Syphilis is a complex sexually transmitted disease caused by a bacterium called Treponema pallidum. It is transmitted by contact with infected sores or lesions, from mother to baby or through blood contact. Soon after the organism enters the body it spreads throughout the body via the bloodstream or the lymphatic system. Nearly all organs can be invaded, including the central nervous system. If left untreated, syphilis can persist for decades and eventually be fatal.

At various times, it has been suggested that syphilis is the cause of AIDS, is a co-factor with HIV for AIDS, or causes HIV-associated dementia. None of these ideas has stood up to rigorous scientific investigation. However, as for many sexually transmitted infections, it is extremely likely that syphilis increases the risk of HIV transmission.

In some parts of the world, syphilis remains a common heterosexually transmitted disease. The World Health Organization (WHO) estimated in 1999 that of a global total of 12 million adults with syphilis, 11 million were living in sub-Saharan Africa, Latin America and south and south-east Asia.

In recent years there has been a striking increase in the number of cases of syphilis in Eastern Europe, especially in the former Soviet Union. In Western Europe and North America, while there are some cases reflecting international contacts, there has also been an increase in cases amongst gay men which seem to reflect changing patterns of sexual behaviour and pose a particular risk of increased HIV transmission (Hopkins 2002). Notably, oral sex has been identified as the route of transmission in Chicago in 14% of cases of syphilis, particularly in gay men (Centers for Disease Control and Prevention 2004). However, the increase in syphilis diagnoses in gay men has not yet been followed by an increase in new HIV infections in the United States or the United Kingdom, as originally feared (Dilley 2004; Murphy 2004).

In the United Kingdom, syphilis has re-emerged as a relatively common sexually transmitted disease. Between April and December 2001, the Communicable Disease Surveillance Centre received 207 reports of infectious syphilis from genitourinary medicine clinics in London. The overwhelming majority of cases (73%) were among gay or bisexual men, with the remaining 56 cases occurring among heterosexuals, including 20 women. Fifty-four percent of the gay men with syphilis were known to be HIV-positive, compared with only 2% of heterosexuals with syphilis.

In 2003, there were 1575 cases of syphilis diagnosed in the United Kingdom, mainly clustered in London and Manchester. Most of the cases were in gay men, many of whom are HIV-positive. This represents a 23% increase on 2002, but may be explained in part by more people coming forward for testing. Figures for 2004 continued to show the same trend, with an increase of 37% on the previous year. In comparison with previous years, women and heterosexual men represented an increasingly large proportion of these cases, with rises of 47 and 45% over 2003, respectively.

Symptoms

Syphilis can cause a range of symptoms or none at all, but if left untreated can have very serious effects on the brain and the rest of the nervous system (known as neurosyphilis).

In HIV-negative people, initial infection with syphilis (primary syphilis) may cause a chancre (an ulcer, sore or spot) at the site of infection, usually in the genital region. This does not hurt and heals after a couple of months. The chancre is usually accompanied by swollen glands.

In HIV-positive people  chancres can appear as unusual or multiple ulcers, and may be mistaken for an attack of genital herpes. People with HIV are more likely to be diagnosed when syphilis has reached the secondary stage than HIV-negative people.

Secondary syphilis can cause symptoms of rash, swollen glands, warts, various constitutional symptoms and, less frequently, other symptoms such as meningitis. More sores may occur, especially on the hands and feet.

Neurosyphilis can occur at any stage of syphilis. Syphilitic meningitis and meningovascular syphilis occur early, within the first few years of infection. General paresis and tabes dorsalis occur later, typically five to 30 years after infection. In addition to neurosyphilis, late syphilis can cause lesions in almost any organ of the body.

In people with HIV the course of the disease may be different. There seems to be an increased risk of brain involvement, and unusual symptoms may include skin and mouth ulcers and fever. It is also possible that HIV speeds up the course of syphilis: several recent studies have shown that syphilis can lower CD4 cell counts and raise viral loads in HIV-positive men (Buchacz 2004)^[1].

Diagnosis

When a chancre is present, it may be possible to see the bacteria in a sample taken from the sore under a microscope. T. pallidum has a distinctive spiral appearance.

Two kinds of test are normally used to diagnose syphilis. Both tests detect antibodies, but neither is fully reliable in diagnosing the disease. The choice of test, and how they are used, varies internationally.

