Syphilis incidence in men who have sex with men with human immunodeficiency virus comorbidity and the importance of integrating sexually transmitted infection prevention into HIV care

Abstract

Introduction:

Syphilis continues to be a growing epidemic among men who have sex with men (MSM), particularly for those living with the human immunodeficiency virus (HIV). In 2016, MSM accounted for 80% of primary and secondary syphilis diagnoses in men in the United States; almost half of who were also HIV-infected. The synergistic relationship between HIV and syphilis has significant implications not only for HIV patient management, but also for sexually transmitted infection (STI) control among MSM.

Areas covered:

We review the literature on STI screening and treatment barriers at the patient-, provider-, and health system-levels, and present strategies to incorporate STI prevention into HIV care settings.

Expert commentary:

Integration of STI prevention into HIV care is paramount to stop the epidemic of not only syphilis, but also other curable STIs like gonorrhea and chlamydia. Although guidelines have been established for STI testing in HIV-infected MSM, screening rates continue to be lower than desired. Gonorrhea and chlamydia screening is below 50% in HIV-infected MSM; interventions that improve testing of those two infections must be implemented. For syphilis control, other additional strategies such as chemoprophylaxis should be considered given syphilis screening is above 50% in HIV-infected MSM.

1.0. Introduction

1.1. HIV and syphilis co-infection in HIV-infected MSM

In the United States, the rate of total syphilis cases per 100,000 has steadily increased for the past two decades, more than doubling from 11.2 in 2000 to 27.4 in 2016 [1]. During that time, men who have sex with men (MSM) have continued to represent the majority of syphilis diagnoses. In 2016, MSM accounted for 80.6% of all male primary and secondary syphilis cases; almost half (47%) of whom were co-infected with human immunodeficiency virus (HIV) [1]. In that same year, 7.4% of all HIV-infected MSM were diagnosed with primary or secondary syphilis to compared to only 3.1% of HIV-uninfected MSM [1].

There is no definitive explanation for the higher frequency of syphilis cases in HIV-infected MSM compared to their HIV-uninfected counterparts. That lends to the idea that MSM living with HIV might be more susceptible to Treponema pallidum infection, the bacterium that causes syphilis. Several hypotheses explaining why HIV-infected MSM might be more susceptible to syphilis have been proposed. First, the nature of the progressive depletion of CD4 T-cells in those with HIV-infection decreases the host’s ability to defend itself against pathogens [2]. Secondly, perhaps HIV infection is merely a surrogate for engaging in behaviors that promote transmission of syphilis. It has been proposed that the availability of highly active antiretroviral therapy (HAART) may have indirectly increased syphilis incidence secondary to increased sexual risk behavior, also known as “risk compensation.” HAART may have decreased the fear of HIV transmission in both HIV-infected and uninfected MSM, resulting in more frequent sexual activity, greater number of sex partners, and less condom use. That hypothesis may be supported by the rise in STIs in the post-HAART era. However, a meta-analysis by Crepaz et. al. found no statistically significant difference in prevalence of condomless sex among HIV-infected MSM on HAART compared to those not on HAART [3]. Moreover, HIV-infected MSM may also resort to other risk compensation behaviors like serosorting (i.e. sex partners are exclusively HIV-infected men) or strategic positioning whereby in serodiscordant partners the HIV-infected person assumes the receptive role during anal sex as opposed to the insertive role, which is more likely to transmit HIV. However, a meta-analysis on risk taking behaviors found that the odds of reporting condomless sex was actually lower among HIV-infected persons on HAART compared to those not on treatment (OR=0.73, 95% CI 0.64-0.64, p<0.001) [4]. It has also been proposed that certain antiretrovirals may increase susceptibility to T. pallidum by altering the body’s innate and adaptive immune responses [5]. However, Tuddenham and colleagues challenged that idea by elucidating several limitations of that hypothesis, which was only based on clinical observation and theorized biological mechanisms [6]. Further studies are needed to investigate the possible effects of HAART on T. pallidum acquisition.

Syphilis control in MSM living with HIV is essential because HIV and T. pallidum influence each other’s natural history when both present in the same host. Co-infection with T. pallidum, has been associated with increased HIV viral load and decreased CD4 T-cell counts [7]. Comorbid syphilis also increases the likelihood of HIV transmission by creating open portals of entry for the virus through the disruption of host mucosa and by making cells susceptible to HIV (i.e. those that express CD4 and CCR5 receptors) more likely to be infected by the virus [8]. Similar to other ulcerative infections, the local inflammatory process incited by T. pallidum recruits CD4 T-cells to the area of invasion, making these cells more available for HIV to infect [9]. Furthermore T. pallidum lipoproteins have been found to increase the expression of CCR5 on macrophages [10]. HIV simultaneously exacerbates T. pallidum infection, often times manifesting as syphilis that is difficult to treat and leads to more complications [11–13].

Given that up to a quarter of HIV-infected MSM are unaware of their status and the significant proportion of comorbid syphilis in that population, it is possible that both pathogens may be simultaneously transmitted. The increasing number of syphilis diagnoses in HIV-infected MSM highlights the importance of STI control in this population, not just for the health of the patient, but also for prevention of HIV and syphilis in uninfected persons.

