The relationship between HIV preexposure prophylaxis (PrEP) use and laboratory-confirmed bacterial sexually transmitted infection positivity among a diverse, multicity cohort of sexually active sexual and gender minorities in the US

Abstract

The presence of chlamydia, gonorrhea, or syphilis infection is a significant risk factor for HIV acquisition and transmission and disproportionately impact men who have sex with men (MSM) and transgender women. While HIV pre-exposure prophylaxis (PrEP) reduces HIV risk, its use may influence sexual behaviors, potentially increasing sexually transmitted infection (STI) exposure. Conversely, PrEP users are often more engaged in care, regularly screened and treated for STIs, and may access other prevention tools such as doxycycline post-exposure prophylaxis (doxyPEP). Studies on the relationship between PrEP use and STIs have shown mixed results.

This cross-sectional analysis included 392 participants (381 cisgender MSM; 11 transgender women) enrolled in the U.S.-based MACS/WIHS Combined Cohort Study (MWCCS) between 2021–2024 who were sexually active in the year prior to STI testing and HIV negative at their most recent study visit. We assessed whether bacterial STI positivity (i.e., laboratory-confirmed chlamydia and gonorrhea at the urethral, pharyngeal, and/or rectal sites and/or current/past syphilis infection) differed by current PrEP use (yes/no). Multivariable logistic regression models included sociodemographic and behavioral covariates that were associated with bacterial STI positivity at p<0.05, with the most parsimonious models selected based on the lowest Akaike Information Criterion.

Overall, 32.7% reported current PrEP use. Syphilis was the most prevalent STI (6.8%), followed by chlamydia (3.2%) and gonorrhea (2.1%). 11.7% of PrEP users tested positive for at least one STI, compared with 6.1% of non-PrEP users. Among PrEP users, 37.9% reported stopping or decreasing condom use and 31.6% reported increased number of sex partners after initiating PrEP. In both bivariate and multivariable models, PrEP use was associated with higher odds of gonorrhea positivity (aOR=4.70, 95% CI: 1.10–20.04, p=0.037) and greater odds of being positive for at least one STI (cOR=1.94, 95% CI: 1.06–3.90, p=0.041). No significant differences were observed for chlamydia and syphilis by PrEP use status.

Overall, these findings suggest that current PrEP users (versus non-PrEP users) have an increased odds of bacterial STI positivity, particularly gonorrhea, in a diverse, multi-city cohort of HIV negative, sexually active MSM and transgender women in the US. PrEP remains highly effective in preventing HIV, and our results underscore the importance of integrated sexual health services that support ongoing STI screening and prevention alongside PrEP use among sexual and gender minorities.

INTRODUCTION

According to the Centers for Disease Control and Prevention (CDC), men who have sex with men (MSM) and transgender women have a higher risk of acquiring chlamydia, gonorrhea, and syphilis than any other group in the U.S.^1,2 While higher rates of sexually transmitted infections (STIs) are generally seen in younger adults, prior studies estimating STI prevalence among aging men, including among men in the Multicenter AIDS Cohort Study (MACS), found that STI risk among older MSM remains non-negligible.^3,4 Furthermore, STI incidence rates among men ages 55 and older in the U.S. have substantially increased from 2000–2023, with annual rates of chlamydia increasing from 3.2 to 31.3, gonorrhea increasing from 10.8 to 35, and syphilis increasing from 0.9 to 9.0 cases per 100,000 people.^3–6 Nearly 80% of chlamydia, gonorrhea, and syphilis cases are estimated to be asymptomatic—reducing their likelihood of timely detection and treatment—further increasing HIV acquisition and transmission risk.^7–11

In the U.S., widespread availability of HIV pre-exposure prophylaxis (PrEP) in the last decade has reduced the incidence of HIV among MSM and transgender women, though important differences in PrEP uptake persist by sex, age, and race.¹² An unintended consequence for some taking PrEP may be increased engagement in sexual behaviors which increase STI exposure, such as condomless anal sex and an increase in total number of sex partners. This phenomenon is referred to as “risk compensation” or behavioral adaptation, a theory which suggests that people typically adjust their behavior in response to perceived levels of risk.^13–18 The literature well documents that MSM and transgender women who use PrEP report a higher number of sex partners and decreased condom use compared with non-PrEP users,^19–27 but it is still debated whether individuals changed their behavior on PrEP or whether they maintained a higher level of risk from prior to PrEP initiation.^19–26,28

