HIV and syphilis

Mark Kelly: Armidale Rural and Referral Hospital, Armidale NSW
Diane Rowling : Brisbane Sexual Health and HIV Service, Brisbane Qld
Cheryn Palmer : Princess Alexandra Sexual Health Service, Brisbane Qld

Syphilis may be asymptomatic and regular screening of at-risk patients is a critical public health strategy. Response to therapy is equivalent to that seen in patients without human immunodeficiency virus (HIV), although anecdotal reports of the failure of syphilis treatment in people with HIV infection have led to conservative guidelines both in treatment and follow-up. Controlled data are usually not available to support the more conservative guidelines.

Epidemiology

There is a bi-directional relationship between HIV transmission and syphilis that remains incompletely understood. Cross-sectional studies demonstrate that a history of syphilis or genital ulcer disease is associated with an increased risk of HIV infection.[1] Therefore, all patients with HIV should undergo syphilis testing and vice versa. Sexually active patients with HIV require regular screening for syphilis.

Changes in the prevalence of syphilis have mirrored changes in prevalence of HIV infection. High rates of syphilis recorded in homosexual men in the USA in the late 1970s coincided with unrecognised HIV transmission. Decreased rates of syphilis were observed after the introduction of safer sex HIV prevention campaigns during the 1980s. Rates of infectious syphilis reached a nadir in approximately 2000 in most developed countries including Australia.[2] Since that time, an increase in rates of early syphilis has been observed. Rates of notification of infectious syphilis rose 10 fold from 1999 to 2003 in inner Sydney.[3] A more recent study has demonstrated a 12-fold increase in infectious syphilis among men with HIV infection from 2001 and 2011.[4]

Multiple reasons for the observed increases in syphilis in men who have sex with men have been suggested.[5] An increase in unsafe sex underlies the increase in infectious syphilis, and this increase has been reflected in rising rates of other sexually transmissible infections in men who have sex with men.[6] Factors which have been suggested to cause this behavioural change include: the success of combination antiretroviral therapy (cART); use of the internet to source sex partners; serosorting (finding sex partners with the same HIV status); and the use of illicit (e.g. amphetamines) and licit (e.g. sildenafil) recreational drugs.[7] Finally, oral sex is established as an efficient method of syphilis transmission but not HIV infection. Oral lesions, which may be asymptomatic, are highly infectious. Cohort data suggest that changes in risk behaviour may favour syphilis versus HIV transmission.[8]

A role of early syphilis as a cofactor in the apparent increases in HIV infection in western men who have sex with men populations has been suggested by some but not all studies.[9]

Clinical manifestations

The majority of patients with HIV and syphilis co-infection present with typical manifestations of syphilis. Syphilis presents with protean manifestations while many patients are asymptomatic. There is some debate regarding the manifestations and progression of syphilis in patients with HIV; some studies have suggested an altered clinical presentation and rate of disease progression,[10] while other studies have shown no difference.[11][12] However, studies of syphilis in individuals with HIV before the introduction of cART are limited by the short-term survival of patients, and there are no longitudinal studies of syphilis manifestations following the introduction of cART. Anecdotal reports of unusual manifestations of syphilis in patients with HIV are likely to represent traditionally uncommon rather than unique complications of syphilis.[13]

Primary syphilis

The classic lesion of primary syphilis, the Hunterian chancre, is a single, painless, indurated ulcer with a clean base. Chancres are more likely to be larger, deeper and multiple in persons with HIV.[14][15] Chancres usually appear 14-21 days following infection, but may occur up to 90 days later. There is significant variability in the appearance of the chancre, which makes clinical diagnosis unreliable. Induration is the single most specific sign, and purulence involving less than 30% of the ulcer base is the most sensitive sign.[16] Classically, the margin is sharp. While the lesion is painless, tenderness upon palpation is common. Painless regional lymphadenopathy occurs in up to 80% of patients.

Chancres occur at the site of inoculation. The most common inoculation sites are the coronal sulcus, glans penis, anus and rectum in men, and the labia major, labia minor, fourchette and perineum in women. Extragenital lesions are uncommon and occur in less than 2% of patients. In contrast to genital lesions, extragenital chancres are classically nonindurated and painful.

Secondary syphilis

Typically, the primary lesion heals 8 weeks before the onset of secondary syphilis. However, primary and secondary manifestations of syphilis may coexist in up to one-quarter of patients with HIV infection with secondary syphilis.[17] Conversely, up to 60% of patients with secondary syphilis do not recall a primary lesion. Individuals with HIV are more likely to present with secondary syphilis than those without concurrent HIV infection.[18]

Clinical features of secondary syphilis include rash, fever, generalised lymphadenopathy and malaise. A widespread maculopapular rash is the cardinal feature. Involvement of the palms and soles is classically described. Painless lymphadenopathy involving suboccipital, posterior cervical, posterior auricular and epitrochlear nodes occurs in up to 85% of cases. Mouth ulcers, condyloma lata, alopecia, hepatitis, glomerulonephritis and nephrotic syndrome have been reported. Systemic symptoms include malaise, headache, nausea and anorexia. Arthralgia and jaundice have been reported in a subset of patients. Headache without meningism is commonly reported; however other neurological manifestations may also occur in persons with HIV. The occurrence of neurological symptoms portends a poorer prognosis. This is described as early neurosyphilis and is described later. Uveitis, iritis, cranial nerve dysfunction, tinnitus and hearing loss may also occur in early syphilis and are manifestations of neurosyphilis including ophthalmic and otic syphilis.

