Update on Sexually Transmitted Infections among Persons Living with HIV Stephen A. Berry, MD PhD Assistant Professor of Medicine Johns Hopkins University Division of Infectious Diseases
Abbreviations and note Some abbreviations NG, Neisseria gonorrhoeae CT, Chlamydia trachomatis TP, Treponema pallidum (syphilis) TV, Trichomonas vaginalis HSV, Herpes simplex virus MG, Mycoplasma genitalium Most recommendations based on U.S. Centers for Disease Control and Prevention guidelines
Overview Screening for STIs Four clinical cases that cover: Proctitis Genital Ulcers Vaginitis Urethritis
I. STI SCREENING
The percentage of asymptomaticstis
Periodic screening for STIs in sexually active persons living with HIV MMWR 2003;52(RR12) MMWR 2010;59(RR12) Syphilis Annually Everyone Every 3 6 months Consider based on risk factor(s)* Chlamydia and Gonorrhea Annually MSM; Women 25 years-old Annually (or 3 6 months) Consider based on risk factor(s)* Re-screen at 3 months Following treatment Trichomonas Annually Women Re-screen at 3 months Following treatment * history of STI, multiple or anonymous partners, active substance abuse, inconsistent condom use, sex work, partner with any of above, high local prevalence, risky lifechanges, e.g. dissolution of a relationship
Prevalence of extragenital sexual behaviors ORAL SEX Oral Sex Males Females Active Oral Passive Oral Active Oral Passive Oral Lifetime 77% 79% 68% 73% ANAL SEX Young MSM: 50% Young heterosexual men and women: 14-49% Last sex 27% 28% 19% 28% Michael RT, et al. Sex in America: A Definitive Survey. Little, Brown and Co. UK. 1994 Ekstrand M, et al. AIDS 1999; 13 (12): 1525-33 Halperin D, et al. AIDS Patient Care STDs 1999; 13(12); 717-30
Extragenital NG/CT testing is essential *HIV Clinic with 65% Screening Coverage in 2010 (Unpublished HIV Research Network data) Example clinic: 117 / 175 (67%) cases detected were extragenital < 10% simultaneous positivity at genital sites AIDS Pt Care STDs. 2005;19:495, AIDS Pt Care STDs. 2008;22:947 Among women, ~25% of cases extragenital Sex Transm Dis. 2011;38:783 Opportunity to reduce HIV transmission
Extragenital site screening recommendations MMWR 2003;52(RR12) Gonorrhea and Chlamydia: annually (or 3 6 months based on risk*) Rectum Oropharynx Anyone engaged in receptive anal sex Anyone engaged in receptive oral sex for NG CT not recommended, but potentially beneficial, and negligible downside * history of STI, multiple or anonymous partners, active substance abuse, inconsistent condom use, sex work, partner with any of above, high local prevalence, risky life-changes, e.g. dissolution of a relationship Use a nucleic acid test (NAT) if possible! MMWR 2011;60(1):18 Sensitivity for NG: culture ~50% vs. NAT >90% Extragenital NAT s not FDA approved but available with laboratory validation
II. CLINICAL CASES
Case 1 22 year-old man (CD4 230 / VL 270,000) complains of painful defecation, tenesmus, and blood with wiping. Last sexual encounter, 6 wk ago, involved male and female partners, and included insertive vaginal and receptive rectal intercourse with condom use. Rectal exam notable for tenderness and fecal occult blood test was positive, but no internal or external hemorrhoids or fissures. What next?
Proctitis Neisseria gonorrhoeae Chlamydia trachomatis D-K Chlamydia trachomatis L1-L3 [LGV] Treponema pallidum HSV 1 and HSV-2 Ideal Workup NAT for NG/CT Culture or NAT for HSV TP serology Or what is available NG culture, TP serology?
