Review. Syphilis and HIV: a dangerous combination. For personal use. Only reproduce with permission from The Lancet

Review Syphilis and HIV Syphilis and HIV: a dangerous combination Complete Table of Contents W A Lynn and S Lightman HIV and syphilis affect simila...
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Review

Syphilis and HIV

Syphilis and HIV: a dangerous combination Complete Table of Contents W A Lynn and S Lightman

HIV and syphilis affect similar patient groups and coinfection is common. All patients presenting with syphilis should be offered HIV testing and all HIV-positive patients should be regularly screened for syphilis. Syphilis agent may enhance the transmission of the other, probably through increased incidence of genital ulcers. Detection and treatment of syphilis can, therefore, help to reduce HIV transmission. Syphilis may present with non-typical features in the HIV-positive patient: there is a higher rate of symptomless primary syphilis and proportionately more HIVpositive patients present with secondary disease. Secondary infection may be more aggressive and there is an increased rate of early neurological and ophthalmic involvement. Diagnosis is generally made with serology but the clinician should be aware of the potential for false-negative serology in both primary and, less commonly, in secondary syphilis. All HIV-positive patients should be treated with a penicillinbased regimen that is adequate for the treatment of neurosyphilis. Relapse of infection is more likely in the HIV-positive patient and careful follow-up is required. Lancet Infect Dis 2004; 4: 456–66

Syphilis and HIV are both transmitted sexually and so it is no surprise that a substantial number of people are infected with both agents. HIV has several effects on the presentation, diagnosis, disease progression, and therapy of syphilis.1 Syphilis may increase the risk of HIV transmission and acquisition by causing genital ulcers.2 Genital ulcer disease is linked to increased risk of HIV infection and is most commonly due to herpes simplex virus (HSV) in both HIV positive and negative patients.3 Syphilis continues to affect large numbers throughout much of the world and the past 5 years has seen a number of outbreaks. HIV makes it more likely for syphilis to present with non-typical features.4 Thus, it is important for medical practitioners to be aware of how syphilis may present in patients with underlying HIV infection and its implications for treatment and follow-up. Controversy has surrounded the area of HIV and syphilis co-infection. Some have argued that syphilis has a different clinical presentation and is more aggressive in people with HIV; others suggest there is little difference. There are differences in the interpretation of serological tests for syphilis in the HIV positive but how often does this matter clinically? Finally, some recommend that all HIVpositive patients should be treated as if they had neurosyphilis regardless of the stage at which they present, although the feared epidemic of neurological involvement

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has not materialised. This article will try to answer some of these questions by reviewing the epidemiology, diagnosis, clinical features, and management of syphilis in people infected with HIV. Congenital syphilis was reviewed in the Lancet Infectious Diseases in 2002 and will not be discussed here in detail.5

Epidemiology WHO estimates that approximately 349 million people are actively infected with a treatable sexually transmitted disease.6 Of these, estimates from 1999 suggest an annual rate for syphilis of approximately 12 million active infections.6 Almost two-thirds of these cases are in subSaharan Africa and south/southeast Asia. Recent outbreaks have been reported from many countries on all continents.7–10 In sub-Saharan Africa between 2 and 17% of women test positive for syphilis in antenatal clinics and rates of HIV co-infection are very high. In North America and western Europe the incidence of syphilis is much lower at less than 5/100 000 of the population or less.4,6 There was steady decline in the incidence of syphilis in both Europe and the USA during the second half of the last century, leading to suggestions that endemic syphilis might even be eradicated in these countries.4,11 The past few years, however, have seen an upsurge in syphilis in Europe and isolated outbreaks in North America.1,12,13 The reasons underlying this reversal are complex but include migration of people from high-prevalence countries, population mixing, changes in risk behaviour including the use of the internet to meet partners, use of recreational drugs, and a reduction in safe sex practices in gay men.13 In the UK the incidence of syphilis fell dramatically through the 1980s to less than 1/100 000 of the population. A rise in syphilis incidence has been seen since 1996 with most cases occurring in young men. Over the same time period there has also been an increase in new HIV diagnoses in the UK increasing the likelihood of HIV and syphilis coinfection (figure 1). In 2002 syphilis rates for men in England and Wales ranged from 0·5/100 000 in rural areas to more than 2/100 000 in metropolitan districts with particularly high rates in Brighton, Manchester, and London.14,15 There has been a smaller but still significant rise WAL is at the Institute of Ophthalmology, Moorfields Eye Hospital, London, UK; and both authors are at the Department of Infectious Diseases, Ealing Hospital, Southall, Middlesex, UK. Correspondence: Dr W A Lynn, Infection and Immunity Unit, Ealing Hospital, Southall, Middlesex UB1 3HW, UK. Tel +44 (0)208 967 5120; fax +44 (0)208 967 5677; email [email protected]

