Guidelines for Prevention and Treatment of Opportunistic Infections

Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents Syphilis Slide Set Prepared by the AETC National Resource Center based on recommendations from the CDC, National Institutes of Health, and HIV Medicine Association/Infectious Diseases Society of America

About This Presentation These slides were developed using recommendations published in May 2013. The intended audience is clinicians involved in the care of patients with HIV. Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly. Finally, it is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent. – AETC National Resource Center http: //www. aidsetc. org 2 May 2013 www. aidsetc. org

Syphilis: Epidemiology § Caused by Treponema pallidum § Associated with increased risk of HIV sexual acquisition and transmission § Increased incidence in men who have sex with men § HIV infection may somewhat alter diagnosis, natural history, and management of syphilis, but principles of management are the same with or without HIV infection 3 May 2013 www. aidsetc. org

Syphilis: Clinical Manifestations § HIV may make clinical lesions more apparent and accelerate progression of syphilis § Primary syphilis § Painless nodule at site of contact, rapidly ulcerates (chancre) § In HIV-infected patients, may see multiple or atypical chancres, or no primary lesion 4 May 2013 www. aidsetc. org

Syphilis: Clinical Manifestations (2) Chancres of primary syphilis Credit: Centers for Disease Control and Prevention 5 May 2013 www. aidsetc. org

Syphilis: Clinical Manifestations (3) § Secondary syphilis (2 -8 weeks after primary inoculation) § Protean symptoms, may involve almost any organ system and include: § Rash (macular, maculopapular, papulosquamous, or pustular); or condyloma lata § Generalized lymphadenopathy § Constitutional symptoms (fever, malaise, anorexia, arthralgias, headache) § CNS symptoms § Symptoms last days-weeks § In advanced HIV infection, may be more severe or progress more rapidly § Distinguish from primary HIV infection 6 May 2013 www. aidsetc. org

Syphilis: Clinical Manifestations (4) Rash of secondary syphilis Credit: Centers for Disease Control and Prevention 7 May 2013 www. aidsetc. org

Syphilis: Clinical Manifestations (5) § Latent syphilis: no overt signs/symptoms (but serologic evidence of syphilis), though relapse of manifestations of secondary syphilis may occur § Late syphilis: cardiovascular syphilis, gummatous syphilis; or slowly progressive disease in any organ system 8 May 2013 www. aidsetc. org

Syphilis: Clinical Manifestations (6) Neurosyphilis: May occur at any stage of syphilis, with various symptoms § Cranial nerve dysfunction, stroke, meningitis, acute or chronic mental status change, loss of vibration sense, auditory or ophthalmic abnormalities, similar in HIV-uninfected patients § Concomitant uveitis and meningitis more common in HIV-positive patients 9 May 2013 www. aidsetc. org

Syphilis: Diagnosis § Direct detection of T pallidum § Darkfield microscopy of mucocutaneous lesion, DFATP, biopsy with silver stain § Presumptive serologic diagnosis tests § Nontreponemal serologic tests (VDRL, RPR) § Treponemal tests (eg, FTA-ABS, TP-PA, EIAs, chemiluminescence immunoassays) 10 May 2013 www. aidsetc. org

Syphilis: Diagnosis (2) § Testing algorithms: § Traditional: screening for nontreponemal antibodies + confirmation of reactive tests by treponemal assay § Newer: screening with treponemal test (EIA or CIA), with reflex nontreponemal test if positive § May identify previously treated syphilis infection more often than untreated infection § If positive treponemal screening test and negative reflex nontreponemal test: second treponemal test should be done (using different antigens) to confirm § If second treponemal test is positive: assess risk factors and prior syphilis treatment § If suspected primary syphilis: treat empirically, retest with nontreponemal test in several weeks to confirm diagnosis § If no evidence of primary syphilis: treat for late-latent syphilis (unless past treatment can be confirmed) § If second treponemal test is negative: no treatment indicated 11 May 2013 www. aidsetc. org

