Disclosure Information Julie Stoltey, MD MPH

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1 Courtesy CDC Public Health Image Library The New Yorker Update on Testing, Treatment, and Gonorrhea Resistance Julie Stoltey, MD, MPH STD Control Branch-California Dept. of Public Health Assistant Clinical Professor, UCSF-Infectious Diseases STD Update for Clinicians San Diego, CA Disclosure Information Julie Stoltey, MD MPH I have no financial relationships to disclose I will discuss off label use of NAATs 1

2 Clinical Practice Objectives Identify more CT and GC infections through screening Provide timely and effective treatment Get more partners treated Improve re-testing for CT and GC Overview Clinical syndromes Screening recommendations and diagnostics Treatment updates Antibiotic-resistant gonorrhea Partner treatment Retesting and screening 2

3 Chlamydia Incidence: #1 reported nationally notifiable disease (n=1,441,789 cases reported in 2014) Intracellular bacterium that infects columnar epithelium Causes a range of clinical syndromes Cervicitis, urethritis, epididymitis, proctitis, PID Majority of infections are asymptomatic Gonorrhea Incidence: #2 reported nationally notifiable disease (n=350,062 cases in 2014) Developed resistance to multiple classes of antibiotics Causes a range of clinical syndromes Cervicitis, urethritis, epididymitis, proctitis, PID, disseminated infection Often asymptomatic in cervical, oral, and rectal infections Screening is essential to prevent complications Clinical Syndromes 3

4 Cervicitis, Urethritis, and PID STD Atlas, 1997 Pharyngitis, Epididymitis, and Proctitis STD Atlas,

5 Conjunctivitis STD Atlas, 1997 Disseminated Gonococcal Infection STD Atlas,

6 Reactive Arthritis Conjunctivitis, Oligoarthritis, Circinate Balanitis DOIA Website, 2000 STD Atlas, 1997 Neonatal Conjunctivitis and Pneumonitis STD Atlas,

7 Screening Recommendations Case Scenario - Laura 18 yo female presents for college physical exam No complaints, no prior medical history 1 male sex partner past 6 months On OCPs What should she be tested for? 7

8 Who Should be Screened for CT/GC? Females MSM Hetero males HIV + Patients on PrEP Post-Tx < 25 annually, 25+ if at risk Pregnant <25, if at risk At least annually Exposed sites: genital, rectal, throat High prevalence settings At least annually All exposed sites Every 3 months All patients, 3 months after treatment CDC 2015 STD Tx Guidelines Plus: Guidelines for HIV care and PrEP Why screen? Highly prevalent Frequently asymptomatic Reduces transmission Prevents complications, such as PID HEDIS measure: chlamydia screening in females under 25 years old Standard of care 8

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10 Which women over age 25 should be screened? Infection with CT or GC in past 2 years > 1 sex partner in past 12 months New partner in past 3 months Concurrency: Belief that a partner in the past 12 months may have had other sex partners at the same time Contact to STD New STD diagnosis Case Scenario Laura s in clinic again She s here because her roommate s cat bit her You note that her chlamydia test was positive at last visit You plan to test for gonorrhea and chlamydia What is the optimal GC/CT test in this scenario? 10

11 Major conclusions Nucleic acid amplification tests (NAATs) are recommended for detection of genital tract infections in men and women with and without symptoms - highly sensitive and specific compared to culture - less dependent on specimen collection and handling Optimal specimen types are: First catch urine for men Self collected vaginal swabs from women NAATs are recommended for: detection of rectal and oropharyngeal infections - not FDA-approved for rectal or pharyngeal specimens but remain the preferred testing method over culture Case Scenario Aidan 18 yo male presents for STD screening He reports exclusively male partners, 3 in past 6 months, oral sex, insertive and receptive anal sex sometimes, 1 anonymous partner Good health, no complaints, h/o GC last year HIV test negative yesterday Has had Hepatitis A and B vaccines 11

