1 STD Update Ina Park, MD, MS University of California San Francisco-California Prevention Training Center and California Dept of Public Health

2 Roadmap Epi of Bacterial STDs Screening: how are we doing?Gonorrhea and antibiotic resistance Sexually transmitted meningococcal disease Ocular syphilis STIs, MSM, and the Internet PrEP and STIs

3 Chlamydia Gonorrhea Incidence: #1 reportable disease1,526,658 cases reported in 2015 (↑6%) Intracellular bacterium that infects columnar epithelium Causes a range of clinical syndromes Cervicitis, urethritis, epididymitis, proctitis, PID Majority of infections are asymptomatic Incidence: #2 reportable disease 395,216 cases in (↑13%) 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

4 Primary and Secondary Syphilis — Reported Cases by Sex and Sexual Behavior, 37 States*, 2011–2015* 37 states were able to classify ≥70% of reported cases of primary and secondary syphilis as either MSM†, MSW†, or women for each year during 2011–2015. † MSM = Gay, bisexual, and other men who have sex with men (collectively referred to as MSM); MSW = Men who have sex with women only.

5 Syphilis rates among MSM: a timelineSyphilis rates among MSM will soon be similar to those in the early 1980s Peterman, 2015, Expert Rev Anti Infect Ther

6 Syphilis Cases who Reported Meeting Sex Partners at Specified Venues, MSM, California, 2007–2016Internet Bars/Clubs Bathhouses/ Sex Clubs Rev. 1/2017

7 Anonymous sex? There’s an app for thatLocation-based Select practice, HIV status, sexual role Rapid / local communication Enormous reach (Grindr-196 countries,10 million downloads)

8 Screening thedramadownunder.info

9 STD Screening for WomenSexually Active adolescents & adults <25 years old Routine chlamydia and gonorrhea screening* Others STDs and HIV based on risk Women 25 years of age and older STD/HIV testing based on risk HIV-positive women CT/GC (vaginal, cervical, or urine) CT/GC (rectal, if exposed) GC (pharyngeal, if exposed) Syphilis serology Trichomoniasis Hepatitis BSAg, Hepatitis C (first visit) Annually CDC 2015 STD Tx Guidelines HIVMA/IDSA 2013 Primary Care Guidelines USPSTF 2015

10 * STD Screening for MSM HIV Syphilis Urethral GC and CTRectal GC and CT (if RAI) Pharyngeal GC (if oral sex) HSV-2 serology (consider) Hepatitis B (HBsAg, freq 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

11 Syphilis Screening Recommendations: USPSTF 2016Non-Pregnant Adult/Adolescents Screen in persons at increased risk MSM and HIV+ “Highest risk for syphilis” Other risks: history of incarceration, CSW, geography, race/ethnicity, male <29 yrs Grade “ A” recommendation Optimal screening interval not established More frequent in MSM/HIV+ suggested by some data Every 3 months enhances detection compared to annually

12 Suboptimal STD Screening among MSM in HIV CareN=4217 interviews and chart reviews from Medical Monitoring Project, nationally representative sample of adults in HIV care Mattson, 2016 CID

13 % screened by anatomic site among MSM in STD ClinicsN=21994 MSM in the STD Surveillance Network (SSUN) 11% Urogenital GC+ 8% Pharyngeal GC+ 10% Rectal GC+ 8% Urogenital CT+ 3% Pharyngeal CT+ 14% Rectal CT+ Patton et al CID 2014

14 High Proportion of Extragenital CT/GC Associated with Negative Urine test, STD Surveillance Network (n=21994) Between 70-90% of infections would be missed by only screening with urine Patton et al CID 2014

15 Self-collected rectal/pharyngeal STI testingHighly 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

16 STI and HIV interactionsHSV and bacterial STIs can increase genital HIV viral shedding (urethritis and GC) Syphilis can increase HIV viral load (>0.5 log10copies), even among patients with viral load <500 copies/mL Decreases CD4 by -28uL Meta-analysis 14 studies: with patients on ART, effect of STIs on VL was 0.11 log10copies Champredon 2015, BMC Infect Dis; Jarzebowski 2012, Arch Intern Med; Rotchford 2000, STD