Syphilis: Diagnosis (3) § Early-stage disease: § Nontreponemal serologic tests (VDRL, RPR) may show atypical responses (higher, lower, or delayed) in HIV-infected patients § False-negative tests possible (as in HIVuninfected patients); pursue other diagnostic tests if high suspicion of syphilis (eg, repeat serology, biopsy, DFA of lesion material; exclude prozone phenomenon) 12 May 2013 www. aidsetc. org

Syphilis: Diagnosis (4) § Latent syphilis: § Serologic tests positive but no clinical manifestations § Early latent: evidence of infection <1 year § Late latent: evidence of infection >1 year or duration is not known 13 May 2013 www. aidsetc. org

Syphilis: Diagnosis (5) § Late-stage disease: § Cardiovascular and gummatous: same as for HIV-uninfected patients 14 May 2013 www. aidsetc. org

Syphilis: Diagnosis (6) § Neurosyphilis: § All with syphilis (regardless of stage) should be evaluated for clinical evidence of CNS or ocular involvement § CSF exam should be done for any patient with: § Neurologic, auditory, or ophthalmic symptoms or signs § Tertiary syphilis § Treatment failure (on basis of serologic tests) § CSF abnormalities (elevated protein, mononuclear pleocytosis) common in early syphilis and in HIV, without neurologic symptoms: no evidence that clinical and prognostic significance is different in HIV-infected and HIV-uninfected with early syphilis 15 May 2013 www. aidsetc. org

Syphilis: Diagnosis (7) § Neurosyphilis: § No single test used to diagnose; instead, various combinations of reactive serologic tests, CSF cell count and protein, and reactive CSF-VDRL with or without clinical manifestations support the diagnosis 16 May 2013 www. aidsetc. org

Syphilis: Diagnosis (8) § Neurosyphilis: § CSF examination § Mild mononuclear pleocytosis (6 -200 cells/µL), normal or mildly elevated protein § CSF VDRL § Specific; not sensitive (reactive test establishes neurosyphilis; nonreactive test does not exclude it) § CSF FTA-ABS § Highly sensitive; less specific (reactive test does not establish the diagnosis; nonreactive test excludes neurosyphilis) § PCR-based methods not recommended 17 May 2013 www. aidsetc. org

Syphilis: Diagnosis (9) § Neurosyphilis testing, considerations: § Reactive CSF VDRL plus CSF WBC ≥ 10 cells/µL supports diagnosis of neurosyphilis § Mild mononuclear CSF pleocytosis (6 -15 cells/µL) may be associated with HIV infection itself and may complicate diagnosis of neurosyphilis; using cutoff of >20 cells/µL may improve specificity of neurosyphilis diagnosis in HIV-infected patients § Elevated CSF protein concentration should not be used as sole diagnostic criterion 18 May 2013 www. aidsetc. org

Syphilis: Preventing Exposure § Risk screening should be routine § Client-centered risk-reduction messages; give specific actions to reduce risk of acquiring STIs and for transmitting HIV § Routine serologic testing for syphilis at least annually; Q 3 -6 months if multiple partners, unprotected intercourse, injection drug or methamphetamine use, or partners with risks § Consider referral for behavioral intervention § Evaluate for other STIs 19 May 2013 www. aidsetc. org

Syphilis: Preventing Disease § For persons exposed sexually to someone with syphilis: evaluate clinically and serologically and treat presumptively § Persons exposed within the 90 days preceding diagnosis of primary, secondary, or early-latent syphilis in a sex partner may be infected even if tests are seronegative: treat presumptively § Persons exposed >90 days before diagnosis of primary, secondary, or early-latent syphilis in a sex partner: treat presumptively if serologic test results are not available immediately and follow-up is uncertain 20 May 2013 www. aidsetc. org

