Enabling a Learning Public Health System:Enhanced Surveillance of HIV and Other Sexually Transmitted Infections.

Sexually transmitted infections (STIs) continue to pose a substantial public health challenge in the United States (US). Surveillance, a cornerstone of disease control and prevention, can be strengthened to promote more timely, efficient, and equitable practices by incorporating health information exchange (HIE) and other large-scale health data sources into reporting. New York City patient-level electronic health record data between January 1, 2018 and June 30, 2023 were obtained from Healthix, the largest US public HIE. Healthix data were linked to neighborhood-level information from the American Community Survey. In this casecontrol study, chlamydia, gonorrhea, and HIV-positive cases were compared to controls to estimate the odds of receiving a specific laboratory test or positive result using generalized estimating equations with logit function and robust standard errors. Among 1,519,121 tests performed for chlamydia, 1,574,772 for gonorrhea, and 1,200,560 for HIV, 2%, 0.6% and 0.3% were positive for chlamydia, gonorrhea, and HIV, respectively. Chlamydia and gonorrhea co-occurred in 1,854 cases (7% of chlamydia and 21% of gonorrhea total cases). Testing behavior was often incongruent with geographic and sociodemographic patterns of positive cases. For example, people living in areas with the highest levels of poverty were less likely to test for gonorrhea but almost twice as likely to test positive compared to those in low poverty areas. Regional HIE enabled review of testing and cases using granular and complementary data not typically available given existing reporting practices. Enhanced surveillance spotlights potential incongruencies between testing patterns and STI risk in certain populations, signaling potential under- and over-testing. These and future insights derived from HIE data may be used to continuously inform public health practice and drive further improvements in provision and evaluation of services and programs.

Epigenetic Aging and Musculoskeletal Outcomes in a Cohort of Women Living With HIV.

BACKGROUND: The relationship between accelerated epigenetic aging and musculoskeletal outcomes in women with HIV (WWH) has not been studied. METHODS: We measured DNA methylation age using the Infinium MethylationEPIC BeadChip in a cohort from the Women's Interagency HIV Study (n = 190) with measures of bone mineral density (BMD) and physical function. We estimated 6 biomarkers of epigenetic aging-epigenetic age acceleration (EAA), extrinsic EAA, intrinsic EAA, GrimAge, PhenoAge, and DNA methylation-estimated telomere length-and evaluated associations of epigenetic aging measures with BMD and physical function. We also performed epigenome-wide association studies to examine associations of DNA methylation signatures with BMD and physical function. RESULTS: This study included 118 WWH (mean age, 49.7 years; 69% Black) and 72 without HIV (mean age, 48.9 years; 69% Black). WWH had higher EAA (mean ± SD, 1.44 ± 5.36 vs -1.88 ± 5.07; P < .001) and lower DNA methylation-estimated telomere length (7.13 ± 0.31 vs 7.34 ± 0.23, P < .001) than women without HIV. There were no significant associations between accelerated epigenetic aging and BMD. Rather, measures of accelerated epigenetic aging were associated with lower physical function. CONCLUSIONS: Accelerated epigenetic aging was observed in WWH as compared with women without HIV and was associated with lower physical function in both groups.

Menopause-Associated Changes in Mandibular Bone Microarchitecture Are Site-Specific.

