Intravaginal artesunate pessaries for treatment of cervical intraepithelial neoplasia 2/3 among HIV-positive and HIV-negative women in Kenya: Study protocol for a pilot trial.

Background: Cervical cancer disproportionately affects women in low- and middle-income countries (LMICs), which bear 90% of deaths. Current precancer treatments rely on healthcare workers who may be out of reach for many women. Development of a patient-controlled cervical precancer treatment can significantly improve access in remote areas and promote secondary prevention of cervical cancer. Methods: This is a phase I trial among 18 HIV-positive and HIV-negative women in Kenya, investigating use of artesunate vaginal pessaries as treatment for cervical precancer among women screening positive for cervical precancer who need excisional treatment. The primary objective will be the safety of self-administered artesunate pessaries. Participants will self-administer 200mg of artesunate vaginally daily for 5 days, followed by a drug-free week, repeated for a total of 4 cycles (artesunate self-administration on weeks 1, 3, 5, 7). The total study duration, including participant follow-up is 48 weeks. Safety and adherence will be assessed through review of symptom diaries and biweekly follow-ups during the treatment phase. Data analysis will include quantitative and qualitative methods. Figure 1 illustrates the study schema. Discussion: Considering the challenges associated with excisional treatments for cervical precancer in LMICs where access to care is limited, this study proposes an alternative approach using intravaginal Artesunate. This clinical trial will provide important safety and efficacy data on using artesunate as a topical therapy for both HIV-positive and HIV-negative women. Trial Registration: ClinicalTrials.gov identifier: NCT06165614.

Self-Harm and Suicide Rates Before and After an Early Intervention Program for Patients With First-Episode Schizophrenia.

Importance: Evidence on the association of early intervention services (EISs) with self-harm and suicide among patients with first-episode schizophrenia (FES) at older than 25 years is lacking. Objective: To examine changes in self-harm and suicide rates among patients with FES before and after the implementation of an EIS program. Design, Setting, and Participants: This population-based cohort study conducted among 37 040 patients aged 15 to 64 years with FES between January 1, 2001, and March 31, 2020, used electronic medical records from the Hong Kong Clinical Data Analysis and Reporting System. All patients were followed up from the first diagnosis of schizophrenia (the index date) until the date of their death or the end of the study period (March 31, 2021), whichever came first. Statistical analysis was performed from July to November 2023. Exposure: The EIS extended the Early Assessment Service for Young People With Early Psychosis (EASY) program from patients aged 15 to 25 years to those aged 15 to 64 years (EASY Plus). The exposure was the implementation of the EASY Plus program in April 2011. The exposure period was defined as between April 2012 and March 2021 for the 1-year-time-lag analysis. Main Outcomes and Measures: The outcomes were monthly rates of self-harm and suicide among patients with FES before and after the implementation of the EASY Plus program. Interrupted time series analysis was used for the main analysis. Results: This study included 37 040 patients with FES (mean [SD] age at onset, 39 [12] years; 82.6% older than 25 years; 53.0% female patients). The 1-year-time-lag analysis found an immediate decrease in self-harm rates among patients aged 26 to 44 years (rate ratio [RR], 0.77 [95% CI, 0.59-1.00]) and 45 to 64 years (RR, 0.70 [95% CI, 0.49-1.00]) and among male patients (RR, 0.71 [95% CI, 0.56-0.91]). A significant long-term decrease in self-harm rates was found for all patients with FES (patients aged 15-25 years: RR, 0.98 [95% CI, 0.97-1.00]; patients aged 26-44 years: RR, 0.98 [95% CI, 0.97-0.99]; patients aged 45-64 years: RR, 0.97 [95% CI, 0.96-0.98]). Suicide rates decreased immediately after the implementation of the EASY Plus program among patients aged 15 to 25 years (RR, 0.33 [95% CI, 0.14-0.77]) and 26 to 44 years (RR, 0.38 [95% CI, 0.20-0.73]). Compared with the counterfactual scenario, the EASY Plus program might have led to 6302 fewer self-harm episodes among patients aged 26 to 44 years. Conclusions and Relevance: This cohort study of the EASY Plus program suggests that the extended EIS was associated with reduced self-harm and suicide rates among all patients with FES, including those older than 25 years. These findings emphasize the importance of developing tailored interventions for patients across all age ranges to maximize the benefits of EISs.

