Estimating the epidemiological impact of reaching the objectives of the Florida integrated HIV prevention and care plan in Miami-Dade County.

Background: The US Ending the HIV Epidemic (EHE) initiative aims to reduce national HIV incidence 90% by 2030 and to address the disproportionate burden of HIV among different racial/ethnic populations. Florida's state-wide 2022-2026 Integrated HIV Prevention and Care Plan outlines objectives for reaching EHE goals. In Miami-Dade County, we determined the epidemiological impact of achieving the integrated plan's objectives individually and jointly. Methods: We adapted an HIV transmission model calibrated to Miami-Dade County adjusting access to HIV testing, pre-exposure prophylaxis (PrEP) and antiretroviral treatment to model the effects of each objective between 2022 and 2030. We compared two service scale-up approaches: (a) scale-up proportionally to existing racial/ethnic group access levels, and (b) scale-up according to new diagnoses across racial/ethnic groups (equity-oriented). We estimated reductions in new HIV infections by each objective and approach, compared to the EHE's incidence reduction target. Findings: The single most influential strategy was reducing new HIV diagnoses in Hispanic/Latinx men who have sex with men through increased PrEP uptake, resulting in 907/2444 (37.1%) fewer annual new HIV infections in 2030. Achieving all objectives jointly would result in 1537/2444 (62.9%) and 1553/2444 (63.5%) fewer annual new HIV infections with the proportional and equity-oriented approaches, respectively. Interpretation: Achieving the goals of Florida's integrated care plan would significantly reduce HIV incidence in Miami-Dade County; however, further efforts are required to achieve EHE targets. Structural changes in service delivery and a focus on effective implementation of available interventions to address racial/ethnic disparities will be crucial to ending the HIV epidemic. Funding: This work was supported by the National Institutes of Health/National Institute on Drug Abuse grant no. R01-DA041747.

Opioid agonist therapy and mortality among First Nations and other residents with concurrent alcohol use disorder in British Columbia, Canada: A population-based cohort study.

BACKGROUND: Despite the prevalence of alcohol use among people with opioid use disorder (PWOUD) engaged in opioid agonist therapy (OAT), clinical care guidance for concurrent alcohol use disorder (AUD) and OUD is scarce. We assessed the prevalence and risk of mortality for concurrent AUD among PWOUD who accessed OAT in British Columbia (BC). METHODS: Data were obtained from six linked population-level health administrative datasets to identify PWOUD from January 1996 to March 2020. All-cause age and sex standardized mortality ratios (SMR) were calculated to determine the mortality risk by OAT status (on vs. discontinued), stratified by First Nations and other residents with concurrent AUD and OUD. Adjusted risk ratios compared the relative risk of mortality by AUD status (AUD detected vs. not) among First Nations and other residents. RESULTS: We identified 62,110 PWOUD who received OAT, including 6305 (10.2%) First Nations. OAT substantially lowered the SMR among First Nations (SMR=6.6, 95% CI: 5.4-8.1) and other residents (SMR=6.6; 95% CI: 6.2-7.0) with concurrent AUD and OUD, compared to those who discontinued (SMR=22.7, 95% CI: 20.4-25.1, SMR=17.5, 95% CI: 16.8-18.2 respectively). The risk of mortality was 1.9 (95% CI: 1.6-2.2) times higher for First Nations and 2.0 (95% CI: 1.8-2.2) times higher for other residents with concurrent OUD and AUD compared to those without an indication of AUD. CONCLUSIONS: The protective effect of OAT remained despite the presence of a concurrent AUD among both First Nations and other residents with OUD. Findings have implications for clinical care management of concurrent disorders.

Comparative effectiveness of urine drug screening strategies alongside opioid agonist treatment in British Columbia, Canada: a population-based observational study protocol.

INTRODUCTION: Urine drug tests (UDTs) are commonly used for monitoring opioid agonist treatment (OAT) responses, supporting the clinical decision for take-home doses and monitoring potential diversion. However, there is limited evidence supporting the utility of mandatory UDTs-particularly the impact of UDT frequency on OAT retention. Real-world evidence can inform patient-centred approaches to OAT and improve current strategies to address the ongoing opioid public health emergency. Our objective is to determine the safety and comparative effectiveness of alternative UDT monitoring strategies as observed in clinical practice among OAT clients in British Columbia, Canada from 2010 to 2020. METHODS AND ANALYSIS: We propose a population-level retrospective cohort study of all individuals 18 years of age or older who initiated OAT from 1 January 2010 to 17 March 2020. The study will draw on eight linked health administrative databases from British Columbia. Our primary outcomes include OAT discontinuation and all-cause mortality. To determine the effectiveness of the intervention, we will emulate a 'per-protocol' target trial using a clone censoring approach to compare fixed and dynamic UDT monitoring strategies. A range of sensitivity analyses will be executed to determine the robustness of our results. ETHICS AND DISSEMINATION: The protocol, cohort creation and analysis plan have been classified and approved as a quality improvement initiative by Providence Health Care Research Ethics Board and the Simon Fraser University Office of Research Ethics. Results will be disseminated to local advocacy groups and decision-makers, national and international clinical guideline developers, presented at international conferences and published in peer-reviewed journals electronically and in print.

