4/14/2016. Kimberly A. Workowski, MD, FACP, FIDSA Professor of Medicine Emory University Atlanta, Georgia. Learning Objectives

Transcription

1 A Case of the Clap: Update on Sexually Transmitted Infections in Patients With HIV Infection Kimberly A. Workowski, MD, FACP, FIDSA Professor of Medicine Emory University Atlanta, Georgia FINAL: 04/01/16 Atlanta, Georgia: April 8, 2016 Financial Relationships With Commercial Entities Dr Workowski has served as a scientific advisor to Bristol- Myers Squibb, Gilead Sciences, Inc, and Janssen Pharmaceuticals, Inc. She has received grants or research support from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Inc, and GlaxoSmithKline. (Updated 04/08/16) Slide 2 of 54 Learning Objectives After attending this presentation, participants will be able to: Describe the appropriate screening for sexually transmitted infections (STIs) in persons with HIV infection Describe current recommended treatment options for persons with bacterial STIs List primary and secondary STI prevention approaches Slide 3 of 54 1

2 STIs and their Consequences HIV transmission Impaired fertility STIs Adverse pregnancy outcomes Reproductive tract cancer 20 million estimated annual new cases $17 billion estimated annual direct costs CDC. STD Surveillance Atlanta: U.S.DHHS; 2012 Chesson HW, et al. Perspect Sex Reprod Health 36(1): Chlamydia, gonorrhea and infectious syphilis/congenital syphilis-significant increases Slide 4 of 54 Proportion of MSM* Attending STD Clinics with Primary and Secondary Syphilis, Gonorrhea or Chlamydia by HIV Status, STD Surveillance Network (SSuN), 2014* Slide 5 of 54 Slide 6 of 54 2

3 Slide 7 of adults in HIV primary care clinics in 4 cities GC,CT, syphilis, TV (women) screening (0, 6 mo) 13% with STD at enrollment 94% of incident STDs in MSM (excluding trich) Most common in men: rectal chlamydia, oral GC Risks: polysubstance use, > 4 partners in 6 months 20% of MSM diagnosed with an STD by 6 months Mayer et al. Sex TransmDis 2012 Slide 8 of 54 Slide 9 of 54 STI Testing during HIV care Initial care visit Syphilis serology, NAAT (gonorrhea, chlamydia) MSM (site of exposure) Hepatitis A,B, C Women Trichomonas testing (NAAT, culture) Cervical pap test (HIV OI guidelines) Frequent screening dependent on risk (3-6 mo) New sex partner, partner with concurrent partners or more than one partner, or partner with an STI 2015 Treatment High risk behavior Guidelines, HIVMA 2014 Partner services, prevention counseling 3

4 Author Location Clinic n Prevalence % Infections Type Missed CT GC CT GC Kent San Francisco, CA MSM, STD % 16.7% Gunn San Diego, CA STD 7333 ND 15.8% ND 38 Schachter, San Francisco, STD % 21.2% CA Moncada Bachmann Birmingham, AL HIV, STD % 7.9% Annan Australia HIV, STD % ND 62 ND Manavi United Kingdom STD % ND 56 ND Templeton Australia STD % ND 68 ND Moncada San Francisco, CA STD % 16.5% Ota Canada MSM, % 11.7% STD Slide 10 of 54 Percentage of Men With Rectal and/or Pharyngeal Infections Not Detected if Only Urethral Infections were Diagnosed Schachter J, Philip SS. Sex Transm Dis Percentage increase in prevalence of chlamydia and gonorrhea by different strategies of screening of oropharynx and anorectum in female STD clients Peters RP, Nijsten N, Mutsaers J et al. Screening of oropharynx and anorectum increases prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae infection in female STD clinic visitors. Sex Transm Dis Sep;38(9): Slide 11 of 54 SYPHILIS Slide 12 of 54 4

5 Primary and Secondary Syphilis Rates of Reported Cases by Sex and Male-to-Female Rate Ratios, United States, % increase in % MSM 27% increase in congenital syphilis * Slide 13 of 54 Which diagnostic test is most appropriate for primary syphilis diagnosis? 1. DFA stain of anal ulcer 2. RPR 3. Treponemal EIA 4. Darkfield microscopy of oral lesion 9% 47% 27% 17% Slide 14 of 54 Diagnosis Direct detection methods (not widely available) Darkfield microscopy, PCR Nontreponemal tests (lipoidal antigens) RPR,VDRL,TRUST Treponemal tests (T pallidum proteins) TP-PA, EIAs, CIAs, microbead immunoassays, FTA-ABS Point of care tests (treponemal);hiv/syphilis Slide 15 of 54 5

