on 26-Feb-2024 (Mon)

Manuals for LilyPond 2.24.3

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Some studies suggest that HIV infection may modulate the clinical presentation of syphilis (eg, greater organ involvement, atypical and florid skin rashes, more rapid progression to neurosyphilis), as well as the clinical and serologic response to syphilis treatment. Syphilis may also have a negative impact on the HIV viral load.

Although the rates of primary and secondary syphilis in the United States declined 90 percent from 1990 to 2000, the rates increased annually from 2001 to 2009.

From 2005 to 2014, the overall number of reported primary and secondary syphilis cases increased significantly from 8724 to 19,999 [ 1,2]. By 2018, the overall number of reported primary and secondary syphilis cases was 35,063, which is the highest rate reported since 1993 [3].

The rise in the rate of reported syphilis cases is primarily attributable to increased cases among men who have sex with men (MSM). The increasing incidence of syphilis among MSM is due in part to rising rates of risky sexual behaviors, such as anonymous sex, unprotected sex (oral and anal), sex with multiple partners, and/or sex under the influence of drugs, especially methamphetamine [4-10].

Available data from the United States Centers for Disease Control and Prevention suggest that approximately 42 percent of MSM with primary and secondary syphilis are HIV infected, compared with 8 percent of men who have sex with women and 4 percent of women [3]. In a study that was conducted among United States military personnel, 5.8 percent of 4239 patients with newly diagnosed HIV infection also had serologic evidence of syphilis infection [11].

Effect of syphilis on HIV — Genital ulcerative diseases, including primary syphilis, can facilitate both sexual and perinatal HIV transmission [12,13,21-24]. In addition, syphilis can have a negative impact on the immunologic (ie, CD4 count) and virologic status of patients with established HIV infection.

HIV transmission – Several studies have reported an increase in the incidence of HIV infection related to incident syphilis [21,23,24]. This was illustrated in a randomized trial evaluating the efficacy of HIV pre-exposure prophylaxis (PrEP), in which 2499 MSM and transgender women without HIV received tenofovir disoproxil fumarate-emtricitabine or placebo [21]. Although there was no difference in the syphilis incidence between the study arms, the incidence of HIV was significantly increased in those patients with incident syphilis (8.0 versus 2.8 cases per 100 person-years)

HIV parameters – Similar to other concomitant infections, such as tuberculosis or herpes simplex, syphilis may have a negative impact on the immunologic and virologic status of a patient with HIV infection [25-29].

In a hospital-based retrospective study, 282 men with HIV who were subsequently diagnosed with primary or secondary syphilis were compared with 1233 controls without syphilis who were matched for age, sexual orientation, and baseline HIV parameters. Compared with controls, patients with syphilis were more likely to have increases in HIV viral load during the period following a syphilis diagnosis (27.3 versus 16.6 percent), and the viral load increases were of greater magnitude (54,000 versus 11,318 copies/mL) [29]. Syphilis infection was associated with a greater risk of having an increase in viral load, even among men on antiretroviral therapy (ART) with a baseline viral load <500 copies/mL. CD4 cell counts also decreased transiently to a greater degree (mean decline 28 cells/microL) following the syphilis diagnosis, but subsequently returned to baseline levels

In a separate study that included 145 patients with HIV and a detectable plasma viral load, the highest cerebrospinal fluid (CSF) levels of HIV RNA were seen among those who had concurrent neurosyphilis, followed by those with serologic evidence of syphilis (but not neurosyphilis), and those without syphilis coinfection [30]. The authors of this study suggested that syphilis may amplify intrathecal HIV replication, possibly through immune activation

Although any increase in HIV viral load associated with syphilis infection can potentially increase the risk of HIV transmission, the clinical significance of these findings is unclear. In an analysis of prospectively collected information on 2239 persons with HIV (of whom 205 had confirmed syphilis), syphilis did not appear to affect HIV progression, despite transient changes in CD4 counts and viral loads [31]. In addition, there are conflicting data regarding the impact of syphilis on HIV viral load, as no association of early syphilis and changes in blood or semen viral load or CD4 count were found in a retrospective study of 63 patients with HIV and early syphilis [26].

Impact of antiretroviral therapy — Several studies suggest that persons with HIV taking potent ART may have better outcomes [32-35]:

● In a study of 231 patients with HIV and syphilis, use of potent ART before diagnosis reduced the odds of neurosyphilis by 65 percent [32].