17 Gonorrhea: a word from our sponsor

18 [Insert Lecture Name Here]Gonorrhea Dual Therapy Uncomplicated Genital, Rectal, or Pharyngeal Infections Azithromycin 1 g orally (preferred) or Doxycycline 100 mg BID x 7 days Ceftriaxone 250 mg IM in a single dose PLUS* Regardless of CT test result CDC 2015 STD Treatment Guidelines Slide 18

19 Gonorrhea Treatment Alternatives Anogenital InfectionsALTERNATIVE CEPHALOSPORINS: Cefixime 400 mg orally once PLUS Azithromycin 1 g (preferred) or doxycycline 100 mg BID x 7 days, regardless of CT IN CASE OF SEVERE ALLERGY: Azithromycin 2 g orally once (Caution: GI intolerance, emerging resistance) Doxy removed as co-treatment (unless azithro allergy) Gentamicin 240 mg IM + azithromycin 2 g PO OR Gemifloxacin 320 mg orally + azithromycin 2 g PO CDC 2015 STD Treatment Guidelines

20 Alternative Urogenital GC Regimens: AVOID MONOTHERAPYNIH-sponsored non-comparative randomized trial in adults with urethral or cervical gonorrhea gentamicin 240 mg IM + azithromycin 2 g PO, or 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: 20

21 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)

22 Antibiotic-Resistant Gonorrhea

23

24 Penicillinase-Producing N. Gonorrhoeae (1970s - 1980s)Just some historical perspective. Waves of resistance to both PCN and CIPROfloxacine primarily originated from Japan, before hitting HI and the west coast before spreading through the US Penicillinase-Producing N. Gonorrhoeae (1970s s) Spread of Ciprofloxacin Resistance (1990s s)

25 Bolan et al. New England Journal of Medicine 2012.

26 The stories you need to read, in one handy email Sign up to The Guardian Today and get the must-read stories delivered straight to your inbox each morning Read more Dr Gwenda Hughes, the head of PHE’s sexually transmitted infections (STI) section, said: “Fortunately, the current outbreak strain can still be treated with ceftriaxone. Nonetheless, we know that the bacterium that causes gonorrhoea can rapidly develop resistance to other antibiotics that are used for treatment, so we cannot afford to be complacent. “If strains of gonorrhoea emerge that are resistant to both azithromycin and ceftriaxone treatment options would be limited as there is currently no new antibiotic available to treat the infection.” PHE said on Sunday there had been 34 confirmed cases since November Since September 2015, 11 cases have been confirmed in the West Midlands and in the south of England, five of them in London. At least 16 cases were first detected in northern England, including 12 in Leeds, where the mutated strand was first recorded, PHE said in September. The strain, which is resistant to first-line antibiotic azithromycin, spread from Leeds to patients in Macclesfield, Oldham and Scunthorpe. Cases have been found in heterosexual men and women, and men who sleep with men (MSMs), PHE said. The British Association for Sexual Health and HIV issued an alert to clinicians urging them to follow up cases of high-level drug-resistant gonorrhoea and trace their sexual partners. Its president, Dr Elizabeth Carlin, told the BBC: “The spread of high-level azithromycin-resistant gonorrhoea is a huge concern and it is essential that every effort is made to contain further spread. Failure to respond appropriately will jeopardise our ability to treat gonorrhoea effectively and will lead to poorer health outcomes for individuals and society as a whole.” There were almost 35,000 cases of gonorrhoea reported in England in 2014 and it is the second most common bacterial sexually transmitted infection in the UK after chlamydia, with the majority

27 Cephalosporin Treatment FailuresOral cephalosporin treatment failures reported worldwide 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 The New Yorker 2012

