Sexually Transmitted Infections in People with HIV

Introduction

STIs encompass a wide variety of pathogens including bacteria (Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, Treponema pallidum), viruses (human immunodeficiency virus, herpes simplex types 1 and 2, Mpox, human papillomavirus (HPV), hepatitis B and C viruses), parasites (Trichomonas vaginalis), and ectoparasites (scabie¹s and lice). The term ‘sexually transmitted disease’ is used when an individual infected with one of these microorganisms is symptomatic.

Epidemiology and trends will be reviewed by pathogen below. Overall, incidence rates of bacterial STIs have been rising steadily for years^1,2. Patients with HIV (PWH) have even higher incidence rates compared to patients without HIV (Figures 1 and 2)³. Additionally, infection with many STIs increases the risk of acquiring and/or transmitting HIV^4-6. Therefore, preventing, diagnosing, and treating patients with STIs is an important component of HIV infection prevention strategies. This review will summarize the screening recommendations for STIs in PWH, as well as important epidemiologic, clinical, diagnostic and treatment details for the major STIs, with emphasis on where these may differ compared to patients without HIV and will conclude with established and emerging strategies for STI prevention.

Figure 1.

Proportion of MSM with Primary and Secondary Syphilis, Urogenital Gonorrhea, or Urogenital Chlamydia by HIV Status, STD Surveillance Network (SSuN), 2021

(Source and figure from CDC 2021 STI Surveillance Report)

Figure 2.

Primary and Secondary Syphilis— Reported Cases by Sex, Sex of Sex Partners, and HIV Status, 2021

(Source and figure from CDC 2021 STI Surveillance Report).

Screening recommendations

Recommendations for STI screening in PWH (Table 1) are similar to those in patients without HIV, with a few notable exceptions: 1) In people who are receptive partners for vaginal intercourse, screening for Trichomonas vaginalis is recommended, 2) screening for gonorrhea, chlamydia, and syphilis is recommended for all. Screening for HPV infection is covered in the sections of this monograph under HIV and Malignancy.

Table 1-.

Sexually transmitted infection screening recommendations in PLWH

	Recommendation timing and frequency	Notes
Chlamydia and Gonorrhea	Screening at first visit and at least annually thereafter (more frequent screening if risk factors*)	-Patient with vagina: vaginal or endocervical specimens favored over urine -Patient with penis: first void urine recommended -Include all exposed sites for MSM (pharynx, rectum, urethra)
Syphilis	At first visit and at least annually thereafter If pregnant, add first and last trimester screening (State policy-dependent)	Consider re-screening every 3-6 months if new partners
Mycoplasma genitalium	No screening recommendation
Trichomonas	All persons having vaginal sex at intake visit and annually (more frequent screening if risk factors*)	-Vaginal or endocervical specimens favored over urine -No screening recommendation for patients without native vaginas
Herpes Simplex Virus (HSV)	Type-specific serology for HSV-2 infection is not generally recommended in patients presenting for STI evaluation, but may be considered in unique cases
Mpox virus	No screening recommendation
Hepatitis B Virus	HBsAg, HBsAb, HBcAb at first visit If non-immune, offer vaccination.	If HBsAb positive, check HBV viral load Anti-HBs should be obtained 1-2 months after completion of vaccine series to assess for vaccine response
Hepatitis C Virus	HCV antibody all patients >18 years old once Annually if ongoing IDU; consider annually for MSM	If HCV antibody positive, check HCV RNA

(MSM: Men who have sex with men; IDU:Injection drug users; HBsAg: Hepatitis B surface antigen; HBsAb- Hepatitis B surface antibody; HBcAb: Hepatitis B core antibody).

^*Risk factors: New or multiple sexual partners, inconsistent use of barrier contraception, transactional sex work, partner with STI and/or other partners.

Nucleic acid amplification testing (NAAT) is the test of choice for diagnosis of chlamydia and gonorrhea including from extragenital sites. For patients with vaginas, vaginal swabs (provider- or patient collected) or endocervical swabs are preferred, as urine testing can be less sensitive. First-void urine samples are preferred in patients with penile sexual exposure. NAAT performance for chlamydia and gonorrhea from these sites are 95-98% specific and 98-100% specific, respectively^7,8. Chlamydia and gonorrhea screening should include genital and extragenital testing and should be based on current anatomy. It is extremely important to screen all sites of exposure (pharynx, rectum, urine) in MSM and/or transgender women, as urine-only testing can miss a significant portion of infections^9,10. Serology-based screening recommendations (syphilis, viral hepatitis) for transgender patients are similar to cis-gender screening guidelines.

While recommended by many guidelines and funding agencies, STI screening rates are often still low. A study examining STI screening in PLW found only approximately 2/3 had appropriate site-specific sexual screening. Test positivity was highest among MSM (3.1%, compared to a low of 0.2% in women). Of patients diagnosed with STI who had multisite testing, 96% were only positive at an extragenital site, indicating that without expanded screening, many infections would be missed¹¹.