Empiric Treatment of Proctitis Drug One (NG) Recommended Ceftriaxone 250mg IM x 1 Alternate Cefixime 400mg PO x 1 Drug Two (NG, CT (D-K and L1-3), TP) Recommended Doxycycline 100mg PO BID x 3 wk Alternate Azithromycin 1g PO qwk x 3 wk Cephalosporin Allergy Consider HSV coverage Azithromycin 2g PO x 1 PLUS Doxycycline 100mg PO BID x 3 wk Valacyclovir 1g PO BID x 7 days MMWR. 2010;59(RR12); MMWR. 2012;61(31)
Case 1 Patient: No shots! >> Cefixime 400mg PO x1 given >> Doxycycline 100mg PO q12hr x 3 weeks begun >> NG/CT NAT, HSV culture, syphilis serology sent
Case 1 -Two days later NG/CT NAT: NG POS/ CT NEG HSV culture: pending Syphilis treponemal test: NEG Patient improving
Do all of the following except... A. Continue doxycycline for 7 days total B. One-week test-of-cure C. Re-screen for NG at 3 mon D. Azithromycin 500mg PO x 1
D. Azithromycin 500mg NOT INDICATED A. Doxycyline 7 days Completion of two-drug course for NG NAT sufficient to rule-out CT (including L1-L3) B. One-week Test-of-Cure Now recommended if any alternative regimen is used for NG MMWR. 2012;61(31) Use culture if available C. Re-screen at three months Recommended after any NG, CT, or TV infection MMWR. 2010;59(RR12) D. Azithromycin Not needed if doxycycline given 1000mg is the dose
Failure of non-preferred NG regimen Assess re-infection risk Ceftriaxone 250mg IM x 1 AND azithromycin 2gm PO x 1 Every effort to culture Report resistance profile to public health dept Failures of preferred regimen (ceftriaxone plus azithromycin)? Infectious Disease consultation Spectinomycin, gentamicin, ertapenem
In vitroresistance in 108 NG isolates in Vietnam, 2011 (Olsen. BMC Infect Dis 2013;13:40) Antimicrobial % Intermediate or Resistant Penicillin, Ciprofloxacin, Tetracycline > 90 Azithromycin 38 Cefixime 1 Ceftriaxone 5 Spectinomycin 0 5% cefixime failure rate in Toronto clinic, 2011 (Allen. JAMA 2013;309(2):163) 9 cases with tests-of-cure, denial of interval sexual activity Cefixime MIC s 0.12 µg/ml 17% Ciprofloxacin resistance in Rio de Janeiro 06-10 (Uehara. JClinMicrob 2011;49(12):4208)
Case 2 33 y.o. woman (CD4 1060, HIV RNA <20) complains of one week of thin, white vaginal discharge. She and her boyfriend recently stopped using condoms in an effort to conceive. She describes receptive vaginal and anal intercourse with only her boyfriend. Scant thin discharge on exam, normal cervix Wet mount normal, ph 7 Which laboratory tests should be performed?
Case 2 Diagnostics Vaginal swab for NG/CT NAT or culture(s) Sensitivity of NAT 95-98% Sex Trans Dis 2005;32:725 Vaginal swab for Trichomonas vaginalis NAT or culture MMWR. 2010;59(RR12) Sensitivity of wet mount ~50-70% Sensitivity of culture ~85% Sensitivity of NAT >95% Syphilis serology Rectal swab for NG/CT NAT
Trichomonas vaginalis (NAT positive) Syndromes Asymptomatic Vaginitis (vaginal ph usually >4.5) Urethritits First-line therapy Tinidazole 2g PO X1 OR Metronidazole 500mg PO BID X 7 days OR Metronidazole 2g PO X1 Partners in the preceding 60 days must be treated 3-month screening because of high reinfection rates Yearly screening for all sexually-active HIV+ women TV probably increases HIV shedding J Infect Dis. 2001;183:1017
Failure to Respond to First Line Consider re-infection Resistance to 5-nitroimidazoles (only class) ~5% of strains have low-level resistance Can be overcome with higher doses Tinidazole vs. metronidazole Longer half-life Higher tissue concentrations MIC s to tinidazole lower If patient fails Rx with metronidazole 2g PO X1 Tinidazole 2 g PO X1 OR Metronidazole 500mg PO BID X 7d If patient has failed one of the above Metronidazole 2g PO QD X 5d OR Tinidazole 2g PO QD X 5d
Case 3 36 y.o. man (CD4 535, HIV RNA 1370), complains of scant, white penile discharge for 4 months. Male partners, intermittent condom use. Exam unremarkable. One month ago: UA: 11-30 WBC / HPF (No nitrates, epi s, RBC) Urine NG/CT NAT NEG Urine culture NEG