BACKGROUND: There are conflicting reports on the effects of decreased estrogen levels on mandibular bone microarchitecture. Whether these effects are consistent throughout the mandible is unclear and may have important implications for treatment planning. PURPOSE: The goal of this study was to evaluate trabecular and cortical bone microstructure in the mandibular condyle and the mandibular basal bone and compare these sites between premenopausal and postmenopausal women. STUDY DESIGN, SETTING, SAMPLE: Participants were recruited for a cross-sectional cohort study at Columbia University Irving Medical Center. Each participant had cone-beam computed tomography taken of their mandibular condyles and the basal bone. Exclusion criteria for the population included a) current chemotherapy or immunotherapy; b) history of bisphosphonate or other osteoporosis therapy; and c) currently pregnant, nursing, or on hormonal birth control. INDEPENDENT VARIABLE: The predictor variables are menopausal status (before or after menopause) and mandibular region of interest (condyle/basal bone). MAIN OUTCOME VARIABLE: Parameters of interest included the following indicators of bone quality: trabecular bone volume fraction, trabecular thickness, trabecular number, trabecular separation, cortical bone volume fraction, cortical thickness, and cortical porosity. COVARIATES: Covariates included demographic variables such as age, estrogen levels, and ethnicity. ANALYSES: Quantitative microstructure analyses were conducted on cone-beam computed tomography images, and differences between groups for continuous measures (including age) were assessed with an unpaired t-test, and demographic variables were assessed by χ2. Statistical significance was recorded at P < .05. RESULTS: The premenopausal and postmenopausal groups each had 31 participants, with the following average age: premenopausal = 43.9 ± 6.9 versus postmenopausal = 57.5 ± 7.6 years old; P < .001, and estrogen levels: premenopausal = 91.77 ± 80.13 pg/ml versus postmenopausal = 41.44 ± 61.62 pg/ml; P < .01). Postmenopausal women had significantly greater condylar trabecular separation (0.61 ± 0.18 vs 0.47 ± 0.11 mm; P < .001) and lower trabecular number (1.03 ± 0.18 vs 1.21 ± 0.19 mm-1; P < .001) compared to premenopausal women. There were no significant differences in the basal bone microarchitectural parameters between the menopausal groups. CONCLUSION AND RELEVANCE: Menopause is associated with mandibular condylar trabecular bone loss but has minimal effects on the mandibular basal bone. This may have important ramifications for treatment planning in advanced-age individuals.

Postmenopausal women with HIV have increased tooth loss.

BACKGROUND: With effective antiretroviral therapy, people with HIV (PWH) are living longer and aging; the majority of PWH in the United States are now over the age of 50 and in women have gone through the menopause transition. Menopause potentiates skeletal bone loss at the spine, hip, and radius in PWH. The alveolar bone which surronds the teeth is different than long bones because it is derived from the neural crest. However, few studies have assessed the oral health and alveolar bone in middle aged and older women with HIV. Therefore, the objective of this study was to evaluate periodontal disease and alveolar bone microarchitecture in postmenopausal women with HIV. METHODS: 135 self-reported postmenopausal women were recruited (59 HIV-, 76 HIV + on combination antiretroviral therapy with virological suppression) from a single academic center. The following parameters were measured: cytokine levels (IFN-γ, TNF-α, IL-1ß, IL-2, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17 A, OPG, and RANKL) in gingival crevicular fluid, bleeding on probing, probing depth, clinical attachment loss, number of teeth present, alveolar crestal height, and alveolar bone microarchitecture. RESULTS: The mean age of participants was 57.04+/-6.25 years and a greater proportion of women with HIV were black/African American (HIV + 68.42%, HIV- 23.73%; p < 0.001). There was no significant difference in bleeding on probing (p = 0.17) and attachment loss (p = 0.39) between women who were HIV infected vs. HIV uninfected. Women with HIV had significantly higher RANKL expression in Gingival Crevicular Fluid (HIV + 3.80+/-3.19 pg/ul, HIV- 1.29+/-2.14 pg/ul ; p < 0.001), fewer teeth present (HIV + 17.75+/-7.62, HIV- 22.79+/-5.70; p < 0.001), ), lower trabecular number (HIV + 0.08+/-0.01, HIV- 0.09+/-0.02; p = 0.004) and greater trabecular separation (HIV + 9.23+/-3.11, HIV- 7.99+/-3.23; p = 0.04) compared to women without HIV that remained significant in multivariate logistic regression analysis in a sub-cohort after adjusting for age, race/ethnicity, smoking status, and diabetes. CONCLUSION: Postmenopausal women with HIV have deterioration of the alveolar trabecular bone microarchitecture that may contribute to greater tooth loss.

Using a Health Information Exchange to Characterize Changes in HIV Viral Load Suppression and Disparities During the COVID-19 Pandemic in New York City.