Chlamydia

Epidemiology

Chlamydia trachomatis (CT; serovars D-K) remains the most prevalent bacterial STI in the United States, with 1,649,716 cases reported in 2022¹, representing a steady increase over the past decades. Younger MSM populations have the highest rates of infection³, thus overlapping with many people living with or at risk for HIV. In general, parsing out bacterial STI rates among PWH has involved relying on sentinel studies and surveillance networks. A 2011 systematic review reported overall mean point prevalence of STIs as 16.3% amongst PWH (from 33 studies with confirmed STI testing from both developed and developing countries), with 5% mean prevalence of chlamydia¹². A 2018 CDC STI surveillance report noted in populations attending sentinel STD surveillance clinics in 2018, urogenital chlamydia positivity was essentially the same in HIV-positive or -negative MSM (6.1% and 6.7%, respectively)¹³.

Lymphogranuloma venereum (LGV), caused by CT serovars L1-L3, is rare, and prior to 2003, had been endemic primarily in Africa, India, and Southeast Asia. An outbreak of proctocolitis due to CT LGV serovars was reported in Amsterdam in 2003. Subsequently, large case reports were published describing hundreds of cases in Europe and the US. HIV co-infection rates reported in these outbreaks were extremely high (upwards of 90%). In Europe, where there has been more monitoring than in the US, LGV rates have trended upwards and are higher amongst PWH. LGV diagnoses among MSM visiting STI clinics in the Netherlands increased from less than 100 in 2010 to greater than 250 in 2017, with LGV positivity rate of all positive CT samples also increasing to approximately 10% by 2017. The vast majority of these cases involved PWH¹⁴.

Clinical manifestations

Chlamydia can infect mucosal tissue of the urogenital tract, oropharynx, rectum, and eye. Infections are most commonly asymptomatic¹⁵. In PWH, there are no significant reports to suggest different manifestations of CT presentation^6,16. Clinical syndromes caused by the common urogenital serovars (D-K) can include urethritis, epididymo-orchitis, cervicitis, vaginal discharge, and pelvic inflammatory disease (PID).

LGV can present as a ulceroglandular syndrome occurring in stages: first with a small painless ulcer at the infection site, then a few weeks later with large, tender inguinal lymph nodes (with risk for perforation) and eventual scarring, lymphatic fibrosis and lymphedema. In outbreaks associated with unprotected anal receptive intercourse (primarily in MSM), the presentation is an acute and/or chronic proctitis/proctocolitis, and if untreated, can lead to rectal fissures and perforation. Infection with CT LGV serovars can also be asymptomatic¹⁷.

Diagnosis

Recommended diagnostics for chlamydia infection rely on NAAT technology and can be done from urogenital sampling (urine, vaginal, endocervical, endourethral), or rectal or pharyngeal swab. The most recent 2021 CDC guidelines suggest that new point-of-care (POC) NAATs (e.g. Cepheid NG/CT GeneXpert) are performing well and can be used reliably, relative to conventional, more time-consuming NAATs¹⁸. Testing does not differ for PWH, except for the emphasis on extragenital screening⁷. High rates of rectal CT have been reported in women who deny anal sex exposure, suggesting either contiguous spread, self-inoculation, or underreported anal receptive intercourse¹⁹. Self-testing has been demonstrated to be well-accepted and also have good performance compared to physician sample collection making it a useful tool that should be incorporated into care, particularly if it increases screening uptake and patient comfort^20,21.

For LGV diagnosis, commercial chlamydia NAAT tests will be able to detect LGV serovars, though these tests do not distinguish between the LGV serovars and the classic urogenital serovars D-K. There are no FDA approved molecular tests to confirm LGV infection. Therefore, the diagnosis of LGV is often clinical and presumptive when a chlamydia NAAT is positive from the rectum in setting of proctitis or proctocolitis symptoms²². Serovar-specific serologic testing for chlamydia is not recommended as it is not standardized nor performance validated for proctitis presentations. Serology may be useful as supportive evidence in patients presenting with inguinal adenopathy (inguinal syndrome) when no material is available for NAAT testing²³.

Management

Treatment recommendations are summarized in Table 2 and is not different in PWH. Treatment for C. trachomatis infection with standard urogenital strains (serovars D-K) has shifted to now recommend doxycycline 100mg BID x 7 days as first-line treatment, relegating azithromycin to an alternative therapy. This change was based on clinical trials that showed approximately 20% greater cure rates of rectal chlamydia with doxycycline than with azithromycin in MSM study populations^24,25. This recommendation is also extended to women who test positive for CT (from genital sites) because of high rates of concomitant rectal infection. One-time azithromycin remains an alternative regimen, particularly if there is concern about treatment completion or in pregnant patients.

Table 2.