● In a study that evaluated treatment outcomes of 110 patients with clinical or serologic evidence of syphilitic meningitis or syphilitic eye disease, 86 (78 percent) were HIV infected [33]. Among those with HIV infection, patients receiving ART were almost four times more likely to have normalization of CSF white blood cells and protein levels and 13 times more likely to have resolution of symptoms compared with those who were not receiving ART.

● Retrospective data suggest that immunologic recovery with ART is associated with lower rates of serologic failure [34].

Early in the HIV epidemic, aggressive and atypical clinical presentations of syphilis at each stage were published in case reports and series [36-38]. However, larger case control and cross-sectional studies have suggested that although some differences in clinical manifestations exist among individuals with HIV compared with those without HIV, clinical manifestations are for the most part similar at each stage, regardless of HIV serostatus (table 1) [39].

Although chancres are usually solitary, multiple chancres have been described more commonly in persons with HIV compared with those without HIV [40]. In one study that compared 25 patients with HIV to 114 patients without HIV, both the median number of ulcers and the percentage of patients with multiple ulcers were greater among those with HIV [36].

Secondary syphilis — Symptoms of secondary syphilis usually occur three to six weeks after the primary stage resolves. Hematogenous dissemination of treponemes early in infection can lead to the diffuse possible findings of secondary syphilis, including dermatologic, neurologic, and ocular manifestations (table 1).

For the most part, studies comparing patients with HIV and patients without HIV but with secondary syphilis have shown no difference in clinical stage at presentation or in severity of disease [36,37,41,42]. However a few differences have been described. As examples:

● In patients with HIV, the early stages of syphilis have been reported to overlap more frequently than in individuals without HIV [36,37]. Specifically, patients with HIV are more likely to have chancres at the same time as they manifest symptoms of secondary syphilis.

● Ulceronodular syphilis (also known as "malignant" lues) is a severe cutaneous form of syphilis (picture 1), which, although rare, has been described more frequently in patients with HIV [38,43-46]. Defective cell-mediated immunity may play an important role in the pathogenesis of malignant lues [47]. In one case report, skin examination revealed fungating, plaque-like lesions; histology demonstrated a dense, granulomatous, noncaseating infiltrate with plasma cells and histiocytes, absent of or with few spirochetes evident [46].

Other rare manifestations of secondary syphilis that have been described in both patients with and without HIV include osteitis/periostitis [48], arthritis, glomerulonephritis, hepatitis, and nephrotic syndrome [49-53].

Late syphilis — The clinical manifestations of late syphilis (often referred to as tertiary syphilis) include cardiac and gummatous lesions. Patients with late syphilis may also have neurologic findings, which are discussed separately below.

Late benign syphilis or gummatous syphilis – The gumma is a granulomatous inflammatory response to a small number of spirochetes. This can occur in any organ system, but the most common sites are in the skeletal, spinal, and mucosal areas.

Central nervous system (CNS) gummas have been reported in individuals with HIV and appear as enhancing lesions on magnetic resonance imaging [54,55]. While gummas generally take 4 to 10 years to develop after initial infection, more rapid progression from the primary chancre to gummatous lesions (eg, over a period of months) has been reported in some patients with HIV [54].

Cardiovascular syphilis – Manifestations of cardiovascular syphilis result from an endarteritis obliterans usually involving the vasa vasorum of the aorta. When the ascending aorta is involved, there may also be involvement of the aortic valve ring with aortic regurgitation and coronary artery stenosis. Cases of rapidly developing aortitis have been reported in persons with HIV [56,57].

Neurosyphilis — The term "neurosyphilis" refers to infection of the CNS. Traditionally, patients have been classified as having neurosyphilis only as a late manifestation of the disease. This is inaccurate, however, and neurosyphilis can occur at any time after initial infection.

There are many case reports of persons with HIV who have presented with neurosyphilis, and early neurological involvement may be more frequently seen in patients with HIV compared with those who are uninfected [51,58-70]. In a prospective study of 231 individuals with HIV and newly diagnosed syphilis, risk factors for developing neurosyphilis included a CD4 count of <350 cells/microL, a rapid plasma reagin titer >1:128, and male gender [32].

Patients with signs and symptoms of neurosyphilis should undergo a lumbar puncture (LP) to see if there is CNS involvement, as results are used to guide treatment and subsequent monitoring. Patients with neurosyphilis can present with neurologic, ocular, or otic manifestations. The specific clinical manifestations depend upon the stage of disease:

● Early neurologic clinical signs and symptoms are usually seen within a few months of infection and may include ophthalmologic (optic neuritis, uveitis), auditory, or cranial nerve abnormalities, as well as acute mental status changes, meningitis, and stroke. Some patients with HIV rapidly progress from early syphilis to clinical neurosyphilis [56], with concomitant symptoms of primary or secondary disease. A more detailed discussion of ocular disease is found below. (See 'Ocular syphilis' below.)