The first kind of test detects antibodies to lipids, called 'reagin' antibodies. The Venereal Disease Research Laboratory (VDRL) test is used on blood or sometimes on cerebro-spinal fluid (CSF) taken from the spinal column by lumbar puncture. The rapid plasma reagin (RPR) test is used only on blood. These tests may be positive when people have a range of other infections, including malaria, or during to pregnancy. Reagin antibody levels due to syphilis go down when syphilis is treated, so these tests can be used to monitor treatment.

A second approach looks for antibodies to proteins made by the syphilis bacteria. These 'treponemal' tests include T. pallidum haemagglutination assay (TPHA), T. pallidum particle agglutination test (TPPA) and fluorescent treponemal antibody absorption test (FTA-abs), along with a number of enzyme immuno-assay (EIA) tests which are similar to HIV antibody tests. These are very specific, but usually remain positive even after a patient has been cured of syphilis.

In the United Kingdom, VDRL tests are generally used for initial screening followed by TPHA tests to confirm a diagnosis of syphilis. In some countries, TPHA or TPPA tests have been used for initial screening.

It can take up to 90 days for the body to develop antibodies to the bacterium that causes syphilis, so a blood test immediately after exposure to syphilis may not detect infection. Some studies have suggested that these tests are not as effective in people with HIV: some HIV-infected people who do have syphilis may test negative.

Guideines for the management of sexually transmitted infections in HIV-positive people developed by the British Association for Sexual Health and HIV in 2006 have recommened that syphilis tests be incorporated into routine HIV blood tests every three months. In addition, due to the increasing prevalence of syphilis among women, the Health Protection Agency has called for antenatal screening for syphilis to become universal, in order to prevent the re-emergence of congenital syphilis.

Treatment

Syphilis is normally treated with a course of antibiotics. Another study comparing HIV-infected and uninfected people with syphilis found the HIV group had a poorer serological response but clinical failures were rare (Rolfs 1997).

In HIV-positive people, syphilis is usually treated with high doses of antibiotics such as penicillin, benzylpenicillin (Crystapen) or doxycycline (Vibramycin / Vibramycin D). A single injection of benzylpenicillin, which remains active for weeks, is usually sufficient to cure syphilis, although some doctors prescribe a course of injections over three weeks. It is usually injected into the buttocks.

WHO's preferred treatment for all forms of syphilis is penicillin. Only if patients are allergic to penicillin should other treatments be given. There is some evidence that ceftriaxone (Rocephin) is also an effective treatment for neurosyphilis in HIV-infected people (Marra 2000).

However, the only set of guidelines developed specifically for HIV-positive people, which were last updated in 2006 by the HIV Special Interest Group of the British Association of Sexual Health and HIV (BASHH), recommend two doses of intramuscular benzathine penicillin G one week apart to treat syphilis.

Since the 1990s, the oral antibiotic azithromycin (Zithromax) has been used by some doctors to treat syphilis. A single dose of 2g is sufficient to cure the condition, and it has the added benefit of being active against other sexually transmitted infections such as Chlamydia. However, there have been recent reports of azithromycin resistant syphilis in gay men in San Francisco, Baltimore, Seattle, and, notably, Dublin, where 88% of samples analysed were found to be resistant to the drug (Lukehart 2004). There have been no reports of penicillin-resistant syphilis.

Treatment for neurosyphilis is similar to that for primary syphilis. Three markers are usually used to assess the effectiveness of treatment: VDRL reactivity, as well as levels of CDF protein and white blood cells in the CSF should normalise within six months of antibiotic therapy. Recently, concern has been raised about the reliability of these markers in HIV-positive patients, particularly those with low CD4 cell counts, due to a higher false positive rate (Marra 2004). However, it remains uncertain whether this reflects a need for more aggressive treatment in neurosyphilis patients with HIV.

Neurosyphilis may occur without other symptoms of primary infection, and may also persist despite treatment with benzathine penicillin in HIV-positive patients.

Research

Buchacz (2004) analysed medical records from 52 HIV-positive men with primary or secondary syphilis seen at 3 clinics in San Francisco and Los Angeles between January 2001 and April 2003. 30 (58%) were receiving antiretroviral therapy. VLs were higher during syphilis than before the infection by a mean of 0.22 log₁₀ (p = 0.02), and CD4 cell counts were lower by a mean of 62 cells/mm³ (p = 0.04). After treatment, VL fell by 0.10 log₁₀ (p = 0.52) and CD4 cell counts rose by 33 cells/mm³ (p = 0.23). The effects of syphilis infection were greatest in men with secondary syphilis (0.33 log₁₀) and those not receiving antiretroviral therapy (0.25 log₁₀).