Rarely, after a prodrome of fever, malaise and headache, disseminated papular-nodular eruptions develop and evolve into pustules with ulcerated necrotic centres. This phenomenon is referred to as malignant secondary syphilis (lues maligna). An association between this rare manifestation of secondary syphilis and HIV infection has been suggested, as 11 of the 12 cases of malignant secondary syphilis reported since 1989 have occurred in people with HIV infection or those at high risk of HIV infection.[19] Classically, patients with this condition experience severe Jarisch-Herxheimer reactions (see below) following initiation of treatment.

Effect of early syphilis on CD4 cell count and HIV viral load

Early syphilis is associated with transient decreases in CD4 T-lymphocyte (CD4) cell count and increases in HIV viral load.[20] These markers return to baseline following treatment of syphilis. The significance of HIV surrogate-marker changes induced by early syphilis remains speculative. Increases in plasma viral load may contribute to the observed increases in HIV transmission in people with genito-ulcerative disease secondary to syphilis. There is no evidence that these transient alterations in HIV surrogate markers accelerate HIV disease progression. Unexplained alterations in these markers should prompt syphilis testing in people with HIV.[21]

Latent syphilis

The latent period of syphilis is defined as the period between the early symptomatic period (which may be unrecognised) and the development of tertiary manifestations. Serological evidence of syphilis in the absence of signs or symptoms is referred to as latent-stage disease. This period is divided into early latent and late latent periods. This distinction is made because of the likelihood of spontaneous mucocutaneous (and infectious) relapse in untreated patients.

About 25% of patients with untreated early symptomatic syphilis will experience a relapse: 90% of relapses occur within 1 year, 94% occur within 2 years and 100% occur within 4 years. Therefore, patients with early latent syphilis are considered infectious because they have about a 25% chance of relapse to secondary syphilis.[22]

In contrast, patients with late latent syphilis are not considered infectious and the primary aim of treatment in this context is to reduce the risk of disease progression. Although uncommon in the setting of HIV infection, congenital syphilis has occurred at all stages of syphilis infection. There are slight differences between international definitions of early and late latent disease.

Tertiary syphilis

Classically tertiary syphilis refers to parenchymal disease due to long-term inflammatory damage initiated by syphilis infection. This may involve disease of nervous system, cardiac valves or other space-occupying lesions. Anecdotal reports suggested that tertiary syphilis is more common, more likely to present with atypical signs and more rapidly progressive in patients with HIV infection compared with patients without HIV.[23][24][25] However, longitudinal comparative studies have not been performed. Asymptomatic neurosyphilis, defined as the presence of cerebrospinal fluid (CSF) abnormalities in the absence of neurological symptoms or signs, is the most common form of tertiary syphilis.[26] Meningovascular syphilis affects about 10% of patients with neurosyphilis and peaks at 4 to 7 years after infection. The typical clinical scenario is one of a diffuse encephalitic presentation with superimposed focal features.[27] Headache usually precedes the vascular injury.

Neurosyphilis

Spirocaetes invade the neurological system at all stages of syphilis in people with and without HIV infection. Classically neurosyphilis has been classified as either being early or late stage depending on pathological findings. Early neurosyphilis was characterised by meningovascular pathology whereas late neurosyphilis was characterised by parenchymal disease (see table 1). Clinical pathological correlation studies in contemporary HIV have not been conducted. Despite early case reports suggesting that neurosyphilis may be more common and more aggressive in persons with HIV infection,[28][29] it is not known if this is the case. Cohort studies have failed to demonstrate a difference between those with HIV and those without HIV infection. Surveillance studies found no increase in neurosyphilis from 1985 to 1992 despite increases in HIV infection in California.[30] However recent reports of neurosyphilis have generally occurred in people with HIV. No contemporary comparative studies have been conducted. One recent cohort study reported 41 cases of neurosyphilis in 231 cases of newly diagnosed syphilis in patients with HIV spanning a period of 16 years.[31] Immune dysfunction as indicated by both low CD4 cell count and absence of antiretroviral therapy predicted neurosyphilis (as did rapid plasma reagin (RPR)>1:32) in this cohort.

There are three distinct entities of neurosyphilis. These include early, asymptomatic and tertiary neurosyphilis. Ocular and otic syphilis are discussed in the following section to emphasise their importance in the setting of HIV infection; their usual presentation in early syphilis and similar treatment approaches of patients with neurosyphilis and those with ocular or otic syphilis are summarised in Table 1.