CDC-Recommended Treatments for selected STIs in HIV-infected patients

Infection	Preferred Treatment	Alternative Treatment(s)	Notes
Chlamydia	Doxycycline 100 mg PO BID x 7 days	Azithromycin 1 gm PO x 1	-Do not use doxycycline in pregnancy -TOC at 4 weeks post-treatment in pregnancy
Gonorrhea-Uncomplicated (urogenital, rectal, pharyngeal)	Ceftriaxone 500 mg IM x 1 (increase dose to 1 gm for people >150 kg)	*Cefixime 800 mg PO x 1 Cephalosporin allergy: Gentamicin 240 mg IM x 1 PLUS azithromycin 2 gm PO x 1	-If it has not been ruled out, add empiric treatment to cover chlamydia -*All non-ceftriaxone regimens less efficacious for pharyngeal GC. -TOC 7-14 days after treatment needed for pharyngeal infection
Gonorrhea-Complicated Disseminated	Ceftriaxone 1 gm IV or IM q 24 hrs x 7 days	Cefotaxime 1 gm IV q 8 hrs or Ceftizoxime 1 gm IV q 8 hrs	Can change to enteral therapy when clinically stable guided by susceptibility results
Syphilis-Early (primary, secondary, early latent)	Benzathine penicillin 2.4 million units IM x 1	Penicillin allergic: Doxycycline 100 mg PO BID x 14 days	-If allergic to penicillin and concern for med adherence, should be desensitized and receive penicillin. -Pregnancy: should be treated per syphilis stage with penicillin. Desensitize if allergic
Syphilis-Late latent and Tertiary syphilis (with normal CSF exam)	Benzathine penicillin 2.4 million units IM weekly x 3 weeks (7.2 mU total)	Penicillin allergic: Doxycycline 100 mg PO BID x 28 days	Pregnancy- weekly benzathine penicillin as per non-pregnant, but cannot go >9 days between injections, or else need to repeat entire antibiotic series
Neurosyphilis	Aqueous penicillin G 18-24 million units divided q 4 hrs x 10-14 days	Procaine penicillin G 2.4 million units IM once daily PLUS Probenecid 500 mg PO QID both for 10-14 days	Can consider benzathine penicillin 2.4 million units IM x 1 dose at completion of IV therapy if infection thought to be present >1 year (e.g., late)
Trichomoniasis	Metronidazole 500 mg PO BID x 7 days	Metronidazole 2 gm PO x 1 Tinidazole 2 gm PO x 1	Sexual partners with penile exposure can be treated with 2 gm one-time dose regimen
Mycoplasma genitalium	Doxycycline 100 mg PO BID x 7 days followed by moxifloxacin 400 mg PO QD x 7 days	If known to be macrolide-susceptible: Doxycycline 100 mg PO BID x 7 days followed by azithromycin 1 gm PO initial dose, then 500 mg PO QD x 3 days (2.5 gm total)	Macrolide susceptibility testing not widely available
Herpes simplex virus- First episode*	Acyclovir 400 pm PO TID x 7-10 days      or Famciclovir 250 mg PO TID x 7-10 days      or Valacyclovir 1 gm PO BID x 7-10 days		*May need to extend course if healing incomplete at day 10
Herpes simplex virus-Episodic	Acyclovir 400 mg PO TID x 5-10 days      or Famciclovir 500 mg PO TID x 5-10 days      or Valacyclovir 1 gm PO BID x 5-10 days
Herpes simplex virus-Suppression	Acyclovir 400-800 mg PO 2-3 times daily      or Famciclovir 500 mg PO BID      or Valacyclovir 500 mg PO BID		-Risk of recurrence highest first 6 months after starting ART-consider suppression during this time. -Suppression associated with lower likelihood of acyclovir resistance compared to episodic
Mpox-	No FDA-approved treatments. Treatment recommended for advanced or poorly controlled HIV or for severe disease	*Tecovirimat	*Not FDA- approved as of October 2021 for Mpox. Available through IND from CDC

PO: Per Os; IM: Intramuscular; IV: Intravenous; TOC: Test of cure; GC: Gonorrhea; ART: antiretroviral therapy; IND: Investigational new drug; CDC: Centers for Disease Control and Prevention

For LGV serovars, longer doxycycline treatment courses (of 21 days) are necessary²⁶. However, given standard NAAT testing does not differentiate serovars and the prevalence of LGV in the US is extremely low, the decision to extend treatment should be based on clinical symptoms If rectal screening is positive without proctitis symptoms, it is reasonable to treat with only the standard 7-day course¹⁸.

Test-of-cure (TOC) is not recommended (except during pregnancy, in which TOC is recommended 4 weeks post-treatment) although rescreening should still be performed 3-4 months post treatment given high reinfection rates.

Gonorrhea

Epidemiology

Gonorrhea (N. gonorrheae) is the second most common bacterial STI reported in the US, steadily increasing annually with 648,056 cases in 2022³. A 2011 systematic review reported an overall median point prevalence of gonorrhea of 9.5% among PWH¹². In the HIV-positive MSM population, urogenital gonorrhea positivity was 12.7% compared to 7.6% among HIV-negative MSM ¹³, highlighting especially high GC rates in some sub-populations of PWH.

Clinical manifestations

Uncomplicated gonorrhea infection may involve the urogenital tract, oropharynx, rectum, or eye, in both men and women. Like chlamydia, the majority of infections can be asymptomatic, with reports of ranges of approximately 50-90% of infections being asymptomatic at either urogenital or extragenital infection sites¹⁷. Diagnosis of gonorrhea should be suspected in patients presenting with urethritis, urethral discharge, acute epididymo-orchitis, cervicitis, pelvic inflammatory disease, or proctitis. Additionally, gonorrhea should be considered when evaluating pharyngitis in sexually active persons. Rare complications include gonococcal conjunctivitis in adults (frequently from autoinoculation) and disseminated gonococcal infection (DGI), which can lead to purulent arthritis or a classic triad of tenosynovitis, dermatitis, and polyarthralgia. There are reports of increased DGI in patients taking eculizumab²⁷, but otherwise no data to suggest immunosuppression, such as that from HIV, contributes to increased DGI risk. In fact, as with CT, no significant data exists to suggest different manifestations of GC infection in PLH^6,16. A study in sub-Saharan Africa comparing HIV-positive patients with and without STIs noted GC urethritis was associated with increased HIV viral load in semen, even when comparing patients with otherwise matched CD4 counts and plasma virus levels. Furthermore, semen virus levels decreased with STI treatment (whereas blood plasma virus levels stayed consistent with STI treatment), demonstrating specificity of the STI effect on semen viral load and highlighting implications for transmission dynamics in high-risk populations⁴.

