Slowing Resurgent Syphilis in People With HIV
Table of Contents
- An Epidemic Ends -- Then Resumes
- Syphilis Prevalence and Incidence Climbing
- HIV Incidence in People With Syphilis
- How Syphilis Starts, and How to Spot It
- Syphilis in the Brain, Syphilis in the Eye
- How Syphilis Affects HIV and Vice Versa
- Syphilis Treatment Response in People With HIV
- Preventing Syphilis: Easy and Hard
After reaching historically low levels in the 1990s, syphilis prevalence began to climb in the United States, Western Europe and elsewhere, largely because of a surge in new infections among men who have sex with men (MSM). In the United States, a large proportion of people with newly diagnosed syphilis also have HIV infection. Like other sexually transmitted infections, syphilis can heighten the risk of HIV transmission. Because signs and symptoms of primary and secondary syphilis may be innocuous or hidden, experts advise routine syphilis screening in sexually active HIV-positive people. HIV infection complicates the course of syphilis and can lower rates of serologic response to syphilis therapy. Some evidence indicates that antiretroviral therapy lowers the risk of neurosyphilis and is associated with a better response to syphilis therapy. CDC treatment advice for syphilis does not differ for HIV-positive people and the general population, although some authorities believe people with HIV may need more intense therapy. Notifying sex partners of people with recently diagnosed syphilis -- and perhaps presumptive treatment of sex partners -- may slow the spread of syphilis.
France's Charles VIII, called "the Affable," didn't win many Italian friends when he invaded the peninsula with 25,000 men, eyeing Naples as his prize and subduing Florence along the way. And his troops probably found Charles less than likable when they left Naples with genital or oral sores and, soon enough, rash on the hands and feet.
They had syphilis, or the Neapolitan disease, or -- from the Neapolitan point of view -- the French disease. And while the French occupation of Naples in 1495 barely earns a footnote in geopolitical history, it marks day 1 of the European syphilis epidemic that claimed Schubert, Napoleon, Nietzsche, and countless less celebrated victims before penicillin offered a cure.
Thanks to Charles's transalpine excursions, syphilis ranks as one of the oldest recognized sexually transmitted infections (STIs). Whether Columbus brought it back from San Salvador, as some speculate, or whether it reached Naples by land, remains unknown.1,2 But epidemics of the Great Pox (so called to distinguish it from smallpox) soon flared in China, Japan, and India.
Within 50 years of the Neapolitan outbreak, Verona's Girolamo Fracastoro, a physician, geographer, and mathematician, published the epic poem "Syphilis sive morbus gallicus" ("Syphilis or the French disease," a title suggesting where Fracastoro's epidemiologic sympathies lay).3 The poem featured a hapless shepherd named Syphilus who ran afoul of Haiti's sun god and got cursed with "disfiguring sores." Sixteen years after penning this edifying epic, Fracastoro advanced the spore theory of epidemic disease, arguing that these vaguely defined entities can transmit infection through direct or indirect contact.4
Because no one knew what caused syphilis -- much less how to treat it -- this three-stage pox spread unabated for centuries. And it spread with great efficiency. Fracastoro's 20th century scions figure that half of sex partners whose bed mate has primary or secondary syphilis get the disease.5 You don't have to pull down your partner's pants, either: Treponema pallidum jumps from oral chancres to oral abrasions with acrobatic ease. Among men who have sex with men (MSM), who spearhead today's syphilis resurgence, researchers estimate that 20% in Chicago, 25% in Sidney, 37% in Brighton, and 46% in Northern Ireland owe their infection to oral sex.6
The 21st century syphilis epidemic has its center among gay and bisexual men with and without HIV, though heterosexual men and women play their part. In the United States, for example, 36% of reported primary and secondary syphilis cases in 2006 involved women or heterosexual men, and new cases of congenital syphilis -- a legacy of T pallidum-positive mothers -- inched up from 339 in 2005 to 349 in 2006.7 But syphilis incidence has climbed most steeply among MSM in North America and Europe, surely in part because of relaxed sexual prudence following the success of combination antiretroviral therapy in the mid-1990s. And the easy oral transmissibility of T pallidum means even men who practice "safer sex" (from an HIV perspective) are not so safe (from a syphilis perspective). Because primary and secondary syphilis can run their course unnoticed, the risk of latent and deadly tertiary syphilis cannot be ignored.
This article analyzes recrudescent syphilis prevalence and incidence in the late 20th and early 21st century, the impact of syphilis on HIV and vice versa, and HIV-specific testing, diagnosis, treatment, and prevention. A companion article in this issue of RITA! takes the same approach with an even more prevalent bacterial pathogen in people with HIV, Chlamydia trachomatis.
Syphilis prevalence in the United States peaked at around 600,000 cases in the last year of World War II,8 40 years after German scientists discovered that the spirochete now called T pallidum causes syphilis9 and 2 years after research showed that penicillin cures it.10 By 1953 Eisenhower administration seers proposed mothballing the Public Health Service venereal disease program because its work was done.11 Primary and secondary syphilis cases in the United States hit a low of 5976 at the turn of the millennium, the nadir since reporting began in 1941.12
Then everything changed.
From 1999 through 2005, California endured over a 700% jump in primary and secondary syphilis cases, 80% of them in MSM.12 Across the country, prevalence climbed from the 5976 low in 2000 to 8724 in 2005, with more than 80% in gay and bisexual men.12 Over the past decade syphilis prevalence rose among MSM in Chicago, Seattle, San Francisco, Southern California, Miami, and New York City, and 20% to 70% of men with syphilis had HIV.13 By 2006 the South accounted for 47.1% of primary and secondary syphilis cases.14 From 2005 to 2006, rates of primary and secondary syphilis rose 15.2% in the West, 13.2% in the South, and 13.0% in the Northeast, while staying flat in the Midwest.14
In 1995 all European Union countries except Germany reported fewer than 300 syphilis cases;1 after 1996 Austria, Belgium, Denmark, France, Germany, Ireland, the Netherlands, the UK, Canada, Australia, and New Zealand all reported big jumps -- and most new cases involved MSM.1 Across the world, researchers estimate that 50% to 60% of MSM with early syphilis have HIV.15
What accounts for the resurgent syphilis epidemic among gay and bisexual men? Research summarized below (see "Syphilis risk factors in gay and bisexual men,") identifies specific risk factors for syphilis in MSM, which researchers group into a few broad categories (Table 1).1,12
|Table 1. Factors that May Contribute to Resurgent Syphilis Among MSM1,12|
Besides prompting gay men and others to abandon safer sex, the advent of potent antiretroviral medleys may have helped spark today's syphilis epidemic by damping the AIDS death rate, the Centers for Disease Control and Prevention (CDC) suggests.16 Before the era of combination antiretroviral therapy, syphilis rates were probably lower in HIV-positive people because they died of other causes before syphilis could be diagnosed -- or before they could get syphilis. So prolonged survival thanks to triple therapy could contribute to the surge in syphilis diagnoses over the past 15 years.