Vaccine effectiveness against anal HPV among men who have sex with men aged 18-45 years attending sexual health clinics in three United States cities, 2018-2023.

BACKGROUND: We assessed human papillomavirus (HPV) vaccine effectiveness (VE) against anal HPV among men who have sex with men (MSM) in 2018-2023. METHODS: Residual anal specimens from MSM without HIV ages 18-45 years were tested for HPV. We calculated adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) for associations between vaccination (≥1 dose) and quadrivalent vaccine (4vHPV)-type prevalence adjusting for city, race/ethnicity, and non-vaccine-type HPV prevalence, stratified by age group (18-26, 27-45). VE was calculated as (1-aPR)x100. RESULTS: Among 2802 persons aged 18-26, 4vHPV-type prevalence was lower in those vaccinated at age <18 (aPR=0.13, CI: 0.08-0.22, VE=87%) and those vaccinated ≥2 years before specimen collection (aPR=0.52, CI: 0.42-0.64, VE=48%), compared with unvaccinated persons. Among 3548 persons aged 27-45, 4vHPV-type prevalence was lower in those vaccinated at ages 18-26 (aPR=0.68, CI: 0.57-0.82, VE=32%) and those vaccinated ≥2 years before specimen collection (aPR=0.66, CI: 0.57-0.77, VE=33%), compared with unvaccinated persons. While we observed no VE in persons vaccinated at age >26 overall, 4vHPV-type prevalence was lower in the subgroup vaccinated ≥2 years before specimen collection (aPR=0.71, CI: 0.56-0.89, VE=29%). CONCLUSIONS: We found high VE against anal 4vHPV-type prevalence among MSM aged 18-26 who were vaccinated at age <18. Lower VE was observed among MSM ages 27-45 who were vaccinated at age 18-26 or ≥2 years before specimen collection. While ideally vaccination should be given at younger ages, vaccination can prevent some future infections in this population.

The effect of youth-friendly health services on risk of pregnancy among adolescent girls and young women in Lilongwe, Malawi: a secondary analysis of the girl power-Malawi study.

In sub-Saharan Africa, adolescent girls and young women aged 15-24 (AGYW) experience high risk of early and unintended pregnancy. We assessed the impact of youth-friendly health services (YFHS) on pregnancy risk among AGYW who participated in the Girl Power study. In 2016, Girl Power randomly assigned four government-run health centers in Lilongwe, Malawi, to provide a standard (n=1) or youth-friendly (n=3) model of service delivery. At six and 12 months, study participants (n=250 at each health center) self-reported their current pregnancy status and received a urine pregnancy test. Because of missing pregnancy test results, we used multiple imputation to correct for outcome misclassification in self-reported pregnancy status, and applied the parametric g-formula on the corrected data to estimate the effect of YFHS on the 12-month risk of pregnancy. After correcting for outcome misclassification, the risk of pregnancy under the scenario where all health centers offered YFHS was 15.8% compared to 23.2% under the scenario where all health centers offered standard of care (risk difference: -7.3%, 95% CI: -15.5%, 0.8%). Access to a model of YFHS that integrates provider training with youth-friendly clinic modifications and community outreach activities may decrease risk of pregnancy among AGYW relative to standard of care.

Safety and adherence to self-administered intravaginal 5-fluorouracil cream following cervical intraepithelial neoplasia (CIN) 2/3 treatment among HIV-positive women in Kenya: A phase 1 clinical trial.

