Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents Disease Specific Recommendations Syphilis Epidemiology       Recent reports indicate a resurgence of infections with Treponema pallidum, the etiologic agent of syphilis, among men in several U.S. cities and in Western Europe, possibly because of relaxed safer sex practices of those who view HIV-1 infection as a disease manageable if not curable with effective ART (309--314). HIV-1 infection appears to alter the diagnosis, natural history, management, and outcome of T. pallidum infection . This section focuses on specific guidelines for the management of syphilis among HIV-1--infected patients. A more comprehensive review of the recommendations for the treatment of syphilis is available . Clinical Manifestations The impact of HIV-1 infection on syphilis pathogenesis, disease severity, response to treatment, and long-term sequelae is not well documented. As among HIV-uninfected persons, primary syphilis commonly presents as a single painless nodule at the site of contact that rapidly ulcerates to form a classic chancre; however, among HIV-infected persons, multiple or atypical chancres occur, and primary lesions might be absent or missed. Progression to secondary syphilis generally follows 2--8 weeks after primary inoculation and reflects ongoing replication and dissemination of T. pallidum in the absence of an effective host immune response. Although more rapid progression or severe disease might be present among HIV-1--infected persons with advanced immunosuppression, the clinical manifestations are similar to those among HIV-uninfected persons. The manifestations of secondary syphilis are protean, involving virtually all organ systems. The most common manifestations appear to be macular, maculopapular, or pustular skin lesions (or condyloma lata in moist genital or intertriginous areas), usually beginning on the trunk and spreading peripherally, characteristically involving palms and soles and accompanied by generalized lymphadenopathy and constitutional symptoms of fever, malaise, anorexia, arthralgias, and headache. Secondary syphilis, particularly acute syphilitic meningitis, must be distinguished from acute primary HIV-1 infection. The previously described constitutional symptoms, along with nonfocal CNS symptoms and CSF abnormalities (e.g., lymphocytic pleocytosis with a mildly elevated CSF protein) are common to both   The signs and symptoms of secondary syphilis might persist from a few days to several weeks before resolving or evolving to latent or later stages. As among HIV-uninfected patients, latent syphilis is not associated with overt clinical signs and symptoms, but relapse of manifestations of secondary syphilis might occur, most commonly in the first 1--4 years following infection. Manifestations of "late" syphilis generally include neurosyphilis, cardiovascular syphilis, and gummatous syphilis, but might present as slowly progressive disease that can affect any organ system. Certain manifestations of neurologic complications or neurosyphilis progress more rapidly or occur earlier in the course of disease among persons with HIV-1 infection and are not truly late complications or manifestations. Asymptomatic neurosyphilis, which might be the most commonly described syndrome, is defined as the absence of symptoms but with one or more abnormalities of CSF (i.e., elevated protein, lymphocytic cellular infiltrate, or positive serologic tests). Manifestations of symptomatic neurosyphilis (i.e., meningitis or meningovascular or parenchymatous disease) among HIV-1--infected persons will probably be similar to those in the HIV-uninfected population. However, concomitant uveitis and meningitis might be more common among HIV-1--infected patients with syphilis. Diagnosis The diagnosis of syphilis depends on a variety of tests that either directly detect the organism (e.g., darkfield microscopy or direct fluorescent antibody-Treponema Pallidum (DFA-TP) or serum antibodies against it (e.g., FTA-ABS and TP-TA), or indirectly indicate the presumptive presence of T. pallidum by detecting nontreponemal antibodies generated during infection (e.g., VDRL and RPR). Clinical experience indicates that concurrent HIV-1 infection probably does not change the performance of standard tests for the diagnosis of syphilis, but this concern has not been formally studied. Early-stage disease (i.e., primary, secondary and early-latent syphilis) among HIV-1--infected patients is confirmed by the identical procedures used for the HIV-uninfected populations (darkfield microscopy of a mucocutaneous lesion sample and standard serologic tests). HIV-1 infection does not decrease the sensitivity or specificity