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New Directions in STD Testing and Treatment. Stephanie Cohen, MD, MPH Medical Director, San Francisco City Clinic San Francisco Department of Public Health Ina Park, MD, MS Chief, Office of Medical and Scientific Affairs CA Dept of Public Health – STD Control Branch.
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New Directions in STD Testing and Treatment Stephanie Cohen, MD, MPHMedical Director, San Francisco City ClinicSan Francisco Department of Public Health Ina Park, MD, MS Chief, Office of Medical and Scientific Affairs CA Dept of Public Health – STD Control Branch
Development of CDC STD Treatment Guidelines Answer the “Key Questions” Enlistment of Subject Matter Experts Guidelines Meeting, April 2013 Rate the quality of the evidence Key Questions Systematic Review of Evidence Identify critical gaps in knowledge (research agenda) Background papers Tables of evidence Write the Guidelines document Online: www.cdc.gov/std/treatment
Authoritative, evidence-based source for STD clinical management Recommended regimens preferred over alternative regimens Alphabetized unless there is a priority of choice Available at www.cdc.gov/std Wall charts, pocket guides, app CDC STD Treatment Guidelines
STD Screening for Women Sexually Active adolescents & up to age 25 Routine chlamydia and gonorrhea screening Others STDs and HIV based on risk Women over 25 years of age STD/HIV testing based on risk Pregnant women Chlamydia Gonorrhea (≤ 25 years of age or at-risk) HIV Syphilis serology HepBsAg Hep C (if high risk) CDC 2010 STD Tx Guidelines www.cdc.gov/std/treatment
STD Screening for MSM* Screen at least annually, q 3-6 mos if high risk* HIV Syphilis Urethral GC and CT Rectal GC and CT (if anal sex) Pharyngeal GC (if oral sex) Also screen for: Hepatitis B (repeat as indicated by risk) Proposed: HIV+ MSM & anal cancer: Annual digital rectal exam may be useful, some centers perform anal Pap and HRA for ASC-US or worse. * High risk: multiple and/or anonymous partners, drug use, or high risk partners CDC 2010 STD Tx Guidelines www.cdc.gov/std/treatment
Hepatitis C screening for HIV+ • Proposed : [In HIV-infected men and women] “HCV antibody tests should be serially monitored, at least yearly and more frequently depending on local circumstances (HCV prevalence, incidence, resources, and other factors), to detect conversion from HCV-antibody-negative to positive).”
Chlamydia TreatmentAdolescents and Adults • New incidence estimates: • 2.8 million cases in US annually • Diagnostic issues: • Self collected rectal swabs for MSM appear as sensitive as clinician collected swabs • Highly acceptable to patients • Pharyngeal screening: • Not routinely recommended • If detected, treat with routine CT tx regimens • Hetero male screening: • Consider in certain venues only (corrections, STD clinics, etc) Satterwhite et al. STD 2013
Chlamydia TreatmentAdolescents 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 in pregnancy Proposed Changes: Add Doxycycline delayed-release 200 mg tablet daily x 7 days • Equally efficacious to generic doxycycline 100mg BID x 7 days • Less GI side effect • More expensive Concerns over amoxicillin use in pregnancy due to chlamydia persistence in vitro • Use only as an “alternative regimen”
Robert • 38 yo HIV positive MSM at primary care visit. • Doing well on atripla, with an undetectable VL and a CD4 450. No STD symptoms. • Routine STD screen: Rectal CT NAAT is positive, treated with Azithromycin 1 g PO x1. • At his next follow-up visit 3 months later, his rectal CT NAAT is again positive and he reports that he has not had any receptive anal sex since his last visit.
Chlamydia Treatment: Areas of Clinical Uncertainty • Observational data suggest azithromycin may be less effective than doxycycline for anorectal Chlamydia infection • Four published studies, 2 abstracts • Not randomized • Most single arm or historical cohort as comparator • Varying times to test of cure • Low rates of follow-up
Treatment of asymptomatic rectal CT SteedmanNM, Int J STD AIDS 2009; Elgalib A, Int J STD AIDS 2011; Drummond F, Int J STD AIDS 2011
Treatment of asymptomatic rectal CT Hathorn E, STI 2012; Khosropour CM, Abstract 2013; Khosropour CM, Abstract 2013.