Reports describing changes in STI incidence after PrEP initiation vary, with several longitudinal studies reporting an increase in STI incidence among MSM in the U.S. (San Francisco: n=657, Seattle: n=183), Australia (n=2,981), Spain (n=110), Canada (n=109), the Netherlands (n=630), and Austria (n=360).^{19,25,29–33} Other studies among MSM and transgender women in Amsterdam (n=367), the United Kingdom (n=544), France and Canada (n=400), multiple countries (Peru, Thailand, South Africa, U.S., Brazil, and Ecuador: n=2,499), and several U.S. cities (San Francisco, Miami, and Washington D.C.: n=557; Philadelphia: n=50) did not detect a change in STI incidence after PrEP initiation.^34–39

One study of MSM (n=365) and transgender women (n=2) in Amsterdam found that STI incidence was 50% lower among event-driven PrEP users compared with daily PrEP users, which the authors attributed to differences in sexual behavior (i.e., event-driven PrEP users had fewer condomless anal sex acts and fewer sexual partners).³⁴ Studies showing increases in STI incidence among daily PrEP users suggest risk compensation as a potential cause, while other studies have found that PrEP users had high baseline levels of sexual risk, and did not alter their sexual behaviors.^40,41 A review of 20 studies reporting primarily stable STI burden among MSM using PrEP suggested that this phenomenon could be explained by PrEP users having increased access to healthcare systems, where regular STI monitoring and treatment is available.⁴² As a result, such persons may also be more likely to be offered biomedical prevention, including not only PrEP, but also doxycycline post-exposure prophylaxis (doxyPEP), an antibiotic taken after sexual exposure to prevent acquisition of bacterial STIs.⁴³ Several of these studies relied either upon self-reported STI data or on data exclusively from PrEP recipients, who are in general monitored for STIs more frequently than non-PrEP users; this disparity by PrEP use can result in uncontrolled confounding of STI estimates, potentially leading to misinterpretation of findings and discouraging PrEP as an effective HIV prevention strategy.⁴⁴

Across published studies, inconsistent findings related to PrEP use-associated STI risk behavior compensation highlight the need for further investigation of the relationship of PrEP use with changes to sexual risk behavior and STIs.^{19,25,29–32,34–39} This study used cross-sectional data from a large, diverse cohort to assess whether the prevalence of laboratory-confirmed STI positivity at routine study visits differed by PrEP use status among aging, sexually active HIV-seronegative cisgender MSM and transgender women enrolled in the MACS/WIHS Combined Cohort Study (MWCCS).

METHODS

Study Population

The MWCCS is the longest-running U.S. cohort that includes both individuals living with and without HIV. The study data were collected at MWCCS clinical research sites between 2021–2024 and grouped into four geographic subregions: Mid-Atlantic/Northeast (Brooklyn, NY; Bronx, NY; Baltimore, MD; Washington, DC); South (Birmingham, AL; Jackson, MS; Atlanta, GA; Chapel Hill, NC; Miami, FL); Midwest (Pittsburgh, PA; Columbus, OH; Chicago, IL), and West Coast (Los Angeles, CA; San Francisco, CA). The study was approved by institutional review boards at each study MWCCS site, and all participants provided informed consent prior to study enrollment. More details about the MWCCS can be found at: https://statepi.jhsph.edu/mwccs/.

Participants (N=392) included in the current analysis were cisgender MSM (n=381) and transgender women (n=11) who completed STI screening for chlamydia, gonorrhea, or syphilis using at-home testing kits. The study sample was further restricted to persons who were sexually active within the past year and were confirmed via laboratory testing to be HIV-seronegative at the time the STI samples were collected. Cisgender women were not included in the current analysis because they were not tested for rectal or pharyngeal gonorrhea or chlamydia, and because they had a low prevalence of PrEP use (2.2%);⁴⁵ likewise, cisgender women and men not living with HIV who reported only have sex with women (lifetime) were excluded due to low overall response rates to the self-reported PrEP use questions (18.6% and 12.4% response rates, respectively).⁴⁵

Data Collection

MWCCS participants completed in-depth quantitative surveys every 6 months, including addressing sociodemographic characteristics, substance use, sexual behavior, medication use, and health history.