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in syphilis in women with by far the A 3500 greatest number of cases reported Sex between men from London. An enhanced syphilis Sex between men and women 3000 surveillance programme run by Injecting drug use Blood/tissue the UK Health Protection Agency 2500 Mother to infant indicated that, in 2002, 57% of Other/undetermined 2000 reported cases were from gay men, a proportion of whom are co-infected 1500 with HIV.15,16 More detailed analysis 1000 of the outbreak in Manchester highlighted unprotected oral sex 500 as a major risk factor for syphilis 10 transmission amongst gay men. 0 Many of these men followed safe sex practices including the use of condoms for anal intercourse but were Year of diagnosis B unaware that syphilis could be orally 10 transmitted. 45 5 being studied, along with individual 4 risk factors. Blocker and colleagues17 3 reviewed 30 studies that looked at HIV rates in people with syphilis in the 2 USA. They reported an overall 1 median seroprevalence for HIV of 0 15·7% (27·5% in men and 12·4% in women). This gave an odds ratio for having HIV of 8·8 for men and 3·3 for Men Women women presenting with syphilis.17 Furthermore, much higher rates of Figure 1. Number of new HIV-positive cases per year in the UK (A) and yearly syphilis rates by sex HIV co-infection were detected in and age (B). Courtesy of the UK Health Protection Agency. relation to specific risk factors, for example intravenous drug use (22·5–70·6%) and gay sex Control (CDC) on the incidence of syphilis in 40 US states (68–90%).17 In one Spanish study of 1161 HIV-positive over a 14-year period.21 There was a 90% reduction in patients followed-up for 38 months the baseline syphilis syphilis cases between 1990 and 2000. Mathematical seroprevalence was 13% and a further 4% acquired syphilis modelling suggested that AIDS-related mortality was in follow-up.18 The German AIDS Study Group found 151 responsible for between one-third and half of this reduction. cases of active syphilis in 11 368 HIV-positive patients Chesson and colleagues postulate that the decline in HIV (1·33%).19 Of the 151 active cases 17·2% were primary mortality since the development of antiretroviral therapy, syphilis, 36·4% secondary syphilis, 16·6% neurosyphilis, and coupled with continued high-risk sexual behaviour in HIV25·2% latent syphilis. These figures cannot be applied to all infected people22,23 may be responsible for recently reported populations due to variation in underlying prevalence rates rises in syphilis transmission. Syphilis, through genital ulcer disease, may increase and risk factors but stress the high rates of co-infection and ongoing risk of disease acquisition. All patients presenting the risk of HIV transmission.2,24,25 For example, one with a sexually transmitted infection should be offered HIV mathematical model has suggested that approximately 1000 testing and given advice on HIV prevention. Similarly all additional cases of heterosexual HIV transmission occur people presenting with HIV should be screened for syphilis annually in the USA as a result of syphilis.26 Using syphilis and re-screened regularly during follow-up. Reinfection and HIV co-infection data from black Americans in 2000, with syphilis may occur and all patients should receive Chesson et al27 have calculated that 545 cases of HIV advice on safe sexual practices. Current UK recommend- transmission were facilitated by syphilis in couples ations are for annual serological testing for syphilis in all discordant for HIV. The additional health cost of the 545 HIV-infected people with consideration for more frequent potentially preventable HIV infections was estimated at US$113 million. These data come from the USA where the screening in the event of a local disease outbreak.20 The close interaction between HIV and syphilis prevalence of syphilis is much lower than in many countries epidemiology is illustrated by Chesson and colleagues’ with a high burden of HIV infection. These data emphasise analysis of available data from the US Centers for Disease the need to include the surveillance, prevention, and 14

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Table 1. Sensitivity and specificity of serological tests in syphilis in HIV-negative people

Non-specific Specific

Test RPR VDRL TPHA MHA-TP FTA-ABS

Primary sensitivity (%) 86 80 80 76 84

Secondary sensitivity (%) 100 100 100 100 100

Tertiary sensitivity (%) 70 75 95 95 96

Specificity (%) 98 98 99 99 98

RPR=rapid plasma regain; VDRL=venereal disease research laboratory; TPHA=Treponema pallidum haemagluttination assay; MHA-TP=microhaemagluttination assay— T pallidum, FTA-ABS=fluorescent treponemal antibody absorption test. Adapted from GR Kinghorn with permission.4

treatment of syphilis and other sexually transmitted infections within HIV-control programmes. This is particularly relevant to countries with a high prevalence of syphilis, genital ulcer disease, and HIV.