Rectal Chlamydia • No changes to guidelines proposed based on these data • Need RCT • Some sites using doxycycline as 1st line treatment for rectal CT
Greg • 38 yo HIV positive MSM, doing well on atripla, with an undetectable VL and a CD4 450. • Presents with rectal discharge and pain with sex • Presumptively treated with Ceftriaxone 250 mg IM x1 and Doxycycline 100 mg PO BID x 7 days for proctitis • Rectal CT NAAT positive
Proctitis Recommended: Ceftriaxone 250 mg IM once PLUS Doxycycline 100 mg orally BID x 7 days If LGV suspected Doxycycline 100 mg orally BID x 3 weeks Consider LGV: 5-30% symptomatic rectal CT (aka CT proctitis) is LGV Presumptive treatment of LGV for MSM with proctitis and anorectalchlamydia, particularly if the patient is HIV-infected or any of the following symptoms or signs are present: bloody discharge, perianal ulcers or mucosal ulcers Elgalib A, Int J STD AIDS 2011; Hathorn E, STI 2012, Hill Int J STD AIDS 2010, de Vrieze STI 2013.
Non-GonoccocalUrethritis (NGU) Issues discussed: • >1 WBCs per hpf on urethral gram stain/methylene blue stain may be sufficient for diagnosis • M. genitalium is a cause of 15-25% of NGU, no commercial test yet FDA approved • Regional differences exist in T. vaginalis prevalence (testing could be considered in high-prevalence areas)
NGU Treatment Recommended Alternative Erythromycin base 500 mg PO QID x 7 days Erythromycin ethylsuccinate 800 mg QID x 7 days Levofloxacin 500 mg QD x 7 days Ofloxacin 300 mg PO BID x 7 days • Azithromycin 1 gm PO x 1 dose OR • Doxycycline 100 mg PO BID x 7 days
Persistent NGU Treatment If azithromycin NOT given for 1st episode: Azithromycin 1 g orally in a single dose PLUS Metronidazole 2 g orally in a single dose OR Tinidazole2 g orally in a single dose If azithromycin given for 1st episode: Moxifloxacin400 mg orally qd x 7d PLUS Metronidazole 2 g orally in a single dose OR Tinidazole 2 g orally in a single dose
MycoplasmaGenitalium • Good evidence for role in urethritis • 13-41% of men with persistent or recurrent urethritis have M. gent • May play role in PID • No commercially-available test • Azithromycin appears more effective than doxycycline for M. genitalium, but efficacy of AZ for M. gent may be declining (Manhart, CID 2013) • Ongoing debate about whether it gets its own section
Gonorrhea New incidence estimates: 820,000 cases in US annually Diagnostic issues: Self collected pharyngeal swabs: data look favorable but not enough data to recommend (less data than rectal) Self collected rectal swabs (language similar to CT) Satterwhite et al. STD 2013
Evolution of Criteria for GC Treatment Recommendations • Antimicrobial resistance surveillance has guided treatment decisions (GISP, GASP) • Change in antimicrobial if resistance prevalence >5% (MMWR 1987) • GC treatment efficacy • >95% and 95% CI lower bound 95% (Moran, 1995) • Pharmacokinetic/pharmacodynamic factors • Serum concentration at least 4x MIC90 x 10 hr after peak (Jaffe1987) • At least twice the minimum efficacious dose • Other factors • Mechanism of action • Side effects and safety • Cost
Alternative Treatment Approaches Until Newer Agents Available • Increase dose or duration of cephalosporin • Antimicrobial susceptibility profile directed therapy • Antibiotic cycling • Dual therapy
CDC Treatment Recommendations for Gonococcal Infections 2012 • Ceftriaxone 250 mg IM x 1 • PLUS • Azithromycin 1 g po x 1 OR • Doxycycline 100 mg po BID x 7 days • Alternatives • If ceftriaxone not available or for expedited partner therapy (EPT): Dual therapy with cefixime (cefixime PLUS azithro or doxy) • If cephalosporin allergy: Azithromycin 2 g po x 1 • PLUS Test of cure if alternative regimen used