Modeling studies suggest that an interaction between T pallidum and natural immunity may cause cycles in epidemic syphilis, but some analysts are skeptical.1,17 In fact, analyzing longitudinal CDC data in 2008, some experts proposed "it is quite possible that the CDC could be successful in eliminating syphilis within the next few decades."17 But research reviewed in this article suggests eliminating syphilis will require -- for starters -- a tectonic shift in sexual behavior among MSM.
CDC officials chose 1999 to launch their National Plan to Eliminate Syphilis. The timing could not have been better -- or worse. The timing looked good, the CDC explained, because efforts could "capitalize on a decade of declining rates of syphilis" with a strategy focused on groups that seemed most affected at that point -- "heterosexual minority populations, particularly African Americans."18 And between the 1999 launch date and 2004, progress looked promising: primary and secondary syphilis rates among blacks plunged 37%, from 14.3 to 9.0 cases per 100,000 people, and the black-to-white syphilis rate ratio shrunk from 28.6-to-1 to 5.6-to-1.
But the time could not have been worse for a reason few, if any, divined in 1999 -- the surge in syphilis incidence among gay and bisexual men. In the summer of 1999 -- just as the CDC rolled out its elimination plan -- San Francisco saw a spike in early syphilis among MSM who corralled sex mates on the Internet (Figure 1).19 Over the next 4 years, syphilis incidence in San Francisco ballooned from 44 to 522 cases a year.20 The CDC revised its National Plan to Eliminate Syphilis in 2006.
By 2002 San Francisco earned the kind of first-place accolade cities hope to avoid -- most cases of primary and secondary syphilis in any US metropolis.19 MSM accounted for 22% of early syphilis cases in 1998 and 88% in 2002. Among 151 MSM with early syphilis, 67 (44%) said they met sex partners online. Analysis of early-syphilis risk factors in this outbreak determined that having recent Internet partners independently doubled the odds of syphilis (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.0 to 4.3).21 Having HIV infection quadrupled the odds of syphilis (OR 3.9, 95% CI 2.0 to 7.7). The CDC cautioned that Internet access makes it much easier to meet sex partners when traveling, a development that could contribute to the US and pan-European spread of syphilis. But San Francisco public health authorities turned this new partnering tool to their advantage, using e-mail addresses collected by men with early syphilis to alert recent sex mates.19,20
A 27-state CDC analysis of primary and secondary syphilis reported from 2005 through 2008 figured that absolute increases in syphilis prevalence were 8 times higher in black MSM and 2.4 times higher in Hispanic MSM than in white MSM.22 The biggest prevalence jumps in this survey involved MSM from 20 to 29 years old, whereas US studies in the early 2000s found most syphilis cases in men in their 30s.
A CDC study of 73 US metropolitan areas with a population over 500,000 and at least 500 black men between the ages of 13 to 24 cataloged big jumps in new HIV and syphilis diagnoses over the 2004-2008 study period.23 Compared with 2004-2005, HIV diagnoses among young black MSM rose in 62 areas (85%) and new primary or secondary syphilis diagnoses in these men jumped in 51 areas (70%). Average HIV incidence among young black MSM rose 68.7% over the study period, while syphilis incidence vaulted 203.5%.
A 2011 systematic review of STI coinfections in people already positive for HIV focused on 37 studies reported since 2000 from Africa, Asia, Europe, and North and South America.24 Trichomoniasis proved the most prevalent STI at 18.5%, with syphilis and gonorrhea tied for second at 9.5%. Coinfection occurred most often in people with newly diagnosed HIV.
A German study of 1052 MSM newly infected with HIV from 1996 through 2007 logged an overall syphilis prevalence of 26%.25 Syphilis prevalence in these members of the German HIV-1 Seroconverter Cohort surged from 10% in 1996-1999 to 35% in 2005. Syphilis prevalence at HIV diagnosis rose from 2.3% in 2000 to 16.9% in 2003 (P < 0.001), then fell back to 4.3% in 2007.
Although MSM account for most newly recorded syphilis cases in developed countries, syphilis remains a palpable threat to women, especially those with HIV. A 1999-2005 European Collaborative Study of HIV-positive pregnant women showed that syphilis prevalence was lower in European women than in MSM, but syphilis was the most common bacterial STI among women, affecting 2% of these 530 Western European women and 520 Ukrainian women.26
In the United States syphilis incidence dwindled consistently among US women after 1990, but a rebound began in 2004 as syphilis incidence rose from 0.8 per 100,000 women that year to 1.0 per 100,000 in 2006.14 Among US women the rate of primary and secondary syphilis climbed 11.1% from 2005 to 2006, nearly matching the 11.8% jump among US men in that period.
A 2002 CDC study matching reported cases of syphilis and HIV found that 1718 of 6862 cases of primary or secondary syphilis (25%) affected HIV-positive people.27 Syphilis incidence -- the new diagnosis rate -- was 77 times higher in HIV-positive people than in the general population. In 2002 new cases of primary or secondary syphilis occurred in 25 of 100,000 HIV-positive women, 60 of 100,000 HIV-positive men who had sex only with women, and 336 of 100,000 HIV-positive MSM.
