Chlamydia trachomatis: Explorations of correlates, transmission, and treatment

Abstract

Introduction: Chlamydia trachomatis (CT) is the most common bacterial sexually transmitted infection (STI) globally, with an estimated 128.5 million CT infections worldwide in 2020 in people aged 15-49 years. CT can cause severe reproductive tract sequelae, including pelvic inflammatory disease (PID) and infertility. Despite CT being a common cause of reproductive tract morbidity, there are several knowledge gaps in our understanding of CT’s true population burden, its transmission dynamics, and the impact of treatment. As CT infections are primarily asymptomatic, we are unable to fully understand which populations are at greatest risk of CT, unless we use assays that measure serum antibodies to CT in nationally representative populations. Our understanding of CT transmission is limited by the paucity of data on transmission resulting from sequential sexual acts (i.e., sexual acts at different anatomic sites like the rectum, pharynx, and urethra in a particular sequence). Characterizing sequential sexual acts to understand how CT can move within a single person and between partners can inform mathematical models of transmission used to understand the impact of potential interventions. Finally, although CT cure rates after treatment with antibiotics are high, rates differ by anatomic site of infection. In 2016, treatment guidelines in King County were updated to recommend only doxycycline as first-line therapy instead of azithromycin for rectal infection. It is unknown if this change in the guidelines has led to a decline in recurrent/persistent (RP) rectal CT.Methods: We performed three distinct studies to 1) identify correlates associated seroprevalence of CT in females and males in the United States (US), 2) characterize sequential sex practices (SSPs) in opposite-sex partnerships and estimate the association between the most common SSPs and a positive bacterial STI test in men who have sex with only women (MSW), and 3) evaluate the impact of updating rectal CT treatment guidelines to recommend exclusively doxycycline on recurrent/persistent rectal CT (RP-CT) infections among men who have sex with men (MSM) at the Public Health – Seattle & King County Sexual Health Clinic. In our first study, we measured serum antibodies to CT using a mixed peptide enzyme-linked immunosorbent assay (ELISA) in females and males in the US using 3,230 sera collected during the National Health and Nutrition Examination Survey (NHANES) 2017-2018. This allowed us to estimate survey-weighted seroprevalence of CT and Korn-Graubard 95% confidence intervals (CIs) in females and males overall and within subcategories of several potential correlates. We also estimated prevalence ratios using modified Poisson regression with robust standard errors. For our second study, we utilized data from a 6-month cohort study of male urethritis in Seattle, WA (2014-2018); our analysis included MSW aged ≥16 years. Each month, participants completed questionnaires ascertaining their sequential sex practices (SSPs), were evaluated for non-gonococcal urethritis (NGU) and provided urine samples for urethral bacterial STI testing using nucleic acid amplification testing (NAAT). We identified the most frequent SSPs reported at participants’ last sexual encounter before testing and used generalized estimating equations to estimate probability of positive bacterial urethral STI and of NGU. For our third study, we performed a controlled interrupted time series analysis to evaluate the impact of updated treatment guidelines (prescribing only the antibiotic doxycycline not azithromycin for the treatment of rectal CT) at the Public Health – Seattle & King County Sexual Health Clinic on recurrent/persistent rectal chlamydia (RP-CT) infections. We defined recurrent/persistent (RP) infection as a second positive nucleic acid amplification test between 14 and 90 days after the initial positive test. The time periods were denoted as pre-implementation, implementation of clinic-level guidelines, and implementation of national-level guidelines). The population was men who have sex with men at the clinic who were diagnosed with rectal CT or rectal gonorrhea from January 1, 2012, through December 31, 2024. We also evaluated if there were patient demographic and behavioral correlates associated with receipt of azithromycin before and after the change in clinic guidelines. The data was extracted from the clinic’s electronic health record. Results: In our first study, we found that the CT seroprevalence among females aged 14-59 in the US was 39.0%. Among males aged 14-59 years, the CT seroprevalence was 32.6%. This results in an overall prevalence ratio of 1.20 when comparing females to males. Among females, we found that older age group, Black race, being divorced, separated, or widowed, lower income-poverty ratio, and less access to healthcare were all correlates of CT seroprevalence. Females had a substantially higher CT seroprevalence compared to males among people aged 40-49, those who reported their ethnicity as Hispanic but not Mexican American, and those who were divorced, separated, or widowed. We also observed differences in CT seroprevalence between females and males with one sex partner in the past year, CT infection in the past year, and current MG infection. In our second study of sequential sexual practices, 184 participants included in the analysis reported 528 sexual encounters; 76% of sexual encounters included >1 sex act. The most frequently reported SSPs were insertive oral sex followed by vaginal sex (57.4%), vaginal sex only (19.5%), and vaginal sex followed by insertive oral sex (9.5%). Overall, participants had four positive urethral bacterial STI tests and 14 cases of NGU. In our third study, we found a significant relative trend change between RP-CT and RP-GC infections when comparing the period of national implementation to pre-implementation, showing a 16.9% greater reduction in the quarterly trend of RP-CT cases compared to RP-GC cases (control outcome). Self-identifying as White and living with HIV were positively associated with receiving azithromycin for treatment of rectal CT after the change in guidelines at the clinic. Conclusions: The three studies in this dissertation have further expanded our understanding of CT prevalence and correlates, transmission pathways within sexual encounters, and the impacts of updated antibiotic treatment. We completed the first study comparing lifetime CT prevalence between females and males in a nationally representative sample of the US population. Future randomized studies could assess the impact of screening heterosexual males and older age groups (up to age 30 years) on CT infections and associated reproductive health outcomes. This work may guide public health interventions emphasizing CT screening for specific populations and future iterations of the US Centers for Disease Control and Prevention’s (CDC) STI Treatment Guidelines. Our second study found that among MSW, there are clear patterns in the frequency of types of sex and SSPs. These data can inform the development of more robust mathematical models of bacterial STI transmission in networks of opposite sex partnerships. We found a significant reduction in the trend change for RP-CT vs. RP-GC when comparing the national implementation of exclusively doxycycline to the pre-implementation period in our third study. This demonstrates the continued importance of national, evidence-based public health guidelines to facilitate implementation of newer treatments.