● Late neurologic disease is typically seen 10 to 30 years following infection. The most common forms involve the brain and spinal cord parenchyma (general paresis of the insane and tabes dorsalis).

Some patients with neurosyphilis may be asymptomatic. Such patients may have had an LP performed for treatment failure or for evaluation of neurosyphilis in the setting of a high serologic titer and are found to have cerebrospinal fluid (CSF) abnormalities (eg, mononuclear pleocytosis, increased protein concentration, and/or a reactive CSF Venereal Disease Research Laboratory [VDRL] slide test). In one study of 117 patients with HIV diagnosed with neurosyphilis, approximately 33 percent were asymptomatic [58].

Ocular syphilis — Syphilis may affect the eye at any stage of the infection. Although ocular syphilis is seen in both individuals with and without HIV, it has been reported more frequently among those with HIV [59,63-65,67,71,72]. As an example, in the United States, an outbreak of ocular syphilis was reported in California and Washington in December 2014; the majority of cases were among HIV-infected men who have sex with men, and several cases resulted in blindness [67]. In a series of 455 patients with HIV and syphilis, 13 percent had ocular syphilis as their primary manifestation [59].

Clinical symptoms of ocular syphilis can vary and may include decreased vision, redness, pain, photophobia, and floaters [73]. Ocular findings typically include uveitis or optic neuritis, although syphilis has been documented to affect almost every structure of the eye [74].

Ocular syphilis may occur with or without CNS involvement. All patients with ocular syphilis should be treated the same way as those with neurosyphilis; the presence or absence of CNS involvement impacts monitoring after therapy. (See 'Treatment' below.)

In three large studies of ocular syphilis, the majority of patients presented with various symptoms and had posterior uveitis and bilateral eye involvement [62,74,75]. Approximately 10 percent of affected patients had permanent visual impairment [73,74]. In a systematic review of 101 patients with HIV and ocular syphilis, approximately 40 percent presented with only visual symptoms, whereas over half had evidence of a rash consistent with secondary syphilis [76]. Posterior uveitis was significantly more common in individuals with a CD4 count <200 cells/microL. Three patients had a negative nontreponemal test at the time of diagnosis but had evidence of syphilis based upon a positive treponemal test.

Latent syphilis refers to the period during which patients infected with Treponema pallidum have no symptoms but have infection demonstrable by serologic testing. Such patients are usually diagnosed through routine screening. (See 'Screening' below.)

In the United States, this period has classically been separated into two categories:

● Early latent syphilis (if infection occurred within the last 12 months)

● Late latent syphilis (if infection occurred after 12 months)

It is often not possible to determine when a patient became infected (this is referred to as syphilis of unknown duration), and such individuals should be treated as late latent syphilis cases.

In general, most experts believe that serologic testing for syphilis can be interpreted in the same manner regardless of HIV status. However, on occasion, unusual serologic responses may be seen in persons with HIV who have syphilis [77]. Such responses can include unusually high serologic titers, false-negative tests, and the delayed appearance of seroreactivity [78-82].

Who should be evaluated for neurosyphilis — The following groups of patients with HIV should have a lumbar puncture (LP) performed to evaluate for neurosyphilis:

● Any patient who is diagnosed with syphilis and has clinical signs or symptoms suggesting neurologic, ocular, or otic involvement [77] (see 'Neurologic/ocular syphilis' above). Treatment should not be delayed while waiting for the LP results. (See 'Cerebrospinal fluid testing' below and 'Preferred regimens' below.)

● Patients diagnosed with syphilis who do not have an appropriate clinical or serologic response to initial therapy. (See 'Approach to treatment failure' below.)

There is controversy as to whether patients with HIV and syphilis should have cerebrospinal fluid (CSF) testing during their initial evaluation if they have no signs or symptoms of neurologic involvement. Our approach, which recommends an LP only in those patients who have neurologic symptoms, is consistent with the 2015 Centers for Disease Control and Prevention sexually transmitted diseases guidelines [77]. Treatment based upon CSF results in the absence of neurologic symptoms has not been associated with improved clinical outcomes. In addition, there are no prospective data assessing the risk of neurosyphilis in patients with early syphilis who have an appropriate decline of RPR titers after benzathine penicillin treatment.

