SYPHILIS AND HIV: A RISKY DUO ON THE DANCE FLOOR

By: Ivana Yulian Hendarsin, Cintya Naya Danastri, Adhella Menur

The blaze of syphilis amidst the HIV epidemic

Syphilis, an age-old sexually transmitted disease (STD), has a history marked by stigma and blame. The disease became an outbreak among French soldiers during their invasion of Naples in the first Italian Wars in 1495, two years after Columbus’s return from Hispaniola in 1493. The disease was stigmatized as disgraceful due to promiscuity, and various countries blamed each other for the outbreak. For example, the French referred to it as the ‘Neapolitan disease’ or the ‘Spanish disease’; the English and Italians called it the ‘French disease’; the Russians named it the ‘Polish disease’; the Polish and the Persians called it the ‘Turkish disease’; and the Turks called it the ‘Christian disease’. At that time, the disease was more severe and deadly, possibly because of its novelty and the lack of immunity in the population. The name “Syphilis” was introduced in 1530 by the Veronese poet and physician Girolamo Fracastoro. In his poem Syphilis sive morbus gallicus, Fracastoro re-counts the tale of a mythical shepherd named Syphilus who offended the Sun God by blaming him for a drought and insulting him. As punishment, the Sun God afflicted Syphilus and his community with a horrendous new illness. Fracastoro’s poem gained attention among scholars, leading to the adoption of the term “Syphilis” to describe the disease.

In 1905, Schaudinn and Hoffman identified spiral-shaped bacteria in syphilis lesions (both fresh and Giemsa-stained specimens) as the etiologic agent, naming them Treponema pallidum. Several diagnostic methods were introduced in the following years, such as Landsteiner’s dark-field microscopy, August Wassermann’s serologic test, and the specific T. pallidum immobilization test (TPI) by Nelson and Mayer. However, the only available treatment at that time involved using toxic metals like mercury and arsenic, often leading to severe side effects and even death. The disease can be devastating, and congenital cases can cause miscarriage, lifelong medical issues, and infant death. Fortunately, penicillin was approved in 1943 and, in combination with aggressive public health interventions including case finding and contact tracing, contributed to a significant decline in the incidence of syphilis in the subsequent decades. Furthermore, in 2000, syphilis cases reached their lowest point in the United States, with an incidence rate of 2.1 cases per 100,000 persons.

Unexpectedly, syphilis has re-emerged as a significant global public health concern. In 2016, an estimated 6 million new cases of syphilis were reported worldwide. Among pregnant women, approximately 7 in every 1000 were found to have syphilis, which led to an estimated 143,000 early fetal deaths and stillbirths, 61,000 neonatal deaths, 41,000 preterm or low-birth-weight births, and 109,000 infants with clinical congenital syphilis. The incidence of syphilis in the U.S. has surged to levels not seen in more than two decades. Reported cases to the U.S. Centers for Disease Control and Prevention (CDC) increased by 81% from 2014 to 2018. More than half of men with new syphilis cases reported having sex with men (MSM), and 20-70% of whom were people living with HIV (PLWH).

Syphilis and HIV co-infection rates have been on a marked rise worldwide in recent years. This rise can be attributed to the fact that both are systemic STDs which share common risk factors, including high-risk sexual activities. Several studies have also highlighted a reciprocal synergistic interaction between syphilis and HIV. The question is, since the HIV epidemic began around the 1980s, why has syphilis surged in recent years? Initially, during the early HIV epidemic, the implementation of syndromic treatment for STDs and widespread adoption of safer sexual practices due to fears of HIV infection contributed to a decline in syphilis prevalence. However, the successful introduction of antiretroviral therapy (ART), pre-exposure prophylaxis (PrEP), and improved survival rates among PLWH have influenced sexual behavior. This high-risk sexual behavior has created opportunities for the resurgence of syphilis as prevention measures have been relaxed or overlooked.