Diagnosis The key to syphilis recognition is a full examination by a skilled medical practitioner familiar with the protean manifestations of the infection. This examination should include all of the skin and mouth as well as the genital region. If syphilis is not suspected then the opportunity for early diagnosis and treatment and public-health intervention will be lost. Serological diagnosis of active syphilis

The mainstay of diagnosis of syphilis in the non-HIV infected adult is serology.4,28,29 Serological tests may be negative in early primary syphilis and here direct identification of the organism by dark field microscopy or within tissue biopsies may confirm the clinical diagnosis.30 Serological investigations are divided into non-treponemal antibody tests, such as the Venereal Diseases Research Laboratory (VDRL) or the rapid plasma reagin (RPR), and specific treponemal antibody tests (table 1).4,29 In general a non-treponemal test plus a specific treponemal tests is used for screening in both HIV-negative and positive people.20 Serological testing in the HIV-negative patient

In the HIV-negative patient, around 14% have negative serology at presentation with primary syphilis but fewer than 1% will have negative tests with secondary disease.30 Without therapy non-treponemal antibody titres peak during secondary syphilis and then gradually decline, so that up to 20–25% of patients with untreated late latent syphilis may have a negative non-treponemal antibody test. Specific treponemal antibody, however, persists in almost all patients with a sensitivity of 97–98% in late syphilis.4 After successful antimicrobial therapy, non-treponemal serological tests generally become negative within 1 year. However, a small proportion of patients (fewer than 5%) have persistently positive results despite effective therapy and are referred to as “serofast”. By contrast, specific treponemal antibody tests remain positive for life in almost all cases. False positive non-treponemal antibody results are seen in a range of conditions associated with phospholipid antibody production including autoimmune diseases, pregnancy, and several infectious agents including other spirochaetal infections and HIV.31 False-positive non-

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treponemal antibody titres are generally low, are not persistent, and the patients have a negative specific treponemal antibody test. False-negative non-treponemal antibody tests are seen in approximately 2% of patients and are due to the prozone effect where blocking antibodies or very high antibody titres interfere with the assay.32 The prozone effect is less common with newer tests but it is important that all physicians testing patients for syphilis are aware of the possibility of a false-negative test. The prozone effect is easily avoided by testing diluted serum. Serological testing in the HIV-positive patient

Case reports have identified potential differences in serological testing for syphilis between HIV-negative and HIV-positive patients although the clinical importance of these differences remains unclear. These differences include an increased rate of negative serological tests in both primary and secondary syphilis,33,34 increased false-negative nontreponemal antibody tests due to the prozone effect,35,36 high rate of failure to clear non-treponemal antibody after therapy (serofast),37 and seroreversion to negative of specific treponemal antibody tests after therapy.38 The difference in serological response in HIV-positive patients is not clearly related to CD4 count but similar events have been reported in non-HIV infected immunocompromised patients.32 Falsepositive non-treponemal antibody tests are encountered more frequently in the HIV-positive individual and may be seen in up to 11% of cases.39 Reinfection with syphilis may occur in HIV-negative or positive patients. It may be difficult to distinguish on serological grounds between the patient who is serofast after effective therapy, treatment failure, and reinfection.40 Patients can present with the typical features of primary or even secondary syphilis but have negative nontreponemal and treponemal antibody results.33 Furthermore, in the German study quoted earlier, of 151 HIV-positive patients with syphilis, false-negative VDRL titres were seen in 11 patients with non-primary syphilis (7·3%), and falsepositive specific treponemal antibody tests in 17 cases (11·25%, Treponema pallidum haemagglutination in one case and 19S-IgM-FTA-ABS-tests in 16).19 By contrast, Gwanzura et al41 studied 709 serum samples from 580 patients in Zimbabwe using the RPR, VDRL, and T pallidum haemagglutination. The prevalence of HIV in the cohort was 19·8% and 78 cases of active syphilis were detected. In particular, the negative predictive value of combined serology was greater than 99% with no difference between the HIV-negative and positive patients.