Objective: To determine the safety, tolerance, and adherence to self-administered intravaginal 5% fluorouracil (5FU) cream as adjuvant therapy following cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3) treatment among women living with HIV (WLWH) in Kenya. Methods: A Phase I Pilot trial was performed among 12 WLWH in Kenya, aged 18-49 years between March 2023-February 2024 (ClinicalTrial.gov NCT05362955). Participants self-administered 2g of 5FU intravaginally every other week for eight applications. Safety was assessed using a standardized grading scale, and adherence was evaluated using self-report, inspection of used applicators, and weighing of the study drug. Results: The mean age and CD4 count were 43.9 years and 781 cells/mm3, respectively. Seven (58%) had an 8th-grade education or less. All 12 reported at least one grade I adverse event (AE), 1 (8%) reported a grade 2 AE, no grade 3 or 4 AEs were reported. Increased vaginal discharge (n=9, 75%) and irritation (n=5, 42%), with a mean duration of 3.2 and 2.8 days, respectively, were the most commonly reported AEs. Provider-observed AEs included grade 1 cervical erythema and superficial abrasions. All participants tolerated all eight 5FU doses, and 96% adherence was demonstrated. Conclusion: Self-administered 5FU following CIN2/3 treatment among WLWH in Kisumu, Kenya, was safe, tolerable, and associated with high adherence. Randomized trials are needed to investigate whether adjuvant 5FU can improve treatment outcomes or serve as primary cervical precancer treatment in sub-Saharan Africa. A self-administered therapy may be transformative in increasing access to treatment and, hence, secondary prevention of cervical cancer.

Selective depletion of HBV-infected hepatocytes by class A capsid assembly modulators requires high levels of intrahepatic HBV core protein.

Capsid assembly mediated by hepatitis B virus (HBV) core protein (HBc) is an essential part of the HBV replication cycle, which is the target for different classes of capsid assembly modulators (CAMs). While both CAM-A ("aberrant") and CAM-E ("empty") disrupt nucleocapsid assembly and reduce extracellular HBV DNA, CAM-As can also reduce extracellular HBV surface antigen (HBsAg) by triggering apoptosis of HBV-infected cells in preclinical mouse models. However, there have not been substantial HBsAg declines in chronic hepatitis B (CHB) patients treated with CAM-As to date. To investigate this disconnect, we characterized the antiviral activity of tool CAM compounds in HBV-infected primary human hepatocytes (PHHs), as well as in HBV-infected human liver chimeric mice and mice transduced with adeno-associated virus-HBV. Mechanistic studies in HBV-infected PHH revealed that CAM-A, but not CAM-E, induced a dose-dependent aggregation of HBc in the nucleus which is negatively regulated by the ubiquitin-binding protein p62. We confirmed that CAM-A, but not CAM-E, induced HBc-positive cell death in both mouse models via induction of apoptotic and inflammatory pathways and demonstrated that the degree of HBV-positive cell loss was positively correlated with intrahepatic HBc levels. Importantly, we determined that there is a significantly lower level of HBc per hepatocyte in CHB patient liver biopsies than in either of the HBV mouse models. Taken together, these data confirm that CAM-As have a unique secondary mechanism with the potential to kill HBc-positive hepatocytes. However, this secondary mechanism appears to require higher intrahepatic HBc levels than is typically observed in CHB patients, thereby limiting the therapeutic potential.

Comparison of the ScreenFire and Xpert HPV assays for the detection of human papillomavirus and cervical precancer among women living with HIV in Malawi.

BACKGROUND: The World Health Organization recommends human papillomavirus (HPV) testing for primary cervical cancer screening, including among women living with HIV (WLWH). Low-and-middle-income countries account for 85% of the cervical cancer burden globally, yet have limited access to HPV-based screening, largely due to cost. This study aims to compare the performance of a rapid, isothermal amplification HPV assay (ScreenFire) to that of the Xpert HPV assay for the detection of HPV and cervical precancer among WLWH in Malawi. METHODS: We utilized stored self- and provider-collected specimens from a prospective cohort study of WLWH in Malawi from July 2020 to February 2022. Specimens were tested with both Xpert and ScreenFire HPV assays. The overall and within-channel non-hierarchical agreement between ScreenFire and Xpert was determined for both self- and provider-collected specimens. Hierarchical ScreenFire HPV positivity by channel was compared to Xpert for each histological diagnosis-cervical intraepithelial neoplasia grade 2 or worse (CIN2+) compared to

Simultaneous detection of pathogens and antimicrobial resistance genes with the open source, cloud-based, CZ ID pipeline.