28 Gonococcal Isolate Surveillance Project (GISP) % of Isolates with CDC "Alert" Values for Selected Cephalosporins in Ca GISP Sites, 1992–May 2016 * * * Cefixime susceptibility was not run in STD Clinic Sites: Long Beach (ended participation in 2007), Los Angeles (added in 2003), Orange, San Diego, San Francisco Rev. 07/2016

29 Gonococcal Isolate Surveillance Project (GISP), Percent of Isolates with CDC "Alert" Values for Azithromycin in Ca GISP Sites, 1992–April 2016 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 1992. 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. 06/2016

30 Azithromycin Treatment Failure in CaliforniaGose et al. STD 2015;42:

31

32 June 17, 2016

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

34 Neisseria meningitidisOxidase-positive, gram-negative coccus Resembles N. gonorrhoeae on gram stain and also grows on chocolate (and other agars) Similarly to N. gonorrhoeae, requires CO2 enriched environment for growth Ferments different sugars than N. gonorrhoeae 5 capsular serogroups associated with most disease: A, B, C, Y, W135 Colonization in oropharynx can rarely be followed by invasive disease (meningitis, sepsis)

35 Meningococcal Urethritis: Older Data as BaselineMeningococcal pharyngeal colonization- 5-20% MSM>heterosexual men and women Meningococcal urethritis Men with urethral oxidase+, gram- diplococci Heterosexual men – 1.1% N. meningitidis MSM – 13% N. meningitidis Slide courtesy of Ned Hook

36 Sexual Transmission of Neisseria meningiditisAssociated sex acts Oral sex (both cunnilingus and fellatio) Penile-vaginal intercourse Oral-anal contact (rimming) Case reports Urethritis PID Cervicitis Vulvovaginitis Rectal isolates (asymptomatic) Edwards & Carne. STI 74:95-100, 1998

37 Meningococcal Urethritis: 2016 SurpriseIsolates non-groupable (not know to be vaccine-preventable)

38 Prevention of Meningococcal UrethritisTreat sex partners, same as for N. gonorrhoeae exposure Advise use of barrier protection for oral sex (dental dams, flavored condoms) ?????Vaccinate with conjugate MenACYW135 vaccine Can’t hurt, may help reduce colonization Vaccinate all those recommended to receive vaccine

39 Meningococcal disease in the happiest Place on earthOutbreak of meningococcal disease in Southern CA (began 3/2016) No cases since 3/2017 All MSM and HIV+ persons in LA, OC, and SD counties should receive MenACWY vaccine HIV+ persons: 2 doses HIV- MSM: 1 dose Booster if vaccinated >5 years ago

40

41 Syphilis Treatment: No changePrimary, 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 million units IV daily administered as 3-4 million IV q 4 hr for d In pregnancy, benzathine penicillin is the only recommended therapy. No alternatives

42 Alert: Shortage of Bicillin® LA and Penicillin G Procaine IMManufacturing delay of Bicillin LA Full recovery expected 4Q2017 (FDA site) Doxycycline is alternative RX: contraindicated in pregnancy and young children Bicillin CR is NOT acceptable as alternative Penicillin G Procaine Injection also currently unavailable https://www.cdc.gov/std/treatment/drugnotices/bicillinshortage.htm

43 What is the maximum time allowed between Penicillin doses?Clinical experience suggests days ok for non-pregnant adults <9 days is best based on limited pharmacologic data In pregnancy, must adhere to strict 7 days between doses 40% of pregnant women are below treponemicidal levels after 9 days If a dose is missed, the entire series must be restarted

45 CLINICAL ADVISORY Ocular SyphilisSeveral cases of ocular syphilis were reported in multiple cities in California and in Seattle, WA Several cases resulted in permanent decline in visual acuity, including blindness In addition to CDPH, CDC and several local health departments have put out health alerts or advisories as well CLINICAL ADVISORY