6 Sensitivity of Serological Tests Stage of Disease (Percent Positive [Range]) Test Primary Secondary Latent Tertiary VDRL 78 (74 87) (88 100) 71 (37 94) RPR 86 (77 99) (95 100) 73 FTA-ABS* 84 (70 100) Treponemal Agglutination* 76 (69 90) (97 100) 94 EIA *FTA-ABS and TP-PA are generally considered equally sensitive in the primary stage of disease. Slide 16 of 54 Syphilis serologic screening algorithms Traditional Reverse sequence Quantitative RPR EIA or CIA RPR+ RPR- EIA/CIA+ EIA/CIA- TP-PA or other trep. test TP-PA+ TP-PA- Syphilis Syphilis (past or unlikely present) RPR+ Syphilis (past or present) Quantitative RPR Early primary, requires RPR (active), false + Active infection, F+, miss early TP-PA MMWR 60(5);2011 TP-PA+ Syphilis (past or present) RPR- TP-PA- Syphilis unlikely Slide 17 of 54 Slide 18 of 54 Reasons for discordant test results (i.e., EIA/CIA+ / RPR-) Treated syphilis Persistence of treponemal antibodies but seroreversion of nontreponemal antibodies Untreated syphilis of long duration Nontreponemal titers decline over time Early primary syphilis Treponemal antibody levels rise before nontreponemal antibody titer becomes positive Prozone phenomenon False-positive treponemal test result Particularly with pregnant women MMWR / February 11, 2011 / Vol. 60 / No. 5; Tuddenham, BMC Infectious Diseases

7 Slide 19 of 54 Slide 20 of 54 Seronegative Syphilis What treatment is indicated for primary syphilis in HIV+? 1. Benz Pcn 2.4 mu IM wkly x 3 2. Benz Pcn 2.4 mu IM x1 3. Doxycycline 100 mg bid x 14 days 4. Azithromycin 2 gm po 28% 65% 3% 4% Slide 21 of 54 7

8 Syphilis Treatment Primary, Secondary, Early Latent Penicillin treatment of choice +/- HIV Benz Pcn 2.4 mu IM x 1 No benefit of additional therapy Enhanced IM+oral (Rolfs 1997) Recent observational studies > 500 HIV+ revealed no difference in serologic outcomes at 12 months comparing 1 to 3 doses of BPG (Ganesan 2014, Yang 2014) PCN alternatives Doxycycline, ceftriaxone (?dose/duration) Azithromycin 2 gm (A2058G, A2059 mutation) MSM>MSW (Su 2012) Do not use in MSM or pregnancy Slide 22 of 54 CDC STD Treatment Guidelines Treatment Failure After BPG: Systematic Review % Failed 95% CI Early Syphilis HIV+ (n=167) HIV- (n=229) Late Syphilis HIV+ (n=228) HIV- (n=14) Slide 23 of 54 Blank L.J. et al. Sex Transm Infect 2011;87 Serologic Treatment Outcomes Systematic review of HIV- and HIV+ after early syphilis Serologic nonresponse <4 fold decline at 6-12 mo Estimated from 20 studies 12% Serofast persistent RPR despite appropriate decline Treatment failure, reinfection, altered immune response Estimated from 2 studies 35-44% Serologic response to treatment Young age, higher baseline RPR, early stage Inconsistent relationship between HIV, CD4, VL Sena, BMC Infect Dis 2015 Slide 24 of 54 8

9 Syphilis in HIV+ Neurologic complaints should prompt consideration of neurosyphilis Visual changes, hearing loss, facial weakness, stuttering stroke symptoms Early forms of neurosyphilis are most common Acute syphilitic meningitis (CN VI, VII, VIII) Meningovascular (stuttering stroke) Ocular syphilis Treat for neurosyphilis regardless of CSF evaluation Slide 25 of 54 CDC Clinical Advisory: Ocular Syphilis Outbreak April 3, 2015 CA and WA reported 15 cases from 12/ / Other states with cases under investigation (> 150 cases) - Most men over 40 yrs, 45% secondary or early latent, CSF 55% (70%+CSF VDRL) Most cases among MSM with HIV (>50%); new HIV diagnosis 30% - A few among HIV-negative persons, including heterosexual men and women Several have resulted in significant sequelae including visual loss, retinal detachment and blindness Slide 26 of 54 For more information: Slide 27 of 54 Evaluation of CNS Involvement Clinical signs (neurologic, ocular, auditory, meningitis, stroke) warrant investigation CNS invasion in early syphilis +/- HIV is common CSF abnormalities Unknown clinical significance in absence of signs or sx Neurosyphilis: CSF tests + reactive RPR + signs/sx LP: neuro/ocular sx, serologic treatment failure, tertiary Some studies in HIV+ showed association with CSF abnormalities* RPR 1:32 and/or CD4 350 Unless neurologic signs/sx, value of LP unknown. * Marra 2004; Libois A, STD 2007; Ghanem CID; Marra CID