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Thus, although individual case reports identify patients presenting Primary with manifestations of syphilis Secondary with negative serology, there are Early latent insufficient data to warrant an Late latent Gummatous alteration to using standard seroCardiovascular logical tests for syphilis screening in Meningeal HIV-positive patients.20 However, it is Meningovascular important that clinicians involved in General paralysis the care of people with HIV are aware Tabes dorsalis that occasional patients may present with manifestations of syphilis and 0 6 12 2 4 6 8 10 20 30 have negative initial syphilis screening Months Years tests. Such patients presenting Time from infection with suspicious genital or other lesions must have investigations Figure 2. Typical presentations of syphilis over time in the HIV-negative patient. Reproduced with aimed at direct identification of the permission from G R Kinghorn. organism—ie, dark-field microscopy of material from lesions or by tissue biopsies.20 All patients A generalised macular rash with palmar-plantar involvement should be referred to a clinic where such facilities are may also occur (figure 4)44 but other types may occur such available and specialist expertise for the diagnosis and as lichenoid,45 papular, papulosquamous, ulcerated, and urticarial lesions with hair loss varying from alopecia46 to management of syphilis is available. involvement of the eyebrows and even total loss of body Clinical manifestations of syphilis in the hair.47 Nodular and annular48 skin lesions over the face, back, HIV-positive patient and limbs are reported as are large plaques on face, neck, and Typically syphilis occurs in three phases—namely primary, upper extremities.49 Nodular skin lesions can be seen in secondary, and tertiary disease. However, this is a gross secondary or tertiary syphilis and clinical and histological oversimplification and the clinical presentation of syphilis is stages may overlap.48 Vesiculobullous skin lesions may occur extremely variable over many years (figure 2).4 Several in congenital syphilis.50 Due to the varied appearances of syphilis manifestations, differences have been reported in the manifestations of syphilis in HIV-positive patients. In particular there seems to and because several other diseases may cause similar be a shift from presentation with primary to secondary appearances, biopsy is common and often establishes the disease and more aggressive disease progression. diagnosis. Histologically a wide range of changes is seen. Furthermore, HIV itself or opportunistic infections may Treponomes are seen in both the epidermis and dermis.51 Plasma cells and lymphocytes (which can be CD4+ confuse clinical and diagnostic findings. In the HIV-negative patient primary syphilis generally lymphocyte, CD8+ lymphocyte, or histiocytic in type)52 can develops after an incubation period of 21 days with a be seen around blood vessels which may have marked painless chancre at the site of inoculation. This pattern holds endothelial swelling and proliferation associated with true for syphilis in the HIV-positive patient but primary increased levels of vascular endothelial derived growth disease is more likely to be symptomless and HIV-positive factor.53 No correlation is seen between types of skin lesion patients more often present with secondary or latent and VDRL titre. Nodular lesions may show sarcoid-like infection. For example, the UK enhanced surveillance granulomata with lymphocytes, histiocytes, oeosinophils, programme in London reported on the presentation of plasma cells, and multinucleated giant cells.54 In patients syphilis in HIV-negative (n=215) and HIV-positive (n=311) with concomitant HIV infection, syphilis is only one of men. Primary syphilis was diagnosed in 42% and 27% and many possible causes of skin rash. Although the skin lesions secondary disease in 40% and 58% of HIV-negative and of syphilis may look similar in HIV-positive or HIV-negative HIV-positive patients, respectively.15 It is important to patients, they may also look different. The rash may seem recognise that with the relative increase in importance of atypical, resulting in the incorrect diagnosis of another oral sex in transmission of syphilis the primary lesion may infection or malignancy.55–57 Biopsy is commonly needed to establish the diagnosis but the histological manifestations of not be in the genital area (figure 3). secondary syphilis are very variable even in the absence of Cutaneous HIV.58 There may also be increased frequency of the lues Skin lesions are a common manifestation of secondary maligna or the ulceronodular type42,59–62 and the disease syphilis (72%)42 and may be the presenting feature. A course may be more aggressive.63–65 Co-pathologies such as number of different types of skin lesions are recognised Kaposi’s sarcoma and other skin lesions may also occur. together with lymphadenopathy, malaise, arthralgia, and With the possibility of falsely negative serology for syphilis in fever. The most common type is of a diffuse maculopapular HIV infection, the diagnosis of syphilis as a cause of skin rash which typically appears about 6 weeks after the primary lesions may be missed. Biopsy remains the key to making the lesions and signifies haematogenous spread of T pallidum.43 diagnosis in these situations.33 4

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Figure 3. Healing syphilitic chancre in an HIV-positive homosexual man. His only risk factor was unprotected receptive oral sex and he remained undiagnosed for 6 weeks despite consulting his regular HIV-physician and dentist. The diagnosis was only made when he finally presented with fever, generalised lymphadenopathy, and the typical cutaneous changes of secondary syphilis.

Bone and joint

Musculoskeletal manifestations can be associated with congenital, secondary, and tertiary syphilis and can mimic a wide range of rheumatic and systemic diseases with joint involvement. Typically syphilitic arthritis is a chronic symmetric polyarthritis. There are several causes of sexually transmitted arthritis and arthralgia, inflammatory arthritis, and neuropathic arthritis may occur during any stage of congenital or acquired syphilis. Syphilitic synovitis responds well to antibiotic therapy,66 but neuropathic lesions cannot be treated effectively.67 Arthritis can also be the initial presentation of syphilis with HIV infection and synovitis may occur in the presence of marked CD4+ lymphocyte depletion. Difficulties occur in diagnosis in HIV infection because of the negative syphilis serology that can occur but also because of autoimmune abnormalities that include positive rheumatoid factor, nuclear antibody, and double-stranded DNA. The arthritis responds well to treatment with penicillin even with HIV infection.68 Clinically significant osteitis and osteomyelitis are rare complications of primary or secondary syphilis in patients who are and are not infected with HIV69 but bone pain is a common feature of bone involvement70 and lytic lesions may occur (figure 5).71 Osteitis of the skull has been reported as a presenting feature of HIV infection70 as has ulnar osteitis complicated by a pathological fracture, which responded to high-dose intravenous penicillin G therapy and surgical intervention.72 Central nervous system

