An Ulcer by Any Other Name: Non-herpes and Non-syphilis Ulcerative Sexually Transmitted Infections.

The myriad presentations of ulcerative sexually transmitted infections, other than genital herpes and syphilis, challenge even the most astute clinician given the considerable overlap in clinical presentation and lack of widely available diagnostic resources, such as nucleic acid testing, to confirm the diagnosis. Even so, case prevalence is relatively low, and incidence of chancroid and granuloma inguinale are declining. These diseases still cause substantial morbidity and increased chance for HIV acquisition, and with the recent advent of mpox as a cause, it remains imperative to identify and treat accurately.

Characterizing HIV-Preventive, Plasma Tenofovir Concentrations-A Pooled Participant-level Data Analysis From Human Immunodeficiency Virus Preexposure Prophylaxis Clinical Trials.

BACKGROUND: Daily dosing of tenofovir disoproxil fumarate, with or without emtricitabine, has high efficacy in preventing human immunodeficiency virus (HIV) infection when individuals are adherent. The target protective plasma concentration of tenofovir (TFV), however, is not fully understood. The aim of this study is to estimate the protective TFV plasma concentration. METHODS: Participant data from TFV-based daily oral and topical active arms of phase 3 trials (iPrEx, VOICE, and Partners PrEP) were pooled (n = 2950). Individual specific risk scores (low and high risk) of acquiring HIV, based on an earlier placebo analysis, were created. Longitudinal TFV pharmacokinetics (PK), HIV outcome, individual risk scores and the effect of sex at birth data were integrated and analyzed using non-linear mixed effects models. RESULTS: Around 50% of the individuals were estimated to be adherent, which differed from self-reported adherence (∼90%) and large variation between longitudinal adherence patterns were identified. Following oral administration, the estimated protective TFV trough concentration was substantially higher in high-risk females (45.8 ng/mL) compared with high-risk males (16.1 ng/mL) and to low-risk individuals (∼7.5 ng/mL). Dosing simulations indicated that high-risk women require full adherence to maintain protective levels. CONCLUSIONS: Using the largest PK-HIV outcome database to date, we developed a population adherence-PK-risk-outcome model. Our results indicate that high-risk females need higher levels of plasma TFV to achieve HIV protection compared with males. HIV protection exceeds 90% in all populations if daily adherence is achieved.

Bacterial Sexually Transmitted Infection Incidence Among Southern Men Who Have Sex With Men With Human Immunodeficiency Virus in the Treatment as Prevention Era, 2014-2019.

In this retrospective analysis of men who have sex with men with human immunodeficiency virus (HIV) in the South from 2014 through 2019, incident bacterial sexually transmitted infections (STIs) increased regardless of virologic control. Clinicians should prioritize STI screening and management in primary HIV care.

Prevalent human papillomavirus infection increases the risk of HIV acquisition in African women: advancing the argument for human papillomavirus immunization.

OBJECTIVE: Vaccine-preventable human papillomavirus (HPV) infection is common, especially in sub-Saharan Africa where HIV risk is also high. However, unlike other sexually transmitted infections (STIs), HPV's role in HIV acquisition is unclear. We evaluated this relationship using data from MTN-003, a clinical trial of HIV chemoprophylaxis among cisgender women in sub-Saharan Africa. DESIGN: A case-control study. METHODS: We matched 138 women who acquired HIV (cases) to 412 HIV-negative controls. Cervicovaginal swabs collected within 6 months before HIV seroconversion were tested for HPV DNA. We estimated the associations between carcinogenic (high-risk) and low-risk HPV types and types targeted by HPV vaccines and HIV acquisition, using conditional logistic regression models adjusted for time-varying sexual behaviors and other STIs. RESULTS: Mean age was 23 (±4) years. Any, high-risk and low-risk HPV was detected in 84, 74 and 66% of cases, and 65, 55 and 48% of controls. Infection with at least two HPV types was common in cases (67%) and controls (49%), as was infection with nonavalent vaccine-targeted types (60 and 42%). HIV acquisition increased with any [adjusted odds ratio (aOR) 2.5, 95% confidence interval (95% CI) 1.3-4.7], high-risk (aOR 2.6, 95% CI 1.5-4.6) and low-risk (aOR 1.8, 95% CI 1.1-2.9) HPV. Each additional type detected increased HIV risk by 20% (aOR 1.2, 95% CI 1.1-1.4). HIV acquisition was associated with HPV types targeted by the nonavalent (aOR 2.1, 95% CI 1.3-3.6) and quadrivalent vaccines (aOR 1.9, 95% CI 1.1-3.2). CONCLUSION: HPV infection is associated with HIV acquisition in sub-Saharan African women. In addition to preventing HPV-associated cancers, increasing HPV vaccination coverage could potentially reduce HIV incidence.