Table 1 Clinical classification of neurosyphilis.
  Manifestation
Early neurosyphilis   Affects meninges, CSF and vessels – weeks to few years following infection
  Neuroinvasion Organism detected in CSF
  Asymptomatic ENS Defined by CSF abnormalities
  Syphilitic meningitis Meningism, fevers and cranial nerve palsies
  Syphilitic meningovasculitis Meningitis with stroke (usually middle cerebral artery)
  Ocular and otologic syphilis Uveitis, sensioneural hearing loss, tinnitus, vertigo
Late neurosyphilis   Affects brain and spinal cord parenchyma – years to decades following infection
  Dementia paralytica (general paralysis of the insane) Rapidly progressive dementia with personality change
  Tabes dorsalis Spinal cord disorder – dorsal columns, sensory ataxia, bowel and bladder dysfunction, Argyll Robertson pupil

CSF: cerebrospinal fluid; ENS: early neurosyphilis

1. Early neurosyphilis

Early neurosyphilis (ENS) is defined as neurological disease occurring in persons with early syphilis.[32] It must be distinguished from uncomplicated secondary syphilis and thorough neurological examination including detailed examination of cranial nerve function is mandatory for all patients presenting with secondary syphilis. ENS is thought to primarily involve the meninges and blood vessels (meningovascular syphilis). Headache is an independent predictor of ENS in patients with HIV. One retrospective study indicated that patients with headache were 4.6 times more likely to have ENS than patients without headache.[33]

ENS is increasingly recognised as a serious complication of syphilis in people with HIV infection. The risk of having neurosyphilis in men who have sex with men with HIV who have early syphilis has been estimated to be 1-2%.[34][35] The risk of having persistent neurological deficit at 6 months despite treatment was estimated to be 0.5%. These data underscore the importance of preventing syphilis in men who have sex with men with HIV infection. Symptoms of ENS include cranial nerve dysfunction, acute meningitis, cerebrovascular accident (usually in the territory of the middle cerebral artery), headache or altered mental status of recent onset. Cranial nerve dysfunction occurs in more than 50% of cases. Ocular, auditory and facial nerves are most commonly affected. Ocular abnormalities, including optic neuritis and iritis, may also occur. These manifestations of syphilis should all be treated as for neurosyphilis.

ENS may be the only manifestation of syphilis in over 50% of patients. Therefore any men who have sex with men presenting with cranial nerve defects or other unexplained neurological deficit should be evaluated for syphilis and HIV.

Ocular syphilis

Ocular involvement has been reported in 4.6% of cases with secondary syphilis and 2.6% of persons presenting with uveitis have syphilis.[36] It is not known if patients with HIV are more likely to present with ocular manifestations of syphilis although some authors have suggested that this may be the case.[37] Patients with syphilitic uveitis present with decreased vision, redness, pain, photophobia, visual field defects and floaters. The most common ocular manifestations are anterior uveitis, vitritis and optic disc oedema. Retinitis, perioptic and retrobulbar neuritis are less commonly described.[38][39] Cutaneous manifestations can occur in up to 40% of patients with ocular syphilis. rapid plasma reagin (RPR) titres are generally high (> 1:16). CSF abnormalities have been reported in 30-70% of cases.[40][41] HIV testing should be offered in all patients who present with ocular syphilis. Delays in diagnosis can lead to irreversible vision loss secondary to optic nerve or retinal atrophy.[42]

Otologic syphilis

This complication may present with asymmetrical hearing loss, tinnitus or vestibular disturbances.[43] All patients diagnosed with syphilis should be assessed for otologic complications. Neurosyphilis treatment is recommended as permanent otological deficits can persist after benzathine treatment. It is not known if these manifestations are more common in people with HIV infection.

2. Asymptomatic neurosyphilis

It is estimated that between 10-25% of asymptomatic patients with HIV and late latent syphilis have CSF findings suggestive of neurosyphilis.[44][45] It is unclear if rates of asymptomatic neurosyphilis are increased in people with HIV infection. Two recent studies have suggested that syphilis may be associated with subsequent decreased cognitive function in those with HIV even accounting for significant confounders such as age, CD4 count and illicit drug use.[46][47] Most patients were assumed to have been treated for syphilis but details of their treatment were not reported. These studies suggest that rates of asymptomatic neurosyphilis in people with HIV and prior syphilis may be greater than generally accepted and may be clinically significant.[48]

Treponemal central nervous system penetration occurs in early syphilis in many patients regardless of HIV status however most patients do not develop neurological complications.[49] Most cases of early clinical neurosyphilis have been reported in people with HIV infection[50] and a correlation between CSF findings suggestive of neurosyphilis and advanced HIV disease[51][52] have lead to the hypothesis that HIV-induced immunological defects result in reduced treponemal CNS clearance with subsequent development of clinical neurosyphilis. This is supported by the observation that patients with HIV and CD4 cell counts less than 200 cells/μL were 3.7 times less likely to normalise CSF abnormalities after being treated for neurosyphilis than those with HIV infection and CD4 cell counts above 200 cells/μL.[53]

3. Tertiary neurosyphilis

Pathologically this type of neurosyphilis involves the blood vessels and brain parenchyma. The classic presentations include general paresis which is a chronic, insidious meningoencephalitis and tabes dorsalis which is a deficit of the posterior columns of the spinal cord causing sensory ataxia, bowel and bladder dysfunction.