of darkfield microscopy. Results of serologic tests (i.e., VDRL and RPR) might be atypical (i.e., higher, lower, or delayed) among HIV-1--infected versus HIV-uninfected patients with early-stage syphilis, but no data indicate that treponemal tests perform differently among HIV-1--infected compared with uninfected patients. Similar to HIV-uninfected persons, false-negative serologic tests have been reported among HIV-1--infected patients with documented T. pallidum infection. Therefore, if the clinical suspicion of syphilis is high and serologic tests do not confirm the diagnosis, other diagnostic procedures (e.g., biopsy, darkfield examination, or direct fluorescent antibody staining of lesion material) should be pursued. By definition, patients presenting with latent syphilis have serological evidence of disease in the absence of clinical or other laboratory abnormalities (i.e., normal CSF profiles). Patients with early-latent syphilis by definition have documented infection of <1 year; patients with late-latent syphilis have documented infection for >1 year, or the duration of infection is not known. The diagnostic testing for detection of late-stage disease (e.g., cardiovascular and gummatous syphilis) among HIV-1--infected patients is the same as for the HIV-uninfected population. Diagnosis of neurosyphilis is established by examination of the CSF, which might indicate mild mononuclear pleocytosis (10--200 cells/µL), normal or mildly elevated protein concentration, or a reactive CSF-VDRL. The CSF-VDRL is specific but not sensitive, and a reactive test establishes the diagnosis of neurosyphilis but a nonreactive test does not exclude the diagnosis. In comparison, CSF treponemal tests (e.g., the CSF FTA-ABS) are sensitive but not specific, and a nonreactive test excludes the diagnosis of neurosyphilis, but a reactive test does not establish the diagnosis. Calculated indices (e.g., ITPA-index) are of limited value in establishing the diagnosis of neurosyphilis. PCR-based diagnostic methods are not recommended as a diagnostic test for neurosyphilis. A reactive CSF-VDRL and a CSF WBC >10 cells/µL support the diagnosis of neurosyphilis; the majority of specialists would not base the diagnosis solely on elevated CSF protein concentrations in the absence of these other abnormalities. HIV-1 infection itself might be associated with mild mononuclear CSF pleocytosis (5--15 cells/µL), particularly among persons with peripheral blood CD4+ T lymphocyte counts >500 cells/µL. Establishing the diagnosis of neurosyphilis might be more difficult among such persons. If neurosyphilis cannot be excluded by a nonreactive CSF treponemal test, such persons should be treated for neurosyphilis, despite the acknowledged uncertainty of the diagnosis. Treatment Recommendations Management of HIV-1--infected patients with syphilis is similar to the management of HIV-uninfected persons with the disease. However, closer follow-up is recommended to detect potential treatment failures or disease progression. All patients with syphilis, regardless of disease stage, should be evaluated for clinical evidence of CNS or ocular involvement. Those with neurologic or ocular symptoms or signs should undergo CSF examination to rule out neurosyphilis. HIV-1--infected patients with late-latent syphilis, including those with syphilis of unknown duration, also should undergo CSF examination. Certain specialists recommend CSF examination for all HIV-1--infected patients with syphilis, regardless of stage. Similar to the HIV-uninfected population, HIV-1--infected patients with active tertiary syphilis (i.e., aortitis and gumma) or who fail treatment for non-neurologic syphilis should undergo CSF examination. Patients with CSF abnormalities consistent with neurosyphilis should be treated for neurosyphilis. HIV-1--infected persons with early-stage (i.e., primary, secondary, or early latent) syphilis should receive a single intramuscular (IM) injection of 2.4 million units of benzathine penicillin G (AII). Alternative therapies, including oral doxycycline, ceftriaxone, and azithromycin, have not been sufficiently evaluated in HIV-1--infected patients to warrant use as first-line treatment. If the clinical situation requires the use of an alternative to penicillin, treatment should be undertaken with close clinical monitoring (BIII). In a randomized clinical trial, amoxicillin administered with probenecid, which increases CSF amoxicillin levels, did not improve clinical outcome of early stage disease and is not recommended  (DII). In HIV-1--infected patients with late-latent syphilis for whom the CSF examination excludes the diagnosis of neurosyphilis, treatment with three weekly