10 Nonsexual transmission of Syphilis -Mouth to mouth transfer of pre-chewed food -Contaminated utensils -Breast feeding -Saliva applied to bottle nipples to test temperature -Human bite Krivatkin 1997, Murrell 1947, Ozturk 1998, Zhou 2009, Echols 1990, Neblett Fanfair 2014 Slide 28 of 54 Slide 29 of 54 Genital Herpes Increasing proportion of anogenital infections HSV-1 (young females, MSM) IgM testing not useful Type specific serologic tests HSV-2 ELISA IgG may be false + at low index values ( )- confirmed with Biokit or WB HSV-1 ELISA IgG insensitive for HSV-1 (80%) Head to head comparison of type specific assays vs WB No change in recommended therapy Antiviral resistance (Foscarnet, topical therapy) 2015 CDC Treatment Guidelines Urethritis Slide #30 Gonorrhea (5-20%) Chlamydia 15-40% M. genitalium 15-25% Ureaplasma 0-20% Trichomoniasis 5-20% HSV,adenovirus Enterics, Candida Slide 30 of 54 10

11 M. genitalium Syndromic therapy for NGU (20%), cervicitis, PID Consider Mg in urethritis treatment failure Doxycycline largely ineffective Axithromycin 1 gram effective; resistance rapidly emerging Moxifloxacin for treatment failure (resistance emerging) Investigational regimens-pleuromutilins, pristinamycin 87% 45% 67% 31% 30% 40% Doxycycline Azithromycin Mena 2009 Schwebke 2011 Manhart 2013 Macrolide Resistance in Europe Slide 31 of 54 CHLAMYDIA Slide 32 of 54 Azithro vs. Doxy RCTs using NAAT Efficacy REF CT + COHORT SYNDROME SAMPLE NAAT SCHEDULED TOC Hillis 196 women Genital CT Cervical, Urine PCR Day 28 Schwebke 111 men NGU Urine TMA Day / Day Slide 33 of 54 Manhart 101 men NGU Urine TMA Day 21 (allowed Day 14-35) 11

12 Azithro or Doxy for Rectal CT using NAAT Efficacy REF CT + Cohort Rx TEST TOC Limitations -Retrospective Drummond 85 MSM Azithro PCR days -45% tested >12 wks Steedman 68 MSM Azithro PCR Rec >21 days Elgalib 165 MSM Doxy SDA/TMA Median 45d IQR 34-88d Hathorn 82 MSM/women 42 Azithro TMA Rec 42 days 40 Doxy Khosropour* 89 MSM 69 Azithro Culture/TMA days (Unplublished) 20 Doxy (majority culture) -Retrospective -Most repeat CT+ sex after Rx -1/3 repeat CT+ tested < 21 days -Retrospective -Long post-rx test interval -Majority rectal CT pts excluded -High lost-to-f/u (~50%) -Treatment bias in doxy Rx phase -Retrospective, prelim data (unpublished) -Culture less sensitive assay -Possible bias of doxy group cultured more Slide 34 of 54 *Analysis shown restricted to day interval (study included testiong up to 180 days) LGV Proctitis MSM proctocolitis -rectal NAATs (chlamydia) PCR based genotyping Protocolitis +/- perianal ulcers should receive presumptive tx for LGV (doxy 100 mg bid x 21 d) Painful perianal ulcers or mucosal ulcers (anoscopy) presumptive therapy for HSV Mucosal ulcers (HSV) Slide 35 of CDC Treatment Guidelines Slide 36 of 54 12

13 GONORRHEA Slide 37 of 54 Prevalence of Penicillin, Tetracycline and Fluoroquinolone Resistance and Cefixime Reduced Susceptibility in Neisseria gonorrhoeae isolates, United States, Percent Tetracycline Resistance Penicillin Resistance 5 Fluoroquinolone Resistance Reduced cefixime susceptibility Slide 38 of 54 Source: Gonococcal Isolate Surveillance Project (GISP), Centers for Disease Control and Prevention CDC STD Treatment Guidelines Uncomplicated Gonococcal Infections of Cervix, Urethra & Rectum Ceftriaxone 250 mg as a single intramuscular dose PLUS Azithromycin 1 g orally (preferred) or Doxycycline 100 mg twice daily for 7 days Slide 39 of 54 13

