STDs in HIV Clinical Care: New Guidelines on Treatment and Prevention Palliative Care Conference Faculty Development Conference August 13, 2015 Steven C. Johnson M.D. Director, University of Colorado HIV/AIDS Clinical Program; Professor of Medicine, Division of Infectious Diseases; University of Colorado School of Medicine
Learning Objectives Recognize the importance of STD detection and treatment in HIV-infected patients Utilize a guidelines-based and risk-based approach to STD screening in your HIV clinical practice Through case studies, learn recent changes in STD prevention and management
Which of the following best describes your current role in HIV care? A. Prescribing provider (MD, DO, NP, PA) B. Pharmacist C. Nurse D. Dentist E. Other health care provider F. Student G. Not a health care provider Prescribing provider (MD... 0% 0% 0% 0% 0% 0% 0% Pharmacist Nurse Dentist Other health care provider Student Not a health care provider
Incidence, Prevalence, and Cost of Sexually Transmitted Infections in the U.S. CDC Fact sheet, February 2013
Proportion of MSM* Attending STD Clinics with Primary and Secondary Syphilis, Gonorrhea or Chlamydia by HIV Status, STD Surveillance Network, 2013 *MSM=men who have sex with men. 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: Six jurisdictions (Birmingham, Chicago, Denver, Hartford/New Haven, New Orleans, and Richmond) contributed data from January through June 2013 and the remaining jurisdictions (Baltimore, Los Angeles, New York City, Philadelphia, San Francisco and Seattle) contributed data for all of 2013.
The HIV Clinical Program I Work With Has a Screening Program for STDs A. Yes B. No C. I don t know 0% 0% 0% Yes No I don t know
Screening for MSM, including those with HIV Infection (At least Annually) Syphilis Serology A urethral test for GC and Chlamydia (preferably NAAT) A rectal test for GC and Chlamydia (preferably NAAT) A pharyngeal test for GC (preferably NAAT) CDC. Sexually Transmitted Diseases Guidelines 2015, MMWR 2015;64(No. RR-3):1-140
STD Screening in HIV+ Individuals Screening Recommendation Comments Chlamydial Infection Gonorrhea Hepatitis C Syphilis Perform annually in patients at risk for STDs Perform annually in patients at risk for STDs Perform annually in patients at risk, e.g. IDU and MSM Perform annually in patients at risk for STDs Trichomoniasis Perform annually in all women More frequent testing may be indicated in patients at high risk for STDs. Repeat in 3 months if +. More frequent testing may be indicated in patients at high risk for STDs. Repeat in 3 months if +. More frequent testing may be indicated in patients at high risk, especially if increases in LFTs. More frequent testing may be indicated in patients at high risk for STDs. Repeat testing 3 months later if positive. Aberg J et al. Clin Infect Dis. (2013) doi:10.1093/cid/cit665
Syphilis in HIV Infection
Treponema pallidum Electron photomicrograph, 36,000 x. Source: CDC/NCHSTP/Division of STD Prevention, STD Clinical Slides
Syphilis Sexually transmitted infection caused by the spirochete, Treponema pallidum Categorized into various stages Primary: chancre at site of acquisition Secondary: disseminated illness, often with a skin rash Latent syphilis: serologic evidence without clinical disease, early latent (within a year) and late latent Tertiary syphilis: neurosyphilis, cardiovascular syphilis, gummatous syphilis 17,375 cases of primary and secondary syphilis were reported in the U.S. in 2013
Primary and Secondary Syphilis
Reported Cases of Syphilis in the U.S., 2013 25000 21,819 20000 16,929 15000 10000 5000 5,204 12,171 Primary Secondary Early Latent Late Latent and Late 0 Reported Cases
Primary and Secondary Syphilis Reported Cases by Sex and Sexual Behavior, 33 Areas*, 2007 2013 *32 states and Washington, DC reported sex of partner data for 70% of cases of P&S syphilis for each year during 2007-2013. MSM=men who have sex with men; MSW=men who have sex with women only. STD Surveillance 2013, www.cdc.gov
Source: Sexually Transmitted Infections in Colorado. 2013 Annual report. CDPHE