Syphilis: Treatment § Management similar to that for HIV-uninfected persons, but rates of serologic treatment failure and neurologic complications may be higher in HIV infection; closer follow-up is recommended § Penicillin is treatment of choice § Patients with penicillin allergy whose compliance or follow-up cannot be ensured: desensitize and treat with penicillin § Use alternatives to penicillin only with close clinical and serologic monitoring § Azithromycin resistance and treatment failure; especially in men who have sex with men (MSM) 21 May 2013 www. aidsetc. org

Syphilis: Treatment (2) Early stage (primary, secondary, early-latent) § Preferred: § Benzathine penicillin G 2. 4 million units IM, single dose § Alternative (for penicillin-allergic patients; monitor closely): § Doxycycline 100 mg PO BID for 14 days § Ceftriaxone 1 g IM or IV QD for 10 -14 days § Azithromycin 2 g PO for 1 dose (note: reports of treatment failure and resistance; should not be used in MSM or pregnant women) 22 May 2013 www. aidsetc. org

Syphilis: Treatment (3) Late-latent (no signs of neurosyphilis) § Preferred: § Benzathine penicillin G 2. 4 million units IM weekly for 3 weeks § Alternative (for penicillin-allergic patients): § Doxycycline 100 mg PO BID for 28 days (not thoroughly evaluated in HIV-infected patients; monitor closely) Late-stage (cardiovascular or gummatous) § CSF examination; consult ID specialist § Preferred: Benzathine penicillin G 2. 4 million units IM weekly for 3 weeks 23 May 2013 www. aidsetc. org

Syphilis: Treatment (4) Neurosyphilis, otic syphilis, ocular syphilis § Preferred: § Aqueous crystalline penicillin G, 18 -24 million units daily, as 3 -4 million units IV Q 4 H or continuous infusion for 10 -14 days § Consider addition of benzathine penicillin 2. 4 million units IM weekly for 3 weeks after completion of IV therapy § Alternative: § Procaine penicillin G 2. 4 million units IM QD + probenecid 500 mg PO QID for 10 -14 days § Consider addition of benzathine penicillin 2. 4 million units IM weekly for 3 weeks after completion of above § Patients with sulfa allergy should not receive probenecid, so this regimen is not recommended for them § Penicillin allergy: § Desensitization to penicillin is preferred; if not feasible, ceftriaxone 2 g IM or IV QD for 10 -14 days 24 May 2013 www. aidsetc. org

Syphilis: Starting ART § No special considerations, no evidence that ART should be delayed until after treatment for syphilis § IRIS is uncommon § Use of ART associated with: § Decreased risk of serologic failure of syphilis treatment § Lower risk of neurosyphilis § Normalization of CSF parameters after treatment 25 May 2013 www. aidsetc. org

Syphilis: Monitoring and Adverse Events § Monitor clinical and serologic response to treatment; assure at least 4 -fold decline from titer done at time of treatment: § Early stage: at 3, 6, 9, 12, 24 months § Late-latent: at 6, 12, 18, 24 months § Consider treatment failure: persistence or recurrence in clinical signs and symptoms or sustained 4 -fold increase in nontreponemal test titer § Neurosyphilis: if CSF pleocytosis present initially, repeat CSF exam at 6 months; also repeat if symptoms recur or nontreponemal titer increases by 4 -fold § Consider retreatment if no decrease in CSF WBC by 6 months or if WBC not normal by 2 years 26 May 2013 www. aidsetc. org

Syphilis: Monitoring and Adverse Events (2) § After successful treatment, nontreponemal tests may remain “serofast, ” ie, reactive at stable titer, usually low (≤ 1: 8) § Sustained ≥ 4 -fold increase in titer indicates reinfection 27 May 2013 www. aidsetc. org

Syphilis: Monitoring and Adverse Events (3) § Jarisch-Herxheimer reaction may occur in the first 24 hours after start of syphilis treatment § Fever, headache, myalgia § Manage symptoms with antipyretics § Most frequent in those with early syphilis, high nontreponemal titers, and prior penicillin treatment 28 May 2013 www. aidsetc. org