Centers for Disease Control and Prevention (2004) reported on the incidence of primary and secondary syphilis in Chicago. Between 1998 and 2002, there were 1582 cases of syphilis recorded by the Chicago Department of Public Health. Incidence has remained steady over this time, between 11.8 and 12.2 cases per 100,000 people, but rates have declined in women by 68% from 9.2 to 2.9 per 100,000, and increased in men by 50% from 14.7 to 22.1 per 100,000. Cases in gay men increased rapidly in 2001, from 30-40 to 180 cases per 100,000 and over 200 per 100,000 in 2002: a 469% increase in white and 462% in Hispanic gay men. 627 diagnosed with syphilis in 2001 and 2002 were interviewed: 20% of the gay men indicated no unprotected sex other than oral sex. There was no association with HIV status and likelihood of transmission (22% HIV-positive vs. 20% HIV-negative).

Dilley (2004) gathered data on cases of syphilis in San Francisco and Los Angeles between 1998 and 2002, and compared rates of infection with HIV status of stored blood samples. The number of syphilis cases increased in both cities (San Francisco: 8 per 100,000 in 1998 to 512 per 100,000 in 2002; Los Angeles: no cases before 2000; 67 cases in 2000; 299 cases in 2002). The number of new HIV infections was stable in both cities over this time period. However, this study did not include men having oral HIV tests.

Lukehart (2004) reported a case of azithromycin resistant primary syphilis in a gay man in San Francisco in July 2003 that was subsequently treated successfully with penicillin. This was followed by sampling of 114 cases of syphilis lesions from patients in San Francisco, Baltimore, Seattle and Dublin. The azithrimycin-resistant Street 14 mutant was found in 88% of the samples from Dublin, 22% from San Francisco, 13% from Seattle and 11% from Baltimore. In San Francisco, prevalence rose from 4% in 2002 to 37% in 2003.

Standard treatment for early syphilis is parenteral penicillin. Benzathine penicillin G (benzylpenicillin) is recommended in the USA; procaine penicillin is standard treatment in the UK. However, prospective studies to establish the most effective drugs and dosages have not been conducted. CDC and WHO recommend a one-time dose of 2.4 million units of benzathine penicillin G administered intramuscularly (usually given as two injections in different sites) for both HIV-negative and HIV-infected patients. Rolfs (1997) reported that there was no significant difference between HIV-positive and HIV-negative patients in the clinical success of this therapy, although HIV-positive patients responded less well serologically than HIV-negative patients. The addition of a 10-day course of amoxicillin and probenecid did not improve the outcome of therapy.

For late latent syphilis of more than one year's duration with no CSF evidence of neurosyphilis, CDC and WHO guidelines recommend three 2.4 million unit intramuscular doses of benzathine penicillin given at weekly intervals. If doxycycline is used, WHO recommends that treatment should be 100mg orally, twice daily for 30 days.

CDC guidelines for neurosyphilis recommend aqueous crystalline penicillin G 2 to 4 million units intravenously every four hours for 10 to 14 days (total dose 12 - 24 million units). Alternative regimens include procaine penicillin 2 to 4 million units intramuscularly daily plus probenecid 500 mg intramuscularly four times daily for 10 to 14 days.

Bordon (1999) reported that 13 HIV-infected people with syphilis (4 primary, 5 latent, 4 neuro) had a good clinical and serological response to standard penicillin treatment fro syphilis.

Tattevin (2002) reported that treatment of latent syphilis with benzylpenicillin G and its repository form benzylpenicillin G benethamine did not improve serological response one year after treatment in 23 HIV-infected people.

Marra (2000) compared intravenous ceftriaxone and penicillin G as therapy for neurosyphilis, in 30 HIV-infected people. Significantly more ceftriaxone recipients had a decline in serum RPR titers (8/10 vs 2/15, p=0.003), even after controlling for baseline differences.