By contrast, other experts (including some UpToDate authors) believe that nearly all patients with HIV and syphilis should have an LP regardless of symptoms, especially those with a CD4 cell count <350 cells/microL and an RPR >1:32 [84-86]. This approach is based in part upon concerns that some patients with HIV may not be able to clear the spirochete from central nervous system (CNS) sites [87]. The rationale for this approach is described in greater detail elsewhere. (See "Neurosyphilis", section on 'Diagnosis'.)

Cerebrospinal fluid testing — As neurosyphilis is notoriously difficult to diagnosis, clinicians rely on suboptimal indicators of CNS involvement. The diagnosis of neurosyphilis usually depends upon various combinations of reactive serologic test results, an abnormal CSF cell count or protein, and/or a reactive CSF Venereal Disease Research Laboratory (VDRL) test.

● The VDRL-CSF is highly specific for neurosyphilis. When this test is reactive in the absence of substantial contamination of CSF with blood, it is considered diagnostic of neurosyphilis.

● However, the VDRL-CSF is insensitive; thus, a negative result does not exclude neurosyphilis. Other testing that supports neurosyphilis in a patient with HIV includes:

• A CSF cell count >20 cells/microL. This threshold is higher than in patients without HIV infection (in whom a white blood cell count >5 cells/microL is suggestive of neurosyphilis) since patients with HIV infection may have a CSF pleocytosis due to HIV itself [86]. (See "Neurosyphilis", section on 'Diagnosis' and "Syphilis: Screening and diagnostic testing", section on 'Testing for neurosyphilis'.)

• A positive CSF FTA-ABS test, which, although less specific, is highly sensitive for neurosyphilis. Neurosyphilis is highly unlikely with a negative CSF FTA-ABS test.

Whom to treat — Patients should be treated for syphilis if they have serologic evidence of untreated infection. (See "Syphilis: Screening and diagnostic testing", section on 'Interpretation of serologic testing'.)

In addition, certain groups of patients should be treated empirically for early syphilis based upon clinical findings (eg, patients with a suspected chancre) or a known recent exposure (presumed incubating syphilis). Patients with primary syphilis may have a negative serologic test early in the course of infection. Empiric treatment is particularly important if a patient is unlikely to follow up.

Preferred regimens — The patient with HIV and syphilis should be treated with the same regimens as those recommended for HIV-seronegative patients (table 1) [77,88]. A baseline Venereal Disease Research Laboratory (VDRL) test or rapid plasma reagin (RPR) titer should be drawn on the day of treatment to help with subsequent monitoring.

Penicillin is the drug of choice for all stages of syphilis. The specific formulation of penicillin varies with the stage of syphilis. Long-acting benzathine penicillin given by intramuscular administration can be used for most stages of disease; however, intravenous therapy should be used for the treatment of ocular, otic, and central nervous system disease (table 1). In addition, patients with ocular syphilis should be comanaged with an ophthalmologist.

Studies have evaluated alternative dosing regimens (eg, extending or adding additional agents) for individuals with HIV since early data suggested that patients with HIV may be at increased risk for treatment failure and may be more likely to progress to neurosyphilis [42,56,89]. However, available data do not justify a change in existing treatment recommendations [42,90-92].

● An open-label randomized clinical trial compared the efficacy of single-dose and three-dose regimens of benzathine penicillin for treatment of early syphilis in 64 individuals with HIV. RPR titers were monitored every three months, and treatment success was defined as a decrease in RPR titers of >2 dilutions during 12-month follow-up [92]. Success rates were 93 percent in single-dose and 100 percent in three-dose arms, with no statistically significant differences between regimens.

● In an observational study of 393 cases of early syphilis that occurred among 350 individuals with HIV, patients were treated with benzathine penicillin; 141 were treated with a single dose, whereas the others were treated with more than one dose [90]. The vast majority of patients (92 percent) responded to treatment (defined as a ≥fourfold decline in nontreponemal titers at 13 months). The response was not affected by the number of benzathine penicillin doses the patient received (hazard ratio 1.11, 95% CI 0.89-1.4).

● A randomized study compared 2.4 million units of benzathine penicillin alone or with a 10-day course of amoxicillin plus probenecid in patients with early syphilis [42]. There were 541 patients enrolled, including 101 (19 percent) who had HIV infection. Enhanced treatment with amoxicillin and probenecid did not improve response to treatment at one year (ie, a decrease in the RPR titer by two or more dilutions or a change to a nonreactive test), regardless of HIV status.