2.0. The current state of STI screening in HIV-infected MSM

In addition to T. pallidum, two other bacterial STIs are also on the rise in MSM—Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG)—the organisms that cause chlamydia and gonorrhea, respectively. From 2010 to 2015, gonorrhea incidence among MSM more than doubled from 1368.6 to 3434.7 cases per 100,000 according to the Centers for Disease Control and Prevention (CDC) [1]. Chlamydia incidence rates in men increased by 26.2% during 2012 to 2016, compared to only a 2.9% increase in women [1]. It is believed that new cases among MSM are the main drivers of that rise over the past several years. The increasing rates of reported syphilis, gonorrhea, and chlamydia may represent a combination of more transmission and improvements in screening, diagnostic methods, and reporting. As seen with syphilis, gonorrhea and chlamydia positivity among MSM appears to be higher in those who are HIV-infected, likely due to similar reasons that were discussed above. In 2016, urogenital infection positivity was higher in HIV-infected MSM: 8.6% for chlamydia and 14.0% for gonorrhea; compared to 6.7% and 9.0% respectively in HIV-uninfected MSM [1], Rieg et. al. reported an STI reinfection incidence rate of 20.8 cases per 100 person years (95% CI 14.8-28.4 cases per 100 person years) among a group of 212 newly HIV-infected MSM within one year of establishing HIV primary care [14]. That statistic is an indication that newly diagnosed HIV does not prevent continued engagement in risky sexual behaviors.

Syphilis, gonorrhea, and chlamydia may not present with any symptoms. Those with no signs of infection serve as reservoirs for ongoing spread of infection because absence of symptoms does not preclude transmissibility. Additionally C. trachomatis and N. gonorrhoeae can be localized at three anatomical sites in men: urethra, pharynx, and rectum. For those reasons, asymptomatic STI screening at all anatomical sites that may have been exposed to infection, prompt treatment, and partner treatment are the pillars of STI control, especially in MSM regardless of HIV-infection status [15].

The CDC recommends at least annual screening of MSM irrespective of HIV-infection status for syphilis via serology and three site sampling for gonorrhea and chlamydia [15]. More frequent screening at three to six month intervals is recommended for MSM who continue to engage in risky behaviors (e.g. condomless sex, multiple sex partners) or whose sex partners have multiple sex partners. The United Kingdom and Australia have similar STI screening guidelines for MSM regardless of HIV status [16,17]. Studies have shown that among MSM, extragenital infections may be more common than urethral infections [18–20]. Some evidence suggests that extragenital STI screening produces a greater yield of detection than urethral screening, thus urethral screening may not be cost-effective in that population [21,22].

Furthermore, screening for asymptomatic urethritis by testing for gonorrhea and chlamydia alone may not be sufficient given that other pathogens (e.g. Trichomonas vaginalis, Herpes simplex viruses, Adenoviruses, Mycoplasma genitalium) can cause urethritis. In a study by Cohen and colleagues in 135 HIV-infected men, seminal HIV RNA concentration was found to be 8 times greater in those with urethritis compared to those without urethritis (p=0.035); after antibiotic treatment, seminal HIV RNA levels significantly decreased [23]. If the goal is to detect and treat asymptomatic urethritis to reduce HIV-infectivity, then the current screening guidelines may miss other urethritis-inducing pathogens. More studies are needed to determine whether other screening methods for asymptomatic urethritis (e.g. Gram stain, urine microscopy, or urine leukocyte esterase) are cost-effective. Thus, in MSM living with HIV infection, prevention and treatment of syphilis and pathogenic causes of urethritis such as gonorrhea and chlamydia are vital. The question is: are HIV-infected MSM being appropriately screened for those infections as per guideline recommendations?

In HIV care clinics, screening rates for gonorrhea and chlamydia at any anatomical site range between 30-40%, while syphilis screening is higher, generally between 50%-70% [24]. Self-reported STI testing history in a group of 110 HIV-infected MSM receiving HIV primary care revealed that almost 20% had not been screened in more than a year [25]. In that same cohort, during their last testing visit only 58% of those who reported performing oral sex received pharyngeal screening, while only 53% of those who reported receptive anal sex underwent rectal screening [25]. The most recent data from the CDC Medical Monitoring Project, which gathers data on HIV-infected patients receiving care in the U.S., shows that testing for syphilis, chlamydia, and gonorrhea improved between 2009 and 2013, but still remains low [26]. Testing for all three bacterial STIs increased from 20% to 36% (p <0.01). For syphilis, testing increased from 55% to 65% (p<0.01) overall and with notable significant improvements among MSM (58% to 69%) and all age groups except for those aged 18 to 29 years. Screening for syphilis is more consistently performed compared to gonorrhea and chlamydia in HIV-infected MSM receiving care from HIV clinics in the U.S [27]. Possible reasons include the ease of adding syphilis serology to regularly collected HIV monitoring labs, the influence of syphilis screening requirements for Ryan White funding, and physician discomfort or inexperience with collecting swabs for rectal testing [28].