46 Ocular Syphilis 200 Cases ocular syphilis in past 2 years from 20 states Majority HIV-infected MSM Few HIV-uninfected heterosexual men and women Significant sequelae including blindness Numerous ophthalmologic manifestations including: Posterior uveitis, panuveitis, anterior uveitis, retintitis, optic neuropathy, interstitial keratitis, retinal vasculitis Prior research has documented neuropathogenic strains (unknown if oculo-tropic strain role in these cases)

47 Ocular Syphilis Be on the AlertBe aware of ocular syphilis: Loss of vision/blurring of vision, a blue tinge in vision, redness, floaters, flashing lights Delays in diagnosis have been associated with visual loss* Order syphilis serology test in patients with: Visual complaints and syphilis risk factors, or Ophthalmologic findings compatible with syphilis, Order both treponemal and nontreponemal tests Patients with syphilis and ocular complaints need immediate ophthalmologic evaluation!!! *Moradi Am J Ophthal 2015

48 Ocular Syphilis ManagementPatients with suspected ocular syphilis should receive a lumbar puncture and be treated for neurosyphilis Note: a negative LP does not rule out ocular syphilis Treatment for ocular syphilis is IV PCN (neurosyphilis regimen) even if the CSF lab tests are negative HIV test Report to local health department within 1 business day. Save and store pre-antibiotic clinical samples at -80°C for molecular typing (coordinated through CDC)

49 Certain T. pallidum strains are associated with neurosyphilisEvaluated in ongoing study of neurosyphilis in Seattle 50% (n=22) of patients with strain type 14d/f had neurosyphilis, compared to 23% (n=9) of patients with other strain types had neurosyphilis Rabbit studies Animals infected with 14a/a strain and 14d/f strain had greatest degree of neuroinvasion Neurosyphilis defined as csf wbc >20/ul or a reactive CSF VDRL Marra et al. JID 2010 Tantalo et al. JID 2005

50

51 STIs

52 Background: STDs predict future HIV RiskRectal GC or CT 1 in 15 MSM were diagnosed with HIV within 1 year.* Primary or Secondary Syphilis 1 in 18 MSM were diagnosed with HIV within 1 year.** No rectal STD or syphilis infection NOTE: This slide has limitations because they are not exact comparisons. P&S Syphilis analysis uses case based surveillance data matching to get the hazard ratio and the annual incidence on the slide. The incidence for all men in the syphilis group was 1/20 within the year. As such, there is no data on syphilis negatives – this makes it a pretend cohort rather than a real cohort. Rectal GC/CT and the no STD category uses an STD clinic cohort that was then matched to HIV case registry data. It seems like a much more valid cohort analysis to me, since we have information on STD-negatives to compare it to. I used incidence among those negative for rectal infection and no syphilis in the past 2 years to get the 1/53 figure. The population for all of these groups was HIV-negative MSM, which is implied but not explicit on this slide. 1 in 53 MSM were diagnosed with HIV within 1 year.* *STD Clinic Patients, New York City. Pathela, CID 2013:57; **Matched STD/HIV Surveillance Data, New York City. Pathela, CID 2015:61

53 PrEP and STIs Kaiser Permanente San FranciscoVolk et al. CID 2015; Slide courtesy J. Volk

54 PrEP and STIs-Part II PrEP Demo Project (NIAID), n=557Liu 2016, JAMA Int Med HIV incidence = cases / 100 py (95% CI ) STI incidence (90 cases/100 py) high but stable over time (P> 0.1) 50.9% of participants had at least one STI during follow-up >75% of GC and >85% of CT infections were asymptomatic

55 Liu et al. JAMA Int Med 2016

56 Prep and STI Part III: screening frequency% infections for which treatment would have been delayed with q6 month, as opposed to q3 month, screening As expected, >80% of rectal and pharyngeal infections were asymptomatic; 18% of urethral GC and 65% of urethral CT asx Percent of cases that were asymptomatic at follow-up [n/N (%)] rectal GC: 78/96 (81.3%) rectal CT: 156/173 (90.2%) pharyngeal GC: 106/125 (84.8%) pharyngeal CT: 25/30 (83.3%) urethral GC: 6/33 (18.2%) urethral CT: 34/52 (65.4%) Cohen # 870 CROI 2016

