Clinical Practice Objectives

STD Essentials for the Busy Clinician Susan S. Philip, MD, MPH Assistant Professor, Division of Infectious Diseases, UCSF Director, STD Prevention and Control Services San Francisco Department of Public Health Disclosures In the past 12 months, Dr. Philip has received research support from Abbott Diagnostics, Roche Diagnostics, Sera Care Life Sciences and Cepheid, Inc. The views expressed herein do not necessarily reflect the official policies of the City and County of San Francisco; nor does mention of the San Francisco Department of Public Health imply its endorsement. Clinical Practice Objectives Identify more CT and GC infections through screening Understand current issues in GC resistance Get more partners treated Review syphilis screening, clinical presentation and management THE source on STD management Diagnosis, treatment, prevention and vaccination Order hard copies www.cdc.gov/std Wall charts, pocket guides 1

Why Diagnose and Treat STDs? Majority of chlamydia, gonorrhea and early syphilis diagnosed outside of the STD Clinic 20 million STDs in US annually Cost: 16 billion (2010) Health consequences Pelvic Inflammatory Disease Ectopic pregnancy Infertility Neonatal HIV, herpes simplex virus (HSV) and congenital syphilis Increase risk of HIV 66% Men 34% 89% 11% Women CDC STD Surveillance 2008 Health Disparities Nationally there are populations who bear a disproportionate share of STDs Men who have sex with men (MSM) Adolescents African Americans Studies demonstrate that individual behaviors do not account for all the increase 1-3 Chlamydia Rates by Age and Sex, United States, 2010 Men Rate (per 100,000 population) Women 3,700 2,960 2,220 1,480 740 0 0 740 1,480 2,220 2,960 3,700 Age 774.3 15 19 1,187.0 20 24 598.0 25 29 309.0 30 34 153.2 35 39 91.3 40 44 39.3 45 54 10.9 55 64 2.8 65+ 233.7 Total 3,378.2 3,407.9 1,236.1 530.9 220.1 94.7 32.8 9.3 2.1 610.6 1 Ellen STD 1998 2 Laumann STD 1999 3 Oster AIDS 2011 2

Chlamydia Rates by Race/Ethnicity, United States, 2001 2010 Male STD Rates (per 100,000) San Francisco 2009-10 Rate (per 100,000 population) 1500 1200 900 American Indians/Alaska Natives Asians/Pacific Islanders Blacks Hispanics Whites MSM 2009 2010 Other Men Rate Ratio MSM Other Men Rate Ratio Chlamydia 1910.89 238.84 8.00 2357.85 259.10 9.10 600 Gonorrhea 1862.61 90.17 20.66 2023.02 92.45 21.88 300 0 2001 2002 2003 2004 2005 Year 2006 2007 2008 2009 2010 Early Syphilis 774.01 2.79 277.43 928.19 10.89 85.23 Guiding Principles in STD Management More than one infection is possible Full STD evaluation is warranted HIV assessment Single dose therapy preferable to maximize adherence Treatment of partners important Empiric treatment of contacts Expedited partner therapy Reinfection common Case 1 A 32 yo male patient presents for a routine visit. His past medical history is notable for hypercholesterolemia. He has sex with men, and reports having 5 sex partners over the last year. He usually asks his partners about their HIV-status and only has sex with HIVnegative men. 3

Case 1 Question 1 STD Screening What STD tests should you obtain today? 1. HIV Antibody test 2. Pharyngeal swab for gonorrhea (GC) and Chlamydia (CT) by nucleic acid amplification (NAAT) 3. Rectal swab for GC and CT by NAAT 4. Syphilis test 5. All of the above H I V A n t i b o d y t e s t 0% 0% P h a r y n g e a l s w a b f o r g o... R e c t a l s w a b f o r G C a n d C... 0% S y p h i l i s t e s t 0% A l l o f t h e a b o v e 100% Obtain a sexual history on all patients Five P s Partners Sex, numbers, concurrency Prevention of pregnancy Protection from STDs Practices Vaginal, anal and oral sex Past history of STDs STD Screening among MSM Perform at least annually: HIV serology Syphilis serology Rectal GC/CT NAAT in men who have had receptive anal intercourse in last year Pharyngeal GC/CT NAAT in men who have had receptive oral intercourse in last year Urine GC/CT NAAT in men who have had insertive anal intercourse in last year Additional screening and prevention recommendations for MSM Hepatitis B Screening (HBsAg) Vaccination against hepatitis A and B if previous infection or immunization cannot be documented Consider screening for hepatitis C Anal pap smears an area of ongoing research and debate 4

