Abstract
Background:
Rectal Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) are increasingly recognized as common infections among women. Little is known about the prevalence of rectal Mycoplasma genitalium (MG), rectal MG/CT/GC co-infection, or MG antimicrobial resistance patterns among women.
Methods:
In 2017–2018 we recruited women at high risk for CT from Seattle’s municipal STD clinic. Participants self-collected vaginal and rectal specimens for CT/GC nucleic acid amplification testing (NAAT). We retrospectively tested samples for vaginal and rectal MG using NAAT, and tested MG-positive specimens for macrolide resistance-mediating mutations (MRM) and ParC quinolone resistance-associated mutations (QRAMs).
Results:
Of 50 enrolled women, 13 (26%) tested positive for MG, including 10 (20%) with vaginal MG and 11 (22%) with rectal MG; 8 (62%) had concurrent vaginal/rectal MG. Five (38%) were co-infected with CT; none with GC. Only 2 of 11 women with rectal MG reported anal sex in the prior year. Of MG-positive specimens, 100% of rectal and 89% of vaginal specimens had a MRM. There were no vaginal or rectal MG-positive specimens with ParC QRAMs previously associated with quinolone failure. Five MG-infected women received azithromycin for vaginal CT, four of whom had a MG MRM detected in their vaginal and/or rectal specimens.
Conclusions:
We observed a high prevalence of macrolide-resistant vaginal and rectal MG among a population of women at high risk for CT. This study highlights how the use of antimicrobials designed to treat an identified infection – in this case CT – could influence treatment outcomes and antimicrobial susceptibility in other unidentified infections.
Keywords: Mycoplasma genitalium, azithromycin, rectal, women
SHORT SUMMARY
Twenty-six percent of female STD clinic patients tested positive for either vaginal or rectal M. genitalium (MG). All rectal specimens and 89% of vaginal specimens were macrolide resistant.
INTRODUCTION
Mycoplasma genitalium (MG) is a bacterial sexually transmitted infection (STI) associated with urethritis in men, and with cervicitis, pelvic inflammatory disease (PID), preterm birth, spontaneous abortion, and infertility in women.1,2 The prevalence of urogenital MG is approximately 1–9% in population-based samples of women3 and is approximately 15–20% in contemporary clinic-based samples of women in the United States (U.S.).4,5
Like Chlamydia trachomatis (CT) and Neisseria gonorrheoae (GC), MG has been detected in female rectal specimens, but little is known about the epidemiology of rectal MG among women. Among clinic-attending women in the U.S. and South Africa, the prevalence of rectal MG is approximately 3%−8%6–9, which is in the range of that reported for rectal CT (6–9%) and rectal GC (2%) in comparable populations.10–12 Rectal MG does not appear to be associated with anal sex7,8 and, as has been suggested for rectal CT13, may result from autoinoculation from the vagina. The health implications of rectal MG among women are largely unknown. Rectal MG is often asymptomatic, but could serve as a reservoir of transmission to men via anal or vaginal sex; the latter occurring if women autoinoculate MG from the rectum to the vagina. Although two commercially available MG diagnostic tests were approved by the U.S. Food and Drug Administration in 2019, there are no U.S. guidelines for routine vaginal or rectal MG screening.
The 2015 U.S. Centers for Disease Control and Prevention (CDC) STD Treatment Guidelines recommends 1g azithromycin (a macrolide antibiotic) for urethritis, cervicitis, and PID in cases where MG is the suspected causative agent.14 However, reports of MG azithromycin resistance have been increasing for well over a decade15, and MG azithromycin cure rates have substantially declined since 2009.16 Azithromycin treatment failure is associated with genetic mutations in the 23S rRNA gene17, and the prevalence of MG strains with these macrolide resistance-mediating mutations (MRM) varies widely, from 0% in South Africa18 to 63% in Australia19 to 100% in Greenland.20 Alarmingly, treatment failures with the CDC-recommended second-line antibiotic for suspected MG – moxifloxacin (a quinolone antibiotic) – have also been observed. These treatment failures are associated with mutations in the parC gene, mainly in codons coding for amino acides in position S83 or D87 of ParC (quinolone resistance-associated mutations; QRAMs). The correlation with treatment failure is stronger in the presence of concurrent mutations in the gyrA gene.21 A prevalence of the S83I mutation in ParC as high as 84% has been reported in some settings.22 However, the prevalence of MRM and QRAM among rectal specimens from women has not been well-described.
