Syphilis in patients with HIV

INTRODUCTION — Syphilis is a sexually acquired infection, which, if left untreated, is characterized by episodes of active clinical disease interrupted by periods of latent (asymptomatic) infection. 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.

This topic will review the epidemiology, clinical presentation, diagnosis, and treatment of syphilis in patients with HIV. Other topic reviews that discuss syphilis include:

●(See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV".)

●(See "Syphilis: Treatment and monitoring".)

●(See "Syphilis: Screening and diagnostic testing".)

●(See "Neurosyphilis".)

●(See "Syphilis in pregnancy".)

●(See "Congenital syphilis: Clinical manifestations, evaluation, and diagnosis".)

●(See "Congenital syphilis: Management and outcome".)

EPIDEMIOLOGY

Overview — 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].

Syphilis and HIV have similar modes of transmission, and infection with one may enhance the acquisition and transmission of the other. Thus, there is a high rate of HIV coinfection among MSM with syphilis [11-20]. 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).

In pregnant women, syphilis may have implications beyond that of congenital syphilis. As an example, maternal syphilis infection was associated with increased risk of mother-to-child transmission of HIV in a study performed in 155 pregnant women in Malawi [22]. Detailed discussions of congenital syphilis and mother-to-child transmission of HIV are found elsewhere. (See "Congenital syphilis: Clinical manifestations, evaluation, and diagnosis" and "Prevention of vertical HIV transmission in resource-limited settings".)

●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]. As examples:

•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].

Additional discussions of ART are found elsewhere. (See 'When to initiate antiretroviral therapy' below and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

CLINICAL MANIFESTATIONS — 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].

The clinical features that may be unique to patients with HIV are reviewed below. A more detailed discussion of the clinical manifestations seen in patients with syphilis is found elsewhere. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Clinical manifestations'.)

Early syphilis — The clinical manifestations of early syphilis include those associated with primary and secondary disease. The neurologic and ocular manifestations seen in early syphilis are reviewed separately. (See 'Neurologic/ocular syphilis' below.)

Primary syphilis — The first, or primary, stage of syphilis presents as a chancre, which is typically a painless, clean-based, well-demarcated lesion with firm, indurated margins. Regional lymph nodes tend to enlarge bilaterally, and are described as rubbery and nonpainful. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Primary syphilis (chancre)'.)

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). (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Secondary syphilis' and 'Neurologic/ocular syphilis' below.)

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. (See 'Neurologic/ocular syphilis' 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]. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Late syphilis'.)

●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]. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Late syphilis' and "Neurosyphilis", section on 'Late neurosyphilis'.)

Neurologic/ocular syphilis

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). (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Central nervous system'.)

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]. A more detailed discussion of how to diagnose neurosyphilis is found below. (See 'Diagnosis of neurosyphilis' below.)

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 — 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. A more detailed discussion of latent syphilis is presented elsewhere. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Latent syphilis (asymptomatic)'.)

DIAGNOSIS

General approach — The diagnosis of syphilis is made in the same fashion whether or not an individual is HIV infected. The diagnosis is usually a presumptive one based upon the results of serologic testing (nontreponemal testing such as the rapid plasma reagin [RPR], and treponemal testing such as fluorescent treponemal antibody absorption [FTA-ABS]). (See "Syphilis: Screening and diagnostic testing", section on 'Serologic testing algorithms'.)

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]. (See "Syphilis: Screening and diagnostic testing", section on 'Interpretation of serologic testing'.)

Direct methods (eg, darkfield microscopy, direct fluorescent antibody testing), which are used to visualize the organism, are not routinely available in clinical settings because they require special equipment and considerable experience and expertise to properly interpret the results. Thus, for most clinicians, such tests are now viewed as alternative diagnostic tools. However, in some settings (eg, a patient with malignant lues), a biopsy of a skin lesion with requests for silver staining may be useful to confirm the diagnosis [83]. (See "Syphilis: Screening and diagnostic testing", section on 'Direct methods for diagnosis'.)

Diagnosis of neurosyphilis

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. (See "Neurosyphilis", section on 'Diagnosis' and "Syphilis: Screening and diagnostic testing", section on 'Testing for neurosyphilis'.)

TREATMENT

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. (See 'Early syphilis' above and "Syphilis: Treatment and monitoring", section on 'Treatment after an exposure'.)

Treatment regimens

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. (See 'Response to therapy' below.)

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]. As examples:

●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 findings.

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 [103]. Thus, macrolides should not be used to treat early syphilis unless other recommended choices are not feasible, and they should be used in consultation with a knowledgeable specialist.

Patient monitoring

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'.)

Response to therapy

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. The approach to patients who do not achieve a fourfold decline in nontreponemal titer, or have an increase in the titer, is discussed below. (See 'Approach to treatment failure' below.)

Studies that have evaluated the association between HIV infection and poor serologic response following syphilis treatment have yielded conflicting results [106]. In one retrospective study that evaluated 129 patients with HIV and 168 patients without HIV but with syphilis attending a sexually transmitted diseases clinic, patients with HIV were less likely to have a fourfold drop in RPR titer and were more likely to take longer to achieve a successful serologic response [89]. Similarly, in a randomized controlled trial of enhanced therapy for early syphilis in patients with and without HIV, patients with HIV and primary and secondary syphilis were more likely than patients without HIV infection to have serologic treatment failure, although clinically defined failure was uncommon in both groups [42]. In this trial, titers declined more slowly in the patients with HIV, particularly those with primary syphilis and those with a previous history of syphilis.