The dancing duo trend between syphilis and HIV should also be a concern for Indonesia. The country stands out as the only one in the Asia Pacific region experiencing a rise in HIV prevalence. As of 2022, there were estimated 540,000 PLWH in Indonesia, with 79% aware of their status and only 33% receiving ART. Concurrently, there has been an increase in syphilis cases in the country due to uninterrupted transmission and improvements in screening efforts. According to the Indonesia Ministry of Health, the number of syphilis cases surged by around 70% between 2016 and 2022, rising from 12,000 to nearly 21,000. Most of these cases were identified among MSM group (28%) and pregnant women (27%). Unfortunately, comprehensive data on the incidence and prevalence of syphilis among PLWH are still lacking. This underscores the urgent need for intensified efforts to address the dual challenges of syphilis and HIV in Indonesia.

The interplay of syphilis and HIV

Syphilis: Brief description

Syphilis is a highly infectious STD caused by the extracellular spirochete bacterium, Treponema pallidum, which spreads through contact with infectious lesions or body fluids. The crucial initial step of infection is the attachment to host cells and the extracellular matrix. Once beneath the epithelium, the spirochetes multiply locally and disseminate through the lymphatics and bloodstream. T. pallidum is one of the few pathogens capable of crossing specialized endothelial barriers such as the retinal, placental, and blood-brain barriers. Transmission of syphilis occurs primarily through sexual contact or in utero, from mother to child. Given the lack of animal reservoirs, syphilis theoretically could be a disease that we could eradicate. The average incubation period of syphilis is approximately three weeks (10–90 days). Syphilis is often referred to as the “Great Imitator” or “Great Mimicker” because of its varied and sometimes subtle presentations, which can resemble other infections. The classic clinical manifestations of syphilis are divided into early syphilis (primary, secondary, and early latent stages), which is highly infectious, and late syphilis (late latent and tertiary stages). How the pathogen burden is eventually decreased, and how latency is maintained remains a mystery. Equally mysterious is where T. pallidum resides during latency. Its ability to survive for extended periods while evading humoral defenses makes it a “stealth pathogen.”

The primary stage of syphilis manifests as a solitary chancre, indurated and ulcerative, with a clean base at the site of contact or inoculation. The chancre is usually painless and may occur at extragenital sites such as the perirectal area, the rectum, or the oral cavity. Secondary syphilis is a systemic disease resulting from bacteremia, with clinical manifestations including a mild, nonpruritic rash, fever, generalized lymphadenopathy, mucosal lesions, alopecia, periostitis, and occasionally hepatitis or nephritis. Secondary syphilis is followed by a period termed latent syphilis in which no symptoms are present, and diagnosis can only be achieved through serological testing. Latent syphilis is subdivided into early latent (≤1 year after infection) and either late latent or latent syphilis of unknown duration. Tertiary syphilis describes a broad range of manifestations but most commonly includes gummatous (soft, tumor-like growths of the tissues that are highly destructive), cardiovascular, and/or neurological effects and can also cause death. Of note, neurosyphilis can occur at any stage of the disease. Early neurosyphilis includes meningovascular diseases (e.g., meningitis, strokes, seizures), brainstem or cranial nerve abnormalities, ocular syphilis (e.g., blurred vision or blindness), and otosyphilis (auditory vestibular abnormalities). Although there can be substantial overlap, late neuro-syphilis typically affects the brain and spinal cord parenchyma, presenting as dementia, tabes dorsalis, general paresis, sensory ataxia, or bowel or bladder dysfunction.

A detailed history and physical examination construct the diagnosis of syphilis, and both direct and indirect testing are used to establish the diagnosis. Currently, indirect testing with serological assays remains the cornerstone for diagnosis. The traditional serological screening algorithm begins with a non-treponemal test (e.g., a rapid plasma reagin [RPR] or Venereal Disease Research Laboratory [VDRL] test), with reactivity confirmed by a highly sensitive and specific treponemal test (e.g., the T. pallidum hemagglutination assay [TPHA], rapid test [TP rapid], an automated enzyme or chemiluminescence immunoassay). Penicillin remains the drug of choice for all stages of syphilis due to its high effectiveness, and no reports of resistance to it in T. pallidum have been found. Alternative options include ceftriaxone, doxycycline, and erythromycin. Azithromycin should no longer be used due to the detection of global resistance.