We have previously observed a high prevalence of rectal CT (22%) and rectal GC (8%) in a cohort of women at high risk of urogenital CT recruited from a municipal STD clinic in Seattle, Washington.23 The goals of the current analysis were to examine the prevalence of vaginal and rectal MG and co-infection with CT and GC in this same population, and to describe the prevalence of macrolide and quinolone resistance mutations in women with vaginal and rectal MG.
METHODS
Study Design, Setting, and Population
This was a cross-sectional study, using data from the enrollment visit of a prospective study of women at high risk of urogenital CT. We have previously described the prospective study’s methods and population.23 Briefly, patients attending the Public Health – Seattle & King County (PHSKC) STD clinic in Seattle, Washington between September 2017 – April 2018 were invited to participate in the study if they were female sex at birth, ≥16 years old, not pregnant, reported sex with a man in the past 12 months, and self-reported one of the following: being a contact to a partner with CT or GC, urogenital symptoms, or a history of CT. At the enrollment visit, participants completed a detailed sexual behavior questionnaire and collected specimens for vaginal and rectal CT and GC testing, described below. Participants testing positive for vaginal or rectal CT were followed prospectively for up to 8 weeks. The results of the prospective study have been previously reported23 and are not discussed further here.
Participants were paid $30 for completing the enrollment visit. This study was approved by the University of Washington Institutional Review Board. All participants provided written informed consent and consented to future testing of their specimens.
Clinical and Behavioral Data Collection and Measures
Per routine clinic practice, all patients presenting to the PHSKC STD Clinic for a new problem visit complete a computerized patient intake form, which queries patients on reason for visit, symptoms, and sexual behaviors. These data are included in the clinic’s electronic medical record (EMR), which also contains information on clinical exam findings, results of laboratory tests, and treatment(s) received. We used these EMR data to obtain participants’ clinical and treatment information (e.g., diagnosis of cervicitis, bacterial vaginosis [BV], or proctitis, presence of vaginal discharge, and self-reported anal symptoms). Participants also completed a research questionnaire at enrollment that asked about demographics and sexual behaviors in the past 2 and 12 months. Questionnaire data were captured using Research Electronic Data Capture (REDCap).24,25
Specimen Collection and Testing
Women self-collected one vaginal and one rectal specimen for NAAT testing at enrollment. Specimens were tested in real-time for CT and GC using the Aptima Combo-2 assay performed on the fully automatic Panther System (Hologic, Inc., San Diego, CA, USA). Specimens were stored at −80 degrees Celsius for future testing, and were subsequently tested for MG using the Aptima Mycoplasma genitalium transcription-mediated amplification (TMA) assay (Hologic, Inc. San Diego, CA, USA). Women testing positive for CT or GC at enrollment received treatment per clinic protocol. Because MG testing occurred retrospectively (between 6 and 15 months after participants’ enrollment visit) and the test was performed for research only, participants who tested positive for MG did not receive directed treatment as part of this study.
We retrospectively tested specimens that were MG-positive by Aptima for MRM17 and fluoroquinolone resistance-associated mutations in parC.26 We performed DNA extraction from specimens in Aptima transport medium using a MagNA Pure 96 Instrument (Roche, Pleasanton, California) with large volume (1mL) universal pathogen extraction protocol and elution in 50μL. We used PCR and PyroMark Q96 sequencing to detect MRM.27,28 We amplified and sequenced the parC gene by conventional Sanger sequencing.29
Statistical Analysis
We present the prevalence of vaginal and rectal MG detection, co-infection with CT and GC, and the prevalence of MRM and quinolone resistance mutations. We describe characteristics associated with MG test positivity by anatomic site using Fisher’s exact test. Analyses were completed using Stata 13 (StataCorp, College Station, TX).
RESULTS
Of 50 enrolled women, 13 (26%) tested positive for MG, including 10 (20%) who tested positive for vaginal MG and 11 (22%) who tested positive for rectal MG. Of 13 women who tested positive for MG at either anatomic site, 8 (62%) tested positive for both vaginal and rectal MG, 2 (16%) tested positive for vaginal MG only, and 3 (23%) tested positive for isolated rectal MG only.