Cases of Early Syphilis in Denver, 2014 Category Total Number of Cases Cases Among MSM (%) Cases Among HIV+ Persons (%) Primary Syphilis Secondary Syphilis Early Latent Syphilis Total Cases of Early Syphilis 35 58 86 179 29 (83%) 49 (85%) 75 (87%) 153 (86%) 14 (40%) 26 (45%) 43 (50%) 83 (46%) Patient Reporting Investigating Surveillance Manager (PRISM)
Primary and Secondary Syphilis Rates of Reported Cases by State, United States and Outlying Areas, 2013 NOTE: The total rate of primary and secondary syphilis for the United States and outlying areas (Guam, Puerto Rico, and Virgin Islands) was 5.6 per 100,000 population. STD Surveillance 2013, www.cdc.gov
Reported Cases of Primary and Secondary Syphilis, MPAETC/FATC Regions, 2009-2013 State 2009 2010 2011 2012 2013 Alaska 0 3 5 11 23 Colorado 105 138 133 208 163 Idaho 3 6 13 26 15 Kansas 32 19 24 24 51 Montana 4 3 7 2 5 Nebraska 5 12 10 8 41 New Mexico 61 53 71 101 78 North Dakota 4 3 1 4 12 Oregon 57 71 97 212 267 South Dakota 0 4 0 18 44 Utah 31 65 14 42 74 Washington 139 266 328 302 284 Wyoming 3 0 0 4 1
How do you screen for syphilis in your clinical program? A. RPR with reflex to a confirmatory test B. Treponemal test with reflex to an RPR C. Other screening algorithm D. We do not have a screening policy 0% 0% 0% 0% RPR with reflex to a conf... Treponemal test with ref... Other screening algorithm We do not have a screeni..
Diagnostic Tests The organism cannot be grown in vitro. The organism can be seen in tissues using darkfield microscopy or with special stains. A PCR is not typically available but has been used in research studies. Most diagnoses are made clinically and with serologic testing. No single serologic test of syphilis is sufficient as tests can be falsely positive, falsely negative, or unreliable as a measure of disease activity.
Clement M et al. JAMA 2014;312:1905-1917
The Paradigm Shift in Syphilis Testing Old: screen with a non-treponemal test (RPR or VDRL) and confirm with a treponemal test Issue: the false positive RPR New: screen with a treponemal test, reflexing to RPR or VDRL if positive Issue: false positive treponemal test Issue: the reactive treponemal test with a non-reactive RPR Sena et al, Clinical Infectious Diseases 2010;51:700-708
Newer Serologic Tests for Syphilis Newer Treponemal Tests: Enzyme immunoassays and immunochemiluminescent assays Automated with high throughput Excellent sensitivities and specificities Can t distinguish remote from active infection Sena et al, Clinical Infectious Diseases 2010;51:700-708
Case Study 1 A 49 year old male with HIV infection, well controlled on ART, presents for routine clinic follow up. Asymptomatic but reports multiple sexual contacts. One year prior, a palpable rectal nodule was detected and was removed by flexible sigmoidoscopy. Pathology revealed condyloma accuminatum. Physical exam today reveals a new rectal nodule. 7/27/15: CD4 480 cells mm 3, HIV viral load TND Syphilis screening 7/27/15: Treponema antibody reactive, RPR non-reactive 3/16/15: Treponema antibody non-reactive (RPR not done)
What is the most likely explanation for these clinical and laboratory findings? A. Falsely positive Treponema antibody B. Prior treated syphilis C. Early latent syphilis D. Condyloma lata Falsely positive Trepon... 0% 0% 0% 0% Prior treated syphilis Early latent syphilis Condyloma lata
Sensitivity of Serological Tests in Untreated Syphilis Stage of Disease (Percent Positive [Range]) Test Primary Secondary Latent Tertiary VDRL 78 (74 87) 100 95 (88 100) 71 (37 94) RPR 86 (77 99) 100 98 (95 100) 73 FTA-ABS* 84 (70 100) 100 100 96 Treponemal Agglutination* 76 (69 90) 100 97 (97 100) 94 EIA 93 100 100 *FTA-ABS and TP-PA are generally considered equally sensitive in the primary stage of disease. www.cdc.gov
Sensitivity and Specificity of Syphilis Tests Clement M and Hicks C. JAMA 2014;312:1922-1923
Case Study 1: Conclusion The patient had reported recent high risk sexual contacts. The non-reactive RPR was concerning for early syphilis. The RPR should be highly sensitive in patients with secondary syphilis, including C. lata. The patient was treated for early latent syphilis with benzathine penicillin 2.4 million units IM. He has been referred for flexible sigmoidoscopy with biopsy of the rectal lesion.