Musher (1991) proposed higher doses (three 2.4 million unit doses at weekly intervals) in order to prevent possible relapse to neurosyphilis. While ceftriaxone (500mg or 1g intramuscularly every day for 10 days) may be an effective alternative regimen, it has not been conclusively evaluated. In the penicillin-allergic non-pregnant patient with early syphilis, WHO recommends doxycycline 100mg orally, twice daily for 15 days. Alternatives may include desensitization or ceftriaxone.

Haas (1990) evaluated the sensitivity of treponemal tests as a marker of prior syphilis in individuals with HIV infection. The syphilis serology of 109 homosexual men with a documented history of treated syphilis was compared with records of prior results and confirmed on stored serum samples. None of the HIV-seronegative individuals lost reactivity to a treponemal test, whereas 7% of the seropositive asymptomatic individuals and 38% of those with symptomatic HIV infection had loss of reactivity. Symptomatic HIV infection was associated with loss of reactivity, as was a CD4 count below 200, a CD4-to-CD8 ratio below 0.6, a single prior episode of syphilis and a low VDRL titer at the time of the last documented episode of syphilis. Although no conclusions can be drawn about the sensitivity of treponemal tests in patients with active syphilis and HIV infection, these data suggest that treponemal tests may not identify those previously infected with Treponema pallidum.

Rompalo (1992) reported that of 4863 STD patients, 357 (7.3%) had serological evidence of syphilis and 4.9% had HIV infection. Forty patients (0.8% of the total; 11% of those with reactive rapid plasma reagin (RPR) tests) had biological false-positive (BFP) serological tests for syphilis. There were no differences between true syphilis and BFP patients as to sex, age or i.v. drug use. BFP RPR tests were seen in 6 (4%) of 159 HIV-seropositive patients and 34 (0.8%) of 4387 HIV-seronegative patients.

Hutchinson (1994) reported on 108 people with primary syphilis, 116 people with secondary syphilis and 85 people with early latent syphilis, 23% of whom were also HIV-positive. 53% of HIV-positive people presented with secondary syphilis, versus 33% of HIV-negative people. Among those with first episodes of syphilis, 43% of people with HIV who had secondary syphilis presented with persistent chancres, versus 15% of the HIV-negative group. Response to treatment did not appear to differ by HIV status.

Gordon (1994) treated 11 HIV-positive people who had symptomatic neurosyphilis (5 of whom had previously been treated for early syphilis) with penicillin G benzathine (18 - 24 million units/day intravenously for 10 days). Response to treatment was inconsistent. Ten had a resolution or stabilisation of clinical manifestations after treatment. Two participants followed for 6 months had abnormal cell and protein concentrations and CSF VDRL titres that did not change. Two additional participants had persistently abnormal cell counts and protein concentrations despite a substantial reduction or normalisation of the CSF VDRL and serum RPR titres.

Gourevitch (1993) conducted a cohort study of 50 intravenous drug users with syphilis. 31/50 were HIV-positive and 19/50 were HIV-negative. HIV infection did not alter the response to treatment. Most patients had late latent syphilis at presentation (15/31 and 13/19 patients in the HIV-positive and HIV-negative groups, respectively). Follow-up was adequate to assess treatment outcomes in 43 patients (26 HIV-positive and 17 HIV-negative). A variety of treatment regimens were used. Among the evaluable HIV-positive patients, 12 received the standard CDC-recommended regimen of penicillin and 14 received other therapy (either high doses of penicillin or non-penicillin regimens). All responded adequately to therapy. Among the HIV-negative subjects, 9 received standard therapy and 8 received other therapy. One patient (who received two weeks of tetracycline) did not respond adequately.

Dowell (1992) retrospectively compared ceftriaxone (1-2 g/day for 10-14 days) and benzathine penicillin (2.4 million units weekly for three weeks) for late latent syphilis or symptomatic neurosyphilis in HIV-infected patients. 28/44 ceftriaxone recipients and 8/13 benzathine-penicillin recipients responded to treatment. The investigators concluded that ceftriaxone and benzathine penicillin appear equivalent for patients with normal CSF.

Verdon (1994) treated 16 HIV-negative people who presented with primary or secondary syphilis with azithromycin (500 mg/day for 10 days). Three were lost to follow-up. Eleven of the remaining thirteen were considered cured by virtue of resolution of symptoms and serological tests. Five participants reported mild adverse effects including nausea, vomiting, diarrhoea and cramps. In vitro tests suggest that azithromycin blocks the growth of T.pallidum, and it is an effective treatment for syphilis in rabbits.

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