GC/CT NAAT testing for MSM: Which sites should I test? Proportion of asymptomatic rectal and urethral chlamydial and gonococcal infection among MSM San Francisco, 2003 Rectal Infections 14% 16% 86% 84% Urethral Infections Chlamydia n=316 42% Gonorrhea n=264 10% Asymptomatic Symptomatic 58% Kent, CK et al, Clin Infect Dis July 2005 Chlamydia n=315 90% Gonorrhea n=364 Urogenital and Extragenital NAAT Testing, MSM, San Francisco, 2008-2009 100% 80% 14.3% Case 1 (continued) You are able to send the tests to your local lab that has done validation studies to allow their use for clinical care. 60% 40% 20% 85.7% 91.4% Identified infections Missed infections The pharyngeal NAAT is positive for gonorrhea. The Chlamydia NAAT is negative at both the rectum and pharynx. 0% Urethral screening only 8.6% Rectal and pharyngeal screening only How would you manage this patient? 5

Case 1 Question 2 1. Prescribe a single dose of ciprofloxacin 500 mg and obtain a test of cure 2. Treat with a single intramuscular injection of ceftriaxone 250 mg 3. Treat with cefixime 400 mg orally x1 and azithromycin 1 g orally x1 4. Treat with a single intramuscular injection of ceftriaxone 250 mg and azithromycin 1 g orally x 1 5. 3 or 4 P r e s c r i b e a s i... 7% 7% T r e a t w i t h a s... T r e a t w i t h c e f... 0% T r e a t w i t h a s... 29% 57% 3 o r 4 Recommended Gonorrhea Treatment: Pharyngeal or Anogenital Ceftriaxone 250mg IM x 1 + Azithromycin 1g PO x 1 OR Doxycycline 100mg PO bid x 7 days This is dual treatment for GC add the azithromycin or doxycycline regardless of CT result Alternative Gonorrhea Tx: Anogenital only Cefixime 400mg PO x 1 + Azithromycin 1g PO x 1 OR Doxycycline 100mg PO bid x 7 days August 10, 2012 This is Dual treatment for GC add the azithromycin or doxycycline regardless of CT result Any non-ceftriaxone based regimen need NAAT Test of cure at 7 days! 6

Alternative Gonorrhea Tx Cephalosporin allergy Azithromycin 2g PO x 1 * Katz MMWR 2011 Use with Caution: decreased susceptibility has been documented in Hawaii, San Diego, San Francisco* Any non-ceftriaxone based regimen need NAAT Test of cure at 7 days! History of Antibiotics for GC Sulfa 50K units Penicillin PPNG 4800K units Tetracycline 3rd Gen Ceph Spectinomycin Cipro 1937 1943 1976 1985 1993 2007 Penicillinase-Producing N. Gonorrhoeae (1970s - 1980s) Spread of Ciprofloxacin Resistance (1990s - 2000s) Courtesy P. Barry MD MPH 7

? Spread of Cephalosporin Resistance (2000s) Trends in Cephalosporin susceptibility among N. gonorrhea 2000-2010 Cefixime Ceftriaxone MMWR July 8, 2011 NEJM 2012 8

Strain H041, identified in Japanese commercial sex worker, asymptomatic pharyngeal carrier High-level resistance to all cephalosporin-class antibiotics, penicillin G, levofloxacin Reduced susceptibility to azithromycin Susceptible to spectinomycin No secondary cases identified to date 9/133 (6.7%) of patients with cultureconfirmed GC had treatment failure Treatment failure associated with elevated cefixime MIC Allen VG et al. JAMA 2013; Groopman J New Yorker 2012. New guidelines for gonorrhea treatment What about Patients with Penicillin or Cephalosporin Allergies? Dual treatment may hinder development of antibiotic resistance Summary of changes: 1) Ceftriaxone IM preferred over oral cephalosporins 2) Ceftriaxone dose increased to 250 mg IM 3) Dual treatment for gonorrhea regardless of chlamydia test result Clarify that it is a true allergy If rash with PCN, generally ok to treat with ceftriaxone, as low rates of cross-reaction If severe allergy to PCN or cephalosporins, consider consulting your local DPH, can treat with azithromycin 2g PO x 1 Patient should be followed closely for resolution of symptoms (if present) and brought back for NAAT test of cure 9