Case Study 2 A 42 year old female with HIV infection, initially diagnosed in 2001, comes to the clinic to establish care. She is currently on ART with a CD4 count of 545 cells/mm 3 with an undetectable HIV viral load. She reports a prior history of chlamydial infection but no history of syphilis. Laboratory testing reveals a reactive Treponema antibody screen but the RPR is non-reactive. Repeat testing 3 months later reveals the same pattern. She reports no symptoms.
What is the most likely explanation for these laboratory findings? A. Falsely positive Treponema antibody B. Prior treated syphilis (perhaps inadvertently) C. Early latent syphilis D. Tertiary syphilis Falsely positive Trepone.. 0% 0% 0% 0% Prior treated syphilis (p... Early latent syphilis Tertiary syphilis
Clinical Questions 1. Do these results represent prior syphilis exposure that she does not recall or has not disclosed? 2. Could she have active syphilis? 3. Does she need treatment for syphilis? 4. Does she need additional evaluation? 5. If you elect to treat her, what regimen would you use?
Case Study 2: Advice from CDC Guidelines Treponemal Test Positive; RPR or VDRL nonreactive Different Treponemal Test Positive If prior history of syphilis and no evidence of recent exposure, don t treat. If no prior history of syphilis and no evidence of recent exposure, treat for late latent syphilis. Different Treponemal Test Negative No further evaluation or treatment is necessary. 2015 STD Guidelines, www.cdc.gov
Syphilis Treatment by Disease Stage Disease Stage Primary Treatment Alternative Treatment Primary syphilis Secondary syphilis Early latent syphilis Late latent syphilis Cardiovascular and gummatous syphilis Neurosyphilis Benz PCN 2.4 million units IM x 1 dose Benz PCN 2.4 million units IM x 1 dose Benz PCN 2.4 million units IM x 1 dose Benz PCN 2.4 million units IM weekly x 3 doses Benz PCN 2.4 million units IM weekly x 3 doses PCN G 18-24 million units IV daily x 10-14 days 2015 STD Guidelines, www.cdc.gov Doxycycline 100 mg PO BID x 14 days Doxycycline 100 mg PO BID x 14 days Doxycycline 100 mg PO BID x 14 days Doxycycline 100 mg PO BID x 28 days Consult with ID Physician recommended Procaine PCN 2.4 million units daily + probenecid for 10-14 days
Case Study 2: Conclusion A second treponemal test (FTA-ABS) was reactive. Given the lack of symptoms, additional evaluation (e.g. lumbar puncture) was not done. The patient was treated with benzathine penicillin G 2.4 million units IM weekly x 3 doses.
Case Study 3 A 46 year old male with HIV infection, well controlled on ART, presents in January of 2014 for routine follow up. He has a history of syphilis a number of years ago that was treated. On presentation, he has a pruritic rash involving his left hand, left elbow, chin, and right buttock. Laboratory: 1/9/14: CD4 840 cells mm3, HIV viral load TND 1/9/14: Treponema antibody reactive, RPR 1:2 4/30/13: Treponema antibody reactive, RPR reactive < 1:2
What is the most likely explanation for these laboratory findings? A. Secondary syphilis B. Serofast state with random variation C. Early latent syphilis with another cause for his rash D. False positive RPR Secondary syphilis 0% 0% 0% 0% Serofast state with rand.. Early latent syphilis wit... False positive RPR
Case Study 3 He was contacted to return to the clinic for treatment with benzathine penicillin. However, he did not return for treatment. 8 months later, in September of 2014, he saw his PCP and reported an extensive skin rash. Labs were drawn although no additional treatment was provided. He returned for follow up in our clinic in January of 2015. An extensive skin rash was again noted. Laboratory: 9/14: RPR 1:64 (shown to me by patient using his cell phone app) 1/22/15: Treponema antibody reactive, RPR 1:128
Case Study 3: Continued He was diagnosed with secondary syphilis. Treated with benzathine penicillin 2.4 million units IM x 1 dose. In phone follow up, he reported no side effects of treatment and improvement of rash. He has not yet followed up for care.