STI Testing:

STI testing among MWCCS participants has been previously described.⁴⁵ Briefly, self-collected biospecimens for one-time STI surveillance (regardless of sexual activity and symptoms) were collected between 2021–2024. Biospecimens collected included urine, pharyngeal and rectal swabs, microcontainer of blood, and dried blood spots (DBS). Current/past syphilis infection was determined using a reverse testing algorithm:^45,46 if the first treponemal test was reactive, a confirmatory non-treponemal Rapid Plasma Reagin (RPR) test was conducted. If the RPR test was non-reactive, a second treponemal test was conducted for confirmation. Rectal, urethral, and pharyngeal gonorrhea and chlamydia were examined using nucleic acid amplification testing.¹¹ Participants testing positive for any STI were notified and referred for treatment.

Sociodemographic Characteristics:

Sociodemographic variables were self-reported at participants’ MWCCS enrollment visit. These variables included: age (continuous), educational attainment (less than college, 4-year college or beyond), sexual/gender identity (cisgender MSM, transgender woman), race (Black/African American, white, or multi-racial/Other), Latinx/Hispanic ethnicity, employment status (full time, part time/student, retired, unemployed/disability), monthly household income ($3000 or less, $3000-$8333, $8334 or more), and any medical insurance coverage (yes or no).

Substance Use:

Participants self-reported past-year substance use (“yes” or “no”), from which multiple binary substance use variables were derived. These substances included cannabis, heroin, crack/cocaine, poppers/inhalants, speed/methamphetamine, or other illicit drugs including hallucinogens, PCP, psychedelics, LSD, DMT, MDMA, mescaline, ketamine. “Polydrug use” was defined as using three or more of the above specified drugs in the past year. Stimulant use was defined as using crack/cocaine, speed/methamphetamine, or MDMA in the past year. Heavy alcohol use was assessed using the 10-item Alcohol Use Disorders Identification Test (AUDIT-C).⁴⁷

Sexual Behavior:

Sexual behavior measures of interest included 1) self-reported total number of past-year sex partners, and 2) number of past-year male partners with whom the participant engaged in anal sex. Participants who reported PrEP use were also asked whether there was a change to their condom use and number of sexual partners after PrEP initiation. Past-year and current PrEP use were self-reported, and HIV testing was completed with an FDA-approved antigen/antibody combination immunoassay. Substance use and sexual behavior data from the quantitative survey completed nearest to the STI testing date for each participant were used. If the participant did not complete a quantitative survey within 6 months of STI testing, these data were considered missing.

Statistical Analysis

We conducted a cross-sectional analysis of STI testing results, using one data point per participant. For participants who tested negative for all STIs, we used their baseline data. For those who tested positive, we used the visit at which the STI was first detected. Sociodemographic characteristics, sexual behavior, and substance use were summarized using descriptive statistics by PrEP use status (frequencies and percentages for categorical variables; means and standard deviations for continuous variables). Chi-squared/Fisher’s exact tests and Mann-Whitney U tests were used to assess associations between STI prevalence, sociodemographic characteristics, substance use, and sexual behaviors by PrEP use status. Self-reported changes in condom use and total numbers of sexual partners, both after initiating PrEP, were assessed.

Bivariate and Multivariable Logistic Regression Models:

We used logistic regression to examine associations between predictors and STI positivity. The STI outcomes included chlamydia (positive at any anatomical site), gonorrhea (positive at any anatomical site), current or past syphilis infection, or testing positive for any of these three STIs. First, we ran bivariate models to test each predictor’s association with each STI outcome individually. Any predictor with a p-value of less than 0.05 in bivariate analyses was considered for inclusion in adjusted models. Final models were selected using stepwise selection based on the lowest Akaike Information Criterion, followed by a multivariate Wald test. Based on these results, the final adjusted models for each STI outcome included: Chlamydia (educational attainment, stimulants use, number of male partners engaged in any anal sex in the past 12-months); Gonorrhea (race); Current/Past Syphilis (poppers/inhalants use in the past 12- months); Any STI (educational attainment and poppers/inhalants use in the past 12-months).

We used multiple imputation by chained equations (MICE) to handle missing data of covariates.⁴⁸ Twenty imputed datasets were generated using the MICE package in R.⁴⁹ We included key sociodemographic and behavioral factors that were associated with missingness in the imputation models (age, race, ethnicity, educational attainment, sexual identity, stimulant use, current or past-year PrEP use). Sensitivity tests confirmed similar results with and without imputed values. Missing data was less than 20% across all variables. All analyses were performed using RStudio (Version 2024.09.0+375), and p-values <0.05 were considered statistically significant.

