The impact of intimate partner violence on PrEP adherence among U.S. Cisgender women at risk for HIV.

BACKGROUND: Cisgender women account for 1 in 5 new HIV infections in the United States, yet remain under-engaged in HIV prevention. Women experiencing violence face risk for HIV due to biological and behavioral mechanisms, and barriers to prevention, such as challenges to Pre-Exposure Prophylaxis for HIV Prevention (PrEP) adherence. In this analysis, we aim to characterize intimate partner violence (IPV) among cisgender heterosexual women enrolled in a PrEP demonstration project and assess the associations with PrEP adherence. METHODS: Adherence Enhancement Guided by Individualized Texting and Drug Levels (AEGiS) was a 48-week single-arm open-label study of PrEP adherence in HIV-negative cisgender women in Southern California (N = 130) offered daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC). From 6/2016 to 10/2018, women completed a survey reporting HIV risk behavior and experiences of any IPV (past 90-days) and IPV sub-types (past-year, lifetime) and biological testing for HIV/STIs at baseline, and concentrations of tenofovir-diphosphate (TFV-DP) in dried blood spots at weeks 4, 12, 24, 36, and 48. Outcomes were TFV-DP concentrations consistent with ≥ 4 or ≥ 6 doses/week at one or multiple visits. Multivariable logistic regression models were conducted to examine associations. RESULTS: Past-90-day IPV was reported by 34.4% of participants, and past-year and lifetime subtypes reported by 11.5-41.5%, and 21.5-52.3%, respectively. Women who engaged in sex work and Black women were significantly more likely to report IPV than others. Lifetime physical IPV was negatively associated with adherence at ≥ 4 doses/week at ≥ 3 of 5 visits, while other relationships with any IPV and IPV sub-types were variable. CONCLUSION: IPV is an indication for PrEP and important indicator of HIV risk; our findings suggest that physical IPV may also negatively impact long-term PrEP adherence. CLINICAL TRIALS REGISTRATION: NCT02584140 (ClinicalTrials.gov), registered 15/10/2015.

No observed bidirectional effect between tenofovir diphosphate concentrations and gender-affirming hormone concentrations among transgender persons switching from tenofovir disoproxil fumarate/emtricitabine to tenofovir alafenamide/emtricitabine for HIV pre-exposure prophylaxis.

AIMS: Many transgender and gender diverse (TGD) individuals have expressed concerns about the potential for oral pre-exposure prophylaxis to affect hormonal concentrations achieved from taking gender-affirming hormone therapy (GAHT). The purpose of this study was to understand the bidirectional effects between hormone and intraerythrocytic tenofovir diphosphate concentrations when switching from tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) to tenofovir alafenamide/emtricitabine (TAF/FTC) in TGD users/nonusers of GAHT. METHODS: The study evaluated stored blood samples and dried blood spot cards from TGD adults without HIV who took ≥12 weeks of TDF/FTC and then switched to ≥12 weeks of TAF/FTC for pre-exposure prophylaxis. RESULTS: Thirty-nine individuals met the study inclusion criteria. Regardless of sex assigned at birth and the use of GAHT, there were no significant differences in hormone concentrations when individuals taking GAHT were taking TDF/FTC and then switched to TAF/FTC. Further, there was no significant difference in intraerythrocytic tenofovir diphosphate concentrations between users and nonusers of GAHT. CONCLUSION: There are no bidirectional effects between hormone and intraerythocytic tenofovir diphosphate concentrations when switching from TDF/FTC to TAF/FTC in TGD users/nonusers of GAHT.

HIV-1 Incidence, Adherence, and Drug Resistance in Individuals Taking Daily Emtricitabine/Tenofovir Disoproxil Fumarate for HIV-1 Pre-Exposure Prophylaxis: Pooled Analysis From 72 Global Studies.