Suspected GC Treatment Failure Syphilis Consider repeat infection: Ask patient about sexual activity since treatment and ensure partners were treated Re-test with a NAAT and GC culture If GC culture not available on-site, call your local or state public health for resources Re-treat with CTX 500 mg IM and Azithromycin 2 g PO Report to your local or state health department within 24 hours Obtain a test of cure Treponema pallidum Obligate human pathogen Visible by darkfield microscopy Cannot be readily cultured in vitro Primary & Secondary Syphilis, California, 1996-2008 Number of Cases 2,250 2,000 1,750 1,500 1,250 1,000 750 500 250 MEN MSM WOMEN 0 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 Year 10

Primary Syphilis Secondary syphilis Images courtesy of Joe Engelman City Clinic Secondary Syphilis Case 2 One of your new primary care patients is an HIVinfected woman. At her initial visit, you obtain baseline labs. The lab tells you that they have a new protocol for syphilis screening they are using treponemal EIA as the screening test Your patient s results: EIA positive, RPR negative. Now what? Images courtesy of Joe Engelman City Clinic 11

Case 2 Syphilis Screening Paradigm 1. Treat with one shot of Penicillin G 2. Treat with three shots of Penicillin G 3. Tell her you would like to schedule an LP to rule out neurosyphilis, prior to deciding about treatment course 4. Obtain another syphilis test 5. Do nothing further as this is unlikely active syphilis 16% 32% 5% 32% 16% Non-treponemal tests (i.e., RPR, VDRL) Non-specific to TP Quantitative Reactivity declines with time TRADITIONAL reflex to Treponemal tests (i.e., TPPA, FTA-Abs) Specific to TP Qualitative Reactivity persists over time T r e a t w i t h o n e... T r e a t w i t h t h r... T e l l h e r y o u w... O b t a i n a n o t h e r... D o n o t h i n g f u r... Treponemal EIA/CIA Tests Reduce time and labor required for screening If positive, need quantitative RPR/VDRL for confirmation and to guide clinical management Remain detectable for life, even after successful treatment Limited utility as a screening test in previously treated patients Reverse Sequence Syphilis Screening Test Result EIA- EIA+ /RPR+ EIA+/RPR-/TPPA+ Interpretation/ Comments Negative result, no further testing indicated. High negative predictive value > 98% Active syphilis vs. old, treated syphilis History, PHYSICAL EXAM, Quantitative RPR titer 1) Old, treated syphilis or 2) Old, untreated syphilis or 3) Early syphilis or 4) Prozone phenomenon; History and PE EIA+/RPR-/TPPA- Likely false positive; no treatment 12

Back to the patient You order a TPPA which comes back positive (EIA +, RPR-, TPPA+) You perform a thorough physical exam and do not detect any signs of syphilis The patient reports no prior history of syphilis and no known syphilis contacts in last year CD4 200, VL 60,000 Case 2 What now? 1. Treat with one shot of Penicillin G 2. Treat with three shots of Penicillin G 3. Tell her you would like to schedule an LP to rule out neurosyphilis, prior to deciding about treatment course 4. Obtain another syphilis test 5. Do nothing further as this is unlikely active syphilis T r e a t w i t h o n e... 22% T r e a t w i t h t h r... 52% T e l l h e r y o u w... 26% O b t a i n a n o t h e r... 0% D o n o t h i n g f u r... 0% Staging determines Treatment If you cannot ascertain that infection has happened in < 1 year, then must treat for late disease What can help pinpoint timing of infection? Signs or symptoms of primary or secondary Can recall those symptoms in past year Contact to a known case in past year Negative syphilis test in the past year In HIV-infected patients, consider getting syphilis test with every CD4 or VL, so approx every 3-6 months Syphilis Treatment Primary, Secondary & Early Latent: Benzathine penicillin G 2.4 million units IM in a single dose Late Latent and Unknown Duration: Benzathine Penicillin G 7.2 million units total, given as 3 doses of 2.4 million units each at 1 week intervals Neurosyphilis: Aqueous Crystalline Penicillin G 18-24 million units IV daily administered as 3-4 million IV q 4 hr for 10-14 d *** 2010 CDC STD Treatment Guidelines clearly state: No enhanced efficacy of additional doses of Benzathine PCN G, amoxicillin or other antibiotics even if HIV-infected 13