The non-treponemal test also provides titers that are necessary for clinical management and evaluation. With adequate treatment, most patients will return to a non-reactive non-treponemal antibody. Serological cure is defined as a seroconversion (from positive to negative) or as a 4-fold (or two dilutions) decline in non-treponemal antibody titer 6 to 12 months after therapy for early syphilis and 12 to 24 months for late syphilis. Some patients may maintain a low non-treponemal antibody titer for life despite adequate treatment (serofast). Treatment failure is defined as a ≥4-fold rise in non-treponemal titers after treatment in the absence of re-infection. An individual with a previous serological cure might be considered as “re-infected” if a new seroconversion (from negative to positive) or a 4-fold or greater increase in non-treponemal antibody titer occurs. Conversely, antibodies detected in treponemal tests usually remain detectable for life even after successful treatment. Thus, a reactive treponemal test can indicate current or past syphilis infection.

Syphilis and HIV: What’s the dance they play?

The understanding of the interaction between syphilis and HIV has continued to evolve and increase clinical importance, given the rising rates of co-infection and the unique synergy between the duo. Untreated syphilis can increase the risk of transmitting and acquiring HIV infection. In turn, co-infection with HIV can affect the manifestations of syphilis and make it harder to distinguish between its stages, potentially leading to misdiagnosis. Syphilis infection does not lead to immunity against reinfection, and repeated episodes of syphilis can occur predominantly in PLWH, especially in an asymptomatic form. A study in one center reported syphilis reinfections in PLWH, ranging from one to seven episodes. Patients with the duo infection may also face a higher risk of syphilis treatment failure, and their genital ulcers typically take longer to heal compared to those with syphilis alone, which can increase transmission and the risk of exposure to other STDs.

Neurosyphilis in PLWH requires special attention, but diagnosing it remains challenging due to the lack of highly sensitive and specific tests to distinguish cerebrospinal fluid (CSF) findings compatible with neurosyphilis from common abnormalities in PLWH. While a reactive CSF nontreponemal test is highly predictive, it’s less than 80% sensitive. One study found that combining a serum RPR of 1:32 or greater with a CD4+ T cell count of 350 cells/μμL or less increased the likelihood of neurosyphilis. Until more data are available, neurosyphilis should be considered in all PLWH with syphilis, and a lumbar puncture is suggested for those with neurological symptoms, evidence of active tertiary syphilis, late latent syphilis, syphilis of unknown duration, or treatment failure.

The hurdle to stop the risky dance

Iceberg phenomenon

Both HIV and syphilis are stigmatized illnesses, often evoking avoidance and fear in people. The stigma surrounding these diseases persists in society, fueled by many misconceptions about their transmission and the implications of living with HIV and syphilis. Notably, stigma and shame often deter housewives and pregnant women from seeking help. A lack of information, awareness, and outdated beliefs contribute to the unease surrounding these infections, leading to significant underreporting of cases. The complexities of managing syphilis further compound the iceberg phenomenon of dual infection. As previously discussed, syphilis’s reputation as the “Great Imitator” often leads to misdiagnosis, particularly in the early stages when it can mimic other skin or genital diseases. In people living with HIV (PLWH), syphilis diagnosis frequently occurs during the latent stages, resulting in delayed treatment. Additionally, routine laboratory culture media cannot culture T. pallidum, and direct methods like molecular or specialized microscopy techniques are limited by their performance, availability, and costs. Clinicians also struggle with the lack of specificity of non-treponemal tests and the poor correlation of treponemal tests with disease activity.