In California, the epicenter of the US syphilis epidemic, researchers at Kaiser Permanente Northern California counted 622 new diagnoses of syphilis in 9989 HIV-positive people (6.6%) from 1995 through 2005, compared with 3584 new syphilis cases in 4,442,780 HIV-negative people (0.08%).28 Syphilis incidence stood at 62.3 per 1000 person-years in the HIV group versus 0.8 per 1000 person-years in the non-HIV group. Statistical analysis adjusted for age, gender, and HIV status determined that HIV-positive people had an 86 times higher syphilis risk (P < 0.01). In the same analysis, women had a 10% lower syphilis risk than men. In both HIV-positive and HIV-negative people, syphilis incidence waned from 1995 through 2000 but then rose sharply in the HIV group (from 3.1 per 1000 in 2000 to 17.4 per 1000 in 2005). Syphilis incidence did not rise in the HIV-negative group after 2000.
In an Amsterdam Cohort Study of 863 gay men averaging 25 years in age, HIV and STI incidence paralleled each other through 1995.29 At that point -- the threshold of the combination antiretroviral era -- syphilis incidence rose significantly (from 0 to 1.4 cases per 100 person-years), while HIV incidence stayed flat (1.1 to 1.3 cases per 100 person-years).
Studies of MSM in New York City30 and San Francisco21 found that HIV infection independently raised the risk of syphilis -- more than 7 times in New York and almost 4 times in San Francisco (Table 2). All five recent studies on syphilis risk factors in MSM identified some type of risky sex as an independent predictor of syphilis. In New York,30 Brighton,31 and Sydney,32 unprotected anal intercourse made syphilis more likely -- and in Sydney that finding held true in HIV-positive and negative men.
|Table 2. Syphilis Risk Factors in Men Who Have Sex With Men (MSM)|
|Author, Study Year(s)||Site||Number of Participants||Type of Study||Syphilis Risk Factors|
|Paz-Bailey,30 2001||New York City||88 cases, 176 controls||Case-control; cases diagnosed with primary or secondary syphilis and had sex with men in previous year; controls matched by age and type of health provider|
|Wong,21 2002-2003||San Francisco||1318 MSM||Survey of MSM attending city STD clinic|
|Imrie,31 2002-2004||Brighton, UK||50 cases, 108 controls||Case-control study of MSM; cases with early syphilis, controls without syphilis|
|Jin,32 1998-2007||308 MSM with HIV, 1427 MSM without HIV in two community cohorts||Sydney||Syphilis screening and survey of HIV+ and HIV- MSM||HIV+ MSM:|
|Heiligenberg,33 2007-2008||Amsterdam||659 MSM||STI testing and survey of MSM visiting HIV clinic|
cART, combination antiretroviral therapy; fisting, anal penetration with hand; meth, methamphetamine; HR, hazard ratio; methamphetamine; OR, odds ratio; Viagra, sildenafil.
* But having 5 to 9 oral sex partners or 10 or more oral sex partners did not raise the risk of early syphilis compared with controls.
The Brighton study found that having 2 to 4 oral sex partners doubled the syphilis risk compared with control MSM who did not have syphilis,31 and the Amsterdam survey determined that oral-anal sex -- rimming -- hiked the syphilis risk 5 times.33 A 2000-2002 CDC study in Chicago found that 20% of MSM with primary or secondary syphilis reported oral sex as the only kind of sex they had during the study period.34
Having 10 or more casual sex partners doubled the risk of syphilis in Brighton.31 Finding partners on the Internet made syphilis twice as likely in San Francisco, as did reporting a strong gay community affiliation.21 Using methamphetamine with or without sildenafil upped the syphilis odds in San Francisco.21
The New York City researchers tied antiretroviral therapy to syphilis risk, perhaps because good responses to combination therapy led New York MSM to take more risks during sex.30 Among HIV-positive men in that study, 69% with syphilis versus 44% without syphilis reported taking antiretrovirals (P = 0.05), and 58% with syphilis versus 24% without syphilis said they had an undetectable viral load (P = 0.02).
All these studies involve men in big cities with lengthy HIV epidemics, so syphilis risk factors may differ in other MSM populations. And none of these studies identified an intuitive risk factor for syphilis: people who get syphilis once run a high risk of getting it again. Christina Marra, who studies syphilis and HIV at the University of Washington, Seattle, told RITA! that 123 of 901 people in her syphilis cohort (14%) have come back with recurrent infection from 1 to 5 times. Besides persistence of the same risk behaviors, she believes that evolution of the spirochete puts people at risk of reinfection.
The syphilis reinfection rate is even higher in a Baltimore cohort at Johns Hopkins University. In an interview in this issue of RITA!, Khalil Ghanem estimates the overall reinfection rate at 30% in the 3 years of initial syphilis therapy.
Intuition -- if not hard numbers -- suggests that HIV incidence should jump in tandem with syphilis incidence: Syphilitic chancres offer wide portals for HIV to enter the circulation; CD4-cell homing to inflamed lesions provides a brimming population of HIV-susceptible cells; and syphilis-induced immune activation would ratchet up HIV replication.15 Also, syphilis boosts HIV load in already infected people,15 and people with higher viral loads transmit HIV more readily than those with lower loads.
The CDC figures that people with syphilis run a 2 to 5 times greater risk of HIV infection if exposed to HIV when they have syphilis sores.7 But the CDC stresses that -- at least through 2005 -- data collected in the United States make it impossible to say whether HIV incidence climbs among MSM during syphilis outbreaks in this country.15 Findings from San Francisco, Los Angeles, and Seattle-Kings County, Washington, uncovered no hint that HIV incidence jumped among MSM getting tested for HIV during syphilis outbreaks.15 And because most US data on HIV and syphilis incidence come from big cities with large gay populations and established HIV epidemics, those findings cannot explain what's happening across the country.
Data from other countries are mixed. As already noted, syphilis incidence rose significantly after 1995 among MSM in the Amsterdam Cohort, while HIV incidence stalled.29 Germany, on the other hand, saw a surge in coincident HIV and syphilis from 2000 (2.3% of new HIV diagnoses) to 2003 (16.9%), then a decline (to 4.3%) in 2007.25
CDC researchers tried to pin down HIV incidence in men with primary or secondary syphilis in a 2004-2005 study of 357 men in Atlanta, San Francisco, and Los Angeles.35 Most of these men, 85%, were MSM, and 160 (45%) tested positive for HIV. Of those 160, 8 had recent infection, and 7 of those 8 were MSM. The CDC reckoned that HIV incidence among men with primary or secondary syphilis in these three cities stood at 9.5% per year -- and at 10.5% per year in MSM.