BACKGROUND: Oral pre-exposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate (F/TDF) has high efficacy against HIV-1 acquisition. Seventy-two prospective studies of daily oral F/TDF PrEP were conducted to evaluate HIV-1 incidence, drug resistance, adherence, and bone and renal safety in diverse settings. METHODS: HIV-1 incidence was calculated from incident HIV-1 diagnoses after PrEP initiation and within 60 days of discontinuation. Tenofovir concentration in dried blood spots (DBS), drug resistance, and bone/renal safety indicators were evaluated in a subset of studies. RESULTS: Among 17,274 participants, there were 101 cases with new HIV-1 diagnosis (0.77 per 100 person-years; 95% CI 0.63-0.94). In 78 cases with resistance data, 18 (23%) had M184I or V, one (1.3%) had K65R, and three (3.8%) had both mutations. In 54 cases with tenofovir concentration data from DBS, 45 (83.3%), 2 (3.7%), 6 (11.1%), and 1 (1.9%) had average adherence of <2, 2-3, 4-6, and ≥7 doses/week, respectively, and the corresponding incidence was 3.9 (95% CI 2.9-5.3), 0.24 (0.060-0.95), 0.27 (0.12-0.60), and 0.054 (0.008-0.38) per 100 person-years. Adherence was low in younger participants, Hispanic/Latinx and Black participants, cisgender women, and transgender women. Bone and renal adverse event incidence rates were 0.69 and 11.8 per 100 person-years, respectively, consistent with previous reports. CONCLUSIONS: Leveraging the largest pooled analysis of global PrEP studies to date, we demonstrate that F/TDF is safe and highly effective, even with less than daily dosing, in diverse clinical settings, geographies, populations, and routes of HIV-1 exposure.

Determinants of HIV Pre-Exposure Prophylaxis (PrEP) Retention among Transgender Women: A Sequential, Explanatory Mixed Methods Study.

Transgender women (TW) face inequities in HIV and unique barriers to PrEP, an effective biomedical intervention to prevent HIV acquisition. To improve PrEP retention among TW, we examined factors related to retention using a two-phase, sequential explanatory mixed methods approach. In Phase I, we used data from a trial of 170 TW who were provided oral PrEP to examine predictors of 24-week retention. In Phase II, we conducted 15 in-depth interviews with PrEP-experienced TW and used thematic analysis to explain Phase I findings. In Phase I, more participants who were not retained at 24 weeks reported sex work engagement (18% versus 7%) and substantial/severe drug use (18% versus 8%). In Phase II, participants reported drug use as a barrier to PrEP, often in the context of sex work, and we identified two subcategories of sex work. TW engaged in "non-survival sex work" had little difficulty staying on PrEP, while those engaged in "survival sex work" struggled to stay on PrEP. In Phase I, fewer participants not retained at 24 weeks reported gender-affirming hormone therapy (GAHT) use (56% versus 71%). In Phase II, participants prioritized medical gender affirmation services over PrEP but also described the bidirectional benefits of accessing GAHT and PrEP. TW who engaged in "survival sex work" experience barriers to PrEP retention (e.g., unstable housing, drug use) and may require additional support to stay in PrEP care.

Impact of (recurrent) bacterial vaginosis on quality of life and the need for accessible alternative treatments.

BACKGROUND: Bacterial vaginosis (BV) is one of the most common vaginal dysbiosis in women aged 15-44 years old. METHODS: We administered a cross-sectional, single timepoint survey to women ages 18 years or older and who have had bacterial vaginosis (BV). Women completed an anonymous online survey evaluating the impact of BV on their quality of life, how effective different types of treatments were and the amount of self-diagnosed vs. provider diagnosed BV episodes they had. RESULTS: 62 participants completed the anonymous online survey. With a self-reported median number of BV episodes in the past year was 4 (IQR 1-7). Among these women 69.8% reported BV had a negative impact on their sexual health, 67.7% on their physical health, 74.6% on their mental health. More than half of the respondents had used probiotics with oral Lactobacillus sp. (53.2%), mainly by oral route, and over a third had used vaginal boric acid (37.1%). Most women were unaware of Lactobacillus crispatus. Lactobacillus probiotics were more likely to be tried by women who were negatively impacted by BV for overall quality of life (p = 0.033), sexual health (p = 0.002), and mental health (p = 0.006) while boric acid use was more likely to be used by women who were negatively impacted by BV for their sexual health (p = 0.008). CONCLUSIONS: BV is associated with negative quality of life and the women most impacted are seeking alternative treatments such as probiotics (Lactobacillus) and boric acid. There needs to be improvements in BV treatment that include alternative therapy options that have demonstrated efficacy with standardized composition, formulation and dosage.