It is worth noting that the CDC recommends screening HIV-infected MSM for other viral STIs including viral hepatitis and vaccinating against the Hepatitis A (HAV) and Hepatitis B viruses, which are both sexually transmissible [15]. However, implementation of viral hepatitis screening and vaccination in HIV care settings has been suboptimal [29]. Interventions to improve HAV vaccination in HIV-infected MSM are needed given the higher likelihood of fulminant disease with comorbid HIV and the recent outbreaks of HAV in this population [30,31]. While Hepatitis C can be spread through sexual contact, the primary mode of transmission is exposure to blood, commonly among intravenous drug users who share needles. The remainder of this review will focus on bacterial STIs given that those co-infections facilitate HIV transmission.

3.0. Barriers to STI screening of MSM in HIV care settings

For HIV-infected patients, it would seem that the most opportune time to undergo STI screening is during their routine HIV care visits. However, there are many reasons why HIV-infected MSM are not screened according to guidelines at the patient-, provider-, and health-system levels (Table 1).

Table 1.

Strategies to eliminate patient- and provider-level barriers to sexually transmitted infection (STI) screening and prompt treatment in human immunodeficiency virus (HIV) care settings for men who have sex with men.

	Potential Barriers	Strategies
Before HIV provider visit	Patient  •Inconvenience (e.g. need more frequent testing, want easier testing)  •Forgetting to get tested  •Desiring more anonymity  •Insurance coverage Provider  •Lack of knowledge of: STI testing guidelines, nucleic acid amplification testing availability	•Alternative testing locations: nurse-led STI clinics within HIV clinics, STI clinics available to the general population, non-clinic based local outreaches  •Alternative testing options: telehealth-based testing, home-based testing  •Automated patient reminders (e.g., text message, e-mail, smartphone applications)  •Provider reminders to test patient via electronic health record system  •Provider education via alerts or formal training sessions
During HIV provider visit	Patient  •Patient privacy  •Stigma Provider  •Lack of time, competing priorities  •Discomfort discussing sexual practices and doing genital exam  •Afraid of being perceived as judgmental	•Improving sexual behavior risk assessment (e.g., standardized sexual history interview and provider training; self-administered computer-, tablet-, or smartphone-based platforms)  •More efficient specimen collection (e.g., nurse-collection before physician visits patient, patient-collection)  •Standing lab orders for syphilis serology in 4-6 month intervals  •Automated addition of syphilis serology to routine HIV monitoring labs  •Strategic placement of specimen collection materials as a reminder to providers  •Universal collection of genital and extragenital specimens regardless of sexual history
After HIV provider visit	Patient  •Duration of time to receiving results  •Not receiving results Provider  •Time required to deliver results	•Point-of-care testing  •Faster delivery of results (e.g., text messaging, smartphone applications)  •Shifting away from the “no news is good news” provider mentality

3.1. Patient-barriers

Barbee et. al. found that among 110 respondents from a cohort of HIV-infected MSM engaged in HIV primary care, almost one-third sought STI testing outside of their primary care provider (i.e. local STD clinics, local outreach sites) [25]. Cited reasons for seeking testing outside of HIV clinics included wanting easier testing, anonymity, and more frequent and convenient testing [25].

3.2. Provider-barriers

Barriers to STI screening and treatment cited by HIV care providers included lack of knowledge regarding CDC guidelines for testing and treatment, as well as clinical challenges such as lack of time, perceived patient reluctance, provider discomfort with taking a sexual history or doing a genital exam, and fear of appearing judgmental [25]. Carter et. al. collected data from interviews of a diverse group of HIV care providers from six U.S. cities regarding STI screening practices and barriers to risk assessment. Many of the same barriers mentioned above were reported, but other challenges were also pointed out: competing priorities (i.e. more acute or serious health concerns that must be addressed first), difficulty discussing sexual behaviors due to cultural or language differences, preference for a LGBT provider, and privacy or confidentiality concerns [28].

3.3. Health-system barriers

Particularly in the U.S., the organization of the health-system may impede the implementation of screening guidelines. Health insurance plans vary in their coverage of STI screening, which falls under preventative care services. Currently under the Affordable Care Act (ACA), Medicaid in states that have adopted full-scope expansion and most private health insurance plans cover recommended services given an “A” or “B” grade by the U.S. Preventive Services Taskforce (USPSTF) at no cost to the patient. For men that only includes syphilis testing, HPV vaccination up to 26 years of age, STI prevention counseling, and Hepatitis B vaccination. Gonorrhea and chlamydia screening at no cost is not guaranteed under the ACA. Although no cost syphilis screening is guaranteed, the extent to which beyond annual testing is covered is unspecified. Beyond USPSTF recommendations, it is up to the discretion of the insurance company to decide which STI screening services will be covered, how often, and how much the co-payment will be for the patient. For those who are uninsured, safety-net STI clinics may provide same-day, low-cost STI testing. Despite the expansion of health insurance coverage in the U.S., the services that those safety-net clinics provide continues to be in demand, but the number of those clinics is declining [32].