Antimicrobial resistant (AMR) pathogens represent urgent threats to human health, and their surveillance is of paramount importance. Metagenomic next generation sequencing (mNGS) has revolutionized such efforts, but remains challenging due to the lack of open-access bioinformatics tools capable of simultaneously analyzing both microbial and AMR gene sequences. To address this need, we developed the CZ ID AMR module, an open-access, cloud-based workflow designed to integrate detection of both microbes and AMR genes in mNGS and whole-genome sequencing (WGS) data. It leverages the Comprehensive Antibiotic Resistance Database and associated Resistance Gene Identifier software, and works synergistically with the CZ ID short-read mNGS module to enable broad detection of both microbes and AMR genes. We highlight diverse applications of the AMR module through analysis of both publicly available and newly generated mNGS and WGS data from four clinical cohort studies and an environmental surveillance project. Through genomic investigations of bacterial sepsis and pneumonia cases, hospital outbreaks, and wastewater surveillance data, we gain a deeper understanding of infectious agents and their resistomes, highlighting the value of integrating microbial identification and AMR profiling for both research and public health. We leverage additional functionalities of the CZ ID mNGS platform to couple resistome profiling with the assessment of phylogenetic relationships between nosocomial pathogens, and further demonstrate the potential to capture the longitudinal dynamics of pathogen and AMR genes in hospital acquired bacterial infections. In sum, the new AMR module advances the capabilities of the open-access CZ ID microbial bioinformatics platform by integrating pathogen detection and AMR profiling from mNGS and WGS data. Its development represents a critical step toward democratizing pathogen genomic analysis and supporting collaborative efforts to combat the growing threat of AMR.

Serological Evidence of Mpox Virus Infection During Peak Mpox Transmission in New York City, July to August 2022.

BACKGROUND: The extent to which infections may have been undetected in an epicenter of the 2022 mpox outbreak is unknown. METHODS: A serosurvey (July and August 2022) assessed the seroprevalence and correlates of mpox infection among a diverse sample of asymptomatic patients with no prior mpox diagnoses and no known histories of smallpox or mpox vaccination. We present seropositivity stratified by participant characteristics collected via survey. RESULTS: Two-thirds of 419 participants were cismen (281 of 419), of whom 59.1% (166 of 281) reported sex with men (MSM). The sample also included 109 ciswomen and 28 transgender/gender nonconforming/nonbinary individuals. Overall seroprevalence was 6.4% (95% confidence interval [CI], 4.1%-8.8%); 3.7% among ciswomen (95% CI, 1.0%-9.1%), 7.0% among cismen with only ciswomen partners (95% CI, 2.0%-11.9%), and 7.8% among MSM (95% CI, 3.7%-11.9%). There was little variation in seroprevalence by race/ethnicity, age group, HIV status, or number of recent sex partners. No participants who reported close contact with mpox cases were seropositive. Among participants without recent mpox-like symptoms, 6.3% were seropositive (95% CI, 3.6%-9.0%). CONCLUSIONS: Approximately 1 in 15 vaccine-naive people in our study had antibodies to mpox during the height of the NYC outbreak, indicating the presence of asymptomatic infections that could contribute to ongoing transmission.

Comparison of the ScreenFire and Xpert HPV assays for the detection of human papillomavirus and cervical precancer among women living with HIV in Malawi.