Two other US studies suggest frequent HIV transmission just before, just after, or during a period of syphilis acquisition.36,37 Those findings, the CDC says, "are consistent with other studies indicating that a substantial proportion of recently and acutely HIV-infected persons have genital ulcer disease or other STDs and can be identified at the STD clinics."15
But these findings35-37 do not mean HIV incidence billows whenever syphilis incidence climbs. The CDC concluded its 2005 review of HIV incidence in the midst of a syphilis epidemic by cautioning that, "with the limited existing data, we cannot say whether HIV incidence has been increasing among MSM during syphilis outbreaks in the United States."15 But, the CDC analysts add, "we do know that, to date, syphilis outbreaks have been concentrated among urban MSM, the majority of whom are HIV infected."15
What happened after 2005? As already noted,22 a 27-state CDC study confirmed an unabated surge in primary and secondary syphilis among MSM through 2008. Compared with white MSM, black MSM had an 8 times higher absolute increase in the rate of primary or secondary syphilis, and Hispanic MSM had a 2.4 times higher rate increase. Men from 20 to 29 years old endured the biggest syphilis hikes in this analysis. The CDC investigators believe their findings "suggest a marked shift in the epidemiology of primary and secondary syphilis in the United States in recent years, specifically with regard to MSM."22 In the first years of this century, studies disclosed outbreaks of primary and secondary syphilis among MSM in their 30s, but the 2005-to-2008 CDC study found that men under 30 -- and black and Hispanic men -- bore the brunt of new syphilis infections.
These syphilis findings track with the CDC's most recent HIV incidence report, covering the years 2006 through 2009.38 In the United States overall HIV incidence stayed flat in those years, but incidence soared 34% among young MSM and 48% among young black MSM. Among all 13- to 29-year-olds, only MSM had a significant jump in HIV incidence, and among 13- to 29-year-old MSM, HIV incidence rose most among blacks. Together, these studies22,38 suggest that syphilis and HIV incidence are climbing in tandem -- and climbing fastest in young, black MSM.
Treponema pallidum is a spirochete -- a spiral-shaped bacterium that corkscrews its ways through pinpoint spaces between endothelial cells to flood the bloodstream and invade the body.39 (Figure 2). (Borrelia burgdorferi, the Lyme disease provocateur, is the other famous spirochete.) Although an alerted immune system kills billions of treponemes after syphilis infection, enough can survive to kick off primary syphilis (Figure 3).1 T pallidum leaps with dreadful efficiency from someone with primary or secondary syphilis to a sex partner, infecting as many as half of partners whose skin abrades an open sore.5 Transmission risk may be magnified when the infecting partner harbors both T pallidum and HIV, because HIV-positive people tend to have larger, deeper lesions -- and more of them.1
T pallidum starts replicating right at the infection site, dividing once every 30 to 33 hours and inciting an inflammatory response that yields the painless lesion of primary syphilis 10 to 90 days after exposure.39 This chancre heals without treatment after another 3 to 6 weeks.7 But if syphilis is left untreated, secondary syphilis develops, marked by a non-itchy rash on the palms, the soles of the feet, or other areas. (See Figure 2.) Sometimes this rash appears as rough, red, or reddish-brown spots, but it may also mimic rashes seen with other diseases.7 Fever, swollen lymph glands, sore throat, patchy hair loss, headaches, weight loss, muscle aches, and fatigue all may -- or may not -- mark secondary syphilis.
If secondary-stage syphilis remains untreated, it proceeds to early and late latent stages with no signs or symptoms and ultimately to the complicated, life-threatening tertiary stage 10 to 20 years after primary and secondary syphilis in 15% of people (Figure 3).7 Tertiary syphilis may ravage the brain, nerves, eyes, heart, blood vessels, liver, bones, or joints.7 People with late-stage syphilis may have difficulty coordinating movement, they may become numb or even paralyzed, and they may go blind or endure dementia. They may die.
No one becomes immune to syphilis. Infected people who get cured can get syphilis all over again.7
A century ago William Osler called syphilis "the Great Imitator,"8 and clinical diagnosis has not got much easier in the interim. Many people with syphilis -- and their physicians -- may miss primary and secondary infection entirely because the lesions are innocuous or hidden (in the anus, rectum, or vagina) and because the rash is faint or looks like any other rash. As a result, authorities recommend regular syphilis screening for people with HIV.
CDC opportunistic infection guidelines call for universal syphilis screening "conducted on the basis of the local area and institutional prevalence of early (primary, secondary, and early latent) infectious syphilis."40 But those guidelines give little direction to localities and institutions without reliable syphilis numbers, and they offer no specific advice on people with HIV.
For HIV-positive people, the HIV Medicine Association (HIVMA) calls for routine serologic syphilis screening at the first visit then at least annually in sexually active people and every 3 to 6 months in people with (1) multiple partners, (2) a history of unprotected intercourse, (3) a history of sex while using illicit drug use, (4) a methamphetamine habit, or (5) sex partners who participate in such activities.41
In a 2007 review article on syphilis and HIV, Nicola Zetola (University of California, San Francisco) and Jeffrey Klausner (San Francisco Department of Public Health) also recommend at least yearly syphilis screening for people with HIV and screening 2 to 4 times yearly for high-risk groups "such as MSM."12 They call HIV testing "critical for all patients with a new diagnosis of syphilis."12
In an interview in this issue of RITA!, Khalil Ghanem (Johns Hopkins University) says he tries to screen high-risk patients -- such as those who meet anonymous partners on the Internet -- every 3, 2, or even 1 month.