RESULTS

Sociodemographic characteristics, substance use, and sexual behavior are reported among the entire sample and stratified by PrEP use status in Table 1. Approximately one third (32.7%) of participants reported current PrEP use in the past year. The vast majority of PrEP users reported taking daily oral PrEP (96%), while a small number reported using long-acting injectable (LAI) PrEP (4%).

Table 1.

Sociodemographic Characteristics, Substance Use, and Sexual Behavior of the Total Sample and by PrEP Use Status Among Cisgender MSM and Transgender Women Enrolled in the MACS/WIHS Combined Cohort Study, 2021–2024.

	Total (N = 392)		PrEP Users (N = 128)		Non-PrEP Users (N = 264)
	Mean	SD	Mean	SD	Mean	SD
Age (range 29 – 87)	57.62	14.63	50.02	14.06	61.31	13.46
Number of Male Partners - Past 12 Months:
Engaged in Any Anal Sex With	3.24	4.78	6.22	5.82	1.58	3.03
Engaged in Oral Sex With	5.84	7.03	9.40	8.20	3.80	5.30
Number of Female Partners - Past 12 Months:
Engaged in Any Vaginal/Anal Sex With	0.66	1.88	0.18	0.75	0.93	2.25
Engaged in Oral Sex With	0.31	0.97	0.13	0.60	0.42	1.12
Number of Sex Partners - Past 12 Months:
Total Number of Male Sex Partners	6.81	8.51	11.48	10.05	4.11	6.05
Total Number of Female Sex Partners	0.90	2.56	0.31	1.40	1.24	2.98
Overall Total Number of Sex Partners (Any Gender)	13.99	28.95	17.54	30.96	11.97	27.63
	N	%	N	%	N	%
Educational Attainment
Less than College	157	40.2	52	40.6	105	39.9
Completed 4-year College or Beyond	234	59.8	76	59.4	158	60.1
Gender Identity
Cisgender MSM	381	97.2	122	95.3	259	98.1
Transgender Women	11	2.8	6	4.7	5	1.9
Race
Black/African American	94	24.0	34	26.6	60	22.7
White	217	55.4	66	51.6	151	57.2
Multi-Racial and Other	81	20.7	28	21.9	53	20.1
Latinx/Hispanic Ethnicity
No	335	85.5	107	83.6	228	86.4
Yes	57	14.5	21	16.4	36	13.6
Enrollment Region
Mid-Atlantic/Northeast	82	20.9	18	14.1	64	24.2
Midwest	99	25.3	34	26.6	65	24.6
South	85	21.7	49	38.3	36	13.6
West Coast	126	32.1	27	21.1	99	37.5
Employment Status
Full Time	142	44.9	63	66.3	79	35.7
Part Time/Student	37	11.7	10	10.5	27	12.2
Retired	100	31.6	13	13.7	87	39.4
Unemployed/Disability	37	11.7	9	9.5	28	12.7
Monthly Household Income
$3000 or Less	78	27.7	20	22.7	58	29.9
$3001 – $8333	99	35.1	34	38.6	65	33.5
$8334 – More	105	37.2	34	38.6	71	36.6
Any Medical Coverage – Past 12 Months
No	17	5.6	6	6.5	11	5.2
Yes	288	94.4	86	93.5	202	94.8
Heavy Alcohol Use - Past 12 Months
No (AUDIT < 8)	186	76.9	64	74.4	122	78.2
Yes (AUDIT ≥ 8)	56	23.1	22	25.6	34	21.8
Cannabis Use - Past 12 Months
No	165	56.3	53	49.1	112	60.5
Yes	128	43.7	55	50.9	73	39.5
Heroin/Opioids Use - Past 12 Months
No	287	98.3	108	100.0	179	97.3
Yes	5	1.7	0	0.0	5	2.7
Crack/Cocaine Use - Past 12 Months
No	266	91.4	97	89.8	169	92.3
Yes	25	8.6	11	10.2	14	7.7
Speed/Methamphetamine Use - Past 12 Months
No	267	92.1	98	90.7	169	92.9
Yes	23	7.9	10	9.3	13	7.1
Poppers/Inhalants Use - Past 12 Months
No	202	69.4	62	57.4	140	76.5
Yes	89	30.6	46	42.6	43	23.5
Stimulants Usea - Past 12 Months
No	256	87.7	93	86.1	163	88.6
Yes	36	12.3	15	13.9	21	11.4
Polydrug Useb – Past 12 Months
No	267	91.1	94	87.0	173	93.5
Yes	26	8.9	14	13.0	12	6.5
Had Male Sex Partners – Past 12 Months
No	43	15.6	4	3.9	39	22.4
Yes	233	84.4	98	96.1	135	77.6
Had Female Sex Partners – Past 12 Months
No	233	82.6	95	92.2	138	77.1
Yes	49	17.4	8	7.8	41	22.9
Condom Use after PrEP Initiation
I have used condoms less often than I did before starting PrEP	-	-	26	22.4	-	-
I have used condoms more often than I did before starting PrEP	-	-	10	8.6	-	-
I have stopped using condoms since I started PrEP	-	-	18	15.5	-	-
I have used condoms infrequently	-	-	13	11.2	-	-
There has been no change in my condom use	-	-	49	42.2	-	-
Number of Sex Partners after PrEP Initiation
Increased	-	-	37	31.6	-	-
Decreased	-	-	15	12.8	-	-
Stayed the same	-	-	65	55.6	-	-