CDC Treatment Recommendations for Gonococcal Infections (under consideration) • Ceftriaxone 250 mg IM x 1 • PLUS • Azithromycin 1 g po x 1 OR • Doxycycline 100 mg po BID x 7 days • Alternatives • If ceftriaxone not available or for expedited partner therapy (EPT): Dual therapy with cefixime (cefixime PLUS azithro) or doxy • If cephalosporin allergy: Azithromycin 2 g po x 1 • Gentamicin (240mg IM or 5 mg/kg IM) /azithro2 g PO or gemifloxacin320 mg PO /azithro2 g PO • TOC if alternative regimen used for pharyngeal GC at ~14 days 2014
GC Treatment: Areas of Clinical Uncertainty No clinical data to support increasing dose of either ceftriaxone or azithromycin • Higher ceftriaxone and/or azithromycin doses recommended outside U.S. (UK, Japan, etc.) • Ceftriaxone in vitro susceptibility (MIC50 and MIC90) and clinical efficacy data in U.S. stable • Ceftriaxone Rx failures rare, all outside U.S. Azithromycin 1g effectiveness meets lower CI >95% threshold Azithromycin resistance remains low, but can develop quickly When to get a TOC and optimal time to TOC still unclear
GC Dual Treatment Study • Randomized, open-label, non-comparative trial • 401 men and women 15 – 60 years with uncomplicated urogenital gonorrhea (culture-positive) • Treatment with either: • Both combinations were highly effective for treatment of urogenital GC
CT/GC Partner Management Options Partner notification Patient directly notifies partner 3rd party (provider or health department) Internet-based anonymous notification Partner treatment Have patient bring partner to clinic for concurrent treatment (CPPT) Expedited Partner Treatment (EPT) Patient-delivered partner treatment (PDPT) Health department field-delivered treatment Pharmacy-based
Percent of Partners Treated by Partner Management Strategy, California FP Clinics, 2005-2006 Yu Y-Y, STD 2011
The Effectiveness of Expedited Partner Treatment on Re-Infection Rates CHLAMYDIA P=.17 GONORRHEA P=.02 Golden M, et al. N Engl J Med 2005 Feb 17;352(7):676-85.
Partner Management: Key Points Clinical evaluation first-line option Concurrent patient-partner therapy is feasible and effective for many clients PDPT is still a second-line option Safe and effective at reducing reinfection for GC Dual therapy (cefixime 400 mg + azithromycin 1 g) is crucial if PDPT is offered • Proposed: CPPT may be added as recommended strategy • Offer PDPT routinely to heterosexual pts with • CT/GC if partner cannot be promptly treated
Partner Management: Areas of Clinical Uncertainty • PDPT for gonorrhea in current era • Cefixime plus azithro still recommended • PDPT for MSM – remains an area of controversy • Harm reduction approach • Risks: • Missed opportunities for HIV and syphilis screening • Undiagnosed pharyngeal GC
Re-testing for Repeat Infection • Repeat infections are extremely common • Dangerous – exponential increase in PID risk • All patients with CT, GC or syphilis should be retested ~ 3 months after initial treatment • Retesting should occur whenever patient returns to clinic (regardless of reason for visit), anytime within 1-12 months post treatment
Syphilis New incidence estimates: 55,000 cases annually Areas of Clinical Uncertainty • Role of reverse screening algorithm (starting with EIA instead of RPR) • Unclear if EIAs are more sensitive for early syphilis than RPR • Serologic response after treatment • 17-21% patients with early syphilis with not achieve a four-fold decline in nontrep titer at 6-12 months • Neurosyphilis case definition