Characteristics of women with and without MG are presented in Table 1. Women with vaginal or rectal MG were younger than women without MG, though not statistically significantly so. Women with MG were more likely to be Black, non-Hispanic compared to those without MG, but this difference was only statistically significant for rectal MG. There were no women with vaginal MG diagnosed with cervicitis and no women with rectal MG self-reported anal symptoms or were diagnosed with proctitis. Anal sex in the past 12 months was not associated with rectal MG (P=0.47).
Table 1.
Demographic and clinical characteristics and CT and GC co-infection at enrollment, by anatomic site and MG test positivity (N=50)*
| Vagina | Rectum | |||||
|---|---|---|---|---|---|---|
| MG+ (n=10) | MG− (n=40) | MG+ (n=11) | MG− (n=39) | |||
| N (%) | N (%) | P-value | N (%) | N (%) | P-value | |
| Demographics | ||||||
| Age, years | 0.16 | 0.31 | ||||
| <25 | 7 (70.0) | 16 (40.0) | 7 (63.6) | 16 (41.0) | ||
| ≥25 | 3 (30.0) | 24 (60.0) | 4 (36.4) | 23 (59.0) | ||
| Race/ethnicity | 0.63 | 0.001 | ||||
| White, non-Hispanic | 2 (20.0) | 12 (30.0) | 1 (9.1) | 13 (33.3) | ||
| Black, non-Hispanic | 4 (40.0) | 10 (25.0) | 7 (63.6) | 7 (17.9) | ||
| Asian, non-Hispanic | 0 (0.0) | 9 (22.5) | 0 (0.0) | 9 (23.1) | ||
| Other, non-Hispanic | 3 (30.0) | 3 (7.5) | 3 (27.3) | 3 (7.7) | ||
| Hispanic | 1 (10.0) | 6 (15.0) | 0 (0.0) | 7 (17.9) | ||
| Sexual Behaviors | ||||||
| Number of sex partners, page 12 months, median (IQR)** | 4 (3–10) | 4 (2–8) | 0.50 | 4 (3–10) | 4 (2–8) | 0.60 |
| Type of sex, past 12 months | ||||||
| Vaginal | 10 (100) | 38 (95.0) | 1.00 | 11 (100) | 37 (94.9) | 1.00 |
| Anal | 1 (6.3) | 15 (37.5) | 0.14 | 2 (18.2) | 14 (35.9) | 0.47 |
| Symptoms and Clinical Diagnoses | ||||||
| Vaginal discharge on exam | 1 (10.0) | 9 (22.5) | 0.66 | 0 (0.0) | 10 (25.6) | 0.09 |
| Cervicitis | 0 (0.0) | 0 (0.0) | 1.00 | 0 (0.0) | 0 (0.0) | 1.00 |
| Pelvic inflammatory disease | 0 (0.0) | 1 (2.5) | 1.00 | 0 (0.0) | 1 (2.6) | 1.00 |
| Bacterial vaginosis*** | 2 (20.0) | 6 (15.0) | 0.65 | 1 (9.1) | 7 (17.9) | 0.67 |
| Self-reported anal symptoms | 0 (0.0) | 3 (7.5) | 1.00 | 0 (0.0) | 3 (7.7) | 1.00 |
| Proctitis | 0 (0.0) | 0 (0.0) | 1.00 | 0 (0.0) | 0 (0.0) | 1.00 |
| Co-Infection with CT or GC | ||||||
| Vaginal CT | 3 (30.0) | 8 (20.0) | 0.67 | 5 (45.5) | 6 (15.4) | 0.05 |
| Rectal CT | 2 (20.0) | 9 (22.5) | 1.00 | 4 (36.4) | 7 (17.9) | 0.23 |
| Vaginal GC | 0 (0.0) | 3 (7.5) | 1.00 | 0 (0.0) | 3 (7.7) | 1.00 |
| Rectal GC | 0 (0.0) | 4 (10.0) | 0.57 | 0 (0.0) | 4 (10.3) | 0.56 |
CT, Chlamydia trachomatis; GC, gonorrhea; GED; general education development; IQR, interquartile range; MG, Mycoplasma genitalium
Of 50 women, 13 had MG at either anatomic site and 8 had MG at both anatomic sites
Includes oral, vaginal, and anal sex partners; p-value is from t-test
Diagnosed by Gram stain
Among the 10 women with vaginal MG, 3 (30%) were co-infected with vaginal CT and 2 (20%) with rectal CT (Table 1). Forty-five percent (5 of 11) of women with rectal MG had concurrent rectal CT and 36% (4 of 11) had concurrent vaginal CT. There were no women with MG who also tested positive for GC. Of the 11 women with vaginal CT, 3 (27%) had vaginal MG and 5 (45%) had rectal MG.