14 Suspect Treatment Failures Most treatment failure likely due to reinfection If treatment failure suspect, obtain culture/ susceptibility test + ensure partner treatment Slide 40 of 54 If reinfection likely (ceftriaxone/azi ); Rx ceftriaxone 250 mg +azithromycin 1 gram If reinfection likely (cefixime/azi), Rx ceftriaxone 250 mg + azithromycin 2 gram If treatment failure suspected, Rx gemifloxacin 320 mg +azithromycin 2 g or gentamicin 240 IM + azithromycin 2g (Kirkaldy CID 2014) Report to local or state health department Test of cure 7-14 days after retreatment/ (culture/susceptibility test with NAAT) New Clinical Data on Other Regimens Solithromycin 1200 mg (n=22; 22/22 ur/cx, 2/2 rectal, 5/5 pharynx (Hook, CID 2015) 1000 mg vs Ceftriaxone 500 mg (NCT ) Delafloxacin 900 mg vs ceftriaxone 250 mg IM (terminated) GSK mg vs 3000 mg (NCT ) AZD or 3000 mg vs ceftriaxone 500 mg IM Slide 41 of 54 Sexually Transmitted GI Syndromes Proctitis GC, CT, HSV, syphilis Proctocolitis Campylobacter, shigella, salmonella, Entamoeba histolytica, LGV Enteritis Giardia Hepatitis A, B, C Slide 42 of 54 14

15 HCV Infection in MSM Increased awareness of sexually acquired HCV Unprotected receptive anal intercourse Rough or poorly lubricated anal penetration(fisting) Ulcerative STIs (syphilis, LGV) Risk based annual screening per guidelines Acute infection may have negative HCV antibody (CD4 <200) HCV RNA in patients with new, unexplained transaminase elevation Slide 43 of 54. STD Treatment Guidelines, HIV OI Guidelines HPV Slide 44 of 54 Anal Cancer Prevention Primary Prevention Slide 45 of 54 HPV vaccination of MSM 4v or 9v (MMWR 2015;64:300-4) 3 dose schedule (ongoing studies of 2 dose schedule) Secondary Prevention Anal cytology in high risk populations High risk HPV tests not clinically useful (high HPV prevalence) No studies have shown that treatment of anal HSIL reduces the incidence if anal cancer No routine standard treatment for HSIL (ablative) Anchor study- designed to determine if tx of anal HSIL reduces incident anal cancer vs DRE; determine safety of infrared coagulation, electrocautery, imiquimod, laser, 5FU 15

16 ACIP HPV vaccine recommendations Routine vaccination at age 11 or 12 years* Vaccination recommended through age 26 for females and through age 21 for males not previously vaccinated Vaccination recommended for men who have sex with men and immunocompromised men (including HIV-infected persons) through age 26 Vaccination of females is recommended with 2vHPV, 4vHPV, or 9vHPV Vaccination of males is recommended with 4vHPV or 9vHPV *vaccination series can be started at 9 years of age MMWR 2015;64:300-4 Slide 46 of 54 Impact of HPV vaccination in Australia Proportion of Australian born females and males diagnosed as having genital warts at first visit, by age group, Females Males Slide 47 of 54 Ali, et al. BMJ Slide 48 of 54 T vaginalis and HIV infection Screening at entry to care and annually if active APTIMA T vaginalis; BD Probe Tec TV Qx amplified DNA Assay A molecular test-resolved algorithm (negative wet prep followed by NAAT - APTIMA TV - sensitivity %, specificity of % (Nye) Longer treatment course better in women metronidazole 500mg BID x7d (vs. 2g )-less TV at TOC/3 mo RR 0.46, CI: (Kissinger, 2010) Potential factors- BV infection, ARV, changes in vaginal ecology Treatment reduces genital HIV shedding (Kissinger 2009, Anderson 2012) Retesting 3 mo after treatment CDC Treatment Guidelines 16

17 Prevention Strategies High-intensity behavioral counseling Partners, pregnancy, protection, practices, past STIs Pre-exposure vaccination (hepatitis A, B, HPV) Screening per guidelines (syphilis, CT, GC, trichomonas) Male latex condoms Mucosal fluids (HIV, GC, CT, trichomonas) Avoid agents that disrupt anal/vaginal epithelium N9 spermicide, hyperosmolar lubricants Male circumcision reduces risk of HPV, genital herpes (African heterosexuals) Slide 49 of STD Treatment Guidelines Evidence based (IOM report) Diagnostic, treatment, and prevention recommendations MMWR, pocket guide, and wall chart STD Treatment Guide app for Apple and Android Devices Slide 50 of 54 17