Background: HIV viral suppression requires sustained engagement in care. The COVID-19 pandemic challenged care accessibility for many people living with HIV (PLWH). We used health information exchange data to evaluate the effect of pandemic-related disruptions in HIV care on viral load suppression (VLS) and to examine racial/ethnic disparities in VLS. Methods: We performed a retrospective observational cohort study of PLWH using data from a regional health information exchange in the New York City region between 1 January 2018 and 31 December 2022. We established 2 cohorts: PLWH who received HIV care in 2020 (cohort A) and PLWH who did not receive HIV care in 2020 (cohort B). We categorized HIV VLS outcomes as suppressed or not suppressed and calculated the prevalence of VLS between 2018 and 2022. We compared proportions using chi-square tests and used unadjusted and adjusted logistic regression to estimate the association among variables, including race/ethnicity, cohort, and VLS. Results: Of 5 301 578 patients, 34 611 met our inclusion criteria for PLWH, 11 653 for cohort A, and 3141 for cohort B. In 2019, cohort B had a lower prevalence of VLS than cohort A (86% vs 89%, P < .001). Between 2019 and 2021, VLS dropped significantly among cohort B (86% to 81%, P < .001) while staying constant in cohort A (89% to 89%, P = .62). By 2022, members of cohort B were less likely than cohort A to be receiving HIV care in New York City (74% vs 88%, P < .001). Within both cohorts, Black and Hispanic patients had lower odds of VLS than White patients. Conclusions: In New York City, VLS remained high among PLWH who continued to receive care in 2020 and dropped among PLWH who did not receive care. VLS was lower among Black and Hispanic patients even after controlling for receipt of care.

Evaluation of the mandibular condylar bone microarchitecture in people living with HIV.

OBJECTIVES: People living with HIV (PLWH) have been shown to have lower bone density at the spine, hip, and radius. However, whether a similar bone phenotype is seen in craniofacial bones is not known. The goal of this study was to evaluate the bone microarchitecture of the mandibular condyle in PLWH. METHODS: We recruited 212 participants, which included 88 HIV-negative participants and 124 PLWH on combination antiretroviral therapy with virological suppression from a single academic center. Each participant filled out a validated temporomandibular disorder (TMD) pain screening questionnaire and had cone beam computed tomography (CBCT) of their mandibular condyles. Qualitative radiographic evidence of temporomandibular joint disorders-osteoarthritis (TMJD-OA) assessment and quantitative microarchitecture analysis of their mandibular condylar bones were conducted. RESULTS: There was no statistically significant difference in either self-reported TMD or in radiographic evidence of TMJD-OA in PLWH compared with HIV-negative controls. Linear regression analysis revealed that positive HIV status remained significantly associated with increased trabecular thickness, decreased cortical porosity, and increased cortical bone volume fraction after adjusting for race, diabetes, sex, and age. CONCLUSION: PLWH have increased mandibular condylar trabecular bone thickness and cortical bone volume fraction compared with HIV-negative controls.

Associations of Muscle Density and Area With Coronary Artery Plaque and Physical Function.

OBJECTIVE: Skeletal muscle quality and mass are important for maintaining physical function during advancing age. We leveraged baseline data from Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) to evaluate whether paraspinal muscle density and muscle area are associated with cardiac or physical function outcomes in people with HIV (PWH). METHODS: REPRIEVE is a double-blind randomized trial evaluating the effect of pitavastatin for primary prevention of major adverse cardiovascular events in PWH. This cross-sectional analysis focuses on participants who underwent coronary computed tomography at baseline. Lower thoracic paraspinal muscle density (Hounsfield units [HU]) and area (cm 2 ) were assessed on noncontrast computed tomography. RESULTS: Of 805 PWH, 708 had paraspinal muscle measurements. The median age was 51 years and 17% were natal female patients. The median muscle density was 41 HU (male) and 30 HU (female); area 13.2 cm 2 /m (male) and 9.9 cm 2 /m (female). In adjusted analyses, greater density (less fat) was associated with a lower prevalence of any coronary artery plaque, coronary artery calcium score >0, and high plaque burden ( P = 0.06); area was not associated with plaque measures. Among 139 patients with physical function measures, greater area (but not density) was associated with better performance on a short physical performance battery and grip strength. CONCLUSIONS: Among PWH, greater paraspinal muscle density was associated with a lower prevalence of coronary artery disease while greater area was associated with better physical performance. Whether changes in density or area are associated with changes in CAD or physical performance will be evaluated through longitudinal analyses in REPRIEVE.