HIV and COVID-19: Lessons From HIV and STI Harm Reduction Strategies.

PURPOSE OF REVIEW: This review highlights the intersection of the COVID-19, HIV, and STI pandemics and examines how harm reduction strategies can be applied broadly to controlling a pandemic. RECENT FINDINGS: Since the onset of the COVID-19 pandemic, remarkable advances in the understanding of COVID-19 prevention, diagnosis, and treatment have been made at a much faster pace than prior pandemics, yet much more still remains to be discovered. Many of the strategies to control the COVID-19 pandemic mirror those employed to stem the HIV pandemic. Harm reduction principles used in the HIV pandemic can be applied to reduce the morbidity and mortality of the COVID-19 pandemic through effective prevention, detection, and treatment strategies.

Intersecting Epidemics: Incident Syphilis and Drug Use in Women Living With Human Immunodeficiency Virus in the United States (2005-2016).

BACKGROUND: Rates of early syphilis in US women are steadily increasing, but predictors of infection in this group are not clearly defined. METHODS: This retrospective analysis focused on women enrolled in the US CFAR Network of Integrated Clinical Systems cohort between January 2005 and December 2016 with syphilis testing performed. The primary outcome of incident syphilis infection was defined serologically as a newly positive test with positive confirmatory testing after a negative test or a 2-dilution increase in rapid plasma regain titer. Infection rates were calculated for each woman-year in care with testing. Predictors of syphilis were sought among sociodemographics, clinical information, and self-reported behaviors. Multivariable logistic regression models were created; a subgroup analysis assessed predictors in women of reproductive age. RESULTS: The annual rate of incident syphilis among 4416 women engaged in human immunodeficiency virus (HIV) care and tested during the 12-year study period was 760/100 000 person-years. Independent predictors of infection were injection drug use as a risk factor for HIV acquisition (aOR, 2.2; 95% CI, 1.3-3.9), hepatitis C infection (aOR, 1.9; 95% CI, 1.1-3.4), black race (aOR, 2.2; 95% CI, 1.3-3.7 compared with white race), and more recent entry to care (since 2005 compared with 1994-2004). Predictors were similar in women aged 18-49. CONCLUSIONS: Syphilis infection is common among US women in HIV care. Syphilis screening and prevention efforts should focus on women reporting drug use and with hepatitis C coinfection. Future studies should identify specific behaviors that mediate syphilis acquisition risk in women who use drugs.

Use of the dapivirine vaginal ring and effect on cervical cytology abnormalities.