● A retrospective study of 249 patients with early syphilis compared response to therapy (fourfold decrease in VDRL titer 12 months after treatment) of a single- versus a three-dose regimen of benzathine penicillin [91]. Of the patients evaluated, 84 were HIV infected, and the majority of such patients (80 percent) received treatment with three doses. Although there was a nonsignificant increase in the number of patients with HIV who responded to the three-dose regimen (97 versus 88 percent), higher quality evidence is needed to confirm these findi

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Alternative regimens — Alternative regimens for the treatment of syphilis primarily include doxycycline and ceftriaxone. The use of these regimens are discussed in detail elsewhere. (See "Syphilis: Treatment and monitoring", section on 'Alternative regimens for early syphilis' and "Syphilis: Treatment and monitoring".)

Patients who are treated with one of these alternative agents should be monitored closely since there are limited data on the efficacy of these agents, particularly in patients with HIV [93-99]. Data include a retrospective study of 116 patients with early syphilis (80 percent with HIV infection), in which those who received doxycycline, ceftriaxone, or penicillin G benzathine had a similar serologic response [98]. Another study that evaluated 24 patients with HIV and syphilis (primarily early syphilis) also found that ceftriaxone appeared to be a suitable alternative to penicillin [99].

Although data on azithromycin suggest comparable efficacy with penicillin G benzathine for the treatment of early syphilis [100,101], mutations associated with macrolide resistance appear to be highly prevalent in the United States, Western Europe, and China [102]. Such mutations can also be rapidly induced by the use of azithromycin for syphilis treatment [

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Jarisch-Herxheimer reaction — The Jarisch-Herxheimer reaction is an acute febrile reaction that usually occurs within the first 24 hours after any therapy for syphilis. HIV coinfection has not been associated with increased or more severe Jarisch-Herxheimer reactions [104]. A more detailed discussion of the Jarisch-Herxheimer reaction is found elsewhere. (See "Syphilis: Treatment and monitoring", section on 'Jarisch-Herxheimer reaction'.)

Frequency of monitoring — Patients with syphilis should be monitored closely after therapy regardless of their HIV status. However, the frequency of monitoring is greater in patients with HIV compared to those without HIV, as there is concern that patients with HIV infection are at increased risk of treatment failure [42,89].

A baseline VDRL or RPR titer should be drawn on the day of treatment. This titer is used for comparison with subsequent titers that are obtained after treatment to assess response. The same nontreponemal test run by the same laboratory is recommended for monitoring response to treatment.

The frequency of monitoring varies by stage:

● Early syphilis (primary, secondary, and early latent syphilis) – Patients with HIV and early syphilis should be evaluated clinically and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy [77].

● Late syphilis (tertiary syphilis, late latent syphilis), and latent syphilis of unknown duration – In patients with HIV and late syphilis, clinical and serologic follow-up evaluations should be performed at six-month intervals for a two-year period.

● Neurosyphilis – The approach to cerebrospinal fluid (CSF) monitoring depends upon the presence or absence of a CSF pleocytosis:

• In patients with neurosyphilis (including those with ocular or otic syphilis and a CSF pleocytosis or a positive CSF serologic test prior to treatment), CSF examinations should be repeated every six months until the cell count is normal. Resolution of the CSF pleocytosis is the most sensitive indicator of effective treatment in neurosyphilis.

If the CSF cell count does not normalize, either the CSF protein or CSF-VDRL can be followed. Retreatment is recommended if these parameters do not respond by two years. One study suggested that patients with CD4 counts <200 cells/microL were 3.7 times less likely to normalize CSF-VDRL results than were those patients with higher CD4 cell counts [105].

• In patients with ocular or otic syphilis and a normal CSF examination at the time of initial diagnosis, follow-up lumbar punctures are not needed.

Expected response — The expected serologic response to therapy depends upon the stage of disease. A fourfold change in titer, equivalent to a change of two dilutions (such as from 1:32 to 1:8), is considered an adequate therapeutic response if documented within a specific time frame:

● 6 to 12 months after treatment for early syphilis.

● 12 to 24 months after treatment for late syphilis and latent syphilis of unknown duration.

● The CSF (cell count and VDRL) are expected to normalize within two years after treatment in patients with neurosyphilis (in addition to achieving a serologic response).

Many patients who have an appropriate response to therapy will have complete loss of nontreponemal antibodies; however, some will have antibody titers that remain positive at a low level (ie, serofast). The clinical significance of the serofast state is unclear. At a minimum, these persons should receive additional clinical and serologic follow-up.