Microbiota in the oral cavity of school-age children with HIV who started antiretroviral therapy at young ages in South Africa.

BACKGROUND: Infancy is an important developmental period when the microbiome is shaped. We hypothesized that earlier antiretroviral therapy (ART) initiation would attenuate HIV effects on microbiota in the mouth. METHODS: Oral swabs were collected from 477 children with HIV (CWH) and 123 children without (controls) at two sites in Johannesburg, South Africa. CWH had started ART less than 3 years of age; 63% less than 6 months of age. Most were well controlled on ART at median age 11 years when the swab was collected. Controls were age-matched and recruited from the same communities. Sequencing of V4 amplicon of 16S rRNA was done. Differences in microbial diversity and relative abundances of taxa were compared between the groups. RESULTS: CWH had lower alpha diversity than controls. Genus-level abundances of Granulicatella, Streptococcus, and Gemella were greater and Neisseria and Haemophilus less abundant among CWH than controls. Associations were stronger among boys. Associations were not attenuated with earlier ART initiation. Shifts in genus-level taxa abundances in CWH relative to controls were most marked in children on lopinavir/ritonavir regimens, with fewer shifts seen if on efavirenz ART regimens. CONCLUSION: A distinct profile of less diverse oral bacterial taxa was observed in school-aged CWH on ART compared with uninfected controls suggesting modulation of microbiota in the mouth by HIV and/or its treatments. Earlier ART initiation was not associated with microbiota profile. Proximal factors, including current ART regimen, were associated with contemporaneous profile of oral microbiota and may have masked associations with distal factors such as age at ART initiation.

A population pharmacokinetic model of polymyxin B based on prospective clinical data to inform dosing in hospitalized patients.

OBJECTIVES: To develop a population pharmacokinetic (PK) model with data from the largest polymyxin B-treated patient population studied to date to optimize its dosing in hospitalized patients. METHODS: Hospitalized patients receiving intravenous polymyxin B for ≥48 hours were enrolled. Blood samples were collected at steady state and drug concentrations were analysed by liquid chromotography tandem mass spectrometry (LC-MS/MS). Population PK analysis and Monte Carlo simulations were performed to determine the probability of target attainment (PTA). RESULTS: One hundred and forty-two patients received intravenous polymyxin B (1.33-6 mg/kg/day), providing 681 plasma samples. Twenty-four patients were on renal replacement therapy, including 13 on continuous veno-venous hemodiafiltration (CVVHDF). A 2-compartment model adequately described the PK with body weight as a covariate on the volume of distribution that affected Cmax, but it did not impact clearance or exposure. Creatinine clearance was a statistically significant covariate on clearance, although clinically relevant variations of dose-normalized drug exposure were not observed across a wide creatinine clearance range. The model described higher clearance in CVVHDF patients than in non-CVVHDF patients. Maintenance doses of ≥2.5 mg/kg/day or ≥150 mg/day had a PTA ≥90% (for non-pulmonary infections target) at a steady state for minimum inhibitory concentrations ≤2 mg/L. The PTA at a steady state for CVVHDF patients was lower. DISCUSSION: Fixed loading and maintenance doses of polymyxin B seemed to be more appropriate than weight-based dosing regimens in patients weighing 45-90 kg. Higher doses may be needed in patients on CVVHDF. Substantial variability in polymyxin B clearance and volume of distribution was found, suggesting that therapeutic drug monitoring may be indicated.

Performance of a modified fracture risk assessment tool for fragility fracture prediction among older veterans living with HIV.

