Is syphilis being over- or under-treated in HIV-positive individuals?

The most recent figures from the World Health Organization estimate that twelve million new cases of sexually transmitted syphilis – caused by a bacterium called Treponema pallidum – occurred in 1999, more than 90% of them in developing countries, with a rapidly increasing number of cases in eastern Europe.

After almost disappearing from well-resourced countries in the 1990s, syphilis has now made a dramatic comeback across Europe and North America, disproportionally affecting HIV-positive gay men in the United States, United Kingdom and other countries with high proportions of gay men amongst their HIV-positive populations, such as France, Germany and Ireland.

However, syphilis is also on the rise amongst heterosexuals in well-resourced countries, according to recent data from the UK, and in the US the number of new syphilis cases in African Americans also increased in 2004 for the first time in ten years, although this may reflect the recent increases seen amongst all gay men, including those of African American ethnicity.

The opinion on the treatment of syphilis in HIV-positive people is very much divided, even as evidence mounts that standard treatment may be inadequate for people with HIV. A number of reports have described cases when ulcers did not heal, the syphilis bacteria were still detectable, or neurosyphilis developed after standard therapy had been completed.

Although treatment guidelines from the US Centres for Disease Control (CDC), as the well as the World Health Organization (WHO) and the International Union Against Sexually Transmitted Infections (IUSTI) recognise that syphilis in HIV-positive people may be harder to treat, for the most part they recommend standard courses of treatment, comprising a single intramuscular (usually into the buttock) penicillin injection, or a course of three injections over three weeks.

Recently, however, a study from Tanzania that included 50% HIV-positive participants, concluded that a single oral 2 gram dose of azithromycin (Zithromax) provides treatment for early and latent syphilis that is effective and equivalent to a single injection of penicillin.

The only set of treatment guidelines focused specifically on syphilis in HIV-positive people – created in 2002 by the HIV Special Interest Group of the British Association of Sexual Health and HIV (BASHH) – recommend much more aggressive treatment: between 10 and 17 consecutive days of penicillin injections with four probenecid tablets daily. However, in the UK and elsewhere, HIV or sexual health clinicians who subscribe to these guidelines appear to be in the minority, and even those who do tend to find that their patients prefer less painful and time-consuming options.

Since untreated syphilis increases the risk of both transmitting and acquiring HIV, there have been concerns that the recent increase in syphilis infections would lead to an increase in new HIV infections. However, so far this does not appear to be the case. A recent study comparing rates of syphilis and rates of HIV infections in San Francisco and Los Angeles between 1998 and 2002 found that although the number of syphilis cases increased in both cities, the number of new HIV infections was stable in both cities during the same time period.

This may be due to several factors, including the high percentage of syphilis that is transmitted by oral sex. Although oral sex without a condom is considered an inefficient method of HIV transmission compared with unprotected vaginal or oral intercourse, it is a highly efficient method of transmitting and acquiring syphilis. Oral sex without a condom has been identified as the route of transmission in 44% of cases of syphilis in the current London outbreak and was found to be a significant transmission route in Chicago. This fits with the experience of Dr Stephen Taylor, of Birmingham's Heartlands Hospital: “On closer questioning of the patients who have recently acquired syphilis,” he says, “oral sex is often the only described risk factor that they can identify.”

Another clue as to why the syphilis epidemic may not be leading to significantly more HIV infections comes from a UK-based team of researchers who looked at patterns of syphilis outbreaks in the US and who suggest that they have less to do with a population’s sexual behaviour and more to do with the population-wide loss of immunity among those at risk of infection. It may also be the case that, since a higher proportion of people with syphilis are already HIV-positive, many of their high-risk HIV transmission sexual activities are occurring mainly with other HIV-positive people. This is known as sero-sorting, and has been found to occur among HIV-positive people who want to have unprotected anal intercourse, and choose to do so with other HIV-positive people to minimise the risk of HIV transmission – so-called “safer risks” .