Once treated, when should he return for repeat syphilis serology? A. Monthly until a 4-fold drop in titer is demonstrated B. Every 3 months until a 4-fold drop in titer is demonstrated C. In 6 months and 12 months until a 4-fold drop in titer is demonstrated D. Given the efficacy of PCN, serologic follow up is not necessary Monthly until a 4-fold dro... 0% 0% 0% 0% Every 3 months until a 4-... In 6 months and 12 mont.. Given the efficacy of PCN,...
Guidelines for Serologic Follow up For Primary and Secondary syphilis Clinical and serologic evaluation should be done at 6 and 12 months Failure for titers to decline 4-fold could mean either treatment failure or reinfection Serologic decline may be slower in patients with a prior history of syphilis Optimal management of patients who do not have a 4-fold decline is unclear Lower initial titers are less likely to fall 4-fold than higher titers 2015 STD Guidelines, www.cdc.gov
Evidence for Therapy for Each Syphilis Stage Syphilis Stage Primary and Secondary Early latent Late Latent Neurosyphilis Other forms of tertiary syphilis Grade of Evidence of Primary Therapy A = Data from many large randomized clinical trials B = Data from fewer smaller randomized clinical trials, careful analyses of non-randomized studies, or observational registries C = Expert consensus A A C C C Clement M et al. JAMA 2014;312:1905-1917
Incidence of Genital Ulcer Disease in the U.S. in 2013* 306,000 # Cases 10 5,204 Herpes Syphilis Chancroid 0 100000 200000 300000 * Incidence of reported or estimated cases. LGV and Granuloma inguinale not included. CDC. National Overview of Sexually Transmitted Diseases (STDs), 2013. http://www.cdc.gov/std/stats13/natoverview.htm
Gonorrhea and Chlamydial Infection in HIV Infection
Gonorrhea Rates of Reported Cases by State, United States and Outlying Areas, 2013 NOTE: The total rate of reported cases of gonorrhea for the United States and outlying area (Guam, Puerto Rico, and Virgin Islands) was 104.9 per 100,000 population. STD Surveillance 2013, www.cdc.gov
Gonorrhea Proportion of STD Clinic Patients* Testing Positive by Age, Sex, and Sexual Behavior, STD Surveillance Network (SSuN), 2013 *Only includes patients tested for gonorrhea. MSM=men who have sex with men; MSW=men who have sex with women only. NOTE: Six jurisdictions (Birmingham, Chicago, Denver, Hartford/New Haven, New Orleans and Richmond) contributed data from January through June 2013 and the remaining jurisdictions (Baltimore, Los Angeles, New York City, Philadelphia, San Francisco and Seattle) contributed data for all of 2013. STD Surveillance 2013, www.cdc.gov
Chlamydia Rates of Reported Cases by State, United States and Outlying Areas, 2013 NOTE: The total rate of reported cases of chlamydia for the United States and outlying areas (Guam, Puerto Rico, and Virgin Islands) was 443.5 per 100,000 population. STD Surveillance 2013, www.cdc.gov
Chlamydia Proportion of STD Clinic Patients* Testing Positive by Age, Sex and Sexual Behavior, STD Surveillance Network (SSuN), 2013 *Only includes patients tested for chlamydia MSM=men who have sex with men; MSW=men who have sex with women only. NOTE: Six jurisdictions (Birmingham, Chicago, Denver, Hartford/New Haven, New Orleans, and Richmond) contributed data from January through June 2013 and the remaining jurisdictions (Baltimore, Los Angeles, New York City, Philadelphia, San Francisco and Seattle) contributed data for all of 2013. STD Surveillance 2013, www.cdc.gov
Case Study 4 A 24 year old male with HIV infection returns for routine follow up. He has one primary sexual partner but both he and his partner occasionally have other partners. He reports use of condoms on most occasions but not always. He has no new symptoms today and specifically denies sore throat, skin rash, rectal pain, or urinary symptoms. However, he would like an STD check to be sure. Testing included a Treponemal antibody, Hepatitis C antibody, and screening tests for GC and Chlamydia
With regards to GC and Chlamydial infections, how do you screen in your clinical program? A. Urine probe for GC and Chlamydia B. Throat culture or probe for GC and chlamydia C. Rectal culture or probe for GC and Chlamydia D. All of the above E. Other screening algorithm based on risk Urine probe for GC and... Throat culture or probe f.. 0% 0% 0% 0% 0% Rectal culture or probe f.. All of the above Other screening algorith...