Re-infection

Re-infection is possible with syphilis and is detected by an increasing non-treponemal assay titre (usually more than a four-fold rise).[54] Regular syphilis testing is recommended for all sexually active patients with HIV infection and prior syphilis to detect re-infection or relapse. It is difficult to distinguish re-infection from relapse of treated syphilis. This can usually only be done using molecular-based methodology which is generally not available in routine clinical practice.[55] A rare form of relapsing syphilis, chancre redux or monorecidive, has been described in which the chancre reappears in the same anatomical site in untreated or inadequately treated patients.[56]

Diagnosis

The diagnosis depends on clinical findings, examination of lesions for treponemes and serology. The diagnosis of syphilis is the same for patients with and without HIV infection.[57] Syphilis is usually diagnosed on serological grounds (Table 2). Detection of treponemes is reserved for cases where serological diagnosis cannot be confirmed. Treponemal polymerase chain reaction (PCR) on primary lesions may have a role in the diagnosis of early syphilis when serological assays may be falsely non-reactive. Serology should be repeated when early syphilis is suspected and initial screening is negative.

Table 2 Expected serology
  Untreated    Treated 
  Primary Secondary Early Late latent Recent Distant
EIA +/- + + + + +
Non-treponemal assay e.g. RPR +/- + + +/- +/- -
Treponemal assay e.g. TP-PA or FTA-Abs - + + + +* +*
+ = reactive; +/- = may or may not be reactive; - = usually non-reactive; * = treponemal titres may revert to non-reactive in up to 10% of patients EIA = enzyme immunosorbent assay; RPR = rapid plasmin reagin assay; TP-PA = Treponema pallidum particle agglutination test; FTA-Abs = fluorescent treponemal antibody absorption test.      

Detection of treponemes

Darkfield microscopy of lesion exudate was the previous gold-standard test for the diagnosis of lesions suggestive of syphilis. However its role is limited by the need for specialised equipment and training. It is also not useful for the diagnosis of oral or rectal lesions due to the possibility of contaminating non-pathogenic treponemal species. Syphilis PCR assays have been developed for lesional syphilis diagnosis and are now the most common assay used in this context. Sensitivity and specificity greater than 90% and 95% have been reported.[58][59]

Serological diagnosis of syphilis

Screening tests for syphilis involve enzyme immunosorbent assays (EIA), which have high sensitivity and specificity.[60] Syphilis EIA have higher sensitivity (93% v 86%) and equal specificity to traditional assays. There is an appreciable false-positive rate for syphilis EIA, especially in low prevalence settings. Rates of biological false-positive RPR tests are higher in patients with HIV (1-6%) compared with the general population (0.2-0.8%) and more common in injecting drug users with HIV infection.[61][62][63] Biological false positives are also increased in pregnancy.

Positive EIA are then confirmed by traditional serological syphilis assays, which are based on the combination of nontreponemal and treponemal assays. The nontreponemal serological screening tests (Venereal Disease Research Laboratory - VDRL) and RPR are reactive in secondary and untreated latent and tertiary syphilis. The sensitivity of serological tests for the diagnosis of syphilis increases with the duration of infection. It ranges from 75% in primary syphilis to 100% in secondary and later syphilis.[64] These assays perform equally well in patients with HIV infection. There is no conclusive evidence to suggest that patients with HIV infection are more likely to have false-negative results despite some isolated case reports over 2 decades ago.[65][66]

The most commonly used treponemal assays are the serum fluorescent treponemal antibody absorption test (FTA-Abs) and the microhaemagglutination test for Treponema pallidum particle agglutination (TP-PA). There are some data to suggest that nontreponemal titres are higher in patients with primary syphilis who also have HIV disease.[67] These results are not influenced by CD4 cell count. Patients with HIV who do not have suppressed viral replication may have higher nontreponemal titres although this is not well studied. Patients with HIV infection have higher titres of nontreponemal assays.[68] This may be secondary to the characteristic polyclonal B-cell activation that characterises HIV infection. However, the occurrence of a false-positive RPR is not related to the degree of immunodeficiency. RPR titres spontaneously revert to non-reactive in the majority of untreated patients.

Syphilis rapid (point-of-care [POC]) tests have been developed where finger-prick capillary blood (or plasma or serum) can be used. The result is available within 20 minutes. Two assays are commercially available in Australia. These assays detect only treponemal antibodies and will remain positive indefinitely and therefore are unable to distinguish between current and past infection. Furthermore reduced sensitivity of some assays in early syphilis require that such assays need to be supplemented with additional testing in populations where syphilis incidence is high to avoid missing early syphilis cases.[69] POC syphilis testing may play a role in out-break management and increase opportunistic testing in primary care. However these tests must be used in conjunction with other testing and knowledge of patient’s testing history.[70]

Clinicians should be aware of the prozone effect that may account for a false-negative RPR. This effect occurs when a high concentration of treponemal antigen does not permit antigen-antibody complex formation. It is corrected by diluting the sample to reveal a reactive RPR. As most laboratories do not routinely dilute serum in this context the clinician must specifically request dilution to detect a prozone effect.[71]

Treponemal reactivity may also be lost in patients with HIV disease, giving rise to biological false-negative results. In one study, loss of specific treponemal reactivity occurred in 10-14% of patients with HIV compared with no loss of reactivity in HIV-negative patients.[72] Loss of reactivity was associated with symptomatic HIV disease, a single episode of syphilis and a low initial VDRL titre (≤ 1:32). Time since treatment did not influence loss of treponemal reactivity rates. The role of syphilis EIA in identifying false-negative results is yet to be determined.[73] All patients with negative non-specific tests and positive specific tests should be treated if they have not received appropriate treatment in the past.