Even if the current syphilis epidemic is not leading to more HIV infections in well-resourced countries, it is of great concern to people living with HIV that symptoms of syphilis can be both more unusual and more aggressive in HIV-positive individuals, and that syphilis appears to be harder to eradicate with standard treatments. “We are seeing syphilis present in so many different – and often unusual and even unreported – ways,” notes Dr Martin Fisher of Brighton and Sussex University Hospital. “Even the best textbooks were written before the HIV epidemic and so we are having to learn from new experiences, and, hopefully, rewrite the old texts.”

Syphilis can cause a range of symptoms or none at all, but if left untreated it can have very serious effects on the brain and the rest of the nervous system (known as neurosyphilis). In HIV-positive people, the chancre (sore) associated with initial infection (primary syphilis) can appear as unusual or multiple ulcers, and may be mistaken for an attack of genital herpes, which can happen at the same time. It can also be totally missed by both patient and doctor. Consequently, syphilis is more often diagnosed in HIV-positive people when it has progressed to the often symptomatic secondary stage, when it shows up in blood tests. “The experience in Manchester is that more patients with HIV are likely to be symptom-free with their primary disease and yet present with more florid secondary disease,” says Dr Ed Wilkins of North Manchester General Hospital.

It can take up to 90 days for the body to develop antibodies to the bacteria that cause 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; in fact, some HIV-infected people who have syphilis may test negative.

Since 2002, the HIV Special Interest Group of the British Association of Sexual Health and HIV (BASHH), chaired by Martin Fisher, has recommended that in an outbreak situation, a blood test for syphilis should take place every three months, at the same time as routine CD4 counts and viral loads. This is now standard practice at HIV clinics in major UK cities that serve large populations of gay men.

As a result of regular testing, even where there are no symptoms, cases of syphilis have been found. “Since we have been testing for syphilis regularly we have seen a lot of cases where the change from negative to positive antibody tests is the only indication of recently acquired infection,” notes Stephen Taylor. Brighton’s Martin Fisher adds: “A significant proportion of our syphilis diagnoses have been picked up by a policy of routine frequent screening in the absence of any symptoms.”

The minimum standard of treatment set out by the British Association of Sexual Health and HIV (BASHH) guidelines is to treat syphilis with drugs that are strong enough to cause the syphilis bacteria to drop to a level in both the blood and cerebrospinal fluid (CSF, the fluid found in the brain and spinal cord) that will prevent future neurosyphilis.

“By treating all stages of syphilis in HIV adequately [with a regimen that is known to completely kill the bacterium that causes syphilis], future confusion about suboptimal therapy will be avoided should the patient develop neurological or psychiatric symptoms or signs,” say the guidelines, which can be downloaded in full here.

However, some UK clinicians argue that there is no hard evidence to support these recommendations; rather, they are based on expert opinion. Because of this, and also due in part to patient preference, there is currently great variation in treatments across the UK.

The first-line treatment recommended by the BASHH guidelines requires up to 17 consecutive days of somewhat painful intramuscular injections of procaine penicillin (usually into each buttock) along with four probenecid tablets a day to keep blood levels of penicillin high.

In contrast, the standard penicillin treatment for HIV-negative people (and given to HIV-positive people with syphilis in some London treatment centres) is one to three intramuscular injections of benzathine penicillin over one to three weeks.

“Our first-line treatment is to offer all HIV-positive patients daily procaine penicillin,” says Birmingham's Stephen Taylor. “However, many still choose to take weekly benzathene penicillin, despite us explaining the potential risks of treatment failure.”

The first option for patients in Brighton who are allergic to penicillin is to attempt a desensitisation protocol, which requires a day in hospital. “If this is unsuccessful, we use [the oral antibiotic] doxycycline,” says Martin Fisher. However, doxycycline should only be considered in the case of true penicillin allergy, according to the BASHH guidelines, because of the risk that it might not completely eradicate the syphilis bacteria.