12 HIV Syphilis Urethral GC and CT Rectal GC and CT (if anal sex) Pharyngeal GC (if oral sex) * HSV-2 serology (consider) Hepatitis B (HBsAg, frequency not specified) Hepatitis C (HIV+ MSM at least annually) Anal Cancer in HIV+ MSM: Data insufficient to recommend routine screening, some centers perform anal Pap and HRA * At least annually, more frequent (3-6 months) if at high risk (multiple/anonymous partners, drug use, high risk partners) CDC 2015 STD Treatment Guidelines Proportion of MSM* Attending STD Clinics with Primary and Secondary Syphilis, Gonorrhea or Chlamydia by HIV Status, STD Surveillance Network (SSuN), 2014 *MSM=men who have sex with men; P&S = primary and secondary syphilis; GC = gonorrhea; CT = chlamydia.. Excludes all persons for whom there was no laboratory documentation or self-report of HIV status. GC urethral and CT urethral include results from both urethral and urine specimens. NOTE: Includes the six jurisdictions (Baltimore, Los Angeles, New York City, Philadelphia, San Francisco and Seattle) that contributed data for all of Fig X. SR. Pg

13 Majority of Rectal Infections in MSM are Asymptomatic Rectal Infections 86% 84% Urethral Infections Chlamydia n=316 Gonorrhea n=264 10% Asymptomatic Symptomatic 42% Chlamydia n=315 Gonorrhea n=364 Kent, CK et al, Clin Infect Dis July 2005 High Proportion of Extragenital CT/GC Associated with Negative Urine Test, STD Surveillance Network (n=21994) Patton et al CID

14 Suboptimal STD Screening among MSM in HIV Care N=4217 interviews and chart reviews from Medical Monitoring Project, nationally representative sample of adults in HIV care % of sexually active HIV+ MSM screened for STIs, N= Syphilis Chlamydia Gonorrhea Flagg EW, 2015, STD Provider Barriers to Screening Discomfort with sexual history taking or genital examination Lack of knowledge about need for testing Patient reluctance Lack of time Barbee, 2015 STD 14

15 Self-collected Rectal/Pharyngeal STI Testing Highly acceptable, similar performance compared to clinician-collected specimens Self-collection can be performed at laboratory along with blood draw/urine collection or in the exam room before/after the provider visit May save patient an office visit May save the provider time Van der helm, 2009, STD; Sexton, 2013 J Fam Pract; Dodge, 2012 Sex Health Freeman 2011, STD; Alexander 2008, STI; Moncada 2009, STD Major conclusions NAATs recommended for detection of genital tract infections in men and women with and without symptoms Optimal specimen types are: First catch urine for men Self collected vaginal swabs from women NAATs recommended for: detection of rectal and oropharyngeal infections - not FDA-approved for rectal or pharyngeal specimens but remain the preferred testing method over culture 15

16 Chlamydia and Gonorrhea NAA Testing- Rectal and Pharyngeal Sites Commercially-available NAATs have not been cleared by FDA for these indications They can be used by laboratories that have undergone validation procedures and met all regulatory requirements for an off-label procedure CDPH can assist with resources for provider visits or lab protocols cuments/msmtoolkit.pdf MMWR. Mar ;63(No RR-12):1-19. NAAT Laboratory Ordering and Billing Codes Rectal Pharyngeal Company-Specific Ordering Codes for Combined GC/CT Nucleic Acid Amplified Tests (NAATs) LabCorp* Quest* Company-Specific Ordering Codes for CT test only LabCorp NAATs are offered at (or from) any location in the country with these two codes. For information on specimen collection and transportation, clinicians should contact the local reference laboratory representative. CT detection by NAAT GC detection by NAAT CPT Billing Codes *CDC does not endorse these laboratories, however, they represent the largest laboratories nationally. There may be other private laboratories that have verified rectal and pharyngeal testing with NAATs. Many PHLs have also verified rectal and pharyngeal testing. Bolan, CDC webinar March

17 HIV Risk among MSM with Rectal CT/GC or Syphilis Among HIV-uninfected MSM: Rectal GC or CT infections are associated with an increased risk of incident HIV infection Syphilis infection has been associated with HIV acquisition HIV-negative MSM with rectal CT/GC or syphilis are at high risk for HIV acquisition; These are candidates for PrEP. Bernstein JAIDS 2010; 53: Pathela CID 2013;57: Solomon CID 2014;59:1020-6; Katz STD 2016;43: CT/GC Treatment 17