Whole-Genome Sequencing to Predict Antimicrobial Susceptibility Profiles in Neisseria gonorrhoeae.

BACKGROUND: Neisseria gonorrhoeae is a major public health problem due to increasing incidence and antimicrobial resistance. Genetic markers of reduced susceptibility have been identified; the extent to which those are representative of global antimicrobial resistance is unknown. We evaluated the performance of whole-genome sequencing (WGS) used to predict susceptibility to ciprofloxacin and other antimicrobials using a global collection of N. gonorrhoeae isolates. METHODS: Susceptibility testing of common antimicrobials and the recently developed zolifodacin was performed using agar dilution to determine minimum inhibitory concentrations (MICs). We identified resistance alleles at loci known to contribute to antimicrobial resistance in N. gonorrhoeae from WGS data. We tested the ability of each locus to predict antimicrobial susceptibility. RESULTS: A total of 481 N. gonorrhoeae isolates, collected between 2004 and 2019 and making up 457 unique genomes, were sourced from 5 countries. All isolates with demonstrated susceptibility to ciprofloxacin (MIC ≤0.06 µg/mL) had a wild-type gyrA codon 91. Multilocus approaches were needed to predict susceptibility to other antimicrobials. All isolates were susceptible to zoliflodacin, defined by an MIC ≤0.25 µg/mL. CONCLUSIONS: Single marker prediction can be used to inform ciprofloxacin treatment of N. gonorrhoeae infection. A combination of molecular markers may be needed to determine susceptibility for other antimicrobials.

Efficacy of Daily Text Messaging to Support Adherence to HIV Pre-Exposure Prophylaxis (PrEP) among Stimulant-Using Men Who Have Sex with Men.

Background: Men who have sex with men (MSM) who use stimulants are at increased risk for HIV infection. Adherence to pre-exposure prophylaxis (PrEP) reduces the risk of HIV infection. We evaluated the efficacy of the individualized Texting for Adherence Building (iTAB) intervention for PrEP adherence compared to standard of care (SoC) among 119 MSM who use stimulants (cocaine, methamphetamine and/or other amphetamine) from the California Collaborative Treatment Group 595 randomized control trial.Method: Three ordered levels of PrEP adherence (non-adherence, adequate adherence, and near-perfect adherence) were compared between intervention arms across study visits (weeks 12 and 48) using ordinal logistic regressions.Results: The effect of intervention arm was not significant in the final model; however, there was a 38% decrease in odds (OR = 0.62, p=.023) of having near-perfect adherence (versus non-adherence or adequate adherence) at week 48 compared to week 12, indicating a significant effect of time. In a follow-up analysis examining week 48 only, logistic regression examining PrEP adherence showed that receiving iTAB (compared to SoC) trended toward higher odds of near-perfect adherence relative to adequate adherence (OR = 2.48, p=.061). Higher HIV knowledge resulted in higher odds (OR = 1.72, p=.020) of near-perfect adherence (versus non-adherence or adequate adherence).Conclusion: HIV knowledge may influence PrEP adherence, and most notably, the iTAB intervention may support near-perfect adherence relative to adequate adherence.

Gender-Based Violence and Post-traumatic Stress Disorder Symptoms Predict HIV PrEP Uptake and Persistence Failure Among Transgender and Non-binary Persons Participating in a PrEP Demonstration Project in Southern California.