Three-monthly sexually transmissible infection screening is recommended for all sexually active men who have sex with men who have multiple partners or frequent sex on premises venues, in an attempt to curb the marked increase in sexually transmissible infections including syphilis and HIV.[74]

Diagnosis of neurosyphilis

Symptomatic or asymptomatic late latent (or unknown duration) syphilis

CSF analysis is required for the diagnosis of neurosyphilis. Lumbar punctures should be considered for all patients with neurological (including ophthalmologic and otic ) symptoms and positive serum syphilis serology and in all patients with HIV with asymptomatic late latent syphilis or syphilis of unknown duration.[75] Alternative approaches include targeting lumbar punctures in patients with neurological (including ophthalmic or otic manifestations) or otherwise asymptomatic patients who may be at higher risk of neurosyphilis (defined by CSF findings) as suggested by RPR. 1:32 or CD4 count < 200/L.[76] At least 10% of people with HIV infection with latent syphilis will have a positive CSF-VDRL, a specific marker for neurosyphilis.[77] Patients with symptomatic neurosyphilis have more CSF abnormalities than patients with asymptomatic neurosyphillis.[78]

Asymptomatic early syphilis

The definition of asymptomatic neurosyphilis has been problematic in persons with HIV infection with early syphilis. A presumptive diagnosis is made generally on the basis of CSF abnormalities.

CSF markers suggestive of neurosyphilis

The CSF abnormalities seen in neurosyphilis include an elevated lymphocyte count, increased protein and a reactive CSF VDRL. This latter assay has high specificity but lower sensitivity (22- 69%), so that the test may be negative in more than one-third of patients with neurosyphilis.[79] However, there is no consensus as to what particular CSF markers should be used to diagnose neurosyphilis. Most studies use CSF VDRL, which lacks sensitivity, and elevated white cell counts. CSF-FTA Abs and TP-PA have been suggested to be useful in some recent studies.[80][81] The intrathecally produced T. pallidum antigen index may be used to diagnose neurosyphilis when the CSF VDRL is negative.[82][83][84] Most recent studies have not included an elevated CSF protein in the definition of neurosyphilis because there are many other causes of high CSF protein in patients with HIV infection. It should be noted that an increased leukocyte count and increased protein in the CSF are observed in up to 40% of patients with HIV infection without co-existent syphilis. Some studies have defined CSF findings consistent with neurosyphilis as having a high white cell count (> 20 cells/hpf ) in an attempt to increase the specificity of the diagnosis of neurosyphilis.[85][86] Detection of treponemes in the CSF by PCR is currently not recommended due to the low sensitivity of the available assays.[87] Patients with RPR ≥ 1:32 were six times more likely than patients with RPR < 1:32 to have neurosyphilis.[88]

Recent studies have suggested that serum and CSF levels of CXCL13 may be increased in patients with neurosyphilis.[89] CSF CXCL13 was shown to be predictive of neurosyphilis in another small study however an absence of appropriate gold standards makes the findings of these studies difficult to interrupt.[90]

Prognostic significance of CSF abnormalities in asymptomatic patients with HIV infection with early syphilis

The prognostic significance of the CSF abnormalities has not been validated in persons with HIV infection, nor in those with early syphilis, in whom elevated protein and cell counts may occur, but may not develop clinical neurosyphilis.[91][92] In fact, no correlation between CSF abnormalities and clinical manifestations of neurosyphilis was observed in one study.[93] This report supported earlier studies that suggested that CSF findings in early syphilis did not predict the development of clinical neurosyphilis.[94][95] A weak correlation between CSF treponemal detection by PCR and CSF abnormalities was reported in one study,[96] while another study demonstrated a correlation between clinical neurological abnormalities and CSF abnormalities and serum RPR.[97]

There is debate in the literature regarding the association between neurosyphilis and CD4 cell count. Some studies have found that patients with low CD4 cell counts (< 350 cells/μL) are more likely to have CSF abnormalities suggestive of neurosyphilis[98][99] while other studies have not been able to confirm this association.

The role of lumbar puncture in asymptomatic patients with HIV infection with early syphilis

Given the uncertainties outlined above a variety of approaches exist. The exact approach taken, in large part, depends on the intended treatment plan.

A. Lumbar puncture in all asymptomatic patients with HIV and early syphilis

Some authors have recommended that all patients with HIV and syphilis should undergo lumbar puncture to identify those patients with asymptomatic neurosyphilis who are at risk of developing symptomatic neurosyphilis and require enhanced treatment (see below).[100][101]

B. No lumbar puncture in asymptomatic patients with HIV and early syphilis

This approach is supported by the observation that invasion of the CNS is common during this stage of the infection and the CNS findings are not predictive of the development of neurosyphilis.[102]

C. Lumbar puncture only in asymptomatic patients with HIV and early syphilis who are at high risk of neurosyphilis

Some authors have advocated targeting asymptomatic patients who have been identified to be at increased risk of neurosyphilis for lumbar punctures. Those found to have CSF findings suggestive of neurosyphilis should then receive intravenous penicillin based treatment (see later). Some authors suggest that patients with HIV infection with early syphilis and a CD4 cell count < 350 cells/μL and RPR > 1:32 should undergo lumbar puncture and receive treatment for neurosyphilis if CSF findings support this diagnosis.[103][104][105] However, this recommendation is not universally accepted.[106]