OBJECTIVE: Fragility fractures (fractures) are a critical outcome for persons aging with HIV (PAH). Research suggests that the fracture risk assessment tool (FRAX) only modestly estimates fracture risk among PAH. We provide an updated evaluation of how well a 'modified FRAX' identifies PAH at risk for fractures in a contemporary HIV cohort. DESIGN: Cohort study. METHODS: We used data from the Veterans Aging Cohort Study to evaluate veterans living with HIV, aged 50+ years, for the occurrence of fractures from 1 January 2010 through 31 December 2019. Data from 2009 were used to evaluate the eight FRAX predictors available to us: age, sex, BMI, history of previous fracture, glucocorticoid use, rheumatoid arthritis, alcohol use, and smoking status. These predictor values were then used to estimate participant risk for each of two types of fractures (major osteoporotic and hip) over the subsequent 10 years in strata defined by race/ethnicity using multivariable logistic regression. RESULTS: Discrimination for major osteoporotic fracture was modest [Blacks: area under the curve (AUC) 0.62; 95% confidence interval (CI) 0.62, 0.63; Whites: AUC 0.61; 95% CI 0.60, 0.61; Hispanic: AUC 0.63; 95% CI 0.62, 0.65]. For hip fractures, discrimination was modest to good (Blacks: AUC 0.70; 95% CI 0.69, 0.71; Whites: AUC 0.68; 95% CI 0.67, 0.69]. Calibration was good in all models across all racial/ethnic groups. CONCLUSION: Our 'modified FRAX' exhibited modest discrimination for predicting major osteoporotic fracture and slightly better discrimination for hip fracture. Future studies should explore whether augmentation of this subset of FRAX predictors results in enhanced prediction of fractures among PAH.

Assessing the contributions of modifiable risk factors to serious falls and fragility fractures among older persons living with HIV.

BACKGROUND: Although 50 years represents middle age among uninfected individuals, studies have shown that persons living with HIV (PWH) begin to demonstrate elevated risk for serious falls and fragility fractures in the sixth decade; the proportions of these outcomes attributable to modifiable factors are unknown. METHODS: We analyzed 21,041 older PWH on antiretroviral therapy (ART) from the Veterans Aging Cohort Study from 01/01/2010 through 09/30/2015. Serious falls were identified by Ecodes and a machine-learning algorithm applied to radiology reports. Fragility fractures (hip, vertebral, and upper arm) were identified using ICD9 codes. Predictors for both models included a serious fall within the past 12 months, body mass index, physiologic frailty (VACS Index 2.0), illicit substance and alcohol use disorders, and measures of multimorbidity and polypharmacy. We separately fit multivariable logistic models to each outcome using generalized estimating equations. From these models, the longitudinal extensions of average attributable fraction (LE-AAF) for modifiable risk factors were estimated. RESULTS: Key risk factors for both outcomes included physiologic frailty (VACS Index 2.0) (serious falls [15%; 95% CI 14%-15%]; fractures [13%; 95% CI 12%-14%]), a serious fall in the past year (serious falls [7%; 95% CI 7%-7%]; fractures [5%; 95% CI 4%-5%]), polypharmacy (serious falls [5%; 95% CI 4%-5%]; fractures [5%; 95% CI 4%-5%]), an opioid prescription in the past month (serious falls [7%; 95% CI 6%-7%]; fractures [9%; 95% CI 8%-9%]), and diagnosis of alcohol use disorder (serious falls [4%; 95% CI 4%-5%]; fractures [8%; 95% CI 7%-8%]). CONCLUSIONS: This study confirms the contributions of risk factors important in the general population to both serious falls and fragility fractures among older PWH. Successful prevention programs for these outcomes should build on existing prevention efforts while including risk factors specific to PWH.

Ideal cardiovascular health, biomarkers, and coronary artery disease in persons with HIV.

OBJECTIVE: To investigate relationships between Life's Simple 7 (LS7), an assessment of cardiovascular health (CVH), and coronary plaque among people with HIV (PWH). DESIGN: Cross-sectional. METHODS: Coronary computed tomography angiography, immune/inflammatory biomarkers, and characterization of LS7 were collected among a subset of ART-treated PWH enrolled in REPRIEVE, a primary prevention trial. Analyses adjusted for cardiovascular disease risk (ASCVD score). RESULTS: Median age of the 735 participants was 51(±6) years, 16% female, and median (Q1-Q3) CVD risk was 4.5% (2.6-6.9). Forty percent had poor (≤2 ideal components), 51% had intermediate (three or four ideal components), and only 9% had ideal CVH (≥5). Coronary plaque was present in 357 (49%); 167 (23%) had one or more vulnerable plaque features, 293 (40%) had noncalcified plaque, and 242 (35%) had a coronary artery calcium score >0. All three phenotypes were increasingly more prevalent with poorer CVH and these relationships remained after adjusting for ASCVD risk. Poor CVH was associated with higher high-sensitivity C-reactive protein, oxidized low-density cholesterol, and interleukin-6. The relationship of LS7 to plaque remained after adjusting for these biomarkers. CONCLUSIONS: Among PWH, poor CVH as measured by LS7 was associated with coronary plaque presence, vulnerable features, and calcification. LS7 was also associated with selected biomarkers; adjustment for these and ASCVD score reduced but did not eliminate LS7's association with plaque, suggesting the possibility of additional protective mechanisms against atherogenesis and plaque remodeling. Clinical use of LS7 and further exploration of its relationships with coronary artery disease may enhance efforts to reduce cardiovascular morbidity and mortality in PWH. CLINICAL TRIALS REGISTRATION: NCT02344290.