4.0.0. Interventions to improve HIV care-based STI screening

4.1.0. Effective and low-cost clinic-based interventions

A systematic review by Taylor et. al. evaluated 38 studies that implemented clinic-based interventions to improve STI testing, and categorized each by cost and effectiveness [33]. The absolute increase in percent screened defined effectiveness, where “highly effective” indicated at least a 20% increase, and “moderately effective” signified between a 5% to 19% increase. Low cost was defined as an intervention less than 1,000 U.S. dollars. Four studies were specific to HIV-infected MSM [34–37], seven interventions included MSM irrespective of HIV status [38–44], and one intervention targeted HIV-infected persons regardless of gender [45].

Highly effective, low cost interventions tested in HIV-infected MSM included adding syphilis testing to routine HIV clinical monitoring labs [34,35] and using electronic health record (EHR) platforms to automatically add syphilis tests for patients in 4 to 6 month intervals [37]. However, given that those with stable CD4 T-cell counts and undetectable viral loads may only receive HIV medical visits every 6 months, semiannual screening is not sufficient for patients who should be tested as frequently as every 3 months [46]. A moderately effective and low-cost intervention was adding comprehensive three-site STI testing into routine anal cytology screening [36].

In MSM irrespective of HIV status, interventions that were highly effective while low cost incorporated text message and e-mail reminders for patients to repeat STI testing at 3 to 6 month intervals [43,44], Moderately effective, low cost interventions in MSM included the adoption of updated national guidelines into clinic practice [38], EHR reminders for providers to test for syphilis and to follow-up with serologic testing after syphilis treatment [40,41], and EHR alerts to inform providers about recommendations to screen at extragenital sites [42]. Incorporating a sexual health practice nurse in the clinic was found to be moderately effective, but costly [39].

The one intervention that enrolled HIV-infected men and women implemented a chronic care model, which included syphilis screening as one of their seven clinic practice guidelines. The intervention also involved the addition of dedicated staff to fully carry out this model; that was highly effective, but costly [45].

Although not specifically studied in HIV-infected persons and/or MSM, other highly effective and low cost interventions included strategic placement of specimen collection materials as a reminder to providers, and standing orders for the automatic collection of STI specimens [33]. Those strategies improve clinic flow and efficiency, which may remedy the barrier of time constraints faced by providers. Interestingly, interventions that provided patients financial incentives, implemented motivational interviewing, or sought to enhance provider knowledge and awareness of screening recommendations were not effective [33].

4.2.0. Other proposed clinic-based interventions

4.2.1. Risk assessment

Sexual risk behavior assessment is essential in determining frequency of testing and which anatomical sites should be screened. There should be a standardized approach to taking a sexual history. Providers should also be trained on how to ask those questions in an appropriate and nonjudgmental manner. The California STD/HIV Prevention Training Center developed a guide to sexual history taking with MSM, which may be helpful for HIV care providers to use during their patient interviews [47]. It outlines an approach to the process and provides questions that should be asked during each visit. Although good patient-provider rapport may promote adherence to routine screening and other healthy behaviors, one or both parties still may not be comfortable discussing that subject matter in person.

Scarborough and colleagues developed a self-administered sexual risk assessment questionnaire. It was tested on a cohort of 364 HIV-infected MSM receiving care from a Kaiser Permanente HIV clinic [48]. Its implementation resulted in a relative increase in gonorrhea and chlamydia screening at any site by 26.8% (p=0.01) and a relative increase in syphilis testing by 18.8% (p=0.009) [48]. An improvement in gonorrhea and chlamydia screening at each anatomical site was also reported, but only the increase pharyngeal testing was statistically significant [48]. The paper risk assessment tool created for that study could be improved by developing an electronic version, which can be incorporated into the EHR system. It could be converted into a computer-assisted self-interview that may be set up in the clinic or can be administered at home prior to the clinic visit; other possible platforms include tablet or smartphone applications. That could streamline appropriate test ordering by making the process faster for clinicians, while preventing missed screening opportunities and over-testing. Furthermore, that could eliminate the barrier of discomfort that both physicians and patients may encounter when discussing the patient’s sexual history face-to-face, which may increase the accuracy of self-reported behaviors.

4.2.2. Specimen collection

After completing sexual risk assessment, the next challenge is obtaining samples. The method of specimen collection can be modified to facilitate time constraints and patient privacy, while mitigating discomfort felt by some providers when collecting rectal swabs. Instead of having the physician collecting the samples, a nurse can take over this duty as part of the procedures performed before the physician sees the patient. Another option is to have the patient obtain the specimens himself. He may even prefer that method for privacy reasons. A study of 272 MSM that compared patient-taken to nurse-taken extragenital samples found that there was no significant difference in test performance sensitivity or specificity for rectal gonorrhea or chlamydia, and sensitivity for pharyngeal gonorrhea [49]. However there was a small, statistically significant difference in specificity for pharyngeal gonorrhea (91.8% for nurse-taken versus 87.8% for patient-taken, p=0.006) [49]. Nevertheless, because a 4% discrepancy may not be clinically significant, patient-collection seems to be a reasonable method for obtaining samples.