D. No lumbar puncture in patients with asymptomatic neurosyphilis but treat all patients with neuropenetrative penicillin

Alternatively, some advocate that all asymptomatic patients, regardless of CD4 count or RPR, should be treated with neuropenetrative penicillin (see later) avoiding the need for lumbar punctures in people with early neurosyphilis. Retrospective studies using this approach report response rates of over 98% and also high rates of adherence.[107] However the benefit of identifying patients with asymptomatic laboratory-defined neurosyphilis for enhanced penicillin treatment has not been proven. An earlier study using non-contemporary enhanced treatment for patients with early syphilis found no advantage in enhanced treatment over conventional treatment.[108] Although often cited, this study is limited by using non-standard penicillin therapy, lack of power, small numbers of people with HIV and high rates of loss to follow-up.

It is not known if the risk for the development of neurosyphilis can be further stratified by CD4 cell count or serum non-treponemal titre. While people with CD4 cell counts < 350 cells/μL and RPR > 1:32 are more likely to have CSF abnormalities suggestive of neurosyphilis,[109][110] there are no data to suggest that these patients are at increased risk of symptomatic neurosyphilis. These studies grouped patients with early and late syphilis together which may have overcalled those patients with significant CSF abnormalities. These studies were retrospective in nature and thus their findings are limited.

The lack of longitudinal data to support the use of enhanced treatment for neurosyphilis over conventional treatment for early syphilis in patients with HIV infection has lead some to reject these recommendations. Conversely proponents argue that there are no data to suggest that CSF-VDRL is less predictive of neurosyphilis in patients with early versus late syphilis. Similarly there are no data to suggest that a reactive CSF-VDRL in patients with early syphilis is likely to become nonreactive. Using the very strict definition of neurosyphilis (i.e. CSF-VDRL reactive): no asymptomatic patient with a serum RPR of less than 1:32 had a reactive CSF-VDRL and while 15/42 (36%) asymptomatic patients with an RPR ≥ 1:32 met the broader definition of neurosyphilis, 5/42 (12%) had a reactive CSF-VDRL.[111][112] Some have advocated that asymptomatic patients who may be at increased risk of early neurosyphilis should be treated with enhanced neuropenetrative therapy if a lumbar puncture is not undertaken.[113]

Treatment

Primary, secondary and early latent syphilis

There is great diversity among different published guidelines and practice for the treatment of early syphilis in patients with HIV (Table 3). A recent systematic review of treatment of syphilis has been limited by a paucity of data to inform treatment of early syphilis in persons with HIV.[114][115] While most international guidelines recommend a single dose of benzathine penicillin, surveys of infectious diseases physicians in the USA and Europe indicate the use of a more intensive regimen in patients with HIV.[116][117][118] Anecdotally most sexual health doctors in Australia do not use procaine penicillin-based therapy. This approach is largely due to perceptions regarding patient adherence, compliance and logistic problems relating to providing daily procaine penicillin dosing.

Table 3 Management of syphilis in non-penicillin allergic patients with HIV

Syphilis stage

Drug

Dose

Follow-up

Comments

Early

Primary Secondary  
Early latent

Procaine penicillin

 

1.0 - 1.5 g daily for 10 days1

Clinical and serological review at 3 ,6, 12, and 24 months

As for non-HIV patients

Benzathine penicillin

2.4 MU (=1.8g) IM x 1

Late

Late latent

Procainepenicillin

 

1.5 g IM daily for 10-14 days1

Clinical and serological review at 6, 12 and 24 months

LP recommended2

(NB: different from  non-HIV patients)

Benzathinepenicillin

2.4 (=1.8g) MU IM weekly x3

 

Non - neurological tertiary

As for late latent disease

As for late latent disease except duration  extended to 20 days

Clinical and serological review at 6, 12 

and 24 months

LP indicated

 

 

Neurosyphilis  (including ocular  disease)

Aqueous

penicillinG

3-4MU every

4 hours IV for 15 days

Clinicaland

serological review at 6,12 and 24 months

As for non-HIV patients

Failures have been reported in HIV patients treated with recommended doses

1  Probenecid 500 mg four times a day is added to increase penicillin levels

2  See text for discussion relating to the role of lumbar puncture in this clinical scenario

LP=lumbarpuncture; IM=intramuscularly; IV=intravenously.

Procaine penicillin

Procaine penicillin regimens (1.0 and 1.5 g plus probenecid 500 mg four times daily for 10 days) are well tolerated and adherence is easily achieved.[119] Numerous lines of evidence converge to support the use of procaine penicillin. High rates of early neurosyphilis (1.7%) with significant long-term sequelae despite treatment (0.5%) occur in persons with HIV.[120] This suggests that treatment should achieve treponemicidal CSF levels of penicillin in all patients with HIV infection with early syphilis. Procaine penicillin at doses > 0.5 g (i.e. > 5 000 000 units) intramuscularly daily with probenecid 500 mg four times daily has been demonstrated to achieve treponemocidal levels within the CSF.[121][122]

Conversely, anecdotal reports of neurosyphilis developing in patients with HIV despite treatment with benzathine penicillin for early syphilis (suggesting failure of this regimen)[123] and neurological relapse have been reported in up to 10% of patients with HIV with primary or secondary syphilis treated with benzathine penicillin.[124]

Arguments against this approach are that 75% of patients with early syphilis (who have been referred for lumbar puncture in retrospective clinical trials) do not have CSF findings suggestive of neurosyphilis and may not require enhanced treatment above a single dose of benzathine penicillin.[125][126] Furthermore some experts do not favour procaine penicillin on the basis of compliance difficulties, difficulties ensuring weekend administration of procaine penicillin and cost.