Abbreviations:

PrEP Users = No Current or Past 12-Month PrEP use

Non-PrEP Users = Current or Past 12-Month PrEP use

SD = Standard Deviation

N = Number of Cases

AUDIT = Alcohol Use Disorders Identification Test

^aStimulants Use = A composite variable for any stimulant use, including crack/cocaine, speed/methamphetamine, or MDMA.

^bPolydrug Use = >3 drugs used, including: cannabis, heroin, crack/cocaine, poppers/inhalants, speed/methamphetamine, or other illicit drugs including MDMA, PCP, psychedelics, LSD, DMT, mescaline, and Ketamine.

PrEP use was significantly associated with younger age (p<0.001), study enrollment region (p<0.001), employment status (p<0.001), and poppers/inhalants use (p=0.001). PrEP users had a higher number of male partners in the past year (p<0.001) and a lower number of female partners (p=0.001). Total number of past-year sex partners (any gender) was higher among PrEP users (p=0.013). Chlamydia positivity was associated with educational attainment (completing less than 4 years of college, p=0.026), stimulants use (p<0.001), and a higher number of male sex partners with whom participants engaged in any anal sex acts with in the past-year (p=0.014); Gonorrhea positivity was significantly associated with self-reported Black/African American race (p=0.028) and multi-racial/other race (p=0.041), compared to self-reported white race; Current/past syphilis was associated with past-year poppers/inhalant use (p=0.016); testing positive for any of the three STI was associated with educational attainment (completing less than 4 years of college, p=0.008) and past-year poppers/inhalants use (p=0.040).

Among PrEP users, 37.9% reported decreasing or stopping condom use after initiating PrEP, while 8.6% reported more frequent condom use, 42.2% reported no change in their condom use, and 11.2% reported infrequent condom use with no indication as to whether this was different from their condom use prior to initiating PrEP. Among participants on PrEP, 31.6% reported having a greater number of sexual partners after initiating PrEP (compared to before initiating PrEP), 12.8% reported reducing their number of sexual partners, and 55.6% reported that their number of sexual partners remained the same before and after initiating PrEP (Table 1).

Overall, current/past syphilis was the most prevalent STI (6.8%, 19/279), followed by chlamydia (3.2%, 11/341) and gonorrhea (2.1%, 7/341). Prevalences of STIs were consistently higher among PrEP users compared to non-PrEP users; however, these differences were not statistically significant except for gonorrhea: 1) Chlamydia positivity (PrEP users: 5.4%; Non-PrEP users: 2.2%; p=0.187), 2) Gonorrhea positivity (PrEP users: 4.5%; Non-PrEP users: 0.9%; p=0.039), 3) Current/past syphilis positivity: (PrEP users: 9.6%; Non-PrEP users: 5.4%; p=0.291), as well as positivity for any of the three STIs (PrEP users: 11.7%; Non-PrEP users: 6.1%; p=0.081).