A line listing of ParC mutation results is provided in Table 2. We successfully tested 8 of 11 rectal specimens and 9 of 10 vaginal specimens for MRM, representing 13 unique women. Twelve (92%) of 13 women had MRM at either the rectal or vaginal site. All 8 rectal specimens and 8 (89%) of 9 vaginal specimens had MRM. We successfully sequenced the parC gene for 8 of 11 rectal specimens and 8 of 10 vaginal specimens. There were 6 vaginal specimens and 5 rectal specimens with parC mutations, though none were among those that have been associated with moxifloxacin treatment failure.
Table 2.
MRM or ParC mutations and treatment received among women with vaginal or rectal MG (n=13)
| Vaginal Specimens | Rectal Specimens | ||||||
|---|---|---|---|---|---|---|---|
| Participant Number | Treatment Received* | MG NAAT (TMA) | 23S pyrosequencing** | ParC*** | MG NAAT (TMA) | 23S pyrosequencing** | ParC*** |
| 1 | -- | + | A2059G | S83N | + | A2059G | ND |
| 2 | -- | + | WT | P62S | + | ND | ND |
| 3 | AZM | + | ND | ND | − | -- | -- |
| 4 | -- | + | A2059G | WT | + | A2059G | WT |
| 5 | AZM | − | -- | -- | + | A2058G | WT |
| 6 | -- | + | A2059G | WT | + | A2059G | WT |
| 7 | AZM | + | A2059G | Silent C234T | + | A2059G | Silent C234T |
| 8 | -- | − | -- | -- | + | ND | S83N |
| 9 | -- | + | A2058G | ND | − | -- | -- |
| 10 | DOX | + | A2059G | P62S, Silent C234T | + | A2059G | P62S, Silent C234T |
| 11 | -- | + | A2059G | S83N | + | A2059G | S83N |
| 12 | AZM | + | A2059G | S83N | + | ND | ND |
| 13 | AZM | − | -- | -- | + | A2059G | S83N |
Treatment was not for MG infection since samples were tested for MG retrospectively. Treatment was provided per routine clinic protocol for diagnosed vaginal CT (Participant #’s: 5, 7, 10, 12, 13) and presumptive CT (Participant #3)
E. coli numbering. All identified MRM are have been associated with macrolide treatment failure in prior studies
M. genitalium numbering. None of the identified ParC mutations have been associated with quinolone treatment failure in prior studies
AZM, azithromycin 1g; DOX, doxycycline 100mg twice daily for 7 days; NAAT, nucleic acid amplification test; ND, not done; TMA, transcription-mediated amplification; WT, wildtype
Of 13 women with MG, 6 (46%) received standard therapy for diagnosed or presumptive vaginal CT within one week of enrollment, including five women who received azithromycin 1g and one woman who received doxycycline (Table 2). Four of 5 women who received azithromycin for vaginal CT at enrollment had an MG MRM detected in their enrollment vaginal specimen (Participants 7 and 12) and/or rectal specimens (Participants 5, 7, 13).
DISCUSSION
In this cross-sectional study of women at high risk of urogenital CT, we observed a high prevalence of vaginal (20%) and rectal (22%) MG, and most women (62%) with MG were infected at both anatomic sites. Vaginal and rectal MG were not associated with vaginal discharge or cervicitis, or proctitis, respectively, and rectal MG was not associated with reporting anal sex. Approximately 30% of women with vaginal or rectal MG had a CT co-infection at the same anatomic site, but there were no women with MG and GC co-infection. Nearly 50% of women with vaginal CT were co-infected with either vaginal or rectal MG. All MG rectal specimens and nearly 90% of MG vaginal specimens had MRM, but no specimens had mutations in the parC gene associated with fluoroquinolone resistance. Our findings demonstrate that rectal MG has a similar epidemiologic pattern to rectal CT, and highlight the high prevalence of potentially macrolide-resistant vaginal and rectal MG among a population of women routinely being treated with azithromycin for vaginal CT infection.