OBJECTIVE: We aimed to determine if the dapivirine vaginal ring and the ring device alone (flexible silicone matrix polymer) was associated with the development of cervical cytology abnormalities. DESIGN: Secondary analysis comparing cervical cytology results between two randomized controlled microbicide trials (MTN-020/ASPIRE and MTN-003/VOICE). METHODS: Data from ASPIRE, a phase III, placebo-controlled trial of the dapivirine vaginal ring, were used in this analysis. Cervical cytology smears were evaluated at baseline and at the final visit with product use. We compared cytology results between women randomized to dapivirine versus placebo vaginal ring. We further assessed for the effect of the vaginal ring device on cervical cytology by comparing results with data from the oral placebo arm of VOICE, a prior HIV-1 prevention trial conducted in a similar population. RESULTS: Cervical cytology results for 2394 women from ASPIRE (1197 per study arm) were used in this analysis; median time between baseline and final visit with product use was 22.1 months. Cytology smear findings were comparable between dapivirine and placebo vaginal ring arms: at final visit, normal: 90.6 versus 91.5%, ASC-US//LSIL: 7.8 versus 7.4%, ASC-H/HSIL/AGC/AGC-favor neoplastic: 1.7 versus 1.1%, P = 0.44. Cytology data from VOICE had findings (normal: 87.8%, ASC-US/LSIL: 9.8%, ASC-H/HSIL/AGC/AGC-favor neoplastic: 2.4%) comparable with that of both dapivirine (P = 0.93) and placebo vaginal ring arms (P = 0.24). CONCLUSION: These findings indicate that neither use of the dapivirine vaginal ring nor the vaginal ring device alone, over a period of 2 years, is associated with development of cervical cytology abnormalities that could lead to precancerous or cancerous lesions.

Sexually Transmitted Infection Prevalence in Women With HIV: Is There a Role for Targeted Screening?

BACKGROUND: Rates of sexually transmitted infections (STIs) and HIV are highest in the southern United States but vary widely by sex, age, and risk behavior. Current guidelines recommend annual screening for chlamydia, gonorrhea, syphilis, and trichomoniasis in all sexually active women with HIV. METHODS: Screening rates and test positivity for chlamydia, gonorrhea, syphilis, and trichomoniasis were determined per calendar year in this retrospective cohort study of women in care at an urban HIV clinic in Birmingham, Alabama, from 2013 to 2015. Chlamydia, gonorrhea, and trichomonas infections were detected by molecular diagnostics and syphilis by serology. A combined end point for chlamydia/gonorrhea/syphilis (STI-3) was created based on similar test positivity and predictors. Predictors of STI-3 were identified using logistic regression and generalized estimating equations. RESULTS: Among 745 women with HIV, median age was 46.8 years, 78.8% were black, and 61% were sexually active. In 2015, 83.7% of women were tested for STI. Test positivity was 1.0% for chlamydia, 0.5% for gonorrhea, 1.6% for syphilis, and 13.3% for trichomoniasis. Independent predictors of STI-3 were recent chlamydia or gonorrhea (odds ratio [OR], 3.7; 95% confidence interval [CI], 1-13.4; P = 0.047), public insurance compared with private (OR, 3.5; CI, 1-11.8; P = 0.048), and sex after drugs/alcohol (OR, 3.0; CI, 1.2-8.0; P = 0.025). Women 50 years or older were less likely to have STI (OR, 0.3; CI, 0.1-1; P = 0.040). CONCLUSIONS: In a cohort of women engaged in HIV care in the southern United States, detection of chlamydia, gonorrhea, and syphilis was infrequent but trichomoniasis was common. Many women screened for STI were low risk and universal testing strategies warrant evaluation.

Health Care Provider Perceptions of a Sexually Transmitted Infection Self-testing Program in an HIV Care Clinic.