Barbee and colleagues piloted an STI self-screening program on MSM in the setting of an HIV care clinic. Participants were either self-referred to self-testing via pamphlets placed in the waiting room, or referred by the provider at the end of their physician visit. In this innovative intervention, a self-testing room was set up in the clinic that contained STI kits for extragenital swabbing, urine collection cups, as well as instructions on how to collect and label the samples. Patients were then directed to a lab to get blood drawn for syphilis serology. This intervention resulted in a 32% relative increase in pharyngeal testing and 33% increase in rectal screening for gonorrhea and chlamydia. Compared to pre-intervention, there was a 91.8% relative increase in complete testing (i.e. all three anatomical sites) after implementation of the self-testing program (16% vs. 31%, p<0.001) [50]. Although there were statistically significant increases in urethral, pharyngeal, and rectal screening when analyzed separately, screening for gonorrhea and chlamydia was still low with less than 50% of clinic patients tested for each anatomical site. Syphilis screening was above 50%, but there was no significant difference before and after intervention (63.3% vs. 64.6%, p=0.44) [50].

4.2.3. Diagnostic tools

Nucleic acid amplification tests (NAATs) have largely replaced culture in the detection of urethral gonorrhea and chlamydia. However, the Food and Drug Administration (FDA) has yet to approve NAATs for extragenital specimens despite multiple investigators demonstrating their superior sensitivity compared to culture in studies and their recommended use by the CDC [51–54]. Until FDA approval, only labs that demonstrate specifications defined by Clinical Laboratory Improvement Amendments may use NAATs as an aid in the clinical diagnosis of extragenital CT and NG infections. Of note, there is currently an ongoing NIH-funded clinical trial that will generate data to support manufacturers’ claims for FDA clearance of extragenital CT and NG testing. That trial should be completed in 2018 [55].

Although highly sensitive, most NAATs are laboratory-based and can take up to several days for results. Point-of-care testing (POCT) can reduce that turnaround time, making it more likely for patients to receive their results. That would allow for quicker treatment and thus a smaller window of time for the patient to spread infection further. Byrne and colleagues found that after implementing POCT in a sexual health clinic, for every two patients diagnosed with gonorrhea and/or chlamydia, one partner was spared exposure; that equated to 196 partners that avoided exposure during the 8 week study period [56].

The GeneXpert® CT/NG (Cepheid, Sunnyvale, CA) assay is a POCT PCR platform for C. trachomatis and N. gonorrhoeae detection, which has been approved for testing urine, and vaginal and endocervical specimens. Two studies have found that GeneXpert® POCT performed similarly with APTIMA Combo 2® (Hologic, San Diego, CA), a commonly used laboratory-based NAAT platform, in detecting extragenital gonorrhea and chlamydia [57,58]. As one might expect, cost may be a barrier to using POCT for gonorrhea and chlamydia screening in as many as three anatomical sites per patient. Pooled sampling may mitigate the expense of screening, while maintaining speed. Speers et. al. found that using GeneXpert® POCT with pooled specimens performed similarly in comparison to testing individual specimens for extragenital gonorrhea and chlamydia [59].

Using GeneXpert® CT/NG, results can be obtained in 90 minutes or less. The next question is: are patients willing to wait this long for their results especially if they are asymptomatic? One option would be to collect samples in the clinic prior to the patient seeing the provider. Harding-Esch et. al. evaluated that possibility in a sample of men and women in a sexual health clinic in London [60]. That approach was found to be acceptable by the majority of the participants (>90%). However, only 21.4% of rapid test results for gonorrhea and chlamydia were available by the time participants were finished with their clinic visit. Furthermore it may not be acceptable for patients to stay in clinic to wait for their results. According to a survey of 1817 clinic patients in the U.K., only a small minority (8.5%) indicated that they could wait over 90 minutes in clinic for their POCT results [61]. The other option would be to notify patients as soon as their results become available. That is what the Dean Street Express in London implemented. Although not specifically an HIV clinic but rather a sexual health clinic, they adopted POCT for asymptomatic screening and evaluated its turnaround time in comparison to the more traditional approach that required sending off specimens to an offsite lab. Compared to traditional testing, the use of POCT lead to faster times between: testing to informing patient of their positive result (1 day versus 8 days), and testing to treatment (2 days versus 10 days) [62]. Given that on average it took one day between informing and treatment for both groups, it appears that the rate-limiting step is the duration of time between testing to informing the patient. That interval is dependent not only on the turnaround time of the test, but also on how long it takes for the results to be delivered to the patient.

4.2.4. Delivery of results

The method by which patients receive results can either facilitate or delay treatment. First of all, every patient should be notified of the outcome of his test regardless of the result. There should be a complete shift away from the “no news is good news” model whereby from the perspective of the patient, not receiving the result equates to a normal testing outcome with no required follow-up necessary. That approach has the potential for harmful consequences if patients with true infections are not notified regardless of the reason (e.g. incorrect contact information, medical record error, lost specimens, etc.). In addition, getting news of normal results may serve as positive reinforcement and provide more self-assurance. That may motivate patients to continue undergoing STI screening in the future. Fortunately, “no news is good news” is slowly becoming a practice of the past as EHR systems are now nearly universal and the availability of patient access to their health information is becoming more common.