The prevalence of rectal MG in this study (22%) is identical to the prevalence of rectal CT in our study population23, but is two- to three-fold higher than what has been previously reported among women. In three previous U.S. studies in New Orleans, Pittsburg, and Birmingham, the prevalence of rectal MG ranged from 4.3% to 8.1%6,8,9, and in a study in South Africa the prevalence was 2.7%.7 It should be noted, however, that only the study from Pittsburgh9 applied TMA detection of MG similar to the present study, suggesting that methodological aspects may play a role in the difference in prevalence.30 By definition, our study population was at high risk for vaginal CT, and it is likely that the women we enrolled were also at high risk for both vaginal and rectal MG. In fact, compared to two of the aforementioned studies6,7, the prevalence of vaginal MG in our study population was also two-fold higher. However, our findings are in line with two recent multi-site studies in the US4,5, which found that the prevalence of vaginal MG was 15–20%, and the prevalence of vaginal CT and MG co-infection was 4%, which was similar to the 6% (3 of 50) that we observed. It is possible that having a prevalent CT infection provides a favorable environment for MG by some unknown mechanism, but to our knowledge, this has not been previously explored. Despite this high prevalence of vaginal and rectal MG, there were no women with signs or symptoms of cervicitis or proctitis, respectively.
Similar to previous studies, we did not find an association between reporting anal sex and rectal MG. Lillis and colleagues8 in New Orleans found that the prevalence of rectal MG was 6.8% among women who reported anal sex and 4.0% among women who did not report anal sex and Hay and colleagues7 in South Africa found that the prevalence of rectal MG was 7.7% among women who reported anal sex and 2.8% among those who did not report anal sex. Here, we identified rectal MG in 2 (12.5%) of 16 women who reported anal sex and 9 (26.5%) of 34 women who did not report anal sex (P=0.47). It is not clear how women with rectal MG would have acquired their infection in the absence of anal sex, but it is possible that some women may have had persistent rectal MG for several months or years, beyond the recall period of 6–12 months used in our study and others. Alternatively, it is possible – as has been suggested for rectal CT – that women autoinoculate MG from the vagina to the rectum via sexual or hygiene practices (i.e., wiping front to back), which is facilitated by the close proximity of the vagina and anus.13
The high prevalence of vaginal and rectal MG concurrent infection merits discussion. We found that 65% of women with MG were infected at both anatomic sites, and that isolated rectal MG was more common (23% of MG-positive women) than isolated vaginal MG (15% of MG-positive women). This high prevalence of concurrent infection in the absence of anal sex is suggestive of autoinoculation between anatomic sites, and is further supported by our resistance testing data, in which we observed identical mutations from different anatomic sites of the same woman. However, molecular typing is needed to confirm whether the MG strains in different anatomic sites were identical. Of particular concern is the potential for autoinoculation from the rectum to the vagina, which has the potential to result in adverse reproductive health outcomes among women and presents an opportunity for transmission to male partners via vaginal sex. It is important to note, however, that MG NAAT testing detects the presence of nucleic acid, not viable MG, so it is possible that the positive rectal MG tests identified in this study merely indicated the presence of nucleic acid from non-viable MG, or the presence of viable MG in the perianal region but not causing infection.
We were alarmed that all rectal specimens and 90% of vaginal specimens had a MRM. A high prevalence of MRM has been identified in rectal specimens from men who have sex with men (range=75%−88%)1s−6s, but the prevalence of MRM we observed is considerably higher than that previously observed in female rectal specimens (range=12.5%−57%).6,7 Further, the high prevalence of vaginal MG strains with MRM in our study is nearly double that reported in prior studies in Europe, Japan, and the U.S. (range=0%−51%).4,18,7s−9s Although the MRM’s we observed are known to cause treatment failure17 we do not have information on MG positivity subsequent to treatment, so it is unclear if these women had persistent MG detection, subsequently experienced symptomatic infection, or spontaneously cleared their MG infection. In light of this high prevalence of MRM, it is particularly concerning that nearly 50% (5 of 11) of women with vaginal CT were co-infected with vaginal (n=3) or rectal (n=5) MG, of whom four received azithromycin for CT per routine clinical care. These findings highlight the fact that women are often treated for CT without regard to whether or not they have MG, which may lead to the further propagation and transmission of antimicrobial resistant MG.17 In particular, the high prevalence of vaginal CT and rectal MG co-infection underscores the potential for the rectum in women to serve as a reservoir or source of MG-resistant infection and transmission to male partners.