Background: The World Health Organization (WHO) recommends human papillomavirus (HPV) testing for primary cervical cancer screening, including among women living with HIV (WLWH). Low-and-middle-income countries (LMICs) account for 85% of the cervical cancer burden globally, yet have limited access to HPV-based screening, largely due to cost. This study aims to compare the performance of a rapid, isothermal amplification HPV assay (ScreenFire) to that of the Xpert HPV assay for the detection of HPV and cervical precancer among WLWH in Malawi. Methods: We utilized stored self- and provider-collected specimens from a prospective cohort study of WLWH in Malawi from July 2020 to February 2022. Specimens were tested with both Xpert and ScreenFire HPV assays. The overall and within-channel non-hierarchical agreement between ScreenFire and Xpert was determined for both self- and provider-collected specimens. Hierarchical ScreenFire HPV positivity by channel was compared to Xpert for each histological diagnosis - cervical intraepithelial neoplasia grade 2 or worse (CIN2+) compared to

Delays in sexual health care among patients attending New York City Sexual Health Clinics during the COVID-19 pandemic, March 2020 to February 2021.

BACKGROUND: Public health emergencies can lead to reduced or suspended services in sexual health clinics (SHCs), raising questions about optimal ways to maintain access to care. We examined changes in sexual behaviors, HIV pre-exposure prophylaxis (PrEP) use, telehealth preference, and correlates of delayed sexual health care among patients attending New York City (NYC) publicly funded SHCs during the COVID-19 pandemic. METHODS: 470 patients from four SHCs (July-September 2021) completed a self-administered survey that collected data on access to sexual health care, overall and over three distinct time periods [Spring 2020 (COVID-19 wave 1), Summer 2020, Fall 2020/Winter 2021 (COVID-19 wave 2)]. We used log-binomial models to examine factors associated with delayed sexual health care. RESULTS: Participants reporting multiple in-person sexual contacts increased from 28% to 57% (P < 0.0001) between the first and second wave. Almost half of participants (35/72) taking HIV PrEP cited decreased use. Over 90% (423/460) of participants preferred in-person clinic visits over telehealth. Overall, delays in routine and urgent sexual health care were reported by 34% (129/375) and 12% (46/373) of participants, respectively. More men who have sex with men (MSM) and transgender/gender non-conforming/nonbinary (TGNCNB) individuals experienced delayed care compared with women [MSM: aPR 1.43 (95% CI, 1.00-2.03); TGNCNB: 1.67 (1.04-2.69)]. Compared with participants who primarily sought sexual health care from private providers, those who primarily used SHCs experienced significantly more delayed care [1.72 (1.14-2.59)]. CONCLUSIONS: Delays in sexual health care access can have serious implications for certain patient populations. Additional resources are needed to maintain access to sexual health clinic services.

Simultaneous detection of pathogens and antimicrobial resistance genes with the open source, cloud-based, CZ ID pipeline.

Antimicrobial resistant (AMR) pathogens represent urgent threats to human health, and their surveillance is of paramount importance. Metagenomic next generation sequencing (mNGS) has revolutionized such efforts, but remains challenging due to the lack of open-access bioinformatics tools capable of simultaneously analyzing both microbial and AMR gene sequences. To address this need, we developed the Chan Zuckerberg ID (CZ ID) AMR module, an open-access, cloud-based workflow designed to integrate detection of both microbes and AMR genes in mNGS and whole-genome sequencing (WGS) data. It leverages the Comprehensive Antibiotic Resistance Database and associated Resistance Gene Identifier software, and works synergistically with the CZ ID short-read mNGS module to enable broad detection of both microbes and AMR genes. We highlight diverse applications of the AMR module through analysis of both publicly available and newly generated mNGS and WGS data from four clinical cohort studies and an environmental surveillance project. Through genomic investigations of bacterial sepsis and pneumonia cases, hospital outbreaks, and wastewater surveillance data, we gain a deeper understanding of infectious agents and their resistomes, highlighting the value of integrating microbial identification and AMR profiling for both research and public health. We leverage additional functionalities of the CZ ID mNGS platform to couple resistome profiling with the assessment of phylogenetic relationships between nosocomial pathogens, and further demonstrate the potential to capture the longitudinal dynamics of pathogen and AMR genes in hospital acquired bacterial infections. In sum, the new AMR module advances the capabilities of the open-access CZ ID microbial bioinformatics platform by integrating pathogen detection and AMR profiling from mNGS and WGS data. Its development represents a critical step toward democratizing pathogen genomic analysis and supporting collaborative efforts to combat the growing threat of AMR.