Syphilis When to LP? Clinical signs of neurosyphilis Cranial nerve dysfunction, meningitis, stroke, acute or chronic altered mental status, auditory or ophthalmic abnormalities Serologic treatment failure Evidence of active tertiary syphilis (e.g. aortitis and gumma) HIV positive and late latent syphilis or syphilis of unknown duration How to Manage Patients with Serologic Treatment Failure? Optimal approach unknown Treatment failure or reinfection? Slower decline in titers may be observed in HIV patients If lack of 4-fold decline in RPR titers, LP to r/o neurosyphilis: If CSF normal, then re-treat: BPG 2.4 MU qweek x 3 wks If 4-fold decline but still positive ( serofast ) No data to recommend additional treatment Case 3 A 22 year old female patient presents for a pre-travel visit (she s going to Cancun on her college spring break). She has no complaints. The EMR alerts you that her last Chlamydia test was 2 years ago, and there is a standing order in the office that the MA will obtain the test unless the patient opts out Case 3 Your lab is performing nucleic acid amplification testing (NAAT) for C. trachomatis. What is the best specimen to obtain? 1. Clinician collected cervical swab 2. Urine 3. Clinician or patient collected vaginal swab C l i n i c i a n c o l l... 37% 37% U r i n e 26% C l i n i c i a n o r p... 14

Chlamydia screening The United States Preventive Services Task Force (USPSTF) level A (highest) recommendation: C. trachomatis screening in sexually active females <25 Has been a managed care quality assurance (HEDIS) measure since 2000 in sexually active females 16-24 NAAT Specimen types for the diagnosis of CT and GC in women Vaginal Swabs Sensitivity is equal or greater to cervical swabs Option for self-collection allows for further routinization of screening Less specimen processing required at clinical site than with urine Liquid cytology media ok for NAATs Case 3 (continued) This patient was positive for C. trachomatis at screening She was treated appropriately with Azithromycin 1g PO x 1, and given a prescription to take to her partner as expedited partner therapy (EPT) Rescheduled for repeat testing in 3 months Hobbs STD 2008, Chernesky STD 2005 15

Patient Delivered Partner Therapy (PDPT) Meds or prescription given to patient to deliver to partner without prior medical evaluation. 3 RCTs demonstrate effectiveness of PDPT, rate of reinfection (GC> CT) Many states now allow clinicians to provide additional Rx for partners Treatment instructions, appropriate warnings and recommendations to seek personal medical evaluation should accompany PDPT. Patient Delivered Partner Therapy (PDPT) Current legal status of PDPT by jurisdiction: http://www.cdc.gov /std/ept Accessed 6/25/2013 Repeat Chlamydial Infection is Common Repeat Infection is Dangerous Reinfection (%) 40 30 20 10 0 0 2 4 6 8 10 12 Months Follow-up Retesting Prevalence Typical Screening Prevalence Repeat CT infection leads to higher risk of complications: PID, ectopic pregnancy, infertility Most infections are asymptomatic Relative Risk 6 5 4 3 2 1 0 1st Infection 2nd Infection 3rd Infection Pelvic Inflammatory Disease Ectopic Pregnancy Hosenfeld C, et al. Sex Transm Dis. 2009 Aug;36(8):478-89 Hillis SD, et al. (1997). Am J Obstet Gynecol 176(1 Pt 1): 103-7. 16

Retesting Recommendations: Retest all women and men with CT or GC 3 months after treatment If client returns earlier than 3 months, consider retest If client does not return for retesting at 3 months, retest when possible CDC 2010 STD Tx Guidelines, www.cdc.gov/std/treatment Stephanie Cohen, MD, MPH Joe Engelman, MD California STD/HIV Training Center San Francisco City Clinic Susan.Philip@sfdph.org Stephanie.cohen@sfdph.org Thank You! 17