Mu weekly for three weeks is initiated. He presents 12 days following her initial penicillin injection, stating that he was unable to keep her 1 week appointment due to problems at work.

What should the next course of action be? 2015 CDC STD TREATMENT GUIDELINES Late Latent and Tertiary Syphilis

• Benzathine Penicillin G 2.4 Mu IM weekly* x 3

• Penicillin Allergy • 100 mg PO, BID x 28

• Intradose interval of 10-14 days acceptable without re-starting therapy Case 2 (Continued)

1. Restart therapy with benzathine penicillin 2.4 Mu weekly X 3, urging patient to keep future appointments

2. Change to treatment with doxycycline, 100 mg PO BID for 28 days

3. Continue planned therapy, administer 2.4 Mu benzathine penicillin G, inform the patient he needs one more injection in a week. 2015 CDC STD TREATMENT GUIDELINES Late Latent and Tertiary Syphilis – Missed Doses

Pharmacologic considerations suggest that an interval of 10-14 days between doses of benzathine penicillin for late syphilis or latent syphilis of unknown duration might be acceptable before restarting the sequence of injections. Missed doses are not acceptable for pregnant patients receiving therapy for late latent syphilis. 2015 CDC STD TREATMENT GUIDELINES Late Latent Syphilis Response To Therapy

Quantitative nontreponemal serological tests should be repeated at 6, 12, and 24 months

CSF exam should be performed for 1) A 4-fold increase in titers; 2) An initial titer >1:32 fails to decline 4-fold; 3) Signs or symptoms attributable to syphilis develop Latent Syphilis: Response To Therapy Case 3

A 37 YO male presents for evaluation of a genital . On examination there is a solitary, painless, 1.5 cm with an indurated base. You treat him for primary syphilis with 2.4 Mu of benzathine penicillin. Your diagnosis is confirmed by an RPR positive a 1:8 titer and a reactive treponemal EIA test.

He refers his regular partner who is also treated.

At 4 weeks following therapy his RPR has decline to 1:2

5 weeks later he returns, stating that his syphilis “is back”. He denies new exposures for himself and his regular partner

What now? Case 3

1. Retreat with 2.4 Mu benzathine penicillin Mu 2. Retreat with 2.4 Mu Penicillin G weekly X 3 3. Repeat the RPR 4. Perform a herpes PCR test 5. Perform a type-specific herpes serological test Case 3

1. Retreat with IM 2.4 Mu benzathine penicillin Mu 2. Retreat with IM 2.4 Mu Penicillin G weekly X 3 3. Repeat the RPR 4. Perform a herpes PCR test 5. Perform a type-specific herpes serological test

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%) 16 (3%) PCR Negative 116 (22%)

Mertz K et al JID 1998: 178: 1795-9 Why Herpes Is The Most Common Cause of Genital Ulcer Disease, Worldwide

Herpes > 20% in most populations, worldwide, often exceeds 40%. Recurrence of is common

Classical herpes is not typical herpes

Syphilis is a relatively rare, susceptible disease with a time-limited genital ulcer stage

Result: Clinicians are more likely to encounter an infrequent manifestation of a very common disease (HSV) than a classical presentation of one which is far less common (syphilis). Genital Herpes Is Usually Unrecognized

Self-reported genital herpes, sexually active 2.1% Americans 18-59(1) (Women 2.9%) (Men 1.2%)

Serologic evidence of HSV-2 infection, Americans 16-74 1978 (2) 16.4% (Women 19.4%) (Men 13.2%)

1990 (3) 21.7%

Laumann EO, et al. The Social Organization of Sexuality p.382-389 Johnson RE, et al. NEJM 1989. 321:7-12 Johnson RE, et al. Abstracts of the 10th ISSTDR, No. 22, Helsinki, 1993

Genital Herpes: What People Say They Have

Yeast Irritation From: Zipper Cuts Tight Clothes Ingrown Hairs Bike Seats Jock Itch Vigorous Sex Shaving Heat UTIs Clinical Manifestations Zosteriform Herpes on the Buttock ® vesicles ® pustules ® ulcers ® crusts ® healed

Source: Cincinnati STD/HIV Prevention Training Center

Popular Perceptions of Genital Herpes

Genital herpes is easily recognized

Most people with genital herpes know they are infected

Genital herpes is usually transmitted by direct contact

The major benefit of genital herpes treatment is more rapid resolution of lesions and symptoms Asymptomatic Viral Shedding

• No genital lesions present – Between clinical outbreaks – No history of clinical outbreaks

• Immune response present

• Common sites – Women: and perianal region – Men: penile and perianal region

• Greatest in the first 3 months but continues

• Increased with HIV

• Asymptomatic shedding is of briefer than during clinical recurrences

Genital Herpes Usually Occurs When Symptoms Are Absent

144 discordant 14 of 144 partners couples followed Median 334 Days were infected over time (9.7%)

70% of transmission occurred when the index case was asymptomatic

Mertz et al. 1992. Herpes. Ann Intern Med. 116(3) Genital Herpes Diagnosis

Tissue Culture Polymerase Chain Reaction Antigen Detection Cytopathology Serologic Tests Genital Herpes Infection: Viral Shedding

HSV-1 HSV-2

Initial 15% 85%

Recurrent 2% 98% Type-Specific Serologic Tests

NOT recommended for routine screening

RECOMMENDED FOR: – Evaluation of partners of recently diagnosed patients whose infection status is unknown

– Determination of type in persons with recurrence HSV

– Evaluation of patients with plausible or challenging clinical manifestations Type-Specific Serologic Tests • Type-specific and nonspecific to HSV develop during the first several weeks following infection and persist indefinitely

• IgM tests are rarely useful and not recommended

• Presence of HSV-2 indicates anogenital infection

• Presence of HSV-1 does not distinguish anogenital from orolabial infection. Specificity of Focus HSV-2 ELISA

100100 HSV-1 + in 100% of FP 9090 HSV-1 + in 77% of FP

8080

7070

6060 PERCENT POSITIV E BY WB 5050 PERCENT POSITIV E BY BIOKIT % Positive %

% POSITIVE % 4040

3030

2020

1010

0 1.1-1.5 1.5-2.0 2.0-2.5 2.5-3.0 3.0-3.5 >3.5 N= 1.1-1.5 33 N=33 1.5-2.0 N=26 2.0-2.5 N=30 2.5-3.0 N=20 3.5-3.0 N=300>3.5

N=33 N=33Index ValueN=26 RangeN=30 N=20 N=300 INDEX VALUE RANGE Morrow RA, Friedrich D, Meier A, Corey L. BMC Infect Dis 2005; 5:84. 59 Principles of Management of Genital Herpes

Systemic antiviral Counseling Natural history Partially controls symptoms and signs of Sexual transmission herpes episodes Perinatal transmission Does not eradicate Methods to reduce latent virus transmission

Does not affect risk, frequency or severity of recurrences after drug is discontinued Management Antiviral Medications

Systemic antiviral chemotherapy includes 2 oral medications (Famciclovir no longer available): Acyclovir Valacyclovir

Topical antiviral treatment has minimal clinical benefit and is not recommended. Time to Overall Acquisition of HSV-2 Infection in Susceptible Partners 5 P=0.04 Placebo (N=741) HR: 0.52 (95% CI: 0.27,0.99) 4

3 2 Infection -

2

1 (N=743)

% with HSV Valacyclovir

0 0 20 40 60 80 100 120 140 160 180 200 220 240 Time (days)

Adapted from Corey L et al. N Engl J Med. 2004;350:11-20.