Experiences of women participating in a human papillomavirus-based screen-triage-and treat strategy for cervical cancer prevention in Malawi.

Objective: To explore the experiences of Malawian women who underwent a human papillomavirus (HPV)-based screen-triage-treat algorithm for cervical cancer (CxCa) prevention. This algorithm included GeneXpert® HPV testing of self-collected vaginal samples, visual inspection with acetic acid (VIA) and colposcopy for HPV-positive women, and thermal ablation of ablation-eligible women. Method: In-depth interviews were conducted with participants of a trial that evaluated the feasibility of a HPV-based screen-triage-treat algorithm among women living with HIV and HIV negative women in Lilongwe, Malawi. Participants were recruited from 3 groups: 1) HPV-negative; 2) HPV-positive/VIA-negative; 3) HPV-positive/VIA-positive and received thermal ablation. Interviews explored baseline knowledge of CxCa and screening, attitudes towards self-collection, and understanding of test results. Content analysis was conducted using NVIVO v12. Results: Thematic saturation was reached at 25 interviews. Advantages of HPV self-collection to participants were convenience of sampling, same-day HPV results and availability of same-day treatment. There was confusion surrounding HPV-positive/VIA-negative results, as some participants still felt treatment was needed. Counseling, and in particular anticipatory guidance, was key in helping participants understand complex screening procedures and results. Overall, participants expressed confidence in the HPV screen-triage-treat strategy. Discussion: HPV testing through self-collected samples is a promising tool to increase CxCa screening coverage. A multi-step screening algorithm utilizing HPV self-testing, VIA triage and thermal ablation treatment requires proper counseling and anticipatory guidance to improve patient understanding. Incorporating thorough counseling in CxCa screening programs can change women's perspectives about screening, build trust in healthcare systems, and influence healthcare seeking behavior towards routine screening and prevention.

Development of an individualized risk calculator of treatment resistance in patients with first-episode psychosis (TRipCal) using automated machine learning: a 12-year follow-up study with clozapine prescription as a proxy indicator.

About 15-40% of patients with schizophrenia are treatment resistance (TR) and require clozapine. Identifying individuals who have higher risk of development of TR early in the course of illness is important to provide personalized intervention. A total of 1400 patients with FEP enrolled in the early intervention for psychosis service or receiving the standard psychiatric service between July 1, 1998, and June 30, 2003, for the first time were included. Clozapine prescriptions until June 2015, as a proxy of TR, were obtained. Premorbid information, baseline characteristics, and monthly clinical information were retrieved systematically from the electronic clinical management system (CMS). Training and testing samples were established with random subsampling. An automated machine learning (autoML) approach was used to optimize the ML algorithm and hyperparameters selection to establish four probabilistic classification models (baseline, 12-month, 24-month, and 36-month information) of TR development. This study found 191 FEP patients (13.7%) who had ever been prescribed clozapine over the follow-up periods. The ML pipelines identified with autoML had an area under the receiver operating characteristic curve ranging from 0.676 (baseline information) to 0.774 (36-month information) in predicting future TR. Features of baseline information, including schizophrenia diagnosis and age of onset, and longitudinal clinical information including symptoms variability, relapse, and use of antipsychotics and anticholinergic medications were important predictors and were included in the risk calculator. The risk calculator for future TR development in FEP patients (TRipCal) developed in this study could support the continuous development of data-driven clinical tools to assist personalized interventions to prevent or postpone TR development in the early course of illness and reduce delay in clozapine initiation.