Syphilis: Treatment Failure Early stage § Consider CSF evaluation and retreatment if: § ≤ 4 -fold decrease in serum nontreponemal test titer 6 -12 months after therapy, or § Sustained 4 -fold increase in titer after initial 4 -fold reduction after treatment, or § Persistent or recurring signs or symptoms of syphilis § Reinfection is difficult to document and treatment failure is difficult to rule out § If no appropriate titer response after CSF evaluation and retreatment, management is unclear § >15% of early syphilis patients (HIV infected and uninfected) do not have 4 -fold decline in titer after treatment 29 May 2013 www. aidsetc. org

Syphilis: Treatment Failure (2) Early stage § Retreatment: benzathine penicillin G, 2. 4 million units weekly for 3 weeks (if neurosyphilis present, treat for that) 30 May 2013 www. aidsetc. org

Syphilis: Treatment Failure (3) Late-latent stage § Repeat CSF exam and retreat if: § Clinical signs or symptoms of syphilis, or § Sustained 4 -fold increase in titer after initial reduction after treatment, or § ≤ 4 -fold decrease in serum nontreponemal test titer within 12 -24 months after therapy § Treatment: benzathine penicillin G, 2. 4 million units weekly for 3 weeks (if neurosyphilis present, treat for that) 31 May 2013 www. aidsetc. org

Syphilis: Treatment Failure (4) Neurosyphilis § Consider retreatment if: § CSF WBC count has not decreased 6 months after completion of treatment, or § CSF WBC count is not normal 2 years after treatment 32 May 2013 www. aidsetc. org

Syphilis: Preventing Recurrence § Secondary prevention and maintenance therapy not indicated 33 May 2013 www. aidsetc. org

Syphilis: Considerations in Pregnancy § Screening: § At 1 st prenatal visit in all women; in high-prevalence areas or high-risk women, repeat early in 3 rd trimester and at delivery § Transmission to the fetus and adverse pregnancy outcomes highest with early-stage syphilis § Pregnancy does not alter the clinical course or diagnostic test results of syphilis in adults § Syphilis associated with increased risk of perinatal HIV transmission to infants 34 May 2013 www. aidsetc. org

Syphilis: Considerations in Pregnancy (2) § Use penicillin, if possible, as in nonpregnant HIV-infected adults § Penicillin is effective for preventing syphilis transmission to the fetus and for treatment of fetal infection § Optimal penicillin regimen is not clear § In early syphilis, consider second injection of benzathine penicillin G 1 week after first dose § No alternatives to penicillin proven effective and safe for treatment of syphilis during pregnancy or prevention of fetal infection § Pregnant women with syphilis and history of penicillin allergy should undergo desensitization and treatment with penicillin 35 May 2013 www. aidsetc. org

Syphilis: Considerations in Pregnancy (3) § Jarisch-Herxheimer reaction in 2 nd half of pregnancy may precipitate preterm labor or fetal distress § In 2 nd half of pregnancy, sonographic evaluation for fetal or placental syphilis § Consult with OB specialists § After treatment, repeat serologic titers in 3 rd trimester and at delivery § Insufficient data on serologic responses after therapy § Treatment likely inadequate if delivery ≤ 30 days of treatment, if woman has sign of infection at delivery, or if maternal titer is 4 -fold higher than pretreatment titer 36 May 2013 www. aidsetc. org

Websites to Access the Guidelines § http: //www. aidsetc. org § http: //aidsinfo. nih. gov 37 May 2013 www. aidsetc. org

About This Slide Set § This presentation was prepared by Susa Coffey, MD, for the AETC National Resource Center in June 2013 § See the AETC NRC website for the most current version of this presentation: http: //www. aidsetc. org 38 May 2013 www. aidsetc. org