Gender-based violence (GBV) against transgender and nonbinary (TGNB) persons is a pervasive public health issue. GBV has been linked to mental health problems such as depression and posttraumatic stress disorder (PTSD), as well has risk for HIV seroconversion and HIV treatment nonadherence. However, the impact of GBV on HIV pre-exposure prophylaxis (PrEP) use among TGNB persons has yet to be investigated. In the current study we assessed longitudinal PrEP persistence data from dried blood spots (DBS) collected from 172 racially and ethnically diverse TGNB participants during a 48-week PrEP demonstration project in Southern California from June 2017 to September 2020. Participants were categorized into three levels of PrEP uptake and persistence based on their PrEP levels at the start and end of the study: low-low, high-low, and high-high. Individual-, social-, and structural-level variables were then entered into multinomial logistic regression models to predict levels of PrEP uptake and persistence based on hypotheses informed by syndemic and minority stress theories. The models demonstrated that experience of GBV predicted significantly lower odds of PrEP uptake and persistence and greater PTSD symptoms predicted significantly greater odds of early PrEP discontinuation. Higher levels of coping skills, already being on PrEP at baseline, and being in a steady relationship were associated with greater odds of PrEP uptake and persistence. Implications for future GBV research, advocacy, interventions, and much needed structural changes focused on improving the health and safety of TGNB individuals are discussed.

Randomized Trial of Individualized Texting for Adherence Building (iTAB) Plus Motivational Interviewing for PrEP Adherence in Transgender Individuals: The iM-PrEPT Study.

BACKGROUND: Transgender and nonbinary individuals at risk for HIV may benefit from adherence support for pre-exposure prophylaxis. METHODS: Between June 2017 and September 2020, 255 transgender and nonbinary individuals received daily oral tenofovir disoproxil fumarate/emtricitabine for 48 weeks randomized 1:1 to receive individualized Texting for Adherence Building (iTAB) or iTAB plus motivational interviewing (iTAB + MI) through phone for nonadherence. The primary end point was dried blood spot tenofovir diphosphate concentrations at weeks 12 and 48 (or last on-drug study visit) ≥1246 fmol/punch consistent with ≥7 doses/week (ie, near-perfect adherence). Secondary outcomes included dried blood spot tenofovir diphosphate concentrations ≥719 fmol/punch consistent with ≥4 doses/week (ie, adequate adherence) and self-reported adherence by daily text messages. RESULTS: Adherence for the outcome ≥1246 fmol/punch and ≥719 fmol/punch, respectively, was 49.1% and 57.9% for transgender men, 37.7% and 47.2% for nonbinary individuals, and 31.0% and 44.1% for transgender women. No difference was seen in iTAB + MI compared with iTAB alone by drug levels except where it approached significance in transgender women for the outcome of ≥719 fmol/punch in the iTAB + MI group compared with iTAB only (52% versus 35.7%, P = 0.065). There was a significant difference in self-reported daily dose adherence in the iTAB + MI group compared with iTAB alone (57.9% of days versus 46.4%, P = 0.009). In transgender women, the mean percentage of daily doses taken was 58.5% with iTAB + MI and 37.3% with iTAB alone ( P < 0.001). CONCLUSIONS: In addition to automated approaches to adherence promotion, phone-based MI triggered by repeatedly missing doses may improve pre-exposure prophylaxis adherence among transgender women.

Patient and Physician Preferences Regarding Long-Acting Pre-Exposure Prophylaxis and Antiretroviral Therapy: A Mixed-Methods Study in Southern California, USA.

Antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP) are key strategies in ending the HIV epidemic. However, poor adherence to daily ART and PrEP increases the risk of HIV transmission and acquisition. Long-acting ART and PrEP formulations attempt to improve adherence through providing long-lasting forms of the medication delivered through different routes of administration: oral (potentially monthly), injection (1-6 months), and subdermal implant (up to annually). This study explored patient and physician preferences for long-acting ART and PrEP as well as adherence support strategies. Adult patients (n = 42) with experience taking ART or PrEP participated in individual interviews or focus groups. Physicians (n = 13) currently prescribing ART and/or PrEP completed an online questionnaire. Rapid qualitative analysis systematically synthesized qualitative data, and descriptive statistics examined survey responses. Patients supported improved adherence as a top potential advantage of long-acting ART and PrEP, and reduced internal stigma as a strong benefit specific to long-acting ART. Annual coverage offered through subdermal implants had strong appeal; however, oral was the preferred modality for long-acting ART and PrEP. Patients preferred injectable ART and PrEP if concurrently receiving hormone therapy injections. Side effects, medication cost, and treatment accessibility were potential barriers. Patients preferred calendar tracking and text messages/phone reminders for adherence supports. Physicians reported that they would reduce clinic visits and HIV testing for all patients on long-acting PrEP, except men who have sex with men who would continue to complete HIV testing every 3 months. Physicians were mixed on whether they believed long-acting ART and PrEP would improve patient adherence. Overall, findings demonstrate the potential benefits of long-acting ART and PrEP, while highlighting the need to obtain additional information to address treatment concerns.