Are most sexually active MSM in the United States getting tested for syphilis every year? No. A CDC study of 10,030 sexually active, HIV-negative MSM from 2003 through 2005 found that only 39% got an annual syphilis screen.42 Men 18 to 24 years old were twice as likely to get tested annually as men over 44 (OR 2.2, 95% CI 1.8 to 2.5), and men who told their clinician they had sex with men were twice as likely to get tested as men who did not (OR 2.2, 95% CI 2.0 to 2.5). Blacks were 30% more likely to get tested annually than whites (OR 1.3, 95% CI 1.1 to 1.4), as were men with private insurance versus no insurance (OR 1.3 95% CI 1.1 to 1.4).
Can men with HIV be taught to examine themselves for syphilis sores more often? Yes. A study of 689 HIV-positive men attending two big Phoenix-area HIV clinics found that provider counseling consisting of chancre photos, sexual risk assessment, and counseling on the impact of syphilis encouraged men to look for sores more often in oral and rectal areas.43 Self-exam rates rose from 60% to 80% among men with two visits during the study period (P < 0.01) and from 58% to 83% among men with three visits (P < 0.001).
Can MSM be screened for syphilis outside the clinic? Yes. In Brighton, a British seaside resort with a big gay population, researchers offered syphilis testing to MSM at popular gay hangouts, including bars, clubs, cruising haunts, and a sauna.44 Health workers tested 1090 men in 7 weeks, 64% of whom had 2 or more sex partners in the past 90 days. Syphilis diagnosis rates were similar with a blood test (1.4%) and a saliva test validated by the Health Protection Agency (1.8%). Notably, 62% of these men had not attended an STI clinic in the past year.
HIVMA experts say the standard approach to diagnosing syphilis starts with a nontreponemal test such as rapid plasma reagin (RPR) or the Venereal Disease Research Laboratory (VDRL) test.41 If this initial test proves reactive, it should be followed by a treponemal test such as FTA-ABS, MHA-TP, or TPPA. Zetola and Klausner agree these serologic tests can diagnose syphilis in most people with HIV.12 When this standard approach cannot confirm the diagnosis, they advise clinicians to consider direct testing methods such as dark-field microscopy, direct fluorescent antibody-treponema pallidum (DFA-TP), and PCR. They note that a multiplex PCR has sensitivities of 100% for herpes simplex, 98% for Haemophilus ducreyi, and 91% Treponema pallidum.
The CDC's Kevin Fenton and colleagues suggest another approach, noting that the treponemal enzyme immunoassay is "increasingly used as the initial screening test" because of its high specificity, sensitivity, and suitability for automation.1 If the enzyme immunoassay is positive, these experts suggest confirmation with another treponemal test, usually TPPA or TPHA. Then a nontreponemal test can be used to stage the infection.
University of Washington syphilis expert Christina Marra warns clinicians to watch out for false-negative RPR results caused by the prozone phenomenon -- antibody titers so high that they hinder formation of the antigen/antibody complexes that labs read to diagnose syphilis with nontreponemal tests. Marra noted that labs can check for the prozone phenomenon if technicians are the least bit suspicious about results, but sometimes the lab may miss these hints. So when providers have a high index of suspicion that a person has syphilis and the RPR results come back negative, she advises them to ask if the lab checked for the prozone phenomenon.
Syphilis breaches the central nervous system in about one of three people with primary syphilis, regardless of HIV status.12 But unlike HIV-negative people, HIV-positives usually get diagnosed with neurosyphilis when syphilis itself is first detected, a finding suggesting that HIV heightens the risk of neurologic complications.1 CDC guidelines say syphilis should be part of the differential diagnosis of neurologic disease in people with HIV and advise that all HIV-positive people with syphilis and neurologic symptoms should have an immediate spinal tap.40
HIVMA guidelines call for a cerebrospinal fluid (CSF) exam in several circumstances for HIV-positive people:41
- Neurologic or ocular signs or symptoms
- Late latent syphilis (including syphilis of unknown duration)
- Active tertiary syphilis
- Syphilis treatment failure
Health Resources and Services Administration (HRSA) guidelines for HIV care list the same indications for spinal tap, adding that "routine CSF evaluation is not indicated for HIV-infected patients who have early syphilis without neurologic or ophthalmic signs or symptoms."45 Zetola and Klausner do not recommend spinal tap for HIV-positive people with primary, secondary, or early latent syphilis "and a lack of neurologic, visual, or auditory signs or symptoms, regardless of the RPR titer or CD4 cell count."12
Work by Christina Marra and University of Washington colleagues indicates that spinal fluid abnormalities can be predicted by serum RPR titers and a sub-350 CD4 count.46 "If you can predict who is going to have abnormal CSF, then you can target those people for lumbar puncture," Marra suggested in an interview with RITA! "If they have abnormal spinal fluid, treat them for it and prevent them from developing neurologic complications." She also observed that CDC guidelines take a conservative approach on lumbar puncture, recommending it only in people with neurologic symptoms. But Marra worries that HIV clinicians "may not screen for neurologic syphilis symptoms as carefully as might be needed."
Early neurosyphilis affects one third or more people with primary syphilis.12,39 Symptomatic neurosyphilis during primary or secondary syphilis may be more common in people with HIV than in the general population, 47 and HIV-positive people with symptomatic neurosyphilis may have more striking symptoms48 and more severe CSF abnormalities49,50 (Figure 4). But the University of Washington's Christina Marra told RITA! it's hard to say whether neurosyphilis is more common with than without HIV since a good population-based comparison may be impossible because of referral bias. The problem is that clinicians may worry about neurosyphilis more in HIV-positive people and so refer them for lumbar puncture more readily, regardless of symptoms. In contrast, HIV-negative people may be more likely to get referred for lumbar puncture because they have symptoms.