Diagnosis

In evaluating symptomatic urethral discharge, Gram staining is highly sensitive and specific and can be used as a POC test, if available, though definitive testing for both gonorrhea and chlamydia should still be pursued (for state reporting, ruling out chlamydia co-infection). The preferred test for GC is NAAT. Gonorrhea and chlamydia are co-tested on most commercially available NAAT platforms, given the overlapping clinical syndromes caused by these organisms. With the continuous evolution of antimicrobial resistance, gonococcal cultures are necessary when susceptibility testing is desired ²⁸. The CDC supports sentinel sites across the US to routinely perform N. gonorrhoeae culture and susceptibility testing for the purpose of detecting emerging drug resistance.

Diagnosis of disseminated GC infection is more challenging, as yield of culturing the bacteria from sterile non-mucosal areas is often suboptimal. Recommendations for suspected DGI diagnosis include culturing from relevant dissemination sites (e.g., skin, synovial fluid, blood, CNS) as well as simultaneously performing NAAT on any of these samples, and screening at all standard urogenital, pharyngeal, and rectal sites in order to increase chance of diagnosis if present²⁸.

Management

Drug resistance has been a longstanding concern for N. gonorrhoeae, with resistance having developed to prior first-line treatment regimens including penicillins and fluoroquinolones. Ceftriaxone has remained the backbone of therapy for the past few decades, though also not without concern about developing resistance. As summarized in Table 2, there has been a recent major shift in the latest CDC treatment guidelines, which now recommend a larger dose of ceftriaxone (now a one-time 500mg IM dose) in order to try and combat resistance potential²⁹. Despite concerns about possible emerging resistance, cases of ceftriaxone resistance in the US are rare; there were <0.1% of isolates having concerning minimum inhibitory concentrations (MICs) >0.25 mcg/ml and no clinical treatment failures in the US. CDC guidelines also note azithromycin resistance of ~5% in 2018; alternative treatment options are thus quite limited if a true beta-lactam allergy exists, and ceftriaxone remains the only recommended therapy for pharyngeal infection ²⁹.

Test-of-cure is only necessary for pharyngeal infection (where there are more concerns about persistence) and should be performed 7-14 days after initial treatment. Otherwise rescreening is recommended 3 months after treatment, particularly as partners can serve as a reservoir to reinfect patients²⁹.

Mycoplasma

Epidemiology and Clinical

Mycoplasma genitalium (MG) has been an emerging STI since it was first isolated in 1981³⁰. As sensitive NAAT testing has only recently become available, it is not a reportable disease nor are there screening recommendations, thus, broad epidemiologic trends are less well known. It is responsible for up to 20-30% of symptomatic and asymptomatic non-gonococcal urethritis in individuals with a penis^31,32, and associated with a two-fold increase in risk for cervicitis, PID, spontaneous abortion, preterm birth, and infertility³³. This bacterium has also been implicated as a cause of symptomatic proctitis among those engaging in receptive anal sex³⁴. Like other STIs of the urogenital tract, MG causes local inflammation of the affected epithelium. This has been shown to increase trans-epithelial HIV transmission to deeper target cells, thereby serving as a significant route for HIV acquisition³⁵. In cross-sectional analyses, there is a strong association between MG positivity and HIV infection^36,37. A nested case-control study of women in Uganda and Zimbabwe demonstrated a two-fold independent risk of HIV acquisition (adjusted odds ratio 2.45) if she had tested positive for MG in the visit prior to HIV acquisition³⁸. It is noteworthy that although vaginal HIV shedding is higher in those with MG infection, it does not appear to cause increased vertical transmission from mother to child^39,40.

Diagnosis

There are now commercially available NAAT tests to detect MG infection with preferred specimen types of first-void urine or endourethral swabs for penile exposure, and vaginal or endocervical swabs. Test performance of the transcription-mediated assays are excellent (92-98% sensitivity and specificity)^41,42, similar to NAAT performance for CT and GC. Currently, the 2021 CDC STI consensus guidelines recommend reserving testing for men with recurrent or persistent urethritis symptoms and women with recurrent cervicitis, and testing can be considered for women with PID ⁸.

Treatment

The landscape of MG treatment and diagnosis has evolved significantly due to the emergence of macrolide resistance, initially observed in penile urethritis in 2006 ⁴³. The predominant cause of macrolide resistance in MG is attributed to specific mutations, known as macrolide resistance-mediating mutations (MRMs)⁴⁴. These MRMs are responsible for resistance levels that vary by region, but a recent meta-analysis showed on average 35.5% of tested samples had drug resistance⁴⁵. In contrast, MSM with HIV in Alabama had much higher rates of resistance at 70.6% and 80% of urogenital and rectal samples, respectively⁴⁶.

Although the FDA-approved NAATs described above can successfully identify MG, further PCR-based assays are used to ascertain macrolide resistance ⁴⁷. While there are several commercial NAATs available that interrogate these MRMs outside the U.S., they are not FDA-approved at this time. Present guidelines recommend a two-stage, therapeutic approach that utilizes doxycycline followed by moxifloxacin (or azithromycin if the isolate is confirmed to be macrolide susceptible) (Table 2)⁸. Until macrolide resistance testing is more widely available, fluoroquinolone use in lieu of azithromycin is recommended.