Menopausal Hormone Therapy and Subclinical Cardiovascular Disease in Women With and Without Human Immunodeficiency Virus.

BACKGROUND: Estrogen-based hormone therapy (HT) may have beneficial cardiovascular effects when initiated in early menopause. This has not been examined in women with human immunodeficiency virus (HIV), who have heightened immune activation and cardiovascular risks. METHODS: Among 609 postmenopausal women (1234 person-visits) in the Women's Interagency HIV Study, we examined the relationship of ever HT use (oral, patch, or vaginal) with subclinical atherosclerosis: carotid artery intima-media thickness (CIMT), distensibility, and plaque assessed via repeated B-mode ultrasound imaging (2004-2013). We also examined associations of HT with cross-sectional biomarkers of immune activation and D-dimer. Statistical models were adjusted for sociodemographic, behavioral, and cardiometabolic factors. RESULTS: Women (mean age, 51 years; 80% HIV positive) who ever used HT at baseline were older, and more likely to be non-Hispanic White and report higher income, than never-users. Women who ever used HT had 43% lower prevalence of plaque (prevalence ratio, 0.57 [95% confidence interval {CI}, .40-.80]; P < .01), 2.51 µm less progression of CIMT per year (95% CI, -4.60, to -.41; P = .02), and marginally lower incidence of plaque over approximately 7 years (risk ratio, 0.38 [95% CI, .14-1.03; P = .06), compared with never-users, adjusting for covariates; ever HT use was not associated with distensibility. These findings were similar for women with and without HIV. Ever HT use was associated with lower serum D-dimer, but not with biomarkers of immune activation after covariate adjustment. CONCLUSIONS: HT may confer a subclinical cardiovascular benefit in women with HIV. These results begin to fill a knowledge gap in menopausal care for women with HIV, in whom uptake of HT is very low.

Disclosure to South African children about their own HIV status over time.

Disclosure to children living with HIV (CLHIV) about their own status is associated with positive outcomes such as treatment adherence, but prior cross-sectional studies in sub-Saharan Africa report disclosure rates of <50%. This study aims to assess pediatric disclosure over time. 548 CLHIV were followed from 2/2013-4/2018 in Johannesburg, South Africa. Cumulative incidence of disclosure was calculated with Kaplan-Meier analysis, and disclosure characteristics assessed with a Cox model. By end of follow-up, cumulative disclosure was 70.3% (95% confidence interval: 60.0-79.9). Median age at disclosure was 9 years (range: 3-13). Baseline predictors of disclosure included older child age and the child having a history of going hungry. Prior to disclosure, 98.0% of caregivers who disclosed had conversed with their child about their illness or an HIV-related topic, or their child had asked about HIV, versus 88.6% of caregivers who never disclosed. While many children did not receive disclosure during this relatively large, longitudinal study of South African CLHIV, caregivers who had not yet disclosed may have been preparing to do so by discussing their child's health or HIV generally with their child. This highlights the need for clinicians to consistently support caregivers throughout the incremental disclosure process.

The Long-Acting Cabotegravir Tail as an Implementation Challenge: Planning for Safe Discontinuation.