Facilitators of PrEP Persistence among Black and Latinx Transgender Women in a PrEP Demonstration Project in Southern California.

Black and Latinx transgender women in the United States (U.S.) are at disproportionately high risk for HIV. Although HIV pre-exposure prophylaxis (PrEP) reduces the risk of HIV infection, uptake and persistence (i.e., ability to continue taking PrEP over time) can be a challenge for Black and Latinx transgender women due to myriad social and structural forces. In this qualitative study, we present unique data on the facilitators of PrEP persistence from Black and Latinx transgender women who initiated PrEP and exhibited varying levels of persistence during a demonstration project in Southern California. PrEP persistence was assessed by collecting quantitative intracellular tenofovir-diphosphate (TFV-DP) levels on dried blood spot (DBS) samples collected at weeks 12 and 48. Informed by the socioecological framework, we conducted and analyzed interviews using qualitative content analysis to determine themes on the facilitators of PrEP persistence. Individual-level facilitators included the use of reminders, having high individual-level HIV risk perception, feeling empowered to take PrEP, and reporting having improved peace of mind and mental health because of taking PrEP. Interpersonal/Community-level facilitators included feeling motivation to prevent HIV in the community, motivation to prevent HIV in the context of sex work, and having high community-level risk perception. Structural-level facilitators included having positive experiences in affirming healthcare settings and having PrEP visits combined with other gender-related healthcare visits. Interventions aiming to increase PrEP uptake and persistence among Black and Latinx transgender women in the U.S. should harness the multiple levels of support exhibited by those who were able to start and persist on PrEP in the face of the myriad social and structural barriers.

Sustained effect of LACTIN-V (Lactobacillus crispatus CTV-05) on genital immunology following standard bacterial vaginosis treatment: results from a randomised, placebo-controlled trial.

BACKGROUND: Bacterial vaginosis might increase HIV risk by eliciting genital inflammation and epithelial barrier disruption, whereas vaginal Lactobacillus crispatus is associated with immune quiescence and HIV protection. We investigated the effect of a live biotherapeutic containing L crispatus CTV-05 (LACTIN-V) on genital immunology and key vaginal bacteria. METHODS: This substudy included women aged 18-45 years who participated in the randomised, placebo-controlled, phase 2b trial of LACTIN-V to reduce bacterial vaginosis recurrence, conducted at four universities and hospitals in the USA. Women with negative results for sexually transmitted infection, pregnancy, and urinary tract infection were provided a 5-day course of vaginal metronidazole 0·75% gel. Those who met at least three of four clinical Amsel criteria for bacterial vaginosis and had a Nugent score of 4-10 from Gram staining were eligible. Participants in the LACTIN-V trial were randomly assigned (2:1) to receive either LACTIN-V or placebo, applied vaginally once per day for 5 days during the first week and then twice per week for 10 more weeks. Follow-up visits occurred 4, 8, 12, and 24 weeks after enrolment. Soluble immune factors and the absolute abundance of bacterial taxa were assayed by mutliplex ELISA and quantitative PCR. The primary outcomes were vaginal levels of IL-1α and soluble E-cadherin at 24 weeks (ie, 13 weeks after treatment cessation). FINDINGS: Between Feb 21, 2020 and March 18, 2021, we characterised genital immune parameters and the vaginal microbiota in a subset of 66 highly adherent participants who were randomly selected, with no exclusion criteria, from those who had attended all study follow-up visits (n=166) in the larger LACTIN-V clinical trial (n=288). 32 (48%) participants received LACTIN-V and 34 (52%) received placebo. LACTIN-V treatment was significantly associated with lower concentrations of the proinflammatory cytokine IL-1α (ß coefficient 0·310, SE 0·149; p=0·042) and soluble E-cadherin (0·429, 0·199; p=0·035), a biomarker of epithelial barrier disruption. INTERPRETATION: Vaginal administration of LACTIN-V following standard bacterial vaginosis therapy resulted in a sustained reduction in genital inflammation and a biomarker of epithelial integrity. The potential of LACTIN-V to reduce HIV susceptibility merits further investigation. FUNDING: Canadian Institutes of Health Research and the National Institutes of Health National Institute of Allergy and Infectious Diseases.