Neurosyphilis symptoms may include meningitis (marked by headache, fever, stiff neck), visual changes (blurred or lost vision, photophobia, other signs of ocular inflammation), hearing changes or loss, or facial weakness.39 The CDC also lists cranial nerve dysfunction, stroke, acute or chronic altered mental status, and loss of vibration sense as neurosyphilis signals.40 A reactive CSF VDRL indicates neurosyphilis, according to the CDC, if CSF is not substantially contaminated with blood.40
HIV load in CSF is higher in people with neurosyphilis than in those without neurosyphilis,51 a finding suggesting an interaction between syphilis and HIV in the central nervous system.39 Several studies yielded evidence that clinical and CSF abnormalities suggesting neurosyphilis are more common at CD4 counts under 350 cells/mm3 in people with HIV.46,48,52,53
One of these studies, a 1990-2006 prospective cohort study at Johns Hopkins University in Baltimore, found that 41 of 231 HIV-positive people (18%) with newly diagnosed syphilis had neurosyphilis.49 A CD4 count below 350 cells/mm3 at syphilis diagnosis almost tripled the odds of neurosyphilis (OR 2.87, 95% CI 1.18 to 7.02), whereas any combination antiretroviral therapy before a syphilis diagnosis lowered neurosyphilis odds 65% (OR 0.35, 95% CI 0.14 to 0.91). Those findings led other researchers to suggest that treatment-induced immune reconstitution improves the local immune response against T pallidum and so controls syphilis infection better.39
The Hopkins study identified two other factors that more than doubled the odds of neurosyphilis in this HIV cohort -- an RPR titer above 1:128 (OR 2.82, 95% CI 1.11 to 7.26) and male gender (OR 2.46, 95% CI 1.06 to 5.70).49 Two thirds of the people with neurosyphilis had early neurosyphilis. Only 38% had resolution of all CSF abnormalities 1 year after lumbar puncture, and 38% had persistent neurosyphilis symptoms despite what appeared to be adequate treatment of neurosyphilis.
Hopkins researcher Khalil Ghanem stresses in an interview following this article that HIV clinicians should not overlook the possibility of early neurosyphilis and of neurosyphilis after appropriate syphilis therapy.
Ocular syphilis affects a disturbing proportion of HIV-positive syphilis patients, may be the first signal of HIV infection, may not result in abnormal CSF findings, and may not respond to treatment. Those findings emerge from a handful of case series and two systematic reviews of ocular syphilis in people with HIV.
A 5-year study of 509 HIV-positive people in Dijon, France found that 20 (3.9%) had syphilis, and 4 of them (20%) had ocular syphilis.54 In a Berlin series of 24 consecutive patients with ocular syphilis seen between 1998 and 2006, 11 (46%) had HIV infection.55 HIV infection had gone undetected in 7 of these 11 before diagnosis of ocular syphilis, and 6 of those 7 had early (CDC category A) HIV infection. A systematic review of 101 HIV-positive people with ocular syphilis found that ocular syphilis led to the HIV diagnosis in 28 of 54 people (52%) with available data, including some with a CD4 count above 200 cells/mm3.56
Among 12 people with HIV-associated ocular syphilis at a Boston hospital, 6 people had normal CSF results.57 A systematic review of 93 HIV-positive people and 50 HIV-negative people with syphilitic uveitis found that 13 of those with HIV (14%) had normal lumbar puncture results.58 Three of 101 people in the other systematic review had a negative nontreponemal test for syphilis.56
In the 101-person review, 97% of those with impaired vision improved with intravenous penicillin or ceftriaxone.56 Three of 12 people in the Boston case series required retreatment within 1.5 years.57 The 143-person review recorded 13 ocular syphilis treatment failures (9%), 11 of them in people with HIV.58 Among 110 people who had intravenous therapy in this series, some did not recover full vision.
The authors of the 143-person analysis list 4 hours of intravenous penicillin for 10 to 21 days as optimal therapy for ocular syphilis.58 They note, though, that some experts consider 10 days of intramuscular penicillin equivalent to intravenous therapy and that the CDC sanctions daily intramuscular penicillin if given with oral probenecid. (See "Syphilis Treatment Response in People With HIV" below.)
Syphilis infection boosts HIV load and cuts CD4 counts, although those reversals tend to resolve when syphilis is treated.59-62 These trends lack complete consistency from study to study. For example, in a study of 52 US men with HIV, viral load did not flare during primary or secondary syphilis among men with antiretroviral-induced virologic suppression.62 That finding reflects a correlation discovered in a 118-person Spanish study, which associated not taking combination antiretrovirals with a viral load gain during syphilis.61 In an Italian series of 38 HIV-positive patients with syphilis, the group's CD4 count barely changed from before syphilis to syphilis onset to after treatment for syphilis (573 to 589 to 573 cells/mm3), and the same was true for viral load (3.3 to 3.2 to 3.5 log10 copies/mL).63 Considering all these studies, Zetola and Klausner warn that "syphilis may account for otherwise unexplained decreases in CD4 cell counts or increases in the plasma viral load in HIV-infected patients" and suggest that syphilis testing may be prudent when that happens.12
Analysis of data prospectively collected from 2239 people with estimated dates of HIV seroconversion uncovered no hint that syphilis coinfection hastens progression to AIDS or death.64 This study of US military personnel included 205 people with confirmed syphilis (9%) and 66 with probable syphilis (3%). The researchers devised a multivariate model that considered outcomes through the start of combination antiretroviral therapy or the last visit and adjusted for CD4 count, age, race, gender, hepatitis B and C status, and confirmed plus probable syphilis. In this analysis syphilis had no impact on risk of AIDS or death (hazard ratio [HR] 0.99, 95% CI 0.73 to 1.33).
In 2008 French experts offered a concise review of how HIV infection can affect the course and treatment of syphilis.65 Although their list of "atypical features" of syphilis in HIV-positive people rests on only a handful of studies, it is nonetheless daunting (Table 3).66-70 These authors65 observe, however, that "few of these features have been confirmed in large observational studies."12,71
|Table 3. How HIV May Affect the Course and Treatment of Syphilis|
Adapted from Pialoux et al.65
* The prozone phenomenon is a false-negative response resulting from antibody titers so high that they hinder formation of the antigen/antibody complexes read to diagnose syphilis with nontreponemal tests.
† Antiretroviral therapy improves chances of serologic response to standard syphilis therapy. See section on "Syphilis treatment response in people with HIV."
It took medical science 450 years to figure out how to treat syphilis. But once it got an answer, that remedy stuck. Compared with treating HIV infection, or even gonorrhea, treating syphilis remains blessedly simple -- and cheap: Two shots of benzathine penicillin G and you're good to go, even if you have HIV infection (usually).