Syphilis

Epidemiology

Syphilis (caused by Treponema pallidum) incidence rates in the US have been increasing since 2001 and, as of 2022, have reached rates not seen since 1950¹. Syphilis has been disproportionately affecting MSM since the early 2000s, but since 2013 rates have also started to rise in women and concurrently, rates of congenital syphilis have also risen (219% increase from 2017 to 2021). In 2021, in patients with primary or secondary syphilis, 44.8% of cases among MSM were in PWH, compared with 38.3% of cases among men with unknown sex of sex partners, indicating a high level of co-infection (Figure 2). This high coinfection underscores the interplay of enhanced HIV acquisition risk associated with syphilis infection and potential impacts of HIV infection on syphilis diagnosis and management. Syphilis is a complex, multistage infection with clinical stages, diagnostics, and management well summarized in several recent reviews^48,49..

Clinical

Clinical manifestations are largely similar in PWH with some potential exceptions. There have been case reports and series of PWH presenting with more than one primary chancre and increased rates (compared to historic case series) of necrotic ulcerative cutaneous lesions (lues maligna)^50,51. Higher than expected case numbers of PWH with neurosyphilis were described early in the AIDS epidemic pre-antiretroviral therapy (ART)⁵². Early neurologic involvement is common in all patients with syphilis^53,54, so it is posited that difficulty clearing the infection is responsible for this observed increase in cases in PWH.

Diagnosis

The diagnosis of syphilis can be made directly (using darkfield microscopy or immunostaining) or indirectly using sera. Given the availability of and proficiency in darkfield microscopy has greatly diminished over the past 20 years, serology is the mainstay of diagnosis. Serologic diagnosis relies on using a combination of both treponemal-specific and non-treponemal tests. Historically, screening started with the non-treponemal test (assaying antibodies to nonspecific lipoidal antigens) and, if positive, was confirmed with a treponemal-specific test. More recently, many commercial and hospital laboratories have adopted a reverse approach, taking advantage of automated treponemal-specific tests with a suggested algorithm shown in Figure 3⁵⁵. A positive treponemal and non-treponemal test confirms syphilis, but clinical staging relies on a history and physical exam (including a careful neurologic exam) evaluating for signs and symptoms of primary (ulcerative disease), secondary (systemic involvement including rash, alopecia, oral lesions, possible deep organ involvement), early symptomatic neurosyphilis (ocular, otic, cranial nerve abnormalities, aseptic meningitis), or late neurologic manifestations (tabes dorsalis, Argyll-Robertson pupils, cognitive changes). Latent syphilis, defined as seropositivity but without signs or symptoms, is divided into early (likely infected within past 12 months based on history, serial testing, exposure) or late (likely infected greater than 12 months ago or unknown) for treatment purposes. Testing algorithms and interpretation of syphilis serology is unchanged for PWH. Prozone phenomena, which can cause a false-negative non-treponemal test, can be seen in secondary syphilis and has been reported in PWH.

Figure 3.

Syphilis reverse screening algorithm (data from ¹⁰⁰)

Abbreviations: EIA/CIA: Enzyme immunoassay/chemiluminescence immunoassay; RPR: Rapid plasma reagin; TP-PA: Treponema pallidum particle agglutination

*if at high risk can repeat serologic screening in 1-2 weeks

Management

Broadly speaking, syphilis treatment in the HIV-positive population does not differ from recommendations for HIV-negative patients. First-line treatment (for any stage) involves penicillin (see Table 2), with doxycycline as an alternative for true penicillin allergy (though less published experience in PWH)^8,56. All pregnant people allergic to penicillin should undergo evaluation and desensitization as penicillin is the best-studied regimen to prevent congenital syphilis.

Although treatment is the same, there are specific management aspects that should be emphasized in PWH. Given syphilis prevalence in PWH, particularly in MSM, emphasis on partner identification, notification, and treatment should be prioritized, as well as state department of public health (DPH) reporting, in order to attempt to curb the syphilis epidemic. Furthermore, it is important to note that a syphilis diagnosis for someone not on ART should not preclude immediate initiation of ART, with relatively little risk of immune reconstitution inflammatory syndrome (IRIS) compared to other diseases ⁵⁷. Similarly, available data would not suggest an increased risk of Jarisch-Herxheimer reaction in PWH compared to that seen in HIV-negative individuals.

The data surrounding risk of neurosyphilis in PWH is not definitive. Although some older studies suggested increased rates of neurosyphilis in PWH though others did not note a correlation(Rompalo, Karp)^55,61. While some continue to recommend cerebrospinal fluid (CSF) studies in patients with CD4 counts <350 cells/mm³ or rapid plasma reagin (RPR) titer >1:32 given reports these correlate with increased neurosyphilis risk, data do not suggest improved clinical outcomes with this practice^56,58. Furthermore, the effectiveness of standard early syphilis treatment even in the face of CNS abnormalities and concern for neurosyphilis risk, is quite high ⁵⁹. Thus, current guidelines focus on only performing LPs in those with neurologic symptoms or inadequate treatment response. LP is no longer indicated for patients with isolated otic or ocular syphilis. If the diagnosis of neurosyphilis is made, follow-up CSF studies to monitor neurosyphilis treatment response are not recommended, as long as patients are clinically improved with decreasing serum non-treponemal titers⁵⁶. Despite concerns about more prolonged time-to-treatment response in PWH, overall serologic response rates are still quite high in PLWH (>90% regardless of stage⁶⁰). While PWH may be at a slightly increased risk of treatment failure, available data suggests this risk is overall low ⁵⁷. Certainly, it was long ago established that enhanced or additional treatment for syphilis in PWH was not necessary⁶¹.