COVID-19 vaccination elicits an evolving, cross-reactive antibody response to epitopes conserved with endemic coronavirus spike proteins.

The COVID-19 pandemic has triggered the first widespread vaccination campaign against a coronavirus. Many vaccinated subjects are previously naive to SARS-CoV-2; however, almost all have previously encountered other coronaviruses (CoVs), and the role of this immunity in shaping the vaccine response remains uncharacterized. Here, we use longitudinal samples and highly multiplexed serology to identify mRNA-1273 vaccine-induced antibody responses against a range of CoV Spike epitopes, in both phylogenetically conserved and non-conserved regions. Whereas reactivity to SARS-CoV-2 epitopes shows a delayed but progressive increase following vaccination, we observe distinct kinetics for the endemic CoV homologs at conserved sites in Spike S2: these become detectable sooner and decay at later time points. Using homolog-specific antibody depletion and alanine-substitution experiments, we show that these distinct trajectories reflect an evolving cross-reactive response that can distinguish rare, polymorphic residues within these epitopes. Our results reveal mechanisms for the formation of antibodies with broad reactivity against CoVs.

Sex differences in cytokine profiles during suppressive antiretroviral therapy.

OBJECTIVE: Despite lower plasma HIV RNA levels, women progress faster to AIDS than men. The reasons for these differences are not clear but might be a consequence of an elevated inflammatory response in women. METHODS: We investigated sex differences in cytokine profiles by measuring the concentrations of 36 cytokines/chemokines by Luminex in blood of women and men (sex at birth) with chronic HIV infection under suppressive therapy. We initially performed a principal component analysis to see if participants clustered by sex, and then fit a partial least squares discriminant analysis (PLS-DA) model where we used cytokines to predict sex at birth. The significance of the difference in nine cytokines with VIP greater than 1 was tested using Wilcoxon test-rank. Further, potential confounding factors were tested by multivariate linear regression models. RESULTS: Overall, we predicted sex at birth in the PLS-DA model with an error rate of approximately 13%. We identified five cytokines, which were significantly higher in women compared with men, namely the pro-inflammatory chemokines CXCL1 (Gro-α), CCL5 (RANTES), CCL3 (MIP-1α), CCL4 (MIP-1ß), as well as the T-cell homeostatic factor IL-7. The effect of sex remained significant after adjusting for CD4 + , age, ethnicity, and race for all cytokines, except for CCL3 and race. CONCLUSION: The observed sex-based differences in cytokines might contribute to higher immune activation in women compared with men despite suppressive therapy. Increased levels of IL-7 in women suggest that homeostatic proliferation may have a differential contribution to HIV reservoir maintenance in female and male individuals. Our study emphasizes the importance of sex-specific studies of viral pathogenesis.

Sexually transmitted infections among participants in an HIV PrEP adherence trial.

BACKGROUND: HIV PrEP effectiveness is highly dependent on adherence. High STI incidence has been reported among PrEP users. We assessed the relationship between STI incidence (CT, NG, and syphilis) and PrEP adherence. METHODS: We performed a subanalysis of a controlled, open-label, two-arm, randomized clinical demonstration project of a text-message based adherence intervention. Participants had 48 weeks of follow-up and had STI testing every 12 or 24 weeks. PrEP adherence was measured at week 48 using intracellular tenofovir-diphosphate drug concentrations. We calculated incidence rate ratios for STIs among those adherent as compared with those not adherent to PrEP. RESULTS: Of the 381 assessed for CT, NG and syphilis at one or more follow-up visits, there were 16 cases of syphilis or 5.0 per 100 person years (95% CI: 2.6, 7.5); 63 cases of NG or 26.3 per 100 person years (95% CI: 19.8, 32.8); and 81 cases of CT or 36.3 per 100 person years (95% CI: 28.4, 44.2). We found no association between adequate PrEP adherence and STI incidence (aIRR: 0.97 95% CI: 0.67, 1.40). CONCLUSIONS: We found that the incidence of STIs was not significantly different between those adherent to PrEP and those non-adherent. Further research is needed to assess how PrEP use may impact STIs over time.