Patients co-infected with syphilis and HIV present a diagnostic and therapeutic challenge since both syphilis and HIV infection can have neurological involvement, which can be very variable.73,74 This makes the interpretation of cerebrospinal fluid (CSF) analysis, on which the diagnosis of neurosyphilis is based, particularly problematic. Neurosyphilis may affect the brain, spinal cord, or peripheral nerves. In HIV-negative patients, neurosyphilis

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can present in several ways. Neurological involvement may occur in the early post-primary stage or after a gap of many years (figure 2). In 10% of patients it is symptomless and the peak incidence is 12–18 months post primary infection. Meningeal involvement can occur with the patient presenting with aseptic meningitis and acute symptoms such as headache, neck stiffness, and photophobia. Cranial nerve palsies, especially of the VII and VIII nerves, papilloedema, and neuropsychiatric features or seizures can also occur.73,75–78 Meninogovascular syphilis presents 4–7 years after infection and symptoms occur because of vascular ischaemia in the territory of the middle cerebral, basilar, or spinal arteries. Hence patients may present with focal neurological deficits such as hemiparesis, aphasia, or seizures. The necrotising granulomatous gummas of late syphilis within the central nervous system give rise to symptoms and signs of space-occupying lesions. Rarely parenchymatous involvement causes cognitive impairment, psychiatric symptoms, and neurological signs affecting the pupils and causing hypotonia of the face and limbs, intention tremor, and hyper-reflexia.79 The increased prevalence of neurosyphilis in HIV infection is shown in one study where incidence was 23·5% in HIV-positive patients with untreated syphilis.80 This prevalence contrasts with 10% in HIV-negative patients with untreated syphilis.4 In HIV infection, neurosyphilis may be symptomless but a range of presentations may also occur. All types of neurosyphilis as described above are seen including headache, hearing loss (which may be bilateral and severe),81 spastic paraparesis secondary to syphilitic meningomyelitis,82 medullary syndromes,83 stroke (which can be acute or subacute involving the basal ganglia or middle cerebral arteries),77,84 gait disturbances, and optic atrophy or pupillary changes.85 Gummas may mimic the symptoms and signs of a space-occupying intracranial lesion including meningioma with headache and ataxia.77 Personality changes are the commonest symptom of late syphilis with HIV infection and are due to syphilitic vasculitis with lacunar infarcts. In children with AIDS, syphilis may also contribute to the neurological manifestations.86 Neurocognitive impairment is common in HIV patients but is worse in those co-infected with syphilis.87 Furthermore, co-infection with herpes viruses, toxoplasmosis, cryptococci, progressive multifocal leucoencephalopathy and other central nervous system infections may complicate the clinical and diagnostic picture in persons with underlying HIV.74,88 It is also suggested that HIV accelerates and changes the clinical course of neurosyphilis89 and that co-infection with HIV increases the incidence of the neurological complications of syphilis.90 Aggressive neurosyphilis can occur with either high or low CD4+ lymphocyte counts.91 In one recent study a CD4 count of less than 350 indicated a three-fold increased risk of neurological involvement in the HIV-positive patient with syphilis.92 Neurospyhilis in the context of HIV co-infection with HIV is more difficult to diagnose because HIV infection itself is frequently associated with a CSF pleocytosis.93 Significant differences were noted in CSF measurements when HIV-positive patients were compared with HIV-negative patients with syphilis,

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including a higher cell count, higher protein, and lower glucose levels in the HIV-infected group.77 PCR has poor sensitivity for the diagnosis of neurosyphilis in HIV and is therefore not helpful in most patients where there is diagnostic difficulty.94 Measurement of CSF antibodies to syphilis are generally used to confirm neurological involvement. In HIV-negative patients the presence of either non-treponemal or specific treponemal antibodies in CSF indicates neurosyphilis.95 In HIV-positive patients, however, the CSF VDRL may rarely be negative despite neurosyphilis96 and when present CSF treponemal antibodies commonly persist after therapy.97 The CSF VDRL may rarely be negative in the HIV-negative patient with neurosyphilis. Caution should also be used when interpreting blood-contaminated CSF where a positive serological result may come from the blood contamination.20 The problem of neurosyphilis in HIV-positive patients has led some authorities to recommend lumbar puncture in all HIV-positive patients irrespective of the stage of syphilis.98,99 An alternative strategy is to ensure that all HIV-positive patients with syphilis receive a course of therapy that will achieve treponemocidal concentrations of penicillin in both serum and CSF.20 UK guidelines are that a full neurological assessment should take place in all patients and a computed tomography head scan and lumbar puncture are indicated only if clinical abnormalities are found.20 Imaging may be of help in both diagnosis and monitoring the effect of treatment. Computed tomography scanning can show the presence of multifocal, low density lesions with particular characteristics of infarction.100 Contrast-enhanced magnetic-resonance imaging (MRI) can show the extent of involvement by neurosyphilis and may show patchy contrast enhancement involving the basal ganglia and middle cerebral artery territories or a mass which may resolve on treatment.101 MRI is particularly useful in diagnosing spinal cord involvement with syphilis.102,103 Retrospective studies of the treatment of neurosyphilis in the presence of HIV infection suggest that for 23–60% of HIV-infected patients current neurosyphilis therapy with penicillin G does not work.37,97,104 However, the risk of neurological sequelae in HIV-infected patients with early syphilis and abnormal CSF treated with penicillin is unknown.1 Standard treatment is with high-dose penicillin105,106 but there may be persistence.107 At least 3–4 weeks of treatment are recommended.108 Ceftriaxone has excellent activity against T pallidum and has good central nervous system penetration. Case reports of effective use of ceftriaxone have been reported but data are limited and ceftriaxone is not licensed for use in neurosyphilis.109 Ocular involvement