Follow-up

Several studies have documented delayed RPR response to treatment in PWH and more propensity to remain serologically nonresponsive (lack of at least 4-fold decrease in RPR titer after appropriate treatment)^62,63. This has led to recommendations for increased monitoring in HIV-positive syphilis patients (at 3, 6, 9, 12, 24-month intervals) to ensure treatment has resulted in proper resolution of symptoms and appropriate RPR decline. Inadequate response requires initiation of further workup or treatment, with emphasis on concern for previously unappreciated neurosyphilis⁵⁷ .

Treatment failure and need for re-treatment can be difficult to parse out, given high reinfection risk in many PWH. Re-evaluation should occur if signs or symptoms of syphilis persist, there is a sustained (>2 week) >4-fold increase in RPR titer, or a lack of a 4-fold decrease in RPR titer over the appropriate monitoring period (12 months for early syphilis, 24 months for late latent syphilis). In many cases this equates with CSF examination, especially if neurologic complaints are present. If CSF studies suggest a diagnosis of neurosyphilis, treatment for this should occur; otherwise, re-treatment with three weekly penicillin IM injections is recommended. Finally, if detailed history raises concern for reinfection and early disease, proceeding with penicillin IM treatment is also appropriate⁵⁷.

Trichomoniasis

Trichomonas vaginalis (TV) is the most common non-viral STI globally. Data regarding TV rates in HIV-infected individuals, compared to non-HIV infected individuals, are sparse as it is not a reportable disease. However, most studies in the US and Africa report rates of TV infection at 1.5-to 2-fold higher in HIV-infected women, when compared to HIV-negative women⁶⁴. As summarized in a recent systematic review, and like the other STIs discussed above, trichomoniasis has important implications for HIV transmission and acquisition. Across a range of studies in Southern Africa, women with TV were 50% more likely to acquire HIV compared to women without TV⁶⁵. In women with co-infection with Trichomonas who are not virally suppressed, successful treatment of TV was associated with a decrease in cervicovaginal fluid (CVL) HIV viral load⁶⁶.

Most people who are infected with T. vaginalis will be asymptomatic, but when symptomatic, the prototypical vaginal discharge is profuse and malodorous and can be associated with vaginal irritation and dyspareunia. Men can experience urethritis symptoms. The preferred diagnostic test is NAAT on patient- or provider-collected vaginal, endocervical swabs or female urine, with a sensitivity and specificity of 95-100%. Two products are also approved for male urine testing- Max CTGCTV2 assay (Becton Dickinson), GeneXpert TV (Cepheid), the latter of which can be performed in <1 hour⁶⁷. If NAAT testing is not available, rapid antigen tests OSOM-Sekisui Diagnostics) perform better than wet mount microscopy (82-95% sensitivity compared with culture and transcription-mediated assay), though this is not recommended for use on male urine, due to lower reported sensitivity (38%)⁶⁸.

Patients with trichomoniasis should be treated whether symptomatic or not and management should include treatment of sexual partners. The preferred treatment is summarized in Table 2. The oral metronidazole 2-gram single-dose regimen is not preferred for vaginal infection due to lower cure rates in both HIV-positive and HIV-negative patients^69,70. Women who are diagnosed and treated for T. vaginalis should be retested, preferably with a NAAT assay, 3 months after treatment to ensure no reinfection has occurred.

Herpes Simplex Virus

Epidemiology

Seroprevalence rates (estimated by using type-specific glycoprotein assays) for HSV-2 infection in the US is 11% in non-HIV-infected individuals⁷¹, but upwards of 60% in PLH. Co-infected patients can experience increased rates of HSV recurrence, which can be associated with severe ulceration and higher amounts of HSV viral shedding. An association between HSV-2 seropositivity and increased HIV-1 acquisition risk has also been well described^72,73.

Clinical

While HSV-1 (typically acquired through orogenital contact) and HSV-2 can cause both a clinically indistinguishable genital infection, most persistent infection in the genital area is caused by HSV-2. Most patients who acquire HSV-2 do so asymptomatically but can shed virus regardless of symptoms, with rates of shedding increased in PWH⁷⁴. When symptoms do occur, first (primary) episodes typically appear 4-7 days after sexual contact with an infected partner. Patients experience multiple painful shallow ulcerations which can be bilateral, in contrast to the clinical symptoms of recurrence, which are marked by milder symptoms and fewer lesions which are typically unilateral. The risk of genital ulcerations caused by HSV is higher in those with HIV with CD4 count <200 cells/mm³ and risk of ulceration increases within the first three months of starting ART⁷⁵. Individuals with CD4 count <200 cells/mm³ are at increased risk of HSV complications, including disseminated HSV and non-healing ulcers. The central nervous system is a target organ for HSV dissemination, with complications including vasculitis, meningitis, and optic neuritis.