Low incidence and prevalence of hepatitis C in two cohorts of HIV pre-exposure prophylaxis adherence interventions in men who have sex with men in Southern California.

HIV pre-exposure prophylaxis (PrEP) has been associated with incident hepatitis C virus (HCV) infection in men who have sex with men (MSM) due to decreased condom use. We examined rates of HCV among MSM and transgender women at high-risk of HIV on PrEP in Southern California using data from two trials (NCT01761643 and NCT01781806). Five of 599 participants (0.84%, 95% CI, 0.27-1.93) had HCV antibodies detected at entry. Factors associated with HCV seropositivity included being older (p = .002) and lower education level (p < .001). HCV-positive participants had no reported cases of sexually transmitted infection (rectal, urethral or pharyngeal gonorrhoea and/or chlamydia) at entry while HCV-negative participants had a prevalence of 18% (95% CI, 15%-21%). There were no significant differences in substance use and sexual risk behaviour between HCV-positive and HCV-negative participants 1-3 months prior to entry. Among early PrEP adopters, incident HCV did not occur despite ongoing condomless intercourse. Screening intervals for HCV in MSM on PrEP should be led by a risk behaviour assessment.

Genital Inflammation Is Not Associated With Decreased Vaginal Tenofovir Concentrations in Women Taking Oral PrEP.

BACKGROUND: We evaluated the association of inflammation and dysbosis on cervicovaginal fluid (CVF) tenofovir (TFV) concentrations in women taking oral tenofovir disoproxil fumarate/emtricitable for HIV pre-exposure prophylaxis (PrEP) in the United States. SETTING: Thirty-five women in a HIV PrEP implementation study attended their week 24 visit at a San Diego research clinic and provided CVF specimens. METHODS: Women in the Adherence Enhancement Guided by Individualized Texting and Drug Levels study had their CVF specimens evaluated for (1) sexually transmitted bacterial (Neisseria gonorrhoeae, Chlamydia trachomatis, Gardnerella, and Trichomonas vaginalis), viral (human papillomavirus, cytomegalovirus and herpes simplex virus-1/2) and fungal (Candida) infections; (2) microbiome composition by 16 S sequencing (V3-V4 region); and (3) cytokine profiles by enzyme-linked immunoassay (Interleukin-8, macrophage Inflammatory protein-1a, macrophage Inflammatory Protein-1b and interferon-γ-inducible protein-10). Univariate statistical analysis was used to determine factors associated with CVF TFV concentrations. CVF TFV of 100-1000 ng/mL benchmarked typical genital concentrations and TFV-diphosphate in dried blood spots of 700 fmol/punch was considered adequate adherence. RESULTS: Thirty-five women had CVF specimens collected. No factor was associated with CVF TFV concentrations or discordance of blood and vaginal concentrations. Among 27 participants assessed for vaginosis (Candida, Gardnerella or Trichomonas), women with Gardnerella (n = 11) were more likely to have high (>1000 ng/mL) CVF TFV concentrations (82% versus 33%, P = 0.02). CONCLUSIONS: Presence of genital viruses, cytokines, or vaginal community state types were not associated with low CVF TFV concentrations in cisgender women taking oral tenofovir disoproxil fumarate/emtricitable for PrEP. The surprising association observed between presence of Gardnerella and higher vaginal TFV concentrations needs further evaluation.

Metronidazole treatment rapidly reduces genital inflammation through effects on bacterial vaginosis-associated bacteria rather than lactobacilli.