Results from logistic regression models comparing STI positivity between PrEP users and non-users are reported in Table 2. In bivariate models, there were no statistically significant differences in the odds of testing positive for chlamydia (cOR=2.80, 95% CI: 0.91–8.62, p=0.073) and current/past syphilis (cOR=1.73, 95% CI: 0.74–4.03, p=0.203) between PrEP users and non-users. PrEP users had significantly higher odds of testing positive for gonorrhea (cOR=5.82, 95% CI: 1.28–26.39, p=0.023) and at least one STI (cOR=2.13, 95% CI: 1.10–4.24, p=0.031) compared to non-users. In multivariable models, compared to their non-PrEP counterparts, PrEP users had significantly higher odds of gonorrhea positivity (aOR=4.70, 95% CI: 1.10–20.04, p=0.037) and positivity for at least one STI (cOR=1.94, 95% CI: 1.06–3.90, p=0.041). Adjusted odds ratios for chlamydia positivity (aOR=1.41, 95% CI: 0.36–5.63, p=0.622) and current/past syphilis positivity (aOR=1.68, 95% CI: 0.72–3.90, p=0.231) were also positive, suggesting higher odds among PrEP users compared to non-users, but were not statistically significant.

Table 2.

Bivariate and multivariable logistic regression models comparing STI prevalence by PrEP use status

	STI Prevalence* (n / N)	Model 1		Model 2†
		cOR	95% CI	aOR	95% CI
Chlamydia
Non-PrEP Users	2.2 (5/230)	1.00	Ref.	1.00	Ref.
PrEP Users	5.4 (6/111)	2.80	0.91 – 8.62	1.41	0.36 – 5.63
P-value	0.187	0.073		0.622
Gonorrhea
Non-PrEP Users	0.9 (2/230)	1.00	Ref.	1.00	Ref.
PrEP Users	4.5 (5/111)	5.82	1.28 – 26.39	4.70	1.10 – 20.04
P-value	0.039	0.023		0.037
Current/Past Syphilis
Non-PrEP Users	5.4 (10/185)	1.00	Ref.	1.00	Ref.
PrEP Users	9.6 (9/94)	1.73	0.74 – 4.03	1.68	0.72 – 3.90
P-value	0.291	0.203		0.231
Any STI
Non-PrEP Users	6.1 (16/264)	1.00	Ref.	1.00	Ref.
PrEP Users	11.7 (15/128)	2.13	1.10 – 4.24	1.94	1.06 – 3.90
P-value	0.081	0.031		0.041

n: Number of Positive Cases; N: Total Cases; cOR: crude odds ratio; aOR: adjusted odds ratio; CI: confidence interval; Ref.: Reference; Non-PrEP Users: No Current or Past 12-Month PrEP use; PrEP Users: Current or Past 12-Month PrEP use.

^*Prevalence per 100 participants

^†Model 2: Covariates other than PrEP use with p < 0.05 in bivariate analyses were considered for inclusion in adjusted models. Final models were selected based on the lowest Akaike Information Criterion: Chlamydia (educational attainment, stimulants use, and number of male partners engaged in any anal sex in the past 12-months); Gonorrhea (race); Current/Past Syphilis (poppers/inhalants use in the past 12- months); Any STI (educational attainment and poppers/inhalants use in the past 12-months)

DISCUSSION

This study contributes to the growing body of literature describing the potential impacts of risk compensation in the context of STI prevention by leveraging data from one of the longest-running and most comprehensive cohorts of individuals living with or without HIV in the U.S.² PrEP users in our study, compared to non-PrEP users, had significantly higher odds of gonorrhea and any STI (having at least one infection for all 3 STIs assessed) positivity. A higher prevalence of STIs among PrEP users was hypothesized, as PrEP use is generally associated with condomless sex and increased number of sexual partners—risk factors for STI acquisition—behaviors that have been consistently reported.^19–27 Likewise, in our current analysis, PrEP users had higher overall number of past-year male and any gender sex partners. There is considerable debate in the literature regarding the temporal ordering of these variables, on which our study provides some insight. Despite the cross-sectional nature of our analysis, PrEP users in our study were specifically asked to report any changes in their condom usage and the number of sexual partners after initiating PrEP. More than one-third of PrEP users studied (38%) reported decreasing or stopping condom use, while one-third reported increasing their number of sexual partners after PrEP initiation, providing some evidence supporting risk compensation theory. In other words, it is possible that taking PrEP could lead to lower perceived risk for acquiring HIV and therefore lead to reduction in condom use or increase in number of sexual partners, apparently true for some participants in our study. On the other hand, PrEP users may have been engaging in higher risk behaviors for HIV/STI acquisition prior to initiating PrEP, and therefore sought out PrEP as a risk reduction strategy.