A compromise position has been suggested that asymptomatic patients with early syphilis who may be at increased risk of neurosyphilis should undergo CSF analysis (see earlier). Two retrospective studies have reported that patients with RPR > 1:32 have an increased risk of CSF, findings suggestive of neurosyphilis.[127][128] These authors suggest that patients with RPR > 1:32 (and/or CD4 cell count < 350 cells/μL) should undergo CSF analysis. With this approach, approximately 25% of patients will be found to have CSF findings suggestive of neurosyphilis and may benefit from intravenous penicillin therapy. Conversely 75% of patients would only require benzathine penicillin therapy. The Centers for Disease Control and other authors reject this approach.[129]

A recent retrospective trial of 17 days of procaine penicillin and probenecid in patients with HIV and early syphilis reported a response rate of 98% which is a significant improvement on rates of 78-93% reported in a recent systematic review.[130][131] Comparative trials between procaine penicillin and benzathine penicillin have not been performed.[132]

Benzathine penicillin

Some guidelines recommend benzathine penicillin (2.4 MU or 1.8 g intramuscularly once) for all patients with HIV and early syphilis.[133] However there are concerns that this treatment may be inadequate given the insufficient CSF penetration of benzathine penicillin and a recent review published in the Australian literature has suggested a more nuanced approach.[134] There have been reports of clinical failure following benzathine penicillin treatment.[135] Some authorities recommend giving benzathine penicillin weekly for 3 weeks to enhance the perceived inadequate neurological effect of a single dose of benzathine penicillin.[136] While no study has compared clinical outcomes, recent studies have reached conflicting conclusions regarding differences in serological responses in patients with HIV and syphilis who are treated with single versus multiple doses of benzathine penicillin.[137][138] Differences in the definition of serological response and confounding by re-infection have been suggested to account for the conflict. Countering the need to have enhanced therapy for patients with early syphilis is that to date we have not observed an increase in late neurological complications in patients with HIV receiving benzathine however this has not been systematically studied. One small study reported that none of 34 patients with HIV treated with benzathine penicillin for early syphilis had CSF abnormalities consistent with neurosyphilis after receiving therapy.[139] The interval between syphilis treatment and lumbar puncture was not reported. One patient however was excluded because of the development of headache, photophobia and neck stiffness thought to be secondary to re-infection. One of the 36 patients had elevated CSF WCC, 10/34 had elevated CSF protein and no patient had detected CSF RPR. CSF-VDRL was not reported. Further study with long-term clinical follow-up including assessment of cognitive function is warranted.

Oral penicillin regimens

One recent non-comparative, retrospective study reported response rates of greater than 95% in patients with HIV treated with oral amoxicillin and probenecid.[140] This treatment however is not recommended in international guidelines.

Penicillin desensitisation. As the role of non-penicillin-based therapy for syphilis has not been validated (see below), penicillin desensitisation is recommended in all patients with HIV with a history of non-anaphylactoid penicillin hypersensitivity. A variety of schedules are available.[141] Desensitisation should not be considered in persons with prior anaphylactoid reactions to penicillin and non-penicillin-based therapies should only be used in this context.

Non-penicillin-based regimens

  1. Doxycycline (100 mg twice daily for 14 days for early syphilis or 200 mg twice daily for 28 days for late syphilis).[142][143] These studies were not adequately powered to detect a difference in treatment response between patients with and without HIV infection. This regimen is not recommended for patients with HIV. Some however may consider this regimen in patients in whom penicillin desensitisation fails.
  2. Ceftriaxone (1 g intramuscularly for 10 days) has also been used to treat early syphilis.[144][145][146] On the basis of pharmacokinetic data alone, a single dose of ceftriaxone would not be expected to provide adequate therapy for early syphilis.[147] Ceftriaxone (2 g intravenously) daily for 10 to 14 days has been suggested as an alternative to penicillin for neurosyphilis.[148] An open-labelled study compared ceftriaxone with standard intravenous penicillin in patients with CSF abnormalities consistent with neurosyphilis. Serological responses were similar in both groups. Higher rates of prior neurosyphilis in the intravenous penicillin group and higher rates of secondary syphilis in the ceftriaxone group may have obscured a difference in treatment responses.
  3. Azithromycin can no longer be considered, given high rates of resistance, and high levels of treatment failure compared with penicillin-based therapy.[149][150][151]

Jarisch-Herxheimer reaction

This is an acute systemic reaction that occurs 2 to 6 hours after the initial dose of penicillin. It is thought to be secondary to the release of treponemal antigens and endotoxin, although the exact pathogenesis is unknown.[152] It is characterised by fever, malaise, arthralgia and worsening rash. It has been reported to occur at variable rates from 10-80% of patients.[153] Patients with HIV infection are twice as likely to experience Jarisch-Herxheimer reaction than patients without HIV infection.[154] This reaction is more commonly observed in patients with early syphilis and in patients with high RPR titres. Prednisone has been advocated by some to reduce the incidence and severity of the Jarisch-Herxheimer reaction (particularly in those with neuro-, otic- or ophthalmic syphilis) however the evidence to support this approach is limited.