However, some HIV-positive individuals are opting not to have injections whether or not they are allergic to penicillin, instead choosing oral antibiotics. Until a few years ago, the oral antibiotic azithromycin would have been an option for HIV-positive gay men with syphilis. However, since reports emerged 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, its popularity as a first-line treatment for syphilis in HIV-positive gay men in the US and Ireland waned dramatically.

Although the investigators found that azithromycin and penicillin worked equally well in HIV-positive individuals in the recent Tanzanian study, azithromycin-resistant syphilis was not found there. Since the HIV-positive gay syphilis epidemic has been linked to anonymous national and international sexual networks, the likelihood is high that today azithromycin-resistant syphilis is infecting HIV-positive gay men outside of the US and Ireland. Writing in an editorial in the New England Journal of Medicine, that accompanies the Tanzanian study, Dr King K. Holmes from the University of Washington in Seattle, says: "Although we can hope that macrolide-resistant T. pallidum has not and will not spread rapidly from sexual networks of men having sex with men in North America and Ireland to sexual networks elsewhere, it will be wise to ensure close follow-up of any patients treated with azithromycin for early syphilis throughout the world. It is also essential to gather more data on the global prevalence of [azithromycin] resistance in T. pallidumand its effect on treatment."

Of more concern was the fact that the investigators did not obtain samples of cerebrospinal fluid to see whether the azithromycin had eradicated syphilis from the brain and spinal cord. In fact, it is thought that the bacteria that causes syphilis can infect the cerebrospinal fluid in around 70-80% of cases. However, experts are still debating whether HIV-positive patients are more likely to experience syphilis symptoms that affect the brain and the rest of the nervous system.

“Neurosyphilis is more common in HIV-infected persons at all stages of the infection, with several units reporting rates of 21-28%,” says Ed Wilkins. “Although we have seen several cases of early neurosyphilis presenting with meningitis,” he adds, “we have not seen any late cases in our unit to date. Most patients are presenting with minor symptoms such as headache, and are found to have abnormal CSF findings on lumbar puncture [also known as a spinal tap, an invasive procedure that involves the insertion of a needle into the lower spine]. Others are presenting with more florid features of meningitis, including headache, neck stiffness, and photophobia [sensitivity to light].”

Martin Fisher concurs: “We really haven’t seen much true late neurosyphilis, apart from the odd case in HIV-uninfected individuals who have never been tested before and who almost certainly acquired their syphilis a long time ago, although we have seen eye and ear involvement during secondary syphilis.”

Treatment recommendations from the CDC and WHO for neurosyphilis are similar to the BASHH recommendations for all syphilis in HIV-positive individuals. However, last year, a study found that HIV-positive people were two-and-a-half times less likely, and those with CD4 cell counts below 200 cells/mm³ almost four times less likely, to completely eradicate the bacteria that cause syphilis from their CSF, when using any one of three recommended treatments for neurosyphilis.

At the moment, it remains uncertain whether this reflects a need for even more aggressive treatment in neurosyphilis patients with HIV. This is as a concern, but, as Martin Fisher says, “hopefully a proactive approach to identifying early syphilis and a concerted effort for optimal therapy will mean that true neurosyphilis will remain relatively rare.”

A single pill, or a short series of injections might be the most appropriate and convenient treatments according to some experts. However, the BASHH-recommended treatment for syphilis in HIV-positive people regardless of CSF involvement may well be preferable to incomplete symptom resolution and more aggressive treatment later, although it is inconvenient and painful. Nevertheless, it is important that all HIV-positive individuals who are about to have treatment for syphilis are aware of all the pros and cons of their (or their doctor's) treatment choices.

It’s also worth remembering that just like with HIV infection, syphilis prevention is better than cure, and earlier detection better than later detection: “You have to really keep your eyes and ears open,” says Martin Fisher. “It needs to be high up in the level of suspicion of anyone with an undiagnosed problem.”

_{A version of this article first appeared in the March 2005 issue of AIDS Treatment Update.}