"Syphilis sive morbus gallicus," the 1530 admonitory epic that gave syphilis its name, also prescribed a treatment regimen: mercury plus guaiac oil from the palo santo tree.3 Neither did much to relieve syphilis, but mercury probably killed many who took it to treat their pox, possibly including Franz Schubert. "The best method of prescribing mercury is in the form of inunctions [rubbings]," one authority advised, "but these are useless, except in congenital syphilis, unless carried out by a trained rubber."72
Paul Erhlich, the Nobel laureate famed for groundbreaking work in hematology and immunology, coined the term chemotherapy and discovered arsphenamine (Salvarsan), a form of arsenic and the first chemotherapeutic agent for systemic treatment of a microorganism.73 Salvarsan had to be injected weekly for up to a year10 and had "serious adverse consequences (including death)."8 The unhappy history of syphilis therapy reached its nadir with the notorious US Public Health Service "Tuskegee Study of Untreated Syphilis in the Negro Male."74,75 The longest nontherapeutic human trial in medical history, the Tuskegee study ran for 40 years until exposed by the Associated Press.75
The story of effective syphilis therapy began in 1905 with Fritz Schauddin and Erich Hoffmann, the scientists who described the bacterium now called T pallidum.76 Working at the Public Health Service's eponymous Venereal Disease Research Laboratory (VDRL) on Staten Island, John Mahoney discovered the antitreponemal properties of penicillin in 1943.10 Before World War II ended, trials established that penicillin cures syphilis -- as it does today in most people with T pallidum infection.
Parenteral penicillin G remains the preferred drug to treat syphilis, according to CDC guidelines.40 The preparation (benzathine, aqueous procaine, or aqueous crystalline), dose, and duration of treatment depend on the stage and clinical manifestations of the infection. Typically two 1.2 million-U shots of benzathine penicillin G get the job done in people with primary, secondary, or early latent syphilis40 (though some European countries opt for 600,000 IU of procaine penicillin for 10 to 14 days1).
This two-shot advice holds for people with or without HIV. Although some espouse a longer course of penicillin G -- or doxycycline, tetracycline, or ceftriaxone instead of penicillin -- for HIV-positive people, reviews by HIV/syphilis experts (including the CDC) see no merit in these alternatives.1,12,40 For late latent syphilis or syphilis of unknown duration, the CDC calls for 2.4 million units of benzathine penicillin G weekly for 3 weeks.40
The CDC recommends the same regimen for HIV-positive and negative people with neurosyphilis: 18 to 24 million U of aqueous crystalline penicillin G daily given intravenously as 3 to 4 million U every 4 hours or continuously for 10 to 14 days.40 An alternative regimen is 2.4 million U of intramuscular procaine penicillin once daily plus 500 mg of oral probenecid four times daily for 10 to 14 days. All these CDC recommendations also apply to pregnant women. But research summarized below leads some HIV/syphilis experts to question the CDC's advice.
No matter which drug or course one prescribes for syphilis, the same benchmark indicates an appropriate response: a 4-fold drop in nontreponemal titers, for example, from 1:64 to 1:16, after 6 to 12 months.12 Authorities recommend follow-up 1, 3, 6, 12, and sometimes 24 months after treatment, though research suggests only 20% to 40% of syphilis patients get seen that regularly.12
For HIV-positive people treated for syphilis, Zetola and Klausner recommend serologic response monitoring for up to 1 year for early syphilis and up to 2 years for late syphilis, before deciding whether treatment worked.12 But if nontreponemal titers climb during treatment or if symptoms emerge, they advise clinicians to suspect treatment failure or reinfection. Khalil Ghanem, who studies syphilis and HIV at Baltimore's Johns Hopkins University, believes follow-up serology should be done every 3 months for at least 2 years in HIV-positive people with syphilis.77 "This recommendation is critical," Ghanem stresses, "because this population has a higher probability of experiencing treatment failure and enhanced therapy has not been shown to decrease this risk."
A systematic review of syphilis therapy in HIV-positive people suggested to the authors that "the optimal antimicrobial regimen to treat syphilis in HIV-infected subjects is unknown" and that "guideline recommendations in this population are based on little objective data."78 This analysis involved 23 studies with at least 6 months of follow-up. Probability ranges for serologic failure were 6.9% to 22.4% with 2.4 million U of intramuscular benzathine penicillin G, 19.4% to 31.1% with 7.2 million U of benzathine penicillin G for late latent syphilis, and 27.3% to 27.8% with 18 to 24 million units of aqueous penicillin for neurosyphilis. A case-control study of 129 HIV-positive people with syphilis and 168 HIV-negative people with syphilis at Johns Hopkins University determined that HIV inflated the serologic failure risk 6 times (HR 6.0, 95% CI 1.5 to 23.9, P = 0.01).79 This study also found that 64% of 450 HIV-positive people treated for syphilis did not have documented serologic follow-up within 1 year of treatment (see the interview with Khalil Ghanem in this issue).
In their review of syphilis and HIV, Emily Ho and Sheila Lukehart (University of Washington, Seattle) underline the shortcomings of syphilis treatment in people with HIV:39 (1) higher rates of serologic failure, 28,67,79 (2) viable T pallidum in CSF after standard treatment,67,80,81 and (3) longer time to resolve CSF abnormalities after treatment.49,81,82 Pondering these deficits, they note that the CDC still recommends the same syphilis therapy for HIV-positive and negative people and sees no need for lumbar puncture in people without neurologic signs or symptoms regardless of HIV status. "The long-term repercussions of these recommendations for CSF examination," Ho and Lukehart remark, "are unclear at this time."39
But after reviewing many of these same studies, French investigators conclude that "if HIV has an effect on the course of syphilis, it is small and clinically manageable in most cases."83 However, they stress that studies of syphilis treatment in people with HIV are limited by several shortcomings: (1) high rates of loss to follow-up, (2) lack of long-term follow-up, (3) lack of gold-standard criteria for treatment response, (4) small sample size, (5) lack of stratification by syphilis stage, ongoing antiretroviral treatment, CD4 count, or HIV load, and (6) possible publication bias. In their own retrospective study of consecutive syphilis cases from 2000 through 2007 at an academic STI center, the serologic response rate to syphilis therapy in 114 cases was marginally lower in people with HIV (91.8% versus 98.3%, P = 0.14), and median time to serologic response was similar with and without HIV (117 versus 123 days, P = 0.44).84
Some research found that antiretroviral therapy improves chances of serologic response to syphilis or neurosyphilis therapy.49,85,86 A 1990-2006 study of 180 people with 231 cases of syphilis in the Johns Hopkins cohort determined, after a median 5.3 years of followup, that a CD4 count under 200 cells/mm3 at syphilis diagnosis more than doubled the risk of serologic failure (adjusted HR 2.48, 95% CI 1.26 to 4.88).85 Taking an antiretroviral combination lowered the serologic failure risk 60% (adjusted HR 0.40, 95% CI 0.21 to 0.75), regardless of CD4 response to therapy. Among 41 HIV-positive people with neurosyphilis studied by the same Johns Hopkins group, antiretroviral therapy after treatment for neurosyphilis marginally lowered the risk of serologic failure (P = 0.2).49 In the same study, any combination antiretroviral therapy before a syphilis diagnosis cut the risk of neurosyphilis 65% (OR 0.35, 95% CI 0.14 to 0.91).