Late latent syphilis

The recommended treatment is procaine penicillin 1-1.5 g intramuscularly daily and probenecid 500 mg four times daily for 15 days or benzathine penicillin 2.4 MU intramuscularly weekly for three doses.

The recommendations for prolonged therapy in patients with late latent syphilis are made for two reasons. Prolonged therapy is required in latent syphilis, because it is assumed that spirochetes are dividing more slowly during this phase of the illness and that treponemicidal CSF levels of penicillin are required to ensure adequate treatment and to prevent neurosyphilis. Previously, standard therapy for late latent syphilis was benzathine penicillin (2.4 MU intramuscularly weekly for 3 weeks). However, based on the failure to demonstrate treponemicidal levels of penicillin after the administration of benzathine penicillin,[155] as well as anecdotal reports of failure of this regimen, treatment with daily procaine penicillin is preferred. However, it should be noted that these recommendations are not based on clinical trial data. Follow-up serology to demonstrate a four-fold decrease in titre remains important for all patients.

Neurosyphilis

The Centers for Disease Control recommended treatment in patients without HIV infection is aqueous benzylpenicillin (4 MU every 4 hours for 15 days intravenously), or procaine penicillin (2.4 g intramuscularly daily) and probenecid (500 mg four times daily) for 20 days. While there is no consensus in the literature regarding the appropriate treatment of neurosyphilis in patients with HIV, most Australian experts would use intravenous penicillin. Similar treatment approaches are recommended for ocular and otic syphilis.

Neuropenetrative therapy

All patients with historical penicillin allergies should be referred for penicillin desensitisation. While a number of non-penicillin-based regimens have been used, there are little data to support their use in persons with HIV infection. Lumbar puncture is mandated to exclude neurosyphilis and provide a baseline of CSF markers to assess response to treatment.[156] Patients and clinical staff should be aware of the need for careful clinical follow-up in patients with HIV infection who receive non-penicillin-based regimens to treat syphilis.

Assessing treatment response

The assessment of an adequate response to treatment in syphilis is generally the same for patients with HIV infection and those without HIV infection. Clinical failure is defined as the persistence of clinical manifestations 3 months after appropriate therapy, or the development of a new clinical manifestation following therapy. Patients who experience clinical failure require CSF analysis and should receive a second round of treatment.

An appropriate serological response to syphilis treatment is more difficult to define. A four-fold decline in RPR titre over a 6-12 month period is considered satisfactory in patients with and without HIV infection. Serological failure has been recently reported to occur in up to 40% of patients with HIV treated for syphilis.[157] Patients with low CD4 cell counts and those not receiving antiretroviral therapy were more likely to experience serological failure in this study.

Patients with high baseline nontreponemal titres are more likely to be defined as having treatment failure on serological grounds independent of HIV status.[158] Previously reported increased rates of treatment failure on serological grounds in persons with HIV infection treated for early syphilis were likely to be secondary to an apparent slower decline from high baseline nontreponemal titres and to be of no clinical significance. A persistent low level (< 1:8) nontreponemal titre occurs more commonly in patients with HIV.[159] This is not thought to be clinically significant. There are no data to suggest that such patients benefit from further treatment.

A satisfactory response to treatment of neurosyphilis involves resolution of symptoms, a four-fold reduction in serum nontreponemal titres and a normalisation of CSF pleocytosis by 6 months and all other CSF parameters by 24 months.[160] Unsatisfactory treatment responses to neurosyphilis have been reported in up to 30% of patients.[161] CSF serological response to therapy and normalisation of CSF markers for asymptomatic neurosyphilis have been slower in patients with HIV infection versus those without HIV in some uncontrolled studies.[162][163][164]

CSF re-evaluation and retreatment are indicated in patients with persistent or new clinical disease, rising titres or failure of initially high, nontreponemal-specific titres (≥ 1:32) to decrease by 12 to 24 months after therapy. In light of the observation of the delayed serological responses to syphilis treatment in persons with HIV, some authors have suggested that serological responses should be observed for 12 months for early syphilis and 24 months for late syphilis before considering treatment has failed.[165]

Contact tracing

Early identification and treatment of partners of patients with HIV and syphilis potentially limits the spread of both infections. Given high rates of syphilis among men who have sex with men with HIV and the significant rates of early neurosyphilis in this group, renewed efforts to contact trace are warranted in an attempt to reduce the transmission of both infections and reduce the incidence of permanent neurological morbidity in men who have sex with men with HIV following early syphilis. Presumptive treatment is recommended for any sexual contact within the past 90 days of a person with early syphilis. Treatment is one dose of benzathine penicillin 2.4 MU intramuscularly. If the contact was more than 90 days ago, presumptive treatment is not necessary unless follow-up is problematic. There is increasing use of the internet to assist contact tracing using internet-based sexual networks by public health agencies.[166] Alternatively, individuals can leave anonymous messages for contacts (e.g. www.whytest.com.au). These people should be offered testing for HIV and other sexually transmissible diseases.[167]

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