BackgroundBacterial vaginosis (BV) causes genital inflammation and increases HIV risk, whereas a vaginal microbiota dominated by Lactobacillus species is associated with immune quiescence and relative HIV protection. BV treatment reduces genital inflammation, but it is unclear whether this reduction is driven by a decrease in BV-associated bacteria or an increase in Lactobacillus species.METHODSTo evaluate the short-term effect of standard BV treatment on genital immunology and the vaginal microbiota, vaginal swabs were collected immediately before and after metronidazole treatment for BV and analyzed with multiplex ELISA, metagenomic sequencing, and quantitative PCR.RESULTSTopical metronidazole treatment rapidly reduced vaginal levels of proinflammatory cytokines, chemokines, and soluble immune markers of epithelial barrier disruption. Although the vaginal microbiota shifted to dominance by L. iners or L. jensenii, this proportional shift was primarily driven by a 2 to 4 log10-fold reduction in BV-associated bacteria absolute abundance. BV treatment induced no change in the absolute abundance of L. crispatus or L. iners and only minor (<1 log10-fold) increases in L. gasseri and L. jensenii that were not independently associated with reduced inflammation in multivariable models.CONCLUSIONThe genital immune benefits that are associated with Lactobacillus dominance after BV treatment were not directly attributable to an absolute increase in lactobacilli, but rather to the loss of BV-associated bacteria.Trial REGISTRATIONParticipants were recruited as part of a randomized controlled trial (ClinicalTrials.gov NCT02766023) from 2016 to 2019.FUNDINGCanadian Institutes of Health Research (PJT-156123) and the National Institute of Allergy and Infectious Diseases (HHSN2722013000141 and HHSN27200007).

Method of Calculating Renal Function Estimates Could Inappropriately Exclude Transgender Patients Receiving Gender-Affirming Hormone Therapy from Pre-Exposure Prophylaxis Eligibility.

Purpose: Despite the importance of reliable renal function estimation among the growing transgender population, research describing the variability of existing equations is scarce. Study objectives were to (1) quantify the range of renal function estimates that would be observed if different gender coefficients are used in the estimating equations, (2) compare estimates of renal function (creatinine clearance [CLCR] or estimated glomerular filtration rate [GFR]) between users and nonusers of gender-affirming therapies, and (3) quantify the proportion of subjects who would be deemed ineligible for tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for pre-exposure prophylaxis (PrEP) based on the gender coefficient used. Methods: A retrospective analysis was performed among transgender PrEP users enrolled in a multicenter observational study between June 2017 and October 2021. The primary outcome was estimated kidney function, defined using calculated CLCR or GFR before initiating TDF/FTC for PrEP based on the three most commonly used estimating equations. Results: A total of 258 participants were evaluated. Median differences in renal function ranged from 13 to 25 mL/min based on which gender coefficient and equation was used. Regardless of the method used to compute renal function, there were significant differences between users and nonusers of gender-affirming therapy. There were 17 (6.6%) participants where at least one of the methods would potentially render them ineligible to receive TDF/FTC for PrEP. Conclusions: Renal function estimates vary considerably with different estimating equations in the transgender population and are modified by use of gender-affirming therapy. These variations could result in exclusion from drug therapies such as TDF/FTC for PrEP.

COVID-19 vaccination recruits and matures cross-reactive antibodies to conserved epitopes in endemic coronavirus Spike proteins.

The COVID-19 pandemic has triggered the first widespread vaccination campaign against a coronavirus. Most vaccinated subjects are naïve to SARS-CoV-2, however almost all have previously encountered other coronaviruses (CoVs) and the role of this immunity in shaping the vaccine response remains uncharacterized. Here we use longitudinal samples and highly-multiplexed serology to identify mRNA-1273 vaccine-induced antibody responses against a range of CoV Spike epitopes and in both phylogenetically conserved and non-conserved regions. Whereas reactivity to SARS-CoV-2 epitopes showed a delayed but progressive increase following vaccination, we observed distinct kinetics for the endemic CoV homologs at two conserved sites in Spike S2: these became detectable sooner, and decayed at later timepoints. Using homolog-specific depletion and alanine-substitution experiments, we show that these distinctly-evolving specificities result from cross-reactive antibodies as they mature against rare, polymorphic residues within these epitopes. Our results reveal mechanisms for the formation of antibodies with broad reactivity against CoVs.