Furthermore, advancements in HIV management with highly effective antiretroviral therapy (ART) and the understanding that undetectable HIV cannot be transmitted through sex (Undetectable = Untransmittable) have led to declines in previously practiced safer sex behaviors and promoted syphilis transmission. The impact of condomless sex has been further augmented by the introduction of Pre-exposure Prophylaxis (PrEP) and behaviors like “serosorting” (selecting partners with the same HIV status). Increased use of online applications to find sexual partners has also been associated with high-risk behaviors, including having multiple partners and engaging in injectable substance use during sex. Additionally, the misconception that oral sex is “safer” sex and rarely associated with HIV transmission may also play a role in the transmission of syphilis. In Indonesia, syphilis screening is recommended for triple-elimination programs (targeting HIV, syphilis, and Hepatitis B) in pregnant women, women in labor, women with a history of miscarriage or stillbirth, sex workers, MSM groups, and all STD patients. Public health authorities are still working to optimize screening efforts. These issues contribute to enlarging the iceberg base and require prompt attention.

Ping-pong Phenomenon

Sex partners frequently infect and re-infect each other with syphilis, referred to as the “ping-pong phenomenon” or “ping-pong syphilis.” The phenomenon may be more frequent in patients with the duo infection since PLWH experienced more delay in diagnosis, treatment failure, and recurrent cases of syphilis. It is such a really risky duo on the dance floor—high frequency of syphilis re-infection highlighting the need for regular STD screening in sexually active PLWH. The notification of recent sex partners of patients with syphilis and, in particular, of patients with concordant HIV infection is a critical component of disease prevention and control. Early identification and treatment of contacts can potentially prevent the continued spread of both infections. Individuals who had sexual contact within 90 days before the diagnosis of primary, secondary, or early latent syphilis in a sex partner might be infected, even if their serological test is negative. Therefore, these individuals should receive presumptive treatment with Penicillin G benzathine (2.4 million units intramuscularly) once. If the exposure occurred more than 90 days before the diagnosis of early syphilis in a sex partner and serologic results are unavailable or follow-up is uncertain, presumptive treatment is also recommended. Other sex partners are considered at risk and should undergo clinical and serologic evaluation to reduce the likelihood of the ping-pong phenomenon occurring.

Future directions

Improvements in clinical management of HIV and syphilis co-infection are needed in two key areas: enhanced syphilis diagnostic methods and increased efforts in managing and preventing both diseases. While rapid treponemal testing has improved syphilis identification, its limitation in distinguishing active from past infections remains. Developing rapid tests of syphilis combining non-treponemal and treponemal antibodies is promising but requires validation. PCR is being optimized for single syphilis detection or multiplex detection of multiple STDs, though FDA approval and cost remain obstacles. Therefore, up to now, tailoring diagnostic approaches based on understanding syphilis clinical stages is crucial.

The development of syphilis vaccines is imperative, but viable candidates like whole inactivated cell, live attenuated, or genetically engineered vaccines are still years ahead. In the meantime, the use of Doxycycline for prophylaxis in high-risk groups could be considered, with careful attention to antibiotic resistance. Ongoing studies are evaluating the effectiveness of these interventions. Therefore, routine periodic syphilis screening remains the cornerstone of prevention, especially among PLWH, with recommendations every 3 to 6 months. PLWH should receive treatment akin to the general population, with adjustments made for specific scenarios like neurosyphilis or treatment failure. Further research is needed to establish optimal treatment and ensure a cure for syphilis in PLWH.

Integrating syphilis and HIV care is crucial. The dance between the duo is harmful rather than joyful. All the public layers should participate in controlling syphilis and HIV. Health authorities must develop policies that facilitate rational and accessible testing for screening and monitoring while raising awareness about both diseases using innovative media platforms. Clinicians and social workers play a vital role in educating patients, counseling them on safe sexual activities, and regularly screening those at increased risk. Ending the stigma surrounding syphilis and HIV is crucial to creating an environment where people feel comfortable discussing their sexual health and seeking assistance when needed. Together, we can perform a safe and healthy dance!

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