There were no statistically significant differences in odds of chlamydia or current/past syphilis between PrEP users and non-users, even with some participants reporting behavioral changes after PrEP initiation and higher reported number of past-year sex partners. This finding aligns with several prior studies^34–39 that attribute this result to increased access to regular HIV and STI testing services among PrEP users through their PrEP service provider. Additionally, it is possible that some participants connected to PrEP services could have had access to other STI prevention methods, such as doxyPEP. Although data on doxyPEP use were not available for this analysis, it is worth noting that doxyPEP has shown greater efficacy in preventing syphilis and chlamydia than gonorrhea.⁵⁰ This may partially explain why gonorrhea—and not chlamydia or syphilis—was significantly more prevalent among PrEP users in our study. Future analyses should account for doxyPEP use to more accurately assess this possibility.

Four percent of PrEP users in our study reported using LAI PrEP for HIV prevention, and prior research in the MACS cohort demonstrated that older MSM engage in a wide range of combination HIV prevention strategies, including biomedical and behavioral approaches.⁵¹ As LAI PrEP becomes more widely accessible, its implications for STI prevention warrant consideration. While LAI PrEP is a great option for individuals who face challenges with daily adherence, reduced clinical contact may lead to fewer opportunities for routine STI screening. Monitoring for potential changes in sexual behavior will be essential to ensuring that LAI PrEP is implemented in a way that supports comprehensive sexual health.

A key strength of this study was the incorporation of self-collected specimens for STI testing. Research has shown that self-collected samples—such as urine, rectal and pharyngeal swabs, and DBS—are as accurate as clinician-collected specimens.^52–55 This method is not only cost-efficient but also enhances patient acceptability of the collection process. Additionally, it enables testing outside traditional clinical settings, thereby improving access to regular STI screenings. Collecting these test results as part of a routine study visit, rather than when patients present with symptoms, allowed for detection of asymptomatic STIs which may otherwise go undetected without routine screening. Another notable strength is the focus on an aging cohort of MSM and transgender women, a population that remains sexually active and at risk for HIV and STIs, yet is underrepresented in STI research. As such, these findings fill an important gap in the literature.

Our study has some limitations. These include not being able to adequately examine PrEP adherence or numbers of condomless anal or vaginal sex acts (as opposed to numbers of sexual partners). Moreover, the changes in condom use questions were only asked among PrEP users, and hence these variables could not be included in our models. In addition, this analysis examined STI prevalence, but continued collection of longitudinal STI data in the MWCCS will allow for evaluation of additional measures over time to assess STI incidence, long-term PrEP use patterns (including measures of adherence), and changes in sexual risk behaviors, as well as potential temporal effects of the COVID-19 pandemic on STI screening and transmission.⁵⁶ There was inconsistency in STI test administration across MWCCS sites. Some sites distributed testing kits to participants either by mail or during in-person follow-up visits, allowing for home self-collection. In contrast, other sites required participants to use self-collection kits in private restrooms during their visits, with study staff occasionally assisting in specimen collection. Furthermore, a small subset of participants did not use DBS/microtainers; instead, blood samples for syphilis testing were obtained through venipuncture. Further, our sample size of PrEP users was relatively small, potentially impacting our power to detect meaningful differences in STI prevalence by PrEP use status. Our findings may not be generalizable to other populations, as the MWCCS study is closed cohort composed of motivated research participants, some of whom have remained engaged in the study for decades and might have a different baseline risk for STIs than other populations. Lastly, we could not disaggregate findings for transgender individuals, who comprised 2.3% of the sample in the current analysis, from their cisgender peers.

In our study, PrEP users had significantly higher odds of gonorrhea and any STI positivity compared to non-users, while no significant differences were observed for chlamydia or current/past syphilis. These findings highlight the importance of integrating routine STI screening into PrEP care, particularly given the potential for increased exposure through risk compensation. PrEP remains a highly effective tool in ending the HIV epidemic. Sexually active MSM and transgender women should continue to undergo routine STI testing, regardless of symptoms, and may greatly benefit from ongoing education regarding HIV and STI prevention, as well as from biomedical prevention interventions (e.g., PrEP and doxyPEP) provided by their PrEP or primary care providers to reduce the risk of bacterial STI development.

Data availability statement:

Access to individual-level data from the MACS/WIHS Combined Cohort Study Data (MWCCS) may be obtained upon review and approval of a MWCCS concept sheet. Links and instructions for online concept sheet submission are on the study website (http://mwccs.org/).