BACKGROUND: Sexually transmitted infections (STIs) disproportionately affect men who have sex with men. Although clinical practice guidelines recommend routine STI screening of men who have sex with men who have high-risk behaviors, extragenital STI testing rates have been low in HIV clinics across the nation. The University of Washington STD Prevention Training Center implemented an STI self-testing program at a large HIV primary care clinic in Seattle, WA, to facilitate extragenital STI testing. METHODS: We performed a mixed-methods program evaluation to assess health care provider acceptability of the program at 9 months after implementation. Twenty-eight clinicians were invited to complete an online survey. We conducted one-on-one, semistructured interviews with 6 clinicians and a focus group with 7 members of the clinic nursing staff. Survey responses were tallied. Conventional content analysis was performed on survey comments and transcripts from the interviews and focus group. RESULTS: Ninety-one percent of clinicians were either satisfied or very satisfied with the program. Perceived advantages of the program included saving time for clinicians, overcoming patient discomfort, and increasing patient access to testing. Perceived program disadvantages included unclear responsibility of directing patients through the self-testing process and incorrect sample collection and labeling. CONCLUSIONS: Despite perceived disadvantages, the self-testing program was acceptable to clinicians and nursing staff, key population for successful program adoption. Implementation of STI self-testing programs in clinic settings could help to increase extragenital STI testing rates by removing provider and patient barriers to testing.

Sexually transmitted infections: challenges ahead.

WHO estimated that nearly 1 million people become infected every day with any of four curable sexually transmitted infections (STIs): chlamydia, gonorrhoea, syphilis, and trichomoniasis. Despite their high global incidence, STIs remain a neglected area of research. In this Commission, we have prioritised five areas that represent particular challenges in STI treatment and control. Chlamydia remains the most commonly diagnosed bacterial STI in high-income countries despite widespread testing recommendations, sensitive and specific non-invasive testing techniques, and cheap effective therapy. We discuss the challenges for chlamydia control and evidence to support a shift from the current focus on infection-based screening to improved management of diagnosed cases and of chlamydial morbidity, such as pelvic inflammatory disease. The emergence and spread of antimicrobial resistance in Neisseria gonorrhoeae is globally recognised. We review current and potential future control and treatment strategies, with a focus on novel antimicrobials. Bacterial vaginosis is the most common vaginal disorder in women, but current treatments are associated with frequent recurrence. Recurrence after treatment might relate to evidence that suggests sexual transmission is integral to the pathogenesis of bacterial vaginosis, which has substantial implications for the development of effective management approaches. STIs disproportionately affect low-income and middle-income countries. We review strategies for case management, focusing on point-of-care tests that hold considerable potential for improving STI control. Lastly, STIs in men who have sex with men have increased since the late 1990s. We discuss the contribution of new biomedical HIV prevention strategies and risk compensation. Overall, this Commission aims to enhance the understanding of some of the key challenges facing the field of STIs, and outlines new approaches to improve the clinical management of STIs and public health.

Contraceptive Use and Pregnancy Incidence Among Women Participating in an HIV Prevention Trial.

BACKGROUND: Recent HIV prevention trials required use of effective contraceptive methods to fulfill eligibility for enrollment. We compared pregnancy rates in a subset of participants enrolled in the Microbicide Trials Network protocol (MTN-003), a randomized trial of chemoprophylaxis to prevent HIV acquisition among women aged 18-45 years who initiated depot medroxyprogesterone acetate (DMPA) or combined oral contraceptives (COCs) at enrollment, relative to those already using DMPA or COCs. METHODS: Data were analyzed from MTN-003 participants from Uganda. Before enrollment, information on contraceptive type and initiation date was obtained. Urine pregnancy tests were performed at monthly follow-up visits. Cox proportional hazards models were used to compare pregnancy incidence among new users (initiated ≤60 days before enrollment) and established users (initiated >60 days before enrollment). RESULTS: Of 322 women enrolled, 296 were COC or DMPA users, 82 (28%) were new users, and 214 (72%) were established users. Pregnancy incidence was higher among new contraceptive users compared to established users (20.70% vs. 10.55%; adjusted hazard ratio [HR] = 1.66; 95% confidence interval [95% CI] 0.93-2.96). Among DMPA users, pregnancy incidence was 10.20% in new users versus 3.48% in established users (HR = 2.56; 95% CI 0.86-7.65). Among new COC users, pregnancy incidence was 42.67% in new users versus 23.67% in established COC users (adjusted HR = 1.74; 95% CI 0.87-3.48). CONCLUSIONS: New contraceptive users, regardless of method, at the Uganda MTN-003 site had an increased pregnancy risk compared to established users, which may be due to contraceptive initiation primarily for trial eligibility. New users may benefit from intensive contraceptive counseling and additional contraceptive options, including longer acting reversible contraceptives.