Negative Positive Not Syphilis Non-trep test (RPR) Positive Negative 2nd Trep Test Syphilis (past or present) Negative Positive 1) Unconfirmed EIA Unlikely syphilis; if pt at risk retest in 1 month • Past Syphilis • Early Syphilis EIA or CIA Screening with Treponemal Immunoassay APHL-CDC Consultation Report, 1/2009 MMWR 2011/Vol 60 (5)
Syphilis Treatment Primary, 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 18-24 million units IV daily administered as 3-4 million IV q 4 hr for 10 -14 d Only one dose of PCN Is recommended for early syphilis in HIV-infected persons, extra doses not needed
Syphilis TreatmentPrimary, Secondary & Early Latent Alternatives (non-pregnant penicillin-allergic adults): • Doxycycline 100 mg po bid x 2 weeks • Tetracycline 500 mg poqid x 2 weeks • Ceftriaxone 1 g IV (or IM) qd x 10-14 d If penicillin or doxycycline not feasible, consider: • Azithromycin 2 g po in a single dose* * Do NOT use azithromycin in MSM or pregnant women In pregnancy, benzathine penicillin is the only recommended therapy. No alternatives
Jeremy • 26 yr old HIV-positive MSM, on stable cART regimen for 2 years, VL ND • Regularly screened for syphilis and other STDs q 6 months, all neg x 2 yrs • 6/2008- EIA +, RPR-, TP-PA - • No symptoms and signs of syphilis • MD recommends retesting in a month
Jeremy..continued • Returned 6 months later • EIA +, RPR +, titer 1:16 • No current symptoms or signs of syphilis • Denies interim symptoms/signs • Dx with Early Latent Syphilis • PCN-allergic (rash), treated with doxycycline
12/1/08 titer: 1:16 3/25/09 titer: 1:8 6/5/09 titer: 1:8 Jeremy’s Serologic Titers Treatment Six-month F/u
Jeremy: Elevated Titers What option would you choose for this patient LP to rule out neurosyphilis as reason for lack in 4-fold decline in titer Repeat treatment with benzathine penicillin G x 3 weekly doses, consider LP in 6 months if titer still unchanged Continue to follow serologic titers **Talk to him and assess risk of reinfection**
12/1/08 titer: 1:16 3/09 titer: 1:8 6/09 titer: 1:8 12/09 titer: NR Jeremy: Subsequent Follow-up Treatment One-year F/u
Genital Herpes • New prevalence and incidence estimates: • 48.5 million currently infected • 776,000 new infections per year • Diagnosis: Currently culture and serology • Proposed: NAATS are most sensitive and increasingly available • Treatment: No changes proposed • Prevention: Suppressive anti HSV therapy in HIV/HSV-2 co-infected patients does not reduce risk of HIV transmission
This is not: Primary Syphilis and HIV+Presentation mimicking HSV, multiple ulcers San Francisco City Clinic Photos courtesy of Joe Engelman, MD, SF City Clinic
HSV-1 and Genital Herpes • Among MSM <28 yrs of age in Australia, 76% of cases of first episode anogenital herpes in 2004-2006 were due to HSV-1 (up from 17% in 1992-94) • Among MSM in Paris, receptive anilingus was associated with 6 fold increased oddsof anogenital HSV-1 • University setting; 78% of cases first episode genital herpes due to HSV-1 • Whether genital HSV-1 is associated with same increased risk of HIV acquisition as HSV-2 is unknown Ryder et al STI 2009; 85 (416) Janier et al Int J STD AIDS 2006; 17 Roberts et al STD 2003; 30 (10)
HSV Acquisition among Women Aged 18-30 in the Control Arm of the Herpevac trial Included subjects n=3438 No disease suspected N=3196 Suspected Disease n=242 HSV-2 n=27 Not infected n=180 HSV-1 n=35 Not infected n=3075 HSV-1 n=92 HSV-2 n=29 HSV-1 infection rate > 2x the HSV-2 infection rate (2.5 vs 1.1 per 100 person-years) Bernstein, Clin Infect Dis 2013:56
HSV NAATs more sensitive than culture • N=508 participants with anogenital lesions at STD and family planning clinics • 260 HSV-2 and 73 HSV-1 infections identified • Tested with HSV NAAT (BD ProbeTec Qx) culture, PCR (quantitative viral load) Van der Pol, B JCM 2012: 55