Diagnosis

For symptomatic patients, direct testing of clinical specimens using NAAT is recommended, with 17 such assays approved by the FDA as of 2019. While these molecular diagnostics are highly sensitive and specific, sensitivity decreases as ulcers heal. Viral culture is less sensitive than NAAT but can be used on clinical specimens if NAAT testing is unavailable. In symptomatic patients, type-specific serology (HSV-1 and HSV-2 glycoprotein antibody assay) should not be relied upon for diagnostic purposes, as a positive result may not be related to the symptom and can be falsely negative if patients have been recently exposed⁷⁶. Type-specific HSV serology can be a useful diagnostic adjunct for patients with repeatedly negative PCR or viral culture whose symptoms are otherwise compatible with genital HSV⁷⁷.

Treatment

Treatment regimens are summarized in Table 2. Treatment is recommended in all patients for initial episodes. In general, initial episode treatment is similar in PLWH compared to HIV-negative patients, except that time to healing may be protracted requiring a prolonged course. No short courses (less than 5 days) are recommended for episodic treatment. Doses for suppression are generally higher than those recommended for patients without HIV. As mentioned, rates of ulceration in patients infected with HSV-2 increase in the first three months of ART initiation, so suppression may be considered during this time (use for 6 months then re-evaluate)⁷⁵.

Mpox

The orthopoxvirus mpox (formerly monkeypox) was first noted in a human in 1970. This zoonotic disease, which has been endemic to Central and West Africa, had a global resurgence amidst the 2022-2023 outbreak of mpox⁷⁸. The incubation period of mpox can range from a few days to a couple of weeks. Mpox classically presents with a mucocutaneous vesiculopustular rash, associated with fever and lymphadenopathy along with constitutional symptoms. In cases of mpox-associated proctitis, anorectal pain, tenesmus, rectal bleeding, and lesions can also be present. In disseminated disease, pulmonary, cardiac, gastrointestinal, or central nervous system involvement (including ocular involvement) have been reported. Those with HIV-related immunosuppression without virologic suppression (particularly if the CD4 count is <100 cells/mm³) are at risk for severe manifestations and complications of mpox including prolonged or necrotizing skin lesions, lung involvement and secondary infections and sepsis, and death⁷⁹. In addition, secondary infection of skin lesions is also possible⁸⁰.

There are no FDA-approved medications for mpox. Mild cases can be treated with supportive care but for patients with late or poorly controlled HIV or with severe disease, treatment is recommended. The antiviral tecovirimat can be acquired through an expanded investigational new drug (IND) application through the CDC and is dosed 2-3 times per day for 14 days (or longer, if needed based on lesion response). Other potentially effective antivirals include brincidofovir and cidofovir⁸¹. In addition, the JYNNEOS vaccine can also be given as post-exposure prophylaxis, ideally within 4 days of exposure, using the same two-dose interval recommended for primary prevention (see Prevention section for mpox vaccination pre-exposure strategy).

STI Prevention

Barrier protection-

Condoms remain a highly effective method for decreasing transmission of many STIs including chlamydia, gonorrhea, and trichomonas, and Hepatitis B. For HSV, condoms differentially protected against HSV-2 transmission by sex, from men to women by 96% and from women to men by 65%⁸². Correct and consistent condom use should be reviewed at clinic visits, especially for patients with incident bacterial STIs. Risk-reduction counseling is recommended for all adolescents and adults at risk for STIs.

Pre-exposure and post-exposure prophylaxis (PrEP and PEP)

The prophylactic use of antibiotics for the prevention of sexually transmitted infections (STIs) is a concept with historical precedence, dating back to as early as the 1940s ⁸³. This was revisited in a 2015 study of MSM, which demonstrated a significant reduction in incidence of any STI at 48 weeks within the doxycycline arm of the study⁸⁴. Given the alarming rise in STI rates, post-exposure prophylaxis with doxycycline (doxy-PEP) after unprotected sexual intercourse has been examined an intervention to decrease rising STI numbers.

Prominent recent trials—DoxyPEP, DOXYVAC, and IPERGAY—have presented persuasive evidence supporting the use of doxycycline for prevention of chlamydia, syphilis, and to a lesser degree gonorrhea in MSM and transgender women (Table 3)^84-87. A similar study involving cisgender heterosexual women in Kenya did not yield comparable protective effects⁸⁸. It remains unclear whether this discrepancy is mainly attributable to reduced drug levels in the vaginal mucosa, or if other factors such as medication adherence and social acceptability played a significant role. Within the DoxyPEP study, sub-group analyses showed that the cohort of PWH had a similar decrease in incidence as the PrEP cohort with a relative risk reduction of 62% versus 66%, respectively of any STI⁸⁶.

Table 3.

Summary of Selected Doxycycline Post-Exposure Prophylaxis Trials

Clinical Trials of Doxycycline Post-Exposure Prophylaxis
Study	Participants	Any STI Rate *+		Risk Reduction (%) **
		Doxy PEP	Standard of Care	Chlamydia	Syphilis	Gonorrhea
DoxyPEP	501 (PLWH n=174)	11.1/100 PQ	31.4/100 PQ	88	87	55
DOXYVAC	502	5.6/100 PY	35.4/100 PY	89	79	51
IPERGAY	232	37.7/100 PY	67.7 /100 PY	70	73	17

^*DoxyPEP rate includes combination of PrEP and PLWH cohorts. DoxyPEP trial rate in person-quarters (PQ) vs. personyears (PY) in other 2 studies.