However, the above studies were performed prior to the widespread use of effective combination antiretroviral therapy (ART). Subsequent studies have suggested that the risk of a poor serologic response in the setting of HIV infection may be attenuated by the use of ART or the absence of significant immunosuppression [34,107]. As an example, in a prospective study of 180 patients with HIV who experienced 231 cases of syphilis from 1990 through 2006, a total of 71 episodes of serologic failure were documented [34]. A CD4 count <200 cells/microL at the time of syphilis diagnosis was associated with an increased risk of serologic failure (adjusted hazard ratio [AHR], 2.88; 95% CI 1.26-4.88), whereas receipt of ART was associated with a 60 percent reduction in the rate of serologic failure (AHR, 0.40; 95% CI 0.21-0.75) independent of the CD4 cell response.

Approach to treatment failure — Standard definitions of treatment failure, regardless of HIV status, include: recurrence or persistence of symptoms; lack of a fourfold decrease in nontreponemal test titers at 12 months after treatment for early syphilis or 24 months after treatment of late syphilis or latent syphilis of unknown duration; or a sustained (>2 weeks) fourfold increase in nontreponemal test titers at any time after treatment [77].

In some cases, it can be difficult to determine if a patient has failed treatment or has a new infection. Maintaining communication with local or state health departments to verify a patient's latest reported titer and treatment record can assist in further evaluation.

●Reinfection should be suspected if the patient had an appropriate response to their initial treatment and there is evidence of a new infection (eg, a chancre or rash in the setting of a recent exposure). Such patients can be treated for early syphilis (table 1).

●If there is no evidence of new infection, treatment failure should be suspected and a lumbar puncture should be performed to evaluate for neurosyphilis. (See 'Diagnosis of neurosyphilis' above.)

•If the CSF examination is normal, treatment with benzathine penicillin administered as 2.4 million units intramuscularly at weekly intervals for three weeks is recommended [77].

•If the CSF is abnormal, then treatment for neurosyphilis would be indicated (table 1).

Antimicrobial regimens used for the treatment of syphilis are discussed in more detail elsewhere. (See "Syphilis: Treatment and monitoring".)

WHEN TO INITIATE ANTIRETROVIRAL THERAPY — Many patients with HIV will be on antiretroviral therapy (ART) at the time of their diagnosis. For such patients, ART should be continued, as ART may increase the likelihood that a patient will have an adequate response to therapy. (See 'Response to therapy' above.)

However, certain patients may be diagnosed with HIV at the same time they are diagnosed with syphilis. ART is recommended for all patients with HIV infection regardless of their CD4 count. For such patients, we initiate ART as soon as possible [88]. A discussion of how to select an ART regimen is found elsewhere. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

SCREENING AND PREVENTION

Screening — All persons with HIV should be tested for syphilis regardless of symptoms. The approach to syphilis screening in asymptomatic patients is the same for those with and without HIV. (See "Syphilis: Screening and diagnostic testing".)

Current recommendations advise that persons with HIV be tested for syphilis upon entry to HIV-related care, on a yearly basis, and more frequently as indicated by ongoing risk behaviors [83,88,108]. Risk behaviors associated with an increased likelihood of becoming infected with syphilis include [109]:

●Multiple sex partners

●Anonymous sex partners, including those met through the internet and circuit parties

●Engaging in sex in exchange for drugs or money

●Injection drug use or use of "club drugs"

Management after an exposure — Regardless of HIV status, persons exposed sexually to a patient who has syphilis in any stage should be evaluated clinically and serologically. In addition, some patients should be treated empirically for syphilis, regardless of the results of baseline testing. The management of a patient after a known syphilis exposure is presented elsewhere. (See "Syphilis: Treatment and monitoring", section on 'Treatment after an exposure'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opportunistic infections in adults with HIV" and "Society guideline links: Sexually transmitted infections".)

SUMMARY AND RECOMMENDATIONS

●Syphilis is a sexually acquired infection, which, if left untreated, is characterized by episodes of active clinical disease interrupted by periods of latent infection. (See 'Introduction' above.)

●Syphilis can facilitate transmission of HIV. Among men who have sex with men who have syphilis, there is a high rate of HIV coinfection. (See 'Epidemiology' above.)

●The clinical manifestations of syphilis in patients with HIV are generally the same as in those who are HIV uninfected (table 1). However, patients with HIV may be more likely to have multiple chancres and to have chancres present at the same time as symptoms of secondary syphilis. In addition, neurosyphilis may be seen more frequently in patients with HIV infection. (See 'Clinical manifestations' above.)

●The diagnosis of syphilis is often a presumptive one based upon the results of serologic testing. Direct methods (eg, darkfield microscopy, direct fluorescent antibody testing) are not routinely available in clinical settings because they require special equipment, and the results can be difficult to interpret. (See 'General approach' above.)

●Any patient who is diagnosed with syphilis and has clinical signs or symptoms suggesting neurologic, ocular, or otic involvement should be evaluated for neurosyphilis with a lumbar puncture. However, there is controversy as to whether asymptomatic patients with HIV and syphilis require cerebrospinal fluid evaluation. (See 'Diagnosis of neurosyphilis' above.)

●Patients with HIV and syphilis should be treated with the same regimens as those recommended for HIV-seronegative patients (table 1). However, the frequency of monitoring after treatment is greater in patients with HIV compared to those without HIV, since there is concern that patients with HIV infection are at increased risk of treatment failure. (See 'Treatment' above.)

●Certain patients may be diagnosed with HIV at the same time they are diagnosed with syphilis. Antiretroviral therapy is recommended for all patients with HIV infection, regardless of their CD4 count, and should be initiated as soon as possible. (See 'When to initiate antiretroviral therapy' above.)

●Persons with HIV should be tested for syphilis (regardless of symptoms) upon entry to HIV care, on a yearly basis, and more frequently as indicated by ongoing risk behaviors. (See 'Screening and prevention' above.)