The long-acting feature of cabotegravir, an integrase-inhibitor highly effective in preventing acquisition of HIV in adolescents and adults, is both its greatest strength and a challenge to its implementation. Cab-LA is administered at 8-week intervals (after an initial loading dose) but has a long, variable drug "tail" that may leave users vulnerable to future drug resistance if they contract HIV during this critical period. The potential for cab-LA to meaningfully contribute to ending the HIV Epidemic is hindered by, among other factors, limited resources to guide patients and providers on how to safely discontinue injections. We suggest three key strategies to overcome this specific challenge: (1) Comprehensive patient education and counseling about the drug tail; (2) Training and coaching PrEP care teams, including clinical and non-clinical staff, on communication around the tail; (3) Adherence support strategies, including monitoring of cabotegravir drug levels after discontinuation, for a personalized medicine approach to safe discontinuation.

Systemic exposure to hydroxychloroquine and its relationship with outcome in severely ill COVID-19 patients in New York City.

AIM: To investigate the relationship between systemic exposure to hydroxychloroquine (HCQ) and its metabolite desethylhydroxychloroquine (DHCQ) and clinical outcome in severely ill patients treated with a standard oral dose regimen of HCQ during the first wave of COVID-19 in New York City. METHODS: We correlated retrospective clinical data with drug exposure prospectively assessed from convenience samples using population pharmacokinetics and Bayesian estimation. Systemic exposure was assessed in 215 patients admitted to ICU or COVID-ward for whom an interleukin-6 level was requested and who were still alive 24 hours after the last dose of HCQ. Patients received oral HCQ 600 mg twice daily on day 1 followed by 4 days of 400 mg daily. RESULTS: Fifty-three precent of the patients were intubated at 5.4 ± 6.4 days after admission and 26.5% died at an average of 32.2 ± 19.1 days. QTc at admission was 448 ± 34 ms. Systemic exposure to HCQ and DHCQ demonstrated substantial variability. Cumulative area under the serum concentration-time curve up to infinity for HCQ was 71.4 ± 19.3 h mg/L and for DHCQ 56.5 ± 28.3 h mg/L. Variability in systemic exposure was not clearly explained by renal function, liver function or inflammatory state. In turn, systemic exposure did not correlate with intubation status, survival or QTc prolongation. CONCLUSION: This study in severely ill patients was not able to find any relationship between systemic exposure to HCQ and DHCQ and clinical outcome at a routine dose regimen and adds to the growing body of evidence that oral HCQ does not alter the course of disease in COVID-19 patients.

Gut microbiota and plasma metabolites associated with bone mineral density in women with or at risk of HIV infection.

OBJECTIVE: To evaluate gut microbiota (GMB) alterations and metabolite profile perturbations associated with bone mineral density (BMD) in the context of HIV infection. DESIGN: Cross-sectional studies of 58 women with chronic HIV infection receiving antiretroviral therapy and 33 women without HIV infection. METHODS: We examined associations of GMB and metabolites with BMD among 91 women. BMD was measured by dual-energy X-ray absorptiometry (DXA), and T -scores of lumbar spine or total hip less than -1 defined low BMD. GMB was measured by 16S rRNA V4 region sequencing on fecal samples, and plasma metabolites were measured by liquid chromatography-tandem mass spectrometry. Associations of GMB with plasma metabolites were assessed in a larger sample (418 women; 280 HIV+ and 138 HIV-). RESULTS: Relative abundances of five predominant bacterial genera ( Dorea , Megasphaera , unclassified Lachnospiraceae, Ruminococcus , and Mitsuokella ) were higher in women with low BMD compared with those with normal BMD (all linear discriminant analysis (LDA) scores >2.0). A distinct plasma metabolite profile was identified in women with low BMD, featuring lower levels of several metabolites belonging to amino acids, carnitines, caffeine, fatty acids, pyridines, and retinoids, compared with those with normal BMD. BMD-associated bacterial genera, especially Megasphaera , were inversely associated with several BMD-related metabolites (e.g. 4-pyridoxic acid, C4 carnitine, creatinine, and dimethylglycine). The inverse association of Megasphaera with dimethylglycine was more pronounced in women with HIV infection compared with those without HIV infection ( P for interaction = 0.016). CONCLUSION: Among women with and at risk of HIV infection, we identified altered GMB and plasma metabolite profiles associated with low BMD.

The effect of daily oral PrEP use during pregnancy on bone mineral density among adolescent girls and young women in Uganda.