Prevention of Sexually Transmitted Diseases in HIV-Infected Individuals.

Prevention of sexually transmitted infections (STIs) is an important part of the care of the HIV-infected individual. STIs have been associated with increased risk of transmission and acquisition of HIV. Among HIV-infected persons, treatment failures and high recurrence rates of some STIs are more common. Despite the recognized importance of prevention and discussion of sexual health, rates of screening for STIs are suboptimal. Moreover, rates of STIs such as syphilis continue to increase particularly in men who have sex with men (MSM). This review focuses on the most common STIs seen among HIV-infected individuals and recommendations for screening and prevention.

Risk Factors for Incidence of Sexually Transmitted Infections Among Women in a Human Immunodeficiency Virus Chemoprevention Trial: VOICE (MTN-003).

BACKGROUND: In sub-Saharan Africa, there are limited data on the incidence of sexually transmitted infections (STIs) among women, largely because routine screening for asymptomatic infection is not performed. We conducted a secondary analysis to measure STI incidence rates and determine risk factors for new STI acquisition among women enrolled in the VOICE trial. METHODS: We analyzed data from 4843 women screened for chlamydia, gonorrhoea, syphilis, and trichomonas infection at baseline, annually, at interim visits when clinically indicated and at their study termination visit. Risk reduction counseling and condoms were provided throughout the trial. RESULTS: Twenty percent of evaluable participants had one or more curable STIs at baseline. Over 5660 person-years at risk (PYAR) of observation, incidence rates were 13.8% (95% confidence interval [CI], 12.7-14.8) PYAR for chlamydia, 3.5% (95% CI, 3.0-4.1) PYAR gonorrhea, 0.1% (95% CI, 0.6-1.1) PYAR syphilis, and 6.6% (95% CI, 5.8-7.2) PYAR trichomoniasis. South African sites had the highest incidence of chlamydia. The Uganda site had the highest incidence of gonorrhoea and syphilis, and Zimbabwe the lowest incidence overall. The majority of these cases were diagnosed at a routine scheduled testing visit. In multivariate analysis, positive baseline STI, younger than 25 years, being unmarried, and some alcohol consumption were associated with acquiring a new STI. CONCLUSIONS: We observed high rates of STIs during follow up among women in the VOICE study. Women living in human immunodeficiency virus endemic countries should be screened for common STIs.

Implementation and Operational Research: Effectiveness and Patient Acceptability of a Sexually Transmitted Infection Self-Testing Program in an HIV Care Setting.

BACKGROUND: Rates of screening for bacterial sexually transmitted infections (STI) among men who have sex with men in HIV care settings remain low despite high prevalence of these infections. STI self-testing may help increase screening rates in clinical settings. METHODS: We implemented an STI self-testing program at a large, urban HIV care clinic and evaluated its effectiveness and acceptability. We compared measures obtained during the first year of the STI self-testing program (Intervention Year, April 1, 2013-March 31, 2014) to Baseline Year (January 1, 2012-December 31, 2012) to determine: (1) overall clinic change in STI testing coverage and diagnostic yield and; (2) program-specific outcomes including appropriate anatomic site screening and patient-reported acceptability. RESULTS: Overall, testing for gonorrhea and chlamydia increased significantly between Baseline and Intervention Year, and 50% more gonococcal and 47% more chlamydial infections were detected. Syphilis testing coverage remained unchanged. Nearly 95% of 350 men who participated in the STI self-testing program completed site-specific testing appropriately based on self-reported exposures, and 92% rated their self-testing experience as "good" or "very good." CONCLUSIONS: STI self-testing in HIV care settings significantly increases testing coverage and detection of gonorrhea and chlamydia, and the program is acceptable to patients. Additional interventions to increase syphilis screening rates are needed.