18 Chlamydia Treatment Adolescents and Adults Recommended regimens (non-pregnant): Azithromycin 1 g orally in a single dose Doxycycline 100 mg orally twice daily for 7 days Recommended regimens (pregnant*): Azithromycin 1 g orally in a single dose * Test of cure at 3-4 weeks only in pregnancy CDC 2015 STD Treatment Guidelines Chlamydia Treatment Changes in 2015 CDC Tx Guidelines New Alternative Regimen (non-pregnant): Doxycycline (delayed release) 200 mg QD x 7 d Equally efficacious to doxycycline BID, GI side effects More $$$ Moved to Alternative Regimen (pregnant*): Amoxicillin 500 mg po TID x 7 days CT persistence documented in vitro after treatment prompted removal from recommended to alternate 18

19 Azithromycin versus Doxycycline for Treatment of Urogenital Chlamydia RCT comparing azithromycin with doxycycline Directly observed treatment of urogenital chlamydia among adolescents in youth correctional facilities Primary end point was treatment failure at 28 days after treatment initiation Treatment failure determined on basis of NAAT, sexual history, and genotyping of CT strains Efficacy: Azithromycin 97% effective Doxycycline 100% effective Geisler et al. NEJM 2015;373: Is azithro adequate treatment for rectal chlamydia infection? Population Treatment Repeat positive MSM in Australia (N=85) MSM in Seattle (N=407) Azithro 1 g 13% Azithro 1 g 22% (N=95) Doxy 100 BID x 7 8% Based on retrospective uncontrolled observational clinical data: Dummond, Int J STD AIDS 2011; 22:478 and Khosropour, STD 2014; 41:79 19

20 Gonorrhea Dual Therapy Uncomplicated Genital, Rectal, or Pharyngeal Infections Ceftriaxone 250 mg IM in a single dose PLUS* Azithromycin 1 g orally Regardless of CT test result CDC 2015 STD Treatment Guidelines What does dual therapy mean? Ceftriaxone and azithromycin administered on the same day Preferably simultaneously and under direct observation 20

21 Gonorrhea Treatment Alternatives Anogenital Infections ALTERNATIVE CEPHALOSPORINS: Cefixime 400 mg orally once PLUS Azithromycin 1 g, regardless of CT co-infection IN CASE OF SEVERE ALLERGY: Gentamicin 240 mg IM + azithromycin 2 g PO OR Gemifloxacin 320 mg orally + azithromycin 2 g PO CDC 2015 STD Treatment Guidelines Alternative Urogenital GC Regimens: AVOID MONOTHERAPY NIH-sponsored non-comparative randomized trial in adults with urethral or cervical gonorrhea 1. gentamicin 240 mg IM + azithromycin 2 g PO, or 2. gemifloxacin 320 mg PO + azithromycin 2 g PO Per-protocol efficacy: gentamicin + azithromycin = 100% (202/202) gemifloxacin + azithromycin = 99.5% (198/199) Kirkcaldy, CID 2014;59:

22 Any downside to the alternative regimens? Gentamicin Regimen Gemifloxacin Regimen Route IM or IV Oral Nausea 27% 37% Vomiting (<1 hour) 3% 7% Availability OK FDA reported shortage in May 2015 Volume Need 6 cc (40mg/cc) Who needs a test of cure for GC? Patients with pharyngeal GC treated with an alternative regimen Obtain test of cure 14 days after treatment, using either culture or NAAT Cases of suspected treatment failure (culture and simultaneous NAAT) Consider if using non-recommended or monotherapy CDC 2015 STD Treatment Guidelines 22

23 Test of Cure for Anogenital Gonorrhea: Prospective Cohort Study Limited evidence for timing of test of cure using modern NAATs Of 77 patients: 5 self-cleared GC before treatment 10 lost to follow up 62 remaining patients all cleared. Median time to clearance: 2 days Range 1-7 days for RNA-based NAAT Range 1-15 days for DNA-based NAAT Wind et al. Clin Infect Dis 2016;62:

24 Bolan et al. New England Journal of Medicine Neisseria gonorrhoeae Percentage of Isolates with Elevated Ceftriaxone Minimum Inhibitory Concentrations (MICs) ( μg/ml), Gonococcal Isolate Surveillance Project (GISP), Fig 26. SR, Pg 26 24

25 Percent of Isolates Neisseria gonorrhoeae Percentage of Isolates with Elevated Cefixime Minimum Inhibitory Concentrations (MICs) ( 0.25 μg/ml), Gonococcal Isolate Surveillance Project (GISP), *Isolates not tested for cefixime susceptibility in 2007 and Fig 27. SR, Pg 26 Gonococcal Isolate Surveillance Project (GISP), Percent of Neisseria Gonorrhoeae Isolates with CDC "Alert" Values for Selected Cephalosporins in California GISP STD Clinic Sites, 1992 May Cefixime Ceftriaxone '92 '93 '94 '95 '96 '97 '98 ' '01 '02 '03 '04 '05 '06 '07 '08 ' '11 '12 '13 ' '16 Year * Cefixime susceptibility was not run in * * Note: Alert values are set by CDC as markers to look at possible decreased susceptibility. Cefixime alerts have MICs 0.25 μg/ml. Ceftriaxone alerts have MICs μg/ml data are provisional as of 7/12/2016. STD Clinic Sites: Long Beach (ended participation in 2007), Los Angeles (added in 2003), Orange, San Diego, San Francisco Rev. 07/

26 Neisseria gonorrhoeae Percentage of Urethral Isolates with Elevated Ceftriaxone Minimum Inhibitory Concentrations (MICs) ( μg/ml) by Reported Sex of Sex Partner, Gonococcal Isolate Surveillance Project (GISP), *MSM=men who have sex with men; MSW=men who have sex with women only Fig Z. SR. Pg. 75. Cephalosporin Treatment Failures Oral cephalosporin treatment failures reported worldwide t Japan, Hong Kong, England, Austria, Norway, France, South Africa, and Canada Ceftriaxone treatment failures in pharyngeal gonorrhea and a few isolates with high-level ceftriaxone resistance reported 26

27 Percent of Isolates STD Update for Clinicians: San Diego Gonococcal Isolate Surveillance Project (GISP), Percent of Neisseria Gonorrhoeae Isolates with CDC "Alert" Values for Azithromycin in California GISP STD Clinic Sites, 1992 April '92 '93 '94 '95 '96 '97 '98 ' '01 '02 '03 '04 '05 '06 '07 '08 ' '11 '12 '13 ' '16 Year Note: Alert values are set by CDC as markers to look at possible decreased susceptibility. Azithromycin alerts have MICs 2.0 μg/ml. No data before data are provisional as of 6/20/2016. STD Clinic Sites: Long Beach (ended participation in 2007), Los Angeles (added in 2003), Orange, San Diego, San Francisco Rev. 06/

28 Azithromycin Treatment Failure in California Gose et al. STD 2015;42: Fifer et al. NEJM 2016;374:

29 June 17, 2016 Suspected GC Treatment Failure TEST WITH CULTURE AND NAAT: If GC culture not available, call your local health department REPEAT TREATMENT: Gemifloxacin 320 mg + AZ 2g OR Gentamicin 240 mg IM + AZ 2g If reinfection suspected, repeat treatment with CTX AZ 1g REPORT: To your local health department within 24 hours TEST AND TREAT PARTNERS: Treat all partners in last 60 days with same regimen TEST OF CURE (TOC): TOC 7-14 days with culture (preferred) and NAAT 29

30 Partner Treatment When you diagnose a patient with an STD, think about the partner Partner Management Clinical evaluation is first-line option Partner should be examined and counseled and treated for STD of exposure 30

31 CT/GC Partner Management Options: All sexual contacts in past 60 days need treatment Health department referral Expedited partner treatment (EPT) Patient referral Suggest patient bring partner to clinic for concurrent treatment ( CPPT ) Ask patient to notify partner and ensure treatment Internet-based anonymous notification 31