What is the first-line empiric therapy? A. Gentamicin 240mg IM x 1 B. Trim/sulfa (800/160) PO q12 x 3 days C. Azithromycin 1000mg PO x 1 D. Metronidazole 2g PO x 1
Empiric therapy for non-gonococcal urethritis A. Gentamicin 240mg IM x 1 Possible in cephalosporin-resistant NG, but nor currently recommended B. Trim / sulfa (800/160) PO q12 x 3 days Bacterial cystitis unlikely with negative culture C. Azithromycin 1000mg PO x 1 First line empiric therapy MMWR. 2010;59(RR12) Azithromycin 1000mg PO x1 OR Doxycycline 100mg PO q12 x 7 days D. Metronidazole 2g PO x 1 Second-line in empiric algorithm for non-gonoccocal urethritis (Trichomonas coverage)
Non-Gonococcal urethritis (NGU) Confirm urethritis(any of the following) Purulent discharge on exam 5 WBC / HPF on urethral Gram stain 10 WBC on urinalysis Common etiologies Clin Infect Dis. 2013; 56:934 Chlamydia trachomatis (25% cases) Mycoplasma genitalium (15%) Trichomonas vaginalis (2-3%, less common MSM) Ureaplasma urealyticum (25%, controversial) Idiopathic (40%) Uncommon or underdiagnosed: HSV, enterobacteriaceae, Haemophilus, Staphylococcus saprophyticus, adenovirus
Case 3 -Diagnostics Repeat urinalysis Urine NAT for M. genitalium (if available) No US FDA approved assays Urine sensitivity (men) ~90% Vaginal swab sensitivity ~85% J Clin Microbiol 2006;44:3306, J Clin Microbiol 2011;49:1990, Sex Trans Dis 2004;31:499 Urine NAT for NG/CT (repeat) Syphilis serology, oral and rectal NG/CT NAT (screening) Consider: Urine NAT or urethral culture for T. vaginalis, urethral swab for HSV culture or NAT
Case 3 M. genitaliumurethritis Azithromycin 1gm given Test results UA: 11-30 WBC / HPF Urine, rectal, oral NG/CT NATs NEG RPR NEG Urine M. genitaliumnat: POS One-month phone call Slightly better Return visit scheduled
NGU First-line Treatment Failure This MG case Assess reinfection risk First-line MG agents efficacy Azithromycin 40-75% Doxycycline 30-50% Clin Infect Dis. 2013; 56:934 Second-line: moxifloxacin 400mg PO qday x 7d PLOS One. 2008;3(11):e3618 Int J STD AIDS. 2008;19:676 Consider TV urine assay HSV urethral swab assay Without diagnostics Assess reinfection risk
Case 4 41 year-old man presents with 8 weeks of a painful perianal ulcer. Undetectable HIV RNA for 3 years, but CD4 fallen from 800 to 40 amidst chemotherapy for lymphoma Valacyclovir 1000mg TID for 7 weeks Cultures 6 wk ago and 3 wk ago: HSV-2 Exam: 6cm slightly-exudative perianal ulcer with welldefined borders, extending from anal verge What next?
Case 4 Consider co-existing pathology (purulent bacterial superinfection, syphilis, cancer) Acyclovir resistance Thymidine kinase mutations >95% of instances Assay requires culture, 2-3 week turn around Long-term HSV suppression with acyclovir PREVENTS acyclovir resistance J Infect Dis. 2007;196:266 Only test if clinical failure NEJM. 1984;310(24):1545
Agents for acyclovir-resistant HSV Topical Imiquimod Immune modulator 5% cream QOD for 3 weeks Locally irritative Cidofovir 1% gel, compounding pharmacy, QD for 5 days Intravenous Oral Foscarnet Cidofovir q8hr IV for ~3 weeks, fluids and monitoring Qwk IV, less tolerable than foscarnet Thalidomide anecdotes in hypertrophic disease Sex Transm Infect. 2011;87:29 J Infect Dis. 1997;176:892 FDA approved Clin Infect Dis. 2007;44:e96
Major take-home points Screening for TP / NG / CT / TV At least annually for many sexually-active patients Extragenital sites important (if tests available) 3-month screen after any treatment Proctitis: ceftriaxone 250mg + doxy (3 weeks) Non-preferred NG regimen: 1 week test-ofcure Non-gonoccocal urethritis treatment algorithm: include moxifloxacin if previous meds fail Acyclovir-resistant HSV: imiquimod