Barriers to Bacterial Sexually Transmitted Infection Testing of HIV-Infected Men Who Have Sex With Men Engaged in HIV Primary Care.

BACKGROUND: Approximately 15% of HIV-infected men who have sex with men (MSM) engaged in HIV primary care have been diagnosed as having a sexually transmitted infection (STI) in the past year, yet STI testing frequency remains low. METHODS: We sought to quantify STI testing frequencies at a large, urban HIV care clinic, and to identify patient- and provider-related barriers to increased STI testing. We extracted laboratory data in aggregate from the electronic medical record to calculate STI testing frequencies (defined as the number of HIV-infected MSM engaged in care who were tested at least once over an 18-month period divided by the number of MSM engaged in care). We created anonymous surveys of patients and providers to elicit barriers. RESULTS: Extragenital gonorrhea and chlamydia testing was low (29%-32%), but the frequency of syphilis testing was higher (72%). Patients frequently reported high-risk behaviors, including drug use (16.4%) and recent bacterial STI (25.5%), as well as substantial rates of recent testing (>60% in prior 6 months). Most (72%) reported testing for STI in HIV primary care, but one-third went elsewhere for "easier" (42%), anonymous (21%), or more frequent (16%) testing. HIV primary care providers lacked testing and treatment knowledge (25%-32%) and cited lack of time (68%), discomfort with sexual history taking and genital examination (21%), and patient reluctance (39%) as barriers to increased STI testing. CONCLUSION: Sexually transmitted infection testing in HIV care remains unacceptably low. Enhanced education of providers, along with strategies to decrease provider time and increase patient ease and frequency of STI testing, is needed.

Syphilis? An Unusual Cause of Surgical Emergency in a Human Immunodeficiency Virus-Infected Man.

We report on a human immunodeficiency virus-infected man undergoing urgent anorectal surgery, with multi-centimeter fungating masses discovered inside the anus. Initial pathology was inconclusive. After the patient developed a disseminated rash postoperatively determined to be secondary syphilis, the anorectal pathology was reviewed and Treponema pallidum DNA was amplified by polymerase chain reaction from the mass.

Soluble Immune Mediators and Vaginal Bacteria Impact Innate Genital Mucosal Antimicrobial Activity in Young Women.

INTRODUCTION: Innate activity against Escherichia coli in female genital secretions may represent contributions from vaginal bacteria and host soluble immune mediators. We analyzed the relationship between E. coli inhibitory activity, soluble immune mediators, and vaginal bacteria in participants in MTN-004, a placebo-controlled trial of VivaGel(®) , a candidate product for topical HIV pre-exposure prophylaxis. METHODS: Escherichia coli inhibitory activity was quantified by colony reduction assay. Endocervical concentrations of interleukin (IL)-1ß, IL-6, IL-12p40, macrophage inflammatory protein (MIP)-1α, granulocyte-macrophage colony-stimulating factor (GM-CSF), lactoferrin, and secretory leukocyte protease inhibitor (SLPI) were quantified to generate a cumulative mediator score. Vaginal bacteria were characterized by quantitative cultures. RESULTS: In the two placebo arms, higher soluble immune mediator score was associated with greater E. coli inhibitory activity (ß = 17.49, 95% CI [12.77, 22.21] and ß = 13.28, 95% CI [4.76, 21.80]). However, in the VivaGel arm, higher concentrations of E. coli (ß = -3.80, 95% CI [-6.36, -1.25]) and group B Streptococcus (ß = -3.91, 95% CI [-6.21, -1.60]) were associated with reduced E. coli inhibitory activity. CONCLUSIONS: Both host mediators and vaginal bacteria impact E. coli inhibition in genital secretions. The relative contributions of host mediators and bacteria varied between women who used VivaGel vs placebos.