The eyes and visual system can be affected in many different ways by syphilis but none of the signs are pathognemonic. All structures of the eye may be affected110 but the commonest manifestation is uveitis (intraocular inflammation). Uveitis can occur at all stages of syphilis including primary infection111 and may spontaneously resolve but the relapse rate is high without treatment. It may also occur in tertiary syphilis affecting 2·5–5% of the 30%

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Figure 4. Involvement of the palm (A) and soles (B) with a lichenified scaly rash due to secondary syphilis in an HIV-positive man presenting with panretinitis. The rash had been present for several weeks and was thought to be psoriasis by a rheumatologist who was seeing him for a “sero-negative” arthropathy.

untreated patients that progress.112 Several different types of uveitis—anterior uveitis, posterior uveitis, and keratouveitis—are recognised. Patients with posterior uveitis may have vitritis, focal retinitis, chorioretinitis (figure 6),113,114 periphlebitis, retinal haemorrhages, papillitis,115 and exudative retinal detachments.116 Many other signs of intraocular involvement may be seen including optic neuritis, neuroretinitis, and arterial and venous occlusion.117 Patients with neuroretinitis may notice painless fluctuating visual loss and floating spots, which may be associated with retinitis, papillitis, vitritis, and sometimes anterior uveitis. Isolated optic neuritis with unilateral visual loss may occur with signs of meningeal inflammation without any associated uveitis or retinal

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Figure 5. Lytic lesion in the femur of the patient described in figure 4.

vasculitis.118 Paracentral scotomas and blind-spot enlargement related to posterior pole lesions and papillitis are the most common visual field defects. The orbit may also be involved.119 Most patients recover well with penicillin treatment but visual loss can occur from macular oedema and retinal ischaemia from the endarteritis.120 However, not all ocular syphilis can be cured with neurosyphilis regimens and many more will relapse with less intense regimens.115 HIV infection itself can have many effects on the eye and can cause uveitis as well as having associated infections, malignancies and drugs that can cause uveitis.121 Severe ocular manifestations and an accelerated natural course of syphilis along with neurosyphilis may be associated with HIV infection. Eye disease may be the presenting

Syphilis and HIV

symptom/sign of co-infection with HIV.115,122 There are differences in the uveitis seen in patients with syphilis coinfected with HIV—the uveitis may be more severe in the HIV-positive group123—panuveitis is more common than isolated anterior uveitis,124 and a dense vitritis occurs despite a low CD4+ lymphocyte count,125 but this usually responds well to treatment.125 Papillitis, optic neuritis, and retrobulbar optic neuritis126 may all be worse in HIVpositive versus HIV-negative patients127 and there may be concomitant central nervous system disease. Syphilis serology may be negative when patients present with inflamed eyes and co-infection with syphilis and HIV. This may delay the diagnosis of syphilis128 since none of these signs are specific for syphilis and if investigations are negative, it is very likely that these patients will be given systemic corticosteroids with severe sequelae129 instead of disease resolution with penicillin.117 With penicillin treatment 67% of patients have improved vision with reduced inflammatory signs in 92%130 but relapses of ocular disease may also occur despite treatment.123 Cardiovascular

By contrast with neurosyphilis there have been few reports of vascular involvement in HIV-positive patients. Arterial aneurysms can be seen in HIV infection and commonly involve the common carotid artery and abdominal aorta.131 These may be multiple and can also be associated with syphilis.132 In HIV-negative patients vascular disease is one of the late manifestations of syphilis (figure 2). Thus, it is possible that the paucity of reports of vascular syphilis in HIV-positive patients is simply due to the relatively short duration of infection and to the high rate of detection and treatment of latent syphilis in HIV. Other systems

Oral lesions can occur in syphilis with and without HIV infection and are usually seen in secondary disease (figure 7).133 Rarely the lung and pleura can become involved.134 Spirochetes may be detected in pleural fluid associated with pneumonia even in patients with good CD4+ lymphocyte counts.134 Nephrotic syndrome is a recognised complication of HIV infection and progresses to renal failure without antiretroviral therapy.135 In association with syphilis, however, it is reversible with treatment.136

Treatment of syphilis

Figure 6. Retinal photograph from an HIV-positive patient who presented with severe uveitis due to syphilis. This picture after treatment of his syphilis shows healed chorioretinitis with a “salt and pepper” appearance.