Does Your Clinic Use Nucleic Acid Amplification (NAAT) Tests for Throat and Rectal Testing? A. Yes B. No 33% 33% 33% C. I don t know Yes No I don t know
Gonorrhea screening among men who have sex with men: value of multiple anatomic site testing, San Diego, California, 1997-2003. Cultures and NAAT tests from all sites reviewed in MSM attending San Diego STD Clinic, 1997-2003 During this 7-year period, 1157/7333 (15.8%) of men had > 1 site positive for GC Of those who had a urine and either a rectal or pharyngeal specimen, 970 were positive, including 369 who had a negative urine test with a positive other site If the clinic had tested only urine, 33% of GC cases among MSM would have been missed Sex Transm Dis. 2008 Oct;35(10):845-8. doi: 10.1097/OLQ.0b013e318177ec70.
Guidelines for Screening for Gonorrhea and Chlamydial Infection in HIV Infection Men and women should be screened at initial presentation and then annually if at risk for infection. Nucleic acid amplification tests (NAATs) have the highest sensitivity for detecting gonorrhea and chlamydia. Vaginal swabs in women and urine in men are the preferred specimens for genital testing with NAATs. Aberg J et al. Clin Infect Dis. (2013) doi:10.1093/cid/cit665
Guidelines for Screening for Gonorrhea and Chlamydial Infection in HIV Infection Anorectal testing for gonorrhea and chlamydia should be done in those who report receptive anal intercourse. Pharyngeal testing for gonorrhea should be considered if the patient reports receptive oral sex. Testing for oropharyngeal chlamydia is not routinely recommended because its prevalence is generally low. Aberg J et al. Clin Infect Dis. (2013) doi:10.1093/cid/cit665
Neisseria gonorrhoeae Percentage of Isolates, with Penicillin, Tetracycline, and/or Ciprofloxacin Resistance, Gonococcal Isolate Surveillance Project (GISP), 2013 NOTE: PenR=penicillinase-producing Neisseria gonorrhoeae and chromosomally-mediated penicillinresistant N. gonorrhoeae; TetR=chromosomally- and plasmid-mediated tetracycline-resistant N. gonorrhoeae; and QRNG=quinolone-resistant N. gonorrhoeae. STD Surveillance 2013, www.cdc.gov
Primary Antimicrobial Drugs Used to Treat Gonorrhea Among Participants, Gonococcal Isolate Surveillance Project (GISP), 1988 2013 Ceftriaxone 125 mg NOTE: For 2013, Other includes no therapy (0.9%), azithromycin 2g (1.7%), and other less frequently used drugs (<0.1%). STD Surveillance 2013, www.cdc.gov
Treatment of Gonococcal and Chlamydial Infections in Adults and Adolescents Infection Uncomplicated gonococcal infection of the cervix, urethra, or rectum Uncomplicated gonococcal infection of the pharynx Recommended Regimen Ceftriaxone 250 mg IM + azithromycin 1 gm orally Ceftriaxone 250 mg IM + azithromycin 1 gm orally Alternative Regimen Cefixime 400 mg PO + azithromycin 1 gm orally or gemifloxacin 320 mg orally + azithromycin 2 gm orally Unclear. Pharyngeal gonorrhea is more difficult to eradicate than other sites of infection. Chlamydial infection Azithromycin 1 mg orally or doxycycline 100 mg PO BID x 1 week Erythromycin 500 mg QID x 7 days Erythromycin ES 800 mg QID x 7 days Levofloxacin 500 mg QD x 7 days Ofloxacin 300 mg BID x 7 days CDC. Sexually Transmitted Diseases Guidelines 2015, MMWR 2015;64(No. RR-3):1-140
Summary STDs are very common among persons living with HIV infection. Screening for syphilis should be routine, the frequency based on sexual history. Diagnosis of syphilis typically requires interpretation of both treponemal and non-treponemal tests. Screening for GC and Chlamydia should often include multiple body sites, based at least in part on sexual history. Other important STD screens in HIV infection include Hepatitis C, trichomoniasis, and, in patients who are not immune, Hepatitis B.
Questions and Discussion