The traditional method of phone calls to notify a patient about their test results can be time consuming for staff and may require multiple attempts to reach a patient. That can delay treatment and thus increase duration of infectivity. Short message service (SMS), also known as text messaging, may serve as a more efficient form of communication of results for both patients and providers. Menon-Johansson and colleagues found that the median time to treatment for patients who opted to receive their chlamydia test results via SMS was cut in half compared to those who received telephone calls (8.5 days vs. 15 days, p=0.005) [63]. Text messaging rather than phone calls also saved 46 hours of staff time per month [63]. A study by Rodriguez-Hart et. al. also reported shorter test to treatment times on average in those who received text message results compared to phone calls (5.1 days vs. 6.7 days, p=0.036); furthermore, among the SMS group, significantly more participants who called the clinic back were treated within 10 days than those who did not call back (88% vs. 80%, p=0.015) [64].

Smartphone applications have the same ability to quickly deliver results as SMS but with additional features. For the patient, those applications are more secure (i.e. password-protected) and can serve as a way to schedule appointments, display results visually beyond alphanumeric characters (e.g. graphs, charts, scales), allow access to previous records, and provide additional health information via hyperlinks. On the provider side, smartphone applications can verify that patients viewed their results and serve as medium for patient communication. Cohen et. al. investigated the outcomes of incorporating Healthvana, a smartphone application, as a means of STI result delivery in 917 men from eight different AIDS Healthcare Foundation Wellness Centers in the U.S. Implementing Healthvana was associated with a mean reduction time of 3.07 days between testing to notification (95% CI = −5.05, −1.09; p=0.008) [65].

5.0. STI screening interventions outside of HIV care

Many of the screening interventions discussed above did not take place in dedicated HIV care clinics, rather in sexual health clinics such as the Dean Street Express. However, those models can be applied in HIV care settings to improve STI screening. As mentioned previously, up to a quarter of HIV-infected patients seek STI testing or screening outside of their HIV care providers for a variety of reasons. In addition, the recommended frequency of STI testing for some HIV-infected MSM may exceed their number of yearly HIV care visits, necessitating the need to find testing elsewhere. HIV care providers should be knowledgeable about other STI testing sites and options to refer their patients.

Sexual health or STI clinics can fill in those screening gaps as they may offer walk-in or same day appointments that HIV clinics may not be able to offer. Hamlyn and colleagues found an increase in annual STI screening of HIV-infected patients from 39% to 52% after establishing a separate nurse-led STI clinic within an HIV care facility; however this change only approached significance (p=0.06) [66]. Other options are non-clinic-based, local outreach activities that conduct STI testing in the community at locations where MSM may visit such as bathhouses, gay bars, and other social venues. However, the availability of that outreach vary and may not be sustainable [67]. Furthermore, it is important that those who receive screening services from community-based programs be linked to health care for follow-up and treatment.

Telehealth-and Internet-based testing may be the next frontier in STI screening. Levine and colleagues developed and implemented a free online syphilis testing service based in San Francisco that allowed individuals to print out a lab requisition slip to obtain blood for syphilis serology. Results were also available online. From that study, the yield of detected syphilis was similar to that of the local STI clinic [68]. For chlamydia and gonorrhea testing, STI kits that contain materials and instructions for genital and extragenital specimen collection can be delivered to the patient’s residence and shipped out for lab testing. The “I Want the Kit” program (www.iwantthekit.org), available in select U.S. cities, used that model of home-based testing. Among 501 males who utilized that service, 89% found it easy to use and 77% preferred home-based testing to clinic-based testing [69]. Another example of a completely home-based, self-collection STI testing service is myLAB Box (www.mylabbox.com), which is a for-profit commercial entity. A systematic review by Fajardo-Bernal and colleagues found no significant difference between home-based and clinic-based specimen collection with regard to test completion, diagnosis, and treatment [70]. Those home-based testing modalities are convenient and timesaving alternatives to visiting a clinic.

6.0. Partner notification and treatment

It is essential that the sex partners of HIV-infected MSM with bacterial STIs be promptly notified about possible exposure, and if necessary receive treatment. Barriers to partner notification are also experienced at the patient-and provider-level. From the perspective of the infected patient there may be: lack of education given by their provider regarding partner notification, fear and concerns regarding adverse partner reactions, and challenges with contacting previous sex partners [71,72]. At the provider-level, cited barriers include lack of awareness of the importance of partner notification and treatment, poor knowledge of anonymous notification services, and lack of time to address partner notification with patients [72,73].

Providers should encourage partner notification to their patients. For those who prefer not to be identified, there are anonymous partner notification services such as inSPOT (www.inSPOT.org), which sends e-mail notifications to partners, and the Australian-based program, the Drama Down Under (www.thedramadownunder.info), which notifies partners via SMS or e-mail. Those modalities require having the contact information of sex partners, which may not always be available or known. The Internet and smartphone applications (e.g. Grindr, Scruff, Jack’d) have facilitated sex partner seeking and expanded sex networks among MSM, while simultaneously making it more difficult to contact sex partners who were met through these avenues, which often preserve the anonymity of their users [74,75]. Those same platforms have been used to successfully notify partners who could not be tracked down through traditional methods. In one study, partners of those involved in a syphilis cluster were notified using the same Internet chat room where most of the cases originally met [75]. In another example, Pennise and colleagues accessed smartphone applications used for sex partner seeking in order to obtain contact information to notify partners about STI exposure [76].