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Penicillin remains the mainstay of therapy for all stages and sites of syphilis and in all patient groups.105,106,137 Guidelines vary (table 2) but the general principle is one of maintaining prolonged serum treponemocidal concentrations. In HIV-negative

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patients with early syphilis (less than 2 years’ duration) it is not necessary either to investigate for neurosyphilis or to use therapy that achieves treponemocidal concentrations of antibiotics in CSF (table 2).20,105 For example, CDC guidelines recommend a single dose of intramuscular benzathine penicillin for primary and secondary disease.105 In late syphilis (greater than 2 years’ duration) CDC guidelines recommend CSF examination in the presence of ophthalmic or neurological signs, treatment failure, evidence of tertiary syphilis, or if the patient is coinfected with HIV.105 If CSF is normal then benzathine penicillin is still recommended but the duration of treatment is increased to three doses at weekly intervals (table 2). Benzathine Figure 7. Lateral view of the tongue in a patient with secondary syphilis and undiagnosed penicillin does not achieve adequate underlying HIV infection. Patches of oral hairy leucoplakia due to advanced HIV are seen on the CSF concentrations and so is not lateral border (white arrows). There are also serpiginous ulcers and a mucous patch on the tongue recommended where there is evidence of typical of secondary syphilis (black arrow). neurosyphilis. When treating syphilis in the HIV-positive patient it is despite augmenting the weekly benzathine penicillin important to use a drug regimen that will achieve adequate injections with oral amoxicillin.138 Thus, daily intramuscular CSF concentrations.20 This requires intravenous benzyl procaine penicillin plus probenecid should be the penicillin, which is impractical in most cases, or daily recommended first-line therapy for primary, secondary, or intramuscular procaine penicillin plus oral probenecid to latent syphilis in HIV-positive patients (table 2).20 Where reduce renal excretion (table 2). When benzyl penicillin or compliance and personal choice make this regimen procaine penicillin has been used as first-line therapy there is untenable then weekly benzathine penicillin plus oral a low clinical treatment-failure rate. Long-acting benzathine amoxicillin and probenecid may be considered.138 In the penicillin preparations have been reported to have higher penicillin-allergic patient doxycycline is often used as a rates of serological failure, for example 18% in one study second-line agent. There is uncertainty about whether Table 2. Guidelines for the treatment of syphilis in adults in the UK and USA Syphilis stage

USA guidelines (CDC)105

Early disease (2 years since acquisition)

Late disease in HIV positive

Neurosyphilis

Neurosyphilis in HIV positive

UK guidelines20,106,137

Procaine penicillin G 750 mg IM daily  10 days or Benzathine penicillin G 2·4 million units IM in a single dose As above, some clinicians recommend Procaine penicillin 2 million 3 doses at weekly intervals units IM OD + probenecid 500 mg QDS  17 days Benzathine penicillin G 2·4 million Procaine penicillin G 750 mg units IM weekly  3 doses IM daily  17 days or benzathine penicillin G 2·4 million units IM weekly  3 doses Benzathine penicillin G 2·4 million Procaine penicillin 2 million units units IM weekly  3 doses IM OD + probenecid 500 mg QDS for 17 days Aqueous crystalline penicillin Procaine penicillin 2 million units G 18–24 million units per day, IM OD + probenecid 500 mg administered as 3–4 million units IV every QDS  17 days or 4 h or continuous infusion, for 10–14 days. Benzyl penicillin 3–4 million units IV every 4 h for 17 days As above As above

Alternative agents in UK guidelines Doxycycline 100 mg BD  14 days Erythromycin 500 mg QDS 14 days Amoxicillin 500 mg QDS plus probenecid 500 mg QDS  14 days Doxycycline 200 mg BD  28 days Amoxycillin 2 g TDS plus probenecid 500 mg QDS  14 days Doxycycline 200 mg BD  28 days Amoxycillin 2 g TDS plus probenecid 500 mg QDS  14 days Doxycycline 200 mg BD  28 days Amoxycillin 2 g TDS plus probenecid 500 mg QDS  14 days Doxycycline 200 mg BD  28 days Amoxycillin 2 g TDS plus probenecid 500 mg QDS  14 days

As above

IM=intramuscular; IV=intravenous; CDC=US Centers for Disease Control and Prevention; OD=once daily; BD=twice daily;TDS=three times daily; QDS=four times daily.