intramuscular injections of 2.4 million units benzathine penicillin G is recommended (AIII). Alternative therapy with doxycycline 100 mg by mouth twice a day for 28 days has not been sufficiently evaluated in HIV-1--infected patients to warrant use as first-line treatment. If the clinical situation requires the use of an alternative to penicillin, treatment should be undertaken with close clinical monitoring (BIII). HIV-1--infected patients with clinical evidence of late-stage (tertiary) syphilis (cardiovascular or gummatous disease) should have a CSF examination to rule out neurosyphilis before initiating therapy (AIII). The complexity of tertiary syphilis management is beyond the scope of these guidelines and providers treating tertiary disease are advised to consult an infectious disease specialist (AIII). HIV-1--infected patients with clinical or laboratory evidence of neurosyphilis (i.e., CNS involvement including otic and ocular disease, even with a normal CSF) should receive intravenous aqueous crystalline penicillin G, 18--24 million units daily, administered 3--4 million units IV every 4 hours or by continuous infusion for 10--14 days (AII) or procaine penicillin 2.4 million units IM once daily plus probenecid 500 mg orally four times a day for 10--14 days. (BII).  HIV-1--infected patients who are allergic to sulfa-containing medications should not be administered the IM alternative because they are very likely to be allergic to probenecid (DIII). IM procaine penicillin without probenecid does not achieve sufficient penicillin levels in CSF to treat neurosyphilis. Because neurosyphilis treatment regimens are of shorter duration than those used in late-latent syphilis, certain specialists recommend following neurosyphilis treatment with 3 weeks of benzathine penicillin, 2.4 million units IM weekly. However, no consensus has been reached about the need for this practice (CIII). Among penicillin allergic patients, penicillin desensitization followed by one of the penicillin regimens listed previously is the preferred approach (BIII). However, limited data indicate that ceftriaxone (2 g daily IV for 10--14 days) might be an alternative regimen (CIII). Monitoring and Adverse Events Clinical and serologic responses to treatment of early stage (i.e., primary, secondary, and early-latent) disease should be monitored at 3, 6, 9, 12, and 24 months after therapy. Serologic responses to treatment might differ among HIV-1--infected patients compared with HIV-uninfected persons, including temporal pattern of response and proportion of subjects achieving serologically defined treatment success (at least a fourfold decrease in titer). After successful treatment for syphilis among HIV-1--infected and uninfected patients, some might remain "serofast," meaning that serum nontreponemal test titers remain reactive at low and unchanging titers, generally <1:8, for extended periods of time (up to the lifetime of the patient). The clinical significance of the serofast state is unclear, but it probably does not represent treatment failure. Serologic detection of potential re-infection should be based on at least a fourfold increase in titer above the established serofast baseline. Response to therapy of late-latent syphilis should be monitored using nontreponemal serologic tests at 3, 6, 12, 18, and 24 months to ensure at least a fourfold decline in titer. Two retrospective studies reported that concomitant HIV-1 infection was associated with poorer CSF and serologic responses to neurosyphilis therapy  Repeat CSF examination should be performed at 3 and 6 months after completion of therapy and then every 6 months until the CSF white blood cell count is normal and the CSF-VDRL is nonreactive. Because of the complex nature of neurosyphilis, treatment should be undertaken in consultation with an infectious disease specialist. Management of Treatment Failure Re-treatment of patients with early stage syphilis should be considered for those who 1) do not experience at least a fourfold decrease in serum nontreponemal test titers 6--12 months after therapy, 2) have a sustained fourfold increase in serum nontreponemal test titers after an initial reduction after treatment, or 3) have persistent or recurring clinical signs or symptoms of disease (BIII). If CSF examination does not confirm the diagnosis of neurosyphilis, such patients should receive 2.4 million units IM benzathine penicillin G administered at 1-week intervals for 3 weeks (BIII). Certain specialists have also recommended a course of aqueous penicillin G IV or procaine penicillin IM plus probenecid, as described for treatment of neurosyphilis above, in this setting (CIII). If titers fail to respond appropriately