57 PrEP FOR STIs? Pilot RCT of N=30 HIV+ MSM with h/o repeat syphilisDoxycycline 100 mg po daily vs placebo + $ per visit for testing STD-free Outcomes: contracting GC/CT, syphilis, or composite outcome (any GC/CT/syphilis) 76.7% retention through 48 weeks Less infections seen for syphilis (2 vs 7 infections), GC/CT (4 vs 8 infections), NS Composite outcome, doxy superior to placebo, OR 0.27 ( ), p=0.02 Bolan, 2015 STD

58 Let’s put it in the waterdoxy PreP

59 Take home points Bacterial STIs are still highly prevalent among MSM and increasing Serosorting/seroadaptive strategies PrEP Efficient online access to sex STI testing, especially at extragenital sites is key, as rectal GC/CT infections and syphilis predict future HIV acquisition. Self-collected GC/CT testing may help overcome provider barriers, is acceptable to MSM and performs well Still waiting for interventions that can affect behavior change among MSM Interventions that leverage highly trafficked apps may facilitate outreach to high-risk MSM

60 Acknowledgments Kaiser Permanente San Francisco Jonathan VolkSF Dept of Public Health Stephanie Cohen California Dept of Public Health Lindsey Clopp Jessica Frasure Julie Stoltey

61 THANK YOU Any burning questions?

62 Meningococcal Conjugate Vaccine Recommendations (as oF 2005)11-12 year olds Routine vaccination with single-dose MCV4 or MenACWY-CRM 16 year olds Booster dose >=2mos - 55 year olds, complement deficient OR asplenic OR HIV-infected 2 or 4-dose primary series, depending on which vaccine is used Booster dose every 3-5 years, depending on age vaccine first given >55 year olds MPSV4 should be used for higher–risk persons At its February 2005 meeting the Advisory Committee on Immunization Practices voted to recommend routine meningococcal vaccination for several other groups. Meningococcal conjugate vaccine is recommended for all persons at their preadolescent visit, which should occur at ages 11 or 12 years. This is also the time when most children should receive their first TD booster dose. In order to produce a more rapid reduction of meningococcal disease among adolescents ACIP also recommended that for the next 2 to 3 years teens about to enter high school also be vaccinated, at about age 15 years. College freshmen living in a dormitory should be routinely vaccinated because of their increased risk of invasive disease. Other adolescents who wish to reduce their risk for meningococcal disease may elect to receive vaccine. MCV is preferred for all these groups. CDC ACIP CDC ACIP DRAFT 9/14/07

63 Meningococcal Conjugate Vaccines: Additional RecommendationsAdolescents who received first dose at years One-time booster dose administered between years Adolescents who received first dose at or after 16 years No booster dose 2 – 55 year olds at increased risk of exposure (unvaccinated first-year college students in dorms, military recruits, microbiologists, travelers to certain countries): Single dose initially Booster after 3 years in those 2-6 years at previous dose Booster after 5 years in those 7 years or older at previous dose Routine vaccination of healthy persons not at increased risk of exposure not recommended after age 21 years CDC ACIP CDC ACIP DRAFT 9/14/07

64 Meningococcal B Vaccine Recs New as of 2015MenB vaccine series “may be administered” to those years to provide short term protection against most strains of serogroup B meningococcal disease (preferred age is years of age) (Category B) MenB should be administered as either a 2-dose series of MenB-4C or a 3-dose series of MenB-FHbp Same vaccine product should be used for all doses MenB4C and MenB-FHbp may be administered concomitantly with other vaccines indicated for this age, but at a different anatomic site, if feasible Certain persons aged ≥10 yrs at increased risk should receive MenB vaccine (complement def., asplenia, microbiologists, outbreak) CDC ACIP