Potential demand for and access to medication abortion among North Carolina college students.

OBJECTIVE: To estimate demand for medication abortion (MAB) among North Carolina (NC) college students and describe access to nearest clinics offering MAB to each campus. METHODS: We calculated demand using 2019-2020 campus demographics and NC abortion statistics. We used a mystery client technique to gather MAB cost and appointment wait times at the closest clinics and calculated travel distances and times. RESULTS: We estimated that 2,517 NC students seek MAB annually. Twenty-one clinics were closest to NC's 111 colleges and universities, including five in neighboring states. Mean cost was $450, with an average wait time of six days to appointment. The average round-trip travel distance was 58 miles and time to the nearest clinic was 84 min by car. CONCLUSIONS: Many NC college students likely obtain MAB every year and face high costs, long wait times and distances to care, which has likely worsened after the overturning of Roe v. Wade.

Edentulism among diabetic patients compared to non-diabetic controls: A systematic review and meta-analysis.

OBJECTIVE: The purpose of this paper is to systematically and critically appraise the available scientific evidence concerning the prevalence of edentulism among diabetic patients compared to non-diabetic people. METHODS: MEDLINE-PubMed and Cochrane-CENTRAL databases were comprehensively searched up to April 2023 to identify appropriate studies. The inclusion criteria were observational studies conducted in human subjects ≥18 years of age with the primary aim of investigating the prevalence of edentulism among diabetic patients. Based on the extracted data, a meta-analysis was performed. Recommendations based on the body of evidence were formulated using the GRADE approach. RESULTS: Independent screening of 2085 unique titles and abstracts revealed seven publications that met the eligibility criteria. Study size ranged from 293 to 15,943 participants. Data from all seven studies were suitable for meta-analysis. Overall, 8.3% of the studied population was edentulous. The weighted mean prevalence of edentulism among diabetic and non-diabetics was 14.0% and 7.1%, respectively. The overall odds ratio for diabetic patients to be edentulous as compared to non-diabetics was 2.39 (95% CI [1.73, 3.28], p < 0.00001). CONCLUSION: There appears to be moderate certainty that the risk of being edentulous for diabetic patients compared to non-diabetic people is significant, but the odds ratio is estimated to be small.

Lenacapavir: A Novel, Potent, and Selective First-in-Class Inhibitor of HIV-1 Capsid Function Exhibits Optimal Pharmacokinetic Properties for a Long-Acting Injectable Antiretroviral Agent.

Lenacapavir (LEN) is a picomolar first-in-class capsid inhibitor of human immunodeficiency virus type 1 (HIV-1) with a multistage mechanism of action and no known cross resistance to other existing antiretroviral (ARV) drug classes. LEN exhibits a low aqueous solubility and exceptionally low systemic clearance following intravenous (IV) administration in nonclinical species and humans. LEN formulated in an aqueous suspension or a PEG/water solution formulation showed sustained plasma exposure levels with no unintended rapid drug release following subcutaneous (SC) administration to rats and dogs. A high total fraction dose release was observed with both formulations. The long-acting pharmacokinetics (PK) were recapitulated in humans following SC administration of both formulations. The SC PK profiles displayed two-phase absorption kinetics in both animals and humans with an initial fast-release absorption phase, followed by a slow-release absorption phase. Noncompartmental and compartmental analyses informed the LEN systemic input rate from the SC depot and exit rate from the body. Modeling-enabled deconvolution of the input rates from two processes: absorption of the soluble fraction (minor) from a direct fast-release process leading to the early PK phase and absorption of the precipitated fraction (major) from an indirect slow-release process leading to the later PK phase. LEN SC PK showed flip-flop kinetics due to the input rate being substantially slower than the systemic exit rate. LEN input rates via the slow-release process in humans were slower than those in both rats and dogs. Overall, the combination of high potency, exceptional stability, and optimal release rate from the injection depot make LEN well suited for a parenteral long-acting formulation that can be administered once up to every 6 months in humans for the prevention and treatment of HIV-1.