After sex partners are notified, they may now face the same barriers to prompt testing and treatment as already discussed. Expedited partner therapy (EPT) is one way to mitigate that problem. EPT involves providing the infected patient antibiotics to deliver directly to their sex partners without any medical evaluation. EPT is only appropriate for infections that are treated with therapies that can be easily self-administered (i.e. oral administration); that is true for chlamydia and in some cases of gonorrhea. Providing EPT may also encourage MSM to notify their sex partners. Clark et. al. demonstrated that among a cohort of MSM, 81% of those that received EPT notified at least one prior sex partner compared to just 58% of those who were not provided EPT [77]. However, the CDC currently does not recommend EPT for chlamydia or gonorrhea in MSM due to the lack of studies in that population, as well as the risk of co-infection with HIV, which may go undetected since it is feared that medical evaluation is circumvented with EPT [78]. Further studies should explore EPT specifically for HIV-infected partners.

7.0. STI prevention beyond screening and treatment

Although screening, rapid treatment, and partner treatment of syphilis, gonorrhea, and chlamydia are important STI control strategies, other interventions should be considered in the setting of a growing epidemic in HIV-infected MSM. In HIV prevention efforts, pre-exposure prophylaxis (PrEP) has brought attention another method of curbing transmission of infectious diseases. Perhaps a similar approach can be taken with other STIs. That may be feasible with syphilis in particular. Although screening for syphilis is being implemented better than for gonorrhea and chlamydia as already mentioned, the number of reported syphilis cases continues to grow annually. It does not seem likely that achieving near perfect incorporation of syphilis screening per CDC guidelines alone will stop the epidemic.

Wilson et. al. found that chemoprophylaxis was an acceptable method for syphilis prevention for a large group of MSM in Australia, with about 75% indicating that they would likely use it if it would reduce infections in the gay community [79]. In the same study, a mathematical model estimated an 85% reduction of syphilis cases after 10 years, assuming 70% use-effectiveness of chemoprophylaxis, and if taken by half of the MSM population. Bolan and colleagues tested the use of daily doxycycline as syphilis pre-exposure prophylaxis in a small cohort of 30 HIV-infected MSM. They reported a lower number of syphilis infections in the doxycycline arm compared to the control arm (2 cases versus 6 cases), although not significant presumably due to insufficient power [80]. With the dismal trend in syphilis among HIV-infected persons, antibiotic chemoprophylaxis for syphilis should be considered, however larger trials are needed to prove its efficacy in this population.

Molina and colleagues investigated STI post-exposure prophylaxis (STI-PEP) as a possible bacterial STI control strategy in a cohort of 232 HIV-uninfected MSM [81]. Participants who were randomized into the STI-PEP group were instructed to take 200 mg of doxycycline within 72 hours of condomless sex, and no more than 600 mg per week to reduce the risk of developing doxycycline resistance and medication-related adverse events. There was a 46% relative reduction in incidence of any bacterial STI when comparing the PEP group (37.7 events per 100 patient years) to the non-PEP group (69.7 events per 100 patient years), which was a significant finding (HR 0.53, 95% CI 0.33-0.85, p=0.008) [81]. When each STI was analyzed separately, there were large and significant relative incidence reductions in chlamydia and syphilis by 70% and 71%, respectively; that was not observed for gonorrhea, which may be explained by the NG resistance patterns endemic to the region where the investigation took place [81]. Although that study was conducted in HIV-uninfected MSM, perhaps STI-PEP against bacterial STIs should be considered in HIV-infected MSM as well [75].

8.0. Conclusion

We have discussed the necessity of integrating STI prevention, specifically sereening, treatment, and partner treatment into HIV care in the setting of a growing STI epidemic in HIV-infected MSM. Strategies to eliminate barriers to screening were reviewed. In addition, ideas to enhance efficiency and speed of testing, receiving results, and treatment were proposed. A summary can be seen in Table 1.

9.0. Expert commentary

HIV care visits are convenient opportunities to implement STI control strategies for HIV-infected MSM. However for some patients, the number of times that they should be screened annually per CDC guidelines may exceed the number of their HIV care visits per year. In those cases, other avenues such as home-based self-testing services must be available to fill in those gaps. HIV care providers must know the alternative screening options and develop a plan of action with their patients who need more frequent testing. Furthermore, up to a quarter of MSM with known HIV infection may not be receiving any HIV care at all [82]; those men must receive STI testing elsewhere.