after re-treatment, repeat CSF evaluation or re-treatment might not be beneficial (CIII). Patients with late-latent syphilis should have a repeat CSF examination and be retreated if they have clinical signs or symptoms of syphilis, have a fourfold increase in serum nontreponemal test titer, or experience an inadequate serologic response (less than fourfold decline in nontreponemal test titer) within 12--24 months of therapy (BIII). If the CSF examination is consistent with CNS involvement, re-treatment should follow the neurosyphilis recommendations (AIII); those without a profile indicating CNS disease should receive a repeat course of benzathine penicillin, 2.4 million units IM weekly for 3 weeks (BIII), although certain specialists recommend following the neurosyphilis recommendations in this setting (CIII). Re-treatment of neurosyphilis should be considered if the CSF WBC count has not decreased after 6 months after completion of treatment, or if the CSF-VDRL remains reactive 2 years after treatment (BIII). Secondary Prevention and Maintenance Therapy No recommendations have been developed indicating the need for secondary prophylaxis or prolonged chronic maintenance antimicrobial therapy for syphilis in HIV-1--infected patients. Special Considerations During Pregnancy All pregnant women should be screened for syphilis at the first prenatal visit. In areas where syphilis prevalence is high or among women at high risk (e.g., uninsured, women living in poverty, commercial sex workers, and injection-drug users), testing should be repeated at 28 weeks of gestation and at delivery. All women delivering a stillborn infant after 20 weeks of gestation should also be tested for syphilis. Syphilis screening should also be offered at sites providing episodic care to pregnant women at high risk including emergency departments, jails, and prisons. No infant should leave the hospital without documentation of maternal syphilis serology status during pregnancy  The rate of transmission and adverse outcomes of untreated syphilis are highest with primary, secondary, and early latent syphilis during pregnancy and decrease with increasing duration of infection thereafter. Pregnancy does not appear to alter the course, manifestations, or diagnostic test results of syphilis infection among adults. The diagnosis should be made the same as among nonpregnant adults. Concurrent syphilis infection might increase the risk for perinatal transmission of HIV-1 to the infant, although an increased risk has not been consistently reported . Treatment during pregnancy should consist of the same penicillin regimen as recommended for the given disease stage among nonpregnant, HIV-1--infected adults. Because of treatment failures reported after single injections of benzathine penicillin among HIV-uninfected pregnant women, certain specialists recommend a second injection 1 week after the initial injection for pregnant women with early syphilis . Because of additional concerns about the efficacy of standard therapy in HIV-1--infected persons, a second injection 1 week after the first for HIV-1--infected pregnant women should be considered (BIII). No alternatives to penicillin have been proven effective and safe for treatment of syphilis during pregnancy or for prevention of fetal infection. Pregnant women who have a history of penicillin allergy should be referred for skin testing and desensitization and treatment with penicillin.(AIII).  Erythromycin does not reliably cure fetal infection; tetracyclines should not be used during pregnancy because of hepatotoxicity and staining of fetal bones and teeth (EIII). Efficacy data with azithromycin or ceftriaxone are insufficient to support a recommendation for their use in this setting (DIII). A Jarisch-Herxheimer reaction occurring during the second half of pregnancy might precipitate preterm labor or fetal distress . Consideration should be given to providing fetal and contraction monitoring for 24 hours after initiation of treatment for early syphilis of pregnant women who are >20 weeks of gestation, especially in the setting of abnormal ultrasound findings indicative of fetal infection (BIII). Alternatively, women should be advised to seek obstetric attention after treatment if they notice contractions or a decrease in fetal movement. Repeat serologic titers should be performed in the third trimester and at delivery for women treated for syphilis during pregnancy. Titers can be conducted monthly for women at high risk for reinfection. The clinical and antibody response should be appropriate for the stage of disease, although the majority of women will deliver before their serologic response can be definitively assessed.