32 The Effectiveness of Expedited Partner Treatment on Re-Infection Rates 20% 15% GONORRHEA P=.02 CHLAMYDIA P=.17 10% 5% 0% 11% 13% 11% 3% Usual Care EPT Usual Care EPT Golden M, et al. N Engl J Med 2005 Feb 17;352(7): Legal Status of EPT in the U.S. CDC EPT Legal Status Updated July PERMISSIBLE 40 states UNCERTAIN 8 states PROHIBITED 2 states 32

33 Concurrent Patient and Partner Treatment (CPPT) N=241 pregnant women with CT or GC 45 received CPPT 196 standard patient referral CPPT recipients less likely to have a positive TOC (OR =0, p<0.001) or repeat infection (OR=0, p <0.12) No repeat infections among CPPT group compared to 19 infections in standard referral group Mmeje et al. STD 2012 Online Anonymous Partner Referral inspot.org Patients use website to notify partners - Anonymous - Free - Referrals for testing sotheycanknow.org dontspreadit.com 33

34 CT Partner Management Strategies Used in California Family Planning Clinics Concurrent Patient and Partner Tx (CPPT) Patient-Delivered Partner Treatment (PDPT) 20% 14% 54% Patient Referral 12% None/Unknown N=743 female patients Yu Y-Y, et al. STD October 2011 Percent of Partners Treated by Partner Management Strategy, California FP Clinics, Yu Y-Y, STD

35 Partner Management: Take Home Points Clinical evaluation first-line option Concurrent patient-partner therapy can be effective for those with one primary partner Offer expedited partner treatment (EPT) CT/GC if partner cannot be promptly treated Use of prepackaged medication is recommended Dual therapy (cefixime 400 mg + azithromycin 1 g) is crucial if EPT is used for GC CDC 2015 STD Treatment Guidelines: CA EPT Guidelines:

36 Chlamydia/Gonorrhea (CT/GC) Patient-Delivered Partner Therapy (PDPT) Distribution Program CFHC provides free CT + GC meds to eligible clinics Participating clinics dispense STD medication to patients that test positive for CT/GC to give to their sex partner(s) for treatment Learn more about eligibility + program requirements, register for the program + request free partner treatment at cfhc.org/pdpt CT/GC Retesting for Repeat Infection 36

37 Reinfection (%) Case Scenario Laura, again 18yo female seen in follow up for screening results Vaginal swab NAAT positive for chlamydia She receives appropriate treatment with Azithromycin 1 gm 40 Repeat Chlamydial Infection is Common among Females Months Follow-up Hosenfeld C, et al. Sex Transm Dis Aug;36(8):

38 Relative Risk Repeat Infection Increases the Risk of PID and Ectopic Pregnancy Pelvic Inflammatory Disease Ectopic Pregnancy st Infection 2nd Infection 3rd Infection Hillis SD, et al. (1997). Am J Obstet Gynecol 176(1 Pt 1): Testing After an STD Infection Women who test positive for CT/GC, or trichomonas should be rescreened three months following treatment Men who test positive for chlamydia or gonorrhea should be rescreened at three months after adequate therapy All patients with a bacterial STDs or trichomonas should be tested for other STDs including CT/GC, syphilis, and HIV CDC 2015 STD Treatment Guidelines 38

39 Retesting Rates in California FP Clinics Only 36% of women treated for CT are retested within 6 months of treatment BUT, another 24% returned to clinic but were not retested These are missed opportunities! Did not return 40% Returned but NOT Retested 24% Returned & Retested 36% Source: Chow J. FPACT Data, FY11-12 How soon can I retest for CT/GC? Need to wait at least 3 weeks for CT to clear GC clearance within 1-2 weeks (2 weeks for pharyngeal infection) 3 months is the target, but retest opportunistically whenever patient returns in the next 1-12 months CDC 2015 STD Tx Guidelines, 39

40 Appointment and STI Retest Reminders For more information: CT/GC Management in a Nutshell Screen Treat Clients (& offer HIV test) Treat Partners Screen 3 months 40

41 THANK YOU Any burning questions? Clinical Guidelines and Consultation STD Clinical Consultation Network stdccn.org CDPH STD Control Branch Warm line CDC STD Treatment Guidelines App Available now, free Search for STD TX Thanks! 41