Introduction: Oral pre-exposure prophylaxis (PrEP) is recommended during pregnancy for at-risk cisgender women. Pregnancy is known to impede bone growth and tenofovir-based PrEP may also yield detrimental changes to bone health. Thus, we evaluated the effect of PrEP use during pregnancy on bone mineral density (BMD). Methods: We used data from a cohort of women who were sexually active, HIV-negative, ages 16-25 years, initiating DMPA or choosing condoms for contraception and enrolled in the Kampala Women's Bone Study. Women were followed quarterly with rapid testing for HIV and pregnancy, PrEP dispensation, and adherence counseling. Those who became pregnant were counseled on PrEP use during pregnancy per national guidelines. BMD of the neck of the hip, total hip, and lumbar spine was measured using dual-energy x-ray absorptiometry at baseline and annually. We compared the mean percent change in BMD from baseline to month 24. Results: Among 499 women enrolled in the study, 105 pregnancies occurred in 90 women. At enrollment, the median age was 20 years (IQR: 19-21) and 89% initiated PrEP. During pregnancy, 67% of women continued using PrEP and PrEP was dispensed in 64% of visits. BMD declined significantly in women using PrEP during pregnancy compared to women who were not pregnant nor used PrEP: relative BMD change was -2.26% (95% CI: -4.63 to 0.11, p = 0.06) in the femoral neck, -2.57% (95% CI: -4.48 to -0.66, p = 0.01) in total hip, -3.06% (95% CI: -5.49 to -0.63, p = 0.001) lumbar spine. There was no significant difference in BMD loss when comparing PrEP-exposed pregnant women to pregnant women who never used PrEP. Women who became pregnant were less likely to continue PrEP at subsequent study visits than women who did not become pregnant (adjOR: 0.25, 95% CI: 0.16-0.37, p < 0.001). Based on pill counts, there was a 62% reduction in the odds of high PrEP adherence during pregnancy (adjOR = 0.38, 95% CI: 0.27-0.58, p < 0.001). Conclusion: Women who used PrEP during pregnancy experienced a similar reduction in BMD as pregnant women with no PrEP exposure, indicating that BMD loss in PrEP-using pregnant women is largely driven by pregnancy and not PrEP.

Antibiotic-Specific Risk for Community-Acquired Clostridioides difficile Infection in the United States from 2008 to 2020.

Antibiotic exposure is a crucial risk factor for community-acquired Clostridioides difficile infection (CA-CDI). However, the relative risks associated with specific antibiotics may vary over time, and the absolute risks have not been clearly established. This is a retrospective cohort study. Adults were included if they received an outpatient antibiotic prescription within the IBM MarketScan databases between 2008 and 2020. The primary exposure was an outpatient antibiotic prescription, and the receipt of doxycycline was used as the reference comparison. The primary outcome was CA-CDI, defined as the presence of an International Classification of Diseases (ICD) diagnosis code for CDI within 90 days of receiving an outpatient antibiotic prescription, and subsequent treatment for CDI. There were 36,626,794 unique patients who received outpatient antibiotics, including 11,607 (0.03%) who developed CA-CDI. Relative to doxycycline, the antibiotics conferring the highest risks for CA-CDI were clindamycin (adjusted odds ratio [aOR], 8.81; 95% confidence interval [CI], 7.76 to 10.00), cefdinir (aOR, 5.86; 95% CI, 5.03 to 6.83), cefuroxime (aOR, 4.57; 95% CI, 3.87 to 5.39), and fluoroquinolones (aOR, 4.05; 95% CI, 3.58 to 4.59). Among older patients with CA-CDI risk factors, nitrofurantoin was also associated with CA-CDI (aOR, 3.05; 95% CI, 1.92 to 4.84), with a smaller number needed to harm, compared to the fluoroquinolones. While clindamycin, cefuroxime, and fluoroquinolone use declined from 2008 to 2020, nitrofurantoin use increased by 40%. Clindamycin was associated with the greatest CA-CDI risk, overall. Among older patients with an elevated baseline risk for CA-CDI, multiple antibiotics, including nitrofurantoin, had strong associations with CA-CDI. These results may guide antibiotic selection and future stewardship efforts.