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Search strategy and selection criteria Data for this review were identified by searches of Medline, Current Contents, and the Cochrane Database, and by reviewing the bibliographies of papers retrieved using this strategy. All articles published after 1966 were considered, as were articles in all languages. Search terms were “HIV”, “STD”, “STI” “syphilis”, “neurosyphilis”, “ocular”, “uveitis”, “retinitis”, “vitritis”, “cardiovascular”, “bone”, “skin”, “congenital”, and “malignant”. The websites of the World Health Organization, US Centers for Disease Control and Prevention, and the UK Health Protection Agency were searched for epidemiological data.

adequate CSF concentrations of doxycycline are achieved but treatment failure is rare and doxycycline remains a useful agent. Erythromycin is used as a second-line agent in the HIV-negative patient but has very poor CSF penetration and should not be considered in HIV-positive patients.20 Furthermore, recent reports have described the emergence of resistance to erythromycin.139 Azithromycin is a macrolide antibiotic with activity against T pallidum. The long half-life of azithromycin allows for once-daily dosing and small studies have been encouraging.140 Caution must be expressed regarding the use of azithromycin in the light of reports of treatment failure.141 Where an HIV-positive patient has evidence of neurosyphilis, with clinical and/or imaging abnormalities plus an abnormal CSF, then high-dose intravenous benzyl penicillin may be the preferred choice. There are no clear data, however, to suggest that this is superior to intramuscular procaine penicillin plus probenecid (table 2). In both neurosyphilis and pregnancy there is no agreed alternative to penicillin. Treatment failures in neurosyphilis are likely with doxycycline and doxycycline is contraindicated in pregnancy. In this setting consideration can be given to desensitisation for penicillin allergy.106 Ceftriaxone has good treponemocidal activity and CSF penetration. In a small pilot study of HIV-positive patients with neurosyphilis ceftriaxone was been reported to be at least equivalent to procaine penicillin142 but more data are required before ceftriaxone could be routinely recommended. References 1 2 3

4 5 6 7 8

Golden MR, Marra CM, Holmes KK. Update on syphilis: resurgence of an old problem. JAMA 2003; 290: 1510–14. Arora PN, Sastry CV. HIV infection and genital ulcer disease. Indian J Sex Transm Dis 1992; 13: 71–73. Bruisten SM, Cairo I, Fennema H, et al. Diagnosing genital ulcer disease in a clinic for sexually transmitted diseases in Amsterdam, The Netherlands. J Clin Microbiol 2001; 39: 601–05. Kinghorn GR. Syphilis. In: Cohen J, Powderly WG, eds. Infectious diseases, 2nd edn. London: Mosby, 2004: 807–16. Walker DG, Walker GJ. Forgotten but not gone: the continuing scourge of congenital syphilis. Lancet Infect Dis 2002; 2: 432–36. WHO. World Health Organization website. http://www.who.int. Borisenko KK, Tichonova LI, AM R. Syphilis and other sexually transmitted infections in the Russian Federation. Int J STD AIDS 1999; 10: 665–68. van den Hoek A, Yuliang F, Dukers NH, et al. High prevalence of syphilis and other sexually transmitted

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Treatment of syphilis may be complicated by the JarischHerxheimer reaction mediated by cytokine release induced by treponemal lysis after therapy.106 The reaction occurs within 4–24 h of penicillin administration and consists of an acute febrile illness and may include increased inflammation at the site of clinical disease. If the Jarisch-Herxheimer reaction is severe or involves a critical body site then corticosteroids are indicated.106 Jarisch-Herxheimer reactions have been reported in HIV-positive patients but do not seem to be more severe or frequent than in HIVnegative patients. The vast majority of HIV-negative patients will show a steady fall in serum non-treponemal antibody levels and have negative VDRL or RPR tests within 1–2 years of effective therapy. Persistence of serum antibodies is much more likely in HIV-positive patients and does not necessarily indicate inadequate treatment. Current guidelines suggest repeating serology at 3 month intervals for the first year after treatment and then annually for life.20 A fourfold rise in serum VDRL or RPR titre should be considered to indicate relapse or reinfection, and retreatment offered. Best practice would be for all people with syphilis to be counselled regarding safer sexual practices. They should be also be referred for partner notification and contact tracing.

Future prospects So what does the future hold? It is remarkable that penicillin remains the mainstay of therapy and there is little prospect that newer antibiotics will displace penicillin in the near future particularly following the emergence of macrolide resistance. An effective vaccine would offer great hope but insufficient research efforts have directed against syphilis. Despite some success143 our understanding of the determinants of protective immunity to T palllidum remain poor with little prospect for an effective vaccine in the near future. Unless there is a concerted global and politically supported public-health drive to reduce the transmission of syphilis then syphilis will continue to lead to substantial morbidity and further fuel the HIV pandemic. Conflicts of interest

SL is a member of the international advisory board of The Lancet.

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