Despite the high prevalence of MRM in this population, it was reassuring that we did not observe any parC mutations that have been associated with quinolone treatment failure. Specifically, the S83N mutation in the quinolone resistance determining region has been shown to not result in elevated moxifloxacin minimum inhibitory concentrations in vitro.10s This is in line with other contemporary studies of women, which have found that between 0%−14%6,18, 7s, 11s of vaginal specimens and 0% of rectal specimens6 from women have a quinolone resistance-associated mutation, and is consistent with recent data from Seattle noting an absence of key quinolone resistance associated mutations among men who have sex with women.12s
There are several important limitations in this study. First, the number of women enrolled in this study was small (n=50) and was purposefully selected to create a cohort of women at high risk for urogenital CT. As such, the prevalence of MG and genetic mutations may not be representative of other clinic-attending women, and is not generalizable to non-clinic populations. Second, we do not have follow-up MG test results or data on signs/symptoms of infection from these women after enrollment. Only women with CT at enrollment were asked to self-collected vaginal and rectal specimens daily for 8 weeks, and, as described in this report, the majority of women with CT did not have MG. Third, we did not have data on organism load to be able to correlate to the presence of symptoms or to compare load between anatomic sites. Finally, we were unable to test all specimens for resistance mutations due to low levels of MG DNA in samples. Despite these limitations, the robust microbiologic and resistance testing data in this study provide a comprehensive picture of rectal STIs and the potential for transmission of antibiotic resistant infection in this clinic-based population of women.
In conclusion, we observed a high prevalence of rectal and vaginal MG – equivalent to the prevalence of CT in this same population – and found that nearly all MG strains had a macrolide resistance mutation. These findings are particularly concerning, and suggest high levels of previous exposure to azithromycin. Furthermore, nearly half of the women in this study with vaginal CT were co-infected with MG, received azithromycin as part of routine treatment, and likely remained infected with MG. This convergence highlights how the use of antimicrobials designed to treat an identified infection – in this case CT – has the potential to influence antimicrobial susceptibility patterns in other unidentified infections and reinforces the need for thoughtful testing and antibiotic prescribing practices. Our results also reinforce the longstanding concern that we are entering an era of potentially untreatable MG, but also highlight our profound lack of understanding of the epidemiology of MG among women, in particular rectal MG. We do not know how long rectal MG persists in women, if women can autoinoculate MG to the vagina, or if the rectum serves as an incubator of potentially antimicrobial-resistant MG. Answers to these questions will improve our understanding of the health implications of rectal MG to inform screening and treatment guidelines.
Supplementary Material
ACKNOWLEDGEMENTS
The authors thank the women who participated in this study and the STD Clinic staff, clinicians, and disease intervention specialists for their assistance in recruiting participants.
FUNDING
This work was supported by the National Institutes of Health (NIH) [grant U19 AI113173 to C.M.K.]. Study data were collected and managed using Research Electronic Data Capture (REDCap) tools hosted at the University of Washington Institute of Translational Health Sciences and supported by the National Institutes of Health (grant UL1 TR002319).
Footnotes
CONFLICT OF INTERESTS
CMK, MRG, LAB, OOS, and LEM have received donations of specimen collection kits and reagents from Hologic, Inc. LEM and MRG have also engaged in contract work with Hologic, Inc. JSJ has received speaker’s fees from Hologic, Cepheid, BD, and SpeeDx and serves on the scientific advisory board of Roche Molecular Systems, Abbott Molecular Inc., and Cepheid. The Statens Serum Institut has received remuneration for contract work from SpeeDx, Hologic, NYtor, Diagenode, Nabriva, and GlaxoSmithKline. MRG has received research support from GSK. JCD has conducted research unrelated to this work through grants to the University of Washington from Hologic, Curatek and Quidel. All other authors declare that they have no conflicts of interest.
PREVIOUS PRESENTATIONS
Parts of this work were presented at the STI & HIV 2019 World Congress in Vancouver, Canada, July 14–17, 2019.
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