A study of 110 people with HIV and neurosyphilis in Seattle found that normalization of RPR titer predicted treatment success less accurately among those not on antiretroviral therapy.86 The same group studied 59 people treated for neurosyphilis who had repeated lumbar puncture.81 Among the 46 people with HIV, those with a CD4 count above 200 cells/mm3 were almost 4 times more likely to normalize CSF-VDRL reactivity than those with a lower count -- a finding implying that antiretroviral therapy could improve response (HR 3.7, 95% CI 1.2 to 11.2, P = 0.02). Overall, though, people with HIV were 2.5 times less likely to attain normal CSF-VDRL reactivity than people without HIV, even after considering baseline CSF-VDRL titer and stage of syphilis at neurosyphilis diagnosis. Zetola and Klausner note that this study "raised concerns regarding the adequacy of the current recommended treatment for neurosyphilis" in people with HIV.12
Single-dose benzathine penicillin G maintains treponemacidal levels of penicillin for at least 2 to 3 weeks -- long enough to cure early syphilis.87 But benzathine penicillin G does not cross the blood-brain barrier, so it cannot control the T pallidum that has been detected in CSF after single-dose therapy.87
"Although serological and microbiological treatment failures have been reported following [benzathine penicillin G] treatment," observe STI experts David Lewis (National Institute for Communicable Diseases, South Africa) and Sheila Lukehart (University of Washington, Seattle), "these may be due to sequestration of treponemes protected in the central nervous system or to reinfection."87 They add that there have been no documented cases of T pallidum resistance to penicillin or tetracycline, but resistance to macrolides has been verified.
Among people allergic to penicillin, alternatives include tetracycline and doxycycline, the macrolides erythromycin and azithromycin, and third-generation cephalosporins such as ceftriaxone.87 In their review of T pallidum treatment and resistance, Lewis and Lukehart call penicillin desensitization "the preferred option to treating penicillin allergic patients who are pregnant or have neurosyphilis."87 They believe doxycycline and tetracycline are options for nonpregnant patients with penicillin allergy, but because adherence to doxycycline and tetracycline may pose problems, "penicillin is preferred if possible." Table 3 in this freely accessible article spells out current advice on antibiotic therapy for syphilis in light of penicillin allergy and resistance to macrolides (see references for link to article).
Syphilis prevention campaigns have featured a giant, roving penis and a walking, raspberry-like syphilis sore.6 These eye-grabbing ploys may raise public awareness for a few minutes, but slowing the syphilis resurgence probably demands sterner tactics. Preventing syphilis remains frustrating because it is both simple and Sisyphean. It's simple because everyone knows what's required: better public understanding of how syphilis spreads, safer sexual gymnastics, more zealous syphilis and HIV screening, and earlier diagnosis and treatment of both STIs. It's Sisyphean because progress on all these fronts comes slowly.
Even though T pallidum can be transmitted orally, condoms do appear to mitigate transmission risk. Circumcision does not. A systematic review of studies addressing condom use and syphilis risk did more to highlight how poorly designed such studies have been than to suggest a conclusion.88 The two studies that examined both incident syphilis infection and consistent condom use both found that regular rubber wearing did lower syphilis risk, and in one study the association was statistically significant. None of the 12 studies evaluated assessed correct condom use or documented exposure to a sex partner with syphilis.
Researchers who prospectively study a cohort of HIV-positive and negative people in Rakai, Uganda famously demonstrated (with two other groups) that circumcision significantly lowers the risk of HIV acquisition by heterosexual men. Continuing research showed that circumcision also significantly cut HSV-2 infection incidence and HPV infection prevalence.89 But that analysis turned up no evidence that circumcision helps shield heterosexual men from syphilis.
A Cochrane Database review of 8 studies involving 34,999 MSM confirmed that circumcision does not stop syphilis in this population.90
Scientists have sequenced the entire T pallidum genome, a key step in identifying surface molecules and thus in designing a vaccine.6 Warning that development of a protective syphilis vaccine remains "formidable," Ho and Lukehart note that studies are under way to test the ability of a "cocktail of conserved regions on T pallidum antigens" that might confer immunity in a rabbit model.39
In the meantime, notifying sex partners of people with recently diagnosed syphilis -- and perhaps treating them presumptively -- may slow the spread of this sinuous pathogen. HRSA HIV guidelines advise that sex partners of anyone diagnosed with primary, secondary, or early latent syphilis in the past 90 days "should be treated presumptively, as they may be infected with syphilis even if they are seronegative."45 Sex partners exposed more than 90 days after such a diagnosis should be treated presumptively "if serologic test results are not available immediately and their follow-up is in doubt."45 HRSA adds that some specialists recommend presumptive treatment for sex partners of people diagnosed with primary syphilis in the past 3 months, secondary syphilis in the past 6 months, or early latent syphilis in the past year.
From the first days of the US syphilis resurgence, Internet partnering has helped spread T pallidum.19 Zetola and Klauser12 believe public health officials and providers should not overlook the potential of this fluid medium to notify partners of syphilis patients, promote awareness of this tenacious STI, and offer testing to people who may need it.20,91-93
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