For syphilis control, routine screening and treatment are not adequate to halt the increasing syphilis incidence in HIV-infected MSM. Syphilis screening is above 50% for HIV-infected MSM in the HIV care setting, which is much better than for gonorrhea and chlamydia, yet the number of new syphilis diagnoses in that population continues to rise [24]. Pre- or post-exposure chemoprophylaxis against syphilis should be seriously considered given the limited success of increased syphilis screening. Antimicrobial resistance should always be considered when proposing new biomedical interventions that involve the use of antibiotics. Although the chronic use of any antibiotic increases selective pressure, doxycycline prophylaxis is already used and has been found to be safe for medical conditions like acne and malaria with similar dosing implemented by Molina and colleagues for their study on STI-PEP with doxycycline [81,83]. There is some concern that STI-PEP for syphilis and chlamydia may produce resistant bacterial organisms. However, since the introduction of tetracyclines in the early 1950s there have been no documented human cases of doxycycline-resistant T. pallidum or CT to date. The lack of protection against NG with STI-PEP demonstrated by Molina and colleagues is evidence of already existing doxycycline-resistant NG species. Theoretically there is a risk that larger scale implementation of STI-PEP may expand the geographic distribution of doxycycline-resistant NG, however the clinical implications are minimal given that tetracyclines have not been recommended for the treatment of gonorrhea for many years. The benefits of bacterial STI chemoprophylaxis may outweigh the risks of medication-related adverse events or development of resistance if the appropriate subpopulation is targeted—in this case, HIV-infected MSM who engage in high risk sex behaviors.

Unlike with syphilis, less than 50% of HIV-infected MSM in HIV care settings are being screened for gonorrhea and chlamydia [24]; there is much room for improvement. Interventions to address that low percentage must be implemented. Patient-collected specimens, whether performed in a clinic or at home, seems to be the best way to mitigate many barriers for the patient and provider. Furthermore, extragenital sampling has been shown to be more fruitful in detecting gonorrhea or chlamydia compared to urogenital screening in MSM [21,22]. In screening that population, the emphasis must be placed on testing the pharynx and rectum rather than the urethra; however, currently the reverse is more common.

Reducing the window of infectivity with faster testing and treatment can curb transmission. Point-of-care testing and same-day treatment should be the standard in clinics. Results, whether normal or abnormal, must be delivered to patients in a timely and convenient way. Although SMS is better than the traditional phone call for the delivery of results, smartphone applications or mobile-friendly websites are more ideal. In comparison to text messages, those modalities are more secure, can verify that results were viewed, and have the ability to provide more details on treatment and follow-up.

With regard to partner notification, providers and public health officials must foster relationships with the developers of smartphone application and websites used by MSM to seek sex partners, which have become increasingly popular. It would be ideal if anonymous partner notifications could be sent directly to those who can only be found and contacted via those platforms. Lastly, EPT should be considered for the treatment of STIs among partners.

10.0. Five-year view

The rates of STIs in HIV-infected MSM will continue to rise for the reasons already discussed in this review. The CDC’s recent formal recognition that there is effectively no risk of acquiring HIV from a person with an undetectable viral load, combined with the increased use of PrEP are two very promising developments for the field of HIV prevention. On the other hand, those messages may promote increased sexual risk behaviors (i.e. condomless sex, multiple sex partners) that facilitate transmission of other STIs. Sex networks of MSM that may have been previously segregated by HIV status will begin to merge so that the rates of STIs will be homogeneous in MSM.

Technology will continue to advance sexual health services. Automated electronic testing reminders will be more fine-tuned to alert both providers and patients. The availability of POCT for chlamydia and gonorrhea will increase in clinic settings. New research will validate the use of home-based testing for chlamydia, gonorrhea, and syphilis. The use of telemedicine as a method of mitigating testing barriers will expand, as the time-constraints of in-person visits are likely to continue in the future.

HIV care clinics will implement or refer patients to other options for STI testing given the trend towards less frequent HIV monitoring visits for those whose HIV is well-controlled. Examples of alternative testing will include separate STI clinics within HIV care settings, home-based testing, and no-provider testing sites that rely on self-collection of specimens and only require a technician for blood draw for syphilis testing.

Lastly, since not all HIV-infected MSM are aware of their status, and not all who do know are linked to and retained in HIV care, other strategies will be needed. Just as with the HIV, screening and early treatment are not enough to turn the tide on the epidemic. Chemoprophylaxis against syphilis, gonorrhea, and chlamydia for high risk HIV-infected MSM will be more accepted as a form of STI prevention, just as HIV PrEP is today for HIV-uninfected MSM.

11. Key issues:

• The rising epidemic of syphilis, as well as gonorrhea and chlamydia, in HIV-infected MSM has implications for HIV patient management and transmission to STI-uninfected individuals.

• Multiple barriers in the HIV care setting may prevent implementation of screening guidelines in HIV-infected MSM on the patient-, provider-, and healthcare system-levels.

• Interventions that eliminate barriers encountered by HIV-infected MSM anywhere throughout the process from STI screening to treatment have varying degrees of success and cost.

• STI prevention should be implemented into routine HIV care since these visits are opportune times to intervene regularly. However, other screening locations and modalities must be available for HIV-infected MSM whose recommended number of STI screenings per year exceeds their number of annual routine HIV care visits.

• The mainstays of STI control are screening, treatment, and partner treatment; however those strategies may not be enough to curtail the STI epidemic in HIV-infected MSM. Other innovative approaches such as chemoprophylaxis may be required.