^**Risk reduction calculated from relative risk in DoxyPEP and hazard ratio in DOXYVAC and IPERGAY.

⁺DOXYVAC STI rate only chlamydia and syphilis.

Abbreviations: PEP: post-exposure prophylaxis; doxy: doxycycline; PQ: per quarter; PY: per year

Amidst the increased utilization of doxycycline, concerns are emerging about potential antibiotic resistance in STI-related pathogens. Within the DoxyPEP and DOXYVAC trials, no significant difference in gonorrhea resistance was found between baseline and study end timepoints; however, in DoxyPEP, there was higher resistance found within the doxycycline group compared to that of the standard of care group^86,87. The clinical relevance of doxy-PEP use on S. aureus and the broader microbiome continues to be an active area of ongoing investigation.

Vaccination:

Beyond oral antibiotic prophylaxis, vaccination against Neisseria for meningitis has shown varying efficacy in preventing N. gonorrhea infection. This was first supported within ecologic studies that revealed decreased rates of gonorrhea after administration of outer membrane vesicle serogroup B meningococcal vaccination⁸⁹. This was redemonstrated in a retrospective case-control study in New Zealand where vaccination was also associated with decreased rates of gonorrhea⁹⁰. More recently, the MenB-4C vaccine, which is available in the U.S. and contains the same outer membrane vesicle, was shown to be 40% effective in those receiving full (3-dose) vaccination series and 26% in those with a partial series⁹¹. Future studies look to exploit this data to develop a possible vaccine for gonorrhea prevention.

The FDA approved the use of the JYNNEOS vaccine for mpox (and smallpox) based on immunogenicity studies. A real-world analysis of the JYNNEOS vaccine effectiveness in the US mpox outbreak of 2022 estimated effectiveness of 41% after 1 dose and 73% after two doses of the vaccine among immunocompromised patients⁹². Two-dose mpox vaccine is therefore recommended for PWH.

Vaccine effectiveness for prevention of hepatitis A virus (HAV) and hepatitis B virus (HBV) as well as HPV is well-established including in PWH. All sexually active patients with HIV found to be non-immune and not chronically infected with HBV should be vaccinated with reinforced hepatitis B vaccine (40 mcg injections at 0, 1, and 6 months). Anti-HBV surface antibody titers should be checked 1-2 months after the last vaccine dose. Additionally, HAV vaccination is recommended for non-immune persons who inject drugs, MSM, those with chronic liver disease, and patients who are experiencing homelessness. HPV vaccination is indicated for all patients between 9 to 26 years of age and can be considered (through shared decision-making) in patients up to age 46. PWH should receive 3 doses of the 9-valent HPV vaccine⁷.

Conclusion-

Rates of STIs are increasing in the U.S. and are disproportionately higher in PWH. Many STIs are associated with increased rates of HIV acquisition and transmission. Thus, strategies to increase counseling, prevention, complete and regular screening, and evidence-based treatment including partner management are critical to the US goal of getting to zero new HIV infections. Molecular-based testing has expanded to include more pathogens and approval for use at non-genital sites and is becoming increasingly available at the point of clinical care. Increased adoption of self-testing will further decrease diagnostic barriers and expedite timely treatment. Large gains in decreasing the burden of STIs in PWH will come through routine testing and full implementation of prevention science, including established and emerging strategies such as vaccination and doxycycline post-exposure prophylaxis.

Key Points:

• People with HIV (PWH) have higher rates of sexually transmitted illnesses (STIs) compared to patients without HIV, especially among men who have sex with men (MSM).

• Many cases of chlamydia and gonorrhea are missed with urine-only diagnostic testing; routinely asking about sites exposed during sexual activity or adopting universal three-site testing leads to increased rates of diagnosis and treatment.

• Syphilis rates continue to rise, and providers need to be expert in the signs and symptoms of this complex disease, including recognition of symptomatic early neurosyphilis, and ocular and otic disease.

• Vaccines can help prevent some STIs, including human papillomavirus, hepatitis B virus, and mpox, and are in development for gonorrhea. Prevention of chlamydia, gonorrhea, and syphilis using post-exposure prophylaxis with doxycycline is showing promise in certain populations, such as MSM.

Synopsis.

Sexually transmitted infections (STIs) are more commonly seen in PWH. Routine sexual history taking and appropriate multi-site screening practices are key factors that support prompt identification and treatment of patients, which in turn reduces morbidity and spread of STIs including HIV. Nucleic acid amplification testing (NAAT) has high accuracy for diagnosing many of the major STIs. Diagnosis of syphilis remains complex, requiring two-stage serologic testing, along with provider awareness of the myriad symptoms that can be attributable to this disease. Prevention through mechanisms such as vaccines and postexposure prophylaxis hold promise to reduce the burden of STIs in PWH.

Clinics Care Points-.

• Routinize multisite STI screening including extragenital screening

• Vaginal/endocervical swabs are preferred over urine chlamydia and gonorrhea NAATs in people with vaginas

• Patients diagnosed with pharyngeal gonorrhea should have a test of cure 7-14 days after treatment

• Syphilis diagnosis and accurate staging requires knowledge of a wide spectrum of manifestations including those that could affect treatment options (e.g. ocular or otic symptoms, neurologic symptoms)

• STI prevention with doxycycline post-exposure prophylaxis holds promise in reducing incident chlamydia, gonorrhea, and syphilis in MSM and transgender women.