Vaginal microbiome, antiretroviral concentrations, and HIV genital shedding in the setting of hormonal contraception initiation in Malawi.

OBJECTIVE: The aim of this study was to understand how vaginal microbiota composition affects antiretroviral concentrations in the setting of hormonal contraception initiation. METHODS: Cervicovaginal fluid (CVF) concentrations of tenofovir, lamivudine, and efavirenz from 73 Malawian women with HIV were compared before and after initiation of depot-medroxyprogesterone acetate (DMPA) or levonorgestrel implant. We evaluated antiretroviral concentrations and vaginal microbiota composition/structure in the context of contraception initiation and predicted genital shedding using multivariable repeated measurements models fit by generalized estimating equations. RESULTS: Mean lamivudine CVF concentrations decreased 37% 1 month after contraception initiation. Subgroup analyses revealed a 41% decrease in women 1 month after initiating levonorgestrel implant, but no significant difference was observed in DMPA group alone. Tenofovir, lamivudine, and efavirenz CVF concentrations were positively correlated with anaerobic bacteria associated with nonoptimal vaginal microbiota. Risk of genital HIV shedding was not significantly associated with tenofovir or lamivudine CVF concentrations [tenofovir relative risk (RR): 0.098, P = 0.75; lamivudine RR: 0.142, P = 0.54]. Lack of association between genital HIV shedding and efavirenz CVF concentrations did not change when adjusting for vaginal microbiota composition and lamivudine/tenofovir CVF concentrations (RR: 1.33, P = 0.531). CONCLUSION: No effect of hormone initiation on genital shedding provides confidence that women with HIV on either DMPA or levonorgestrel implant contraception will not have compromised ART efficacy. The unexpected positive correlation between antiretroviral CVF concentrations and certain bacterial taxa relative abundance requires further work to understand the mechanism and clinical relevance.

Knowledge and perceptions about Dolutegravir and Dolutegravir counselling: a qualitative study among women living with HIV.

INTRODUCTION: In 2018, the Malawi Ministry of Health adopted the recommendation to switch first-line antiretroviral therapy (ART) from an efavirenz (EFV)-based to a dolutegravir (DTG)-based regimen. Little is known about patients' experience during this transition. We conducted a qualitative study to explore DTG-related counselling challenges among providers of HIV care and factors influencing regimen switching or non-switching among women living with HIV in Lilongwe, Malawi. METHODS: Between February-July 2020, we recruited participants who took part in DTG counselling on reasons to switch, side effects, and benefits from two government health facilities providing HIV care: Area 18 health centre and Bwaila district hospital in Lilongwe, Malawi. We purposively sampled and interviewed 8 women living with HIV who remained on an EFV-based regimen after counselling, 10 women who switched to a DTG-based regimen, and 10 HIV care providers who provided counselling about ART switching. In-depth interviews were used to explore patient's perceptions of DTG, factors affecting the decision to switch, and both patient and provider experience with counselling. Interview data was coded for themes using inductive and deductive codes. Interviews were conducted until thematic saturation was achieved. Data matrices were used for analysis and thematic extraction. RESULTS: Most women in both groups were well versed on DTG's potential side effects and felt well counselled on the benefits of switching, such as quicker viral load suppression. Many women associated DTG with birth defects and expressed concern. However, the primary reason for not switching was concern with how the new medication would be tolerated, especially when they were satisfied with their current regimen. Almost all providers expressed difficulty providing DTG counselling. Primary reasons included feeling inadequately trained and/or not having resources to use during counselling, such as diagrams or brochures. CONCLUSION: DTG counselling was well accepted by women; however, some felt that their concerns were not fully addressed. Providers reflected this sentiment in that they did not feel adequately trained or well-equipped to provide adequate counselling. Training on counselling for new ART regimens should be intensified and utilize patient-centered educational materials to address the concerns raised by both patients and health care providers.