Incremental expenditures attributable to daily dispensation and witnessed ingestion for opioid agonist treatment in British Columbia: 2014-20.

BACKGROUND AND AIM: While daily witnessed opioid agonist treatment (OAT) ingestion is common in British Columbia (BC), Canada, and elsewhere, sparse evidence supports this resource-intensive practice. Many settings across North America relaxed restrictions for take-home dosing during the COVID-19 pandemic and have reported consistent or improved patient outcomes. This study measured excess expenditures attributed to daily witnessed pharmacy dispensing compared with weekly or biweekly dispensation schedules. DESIGN, SETTING AND PARTICIPANTS: This study was a population-level retrospective analysis. We included all methadone, buprenorphine/naloxone and slow-release oral morphine dispensations in BC from 1 January 2014 to 30 December 2020. A total of 24 357 107 OAT dispensations among 51 195 unique individuals with 122 793 person-years of follow-up were included during the study period. MEASUREMENTS: Total expenditures for each person-week of OAT with an estimated expenditure under two scenarios are as follows: (1) a weekly dispensation scenario and (2) a biweekly dispensation scenario. FINDINGS: We estimated excess expenditures attributable to current dispensing practices of between $38 million (2014) and $47.4 million (2018) compared with a hypothetical weekly dispensing schedule, and $43.9 million (2014) to $54.9 million (2018) compared with biweekly dispensing. The majority of these expenditures (58-64%) were attributed to pharmacy dispensing fees ($23 million in 2014 to $30 million in 2018 compared with weekly dispensing; $26.6 million in 2014 to $34.7 million in 2018 compared with biweekly dispensing). CONCLUSION: Daily witnessed opioid agonist treatment ingestion results in more than $30 million in excess expenditures annually in the province of British Columbia, Canada compared with the costs of weekly or biweekly dispensation schedules.

The Testing Imperative: Why the US Ending the Human Immunodeficiency Virus (HIV) Epidemic Program Needs to Renew Efforts to Expand HIV Testing in Clinical and Community-Based Settings.

Data from several modeling studies demonstrate that large-scale increases in human immunodeficiency virus (HIV) testing across settings with a high burden of HIV may produce the largest incidence reductions to support the US Ending the HIV Epidemic (EHE) initiative's goal of reducing new HIV infections 90% by 2030. Despite US Centers for Disease Control and Prevention's recommendations for routine HIV screening within clinical settings and at least yearly screening for individuals most at risk of acquiring HIV, fewer than half of US adults report ever receiving an HIV test. Furthermore, total domestic funding for HIV prevention has remained unchanged between 2013 and 2019. The authors describe the evidence supporting the value of expanded HIV testing, identify challenges in implementation, and present recommendations to address these barriers through approaches at local and federal levels to reach EHE targets.

Translating and disseminating a localised economic model to support implementation of the 'Ending the HIV Epidemic' initiative to public health policymakers.

Background: Despite significant progress in HIV treatment and prevention, the US remains far from its goal of 'Ending the HIV Epidemic' by 2030. Economic models using local data can synthesise the evidence to help policymakers allocate HIV resources efficiently, but persistent research-to-practice gaps remain. Little is known about how to facilitate the use of economic modelling data among local public health policymakers in real-world settings. Aims and objectives: To explore the dissemination of results from a locally-calibrated economic model for HIV prevention and treatment and identify the factors influencing potential uptake of the model for public health decision making at the local level. Methods: Four virtual focus groups with 26 local health department policymakers in Baltimore, Miami, Seattle, and New York City were held between July 2020 and May 2021. Qualitative content analysis of transcripts identified key themes around using the localised economic model in policy decisions. Results: Participants were interested in using local data in their decisions to allocate resources for HIV prevention/treatment. Six themes emerged: 1) importance of understanding local policy context; 2) health equity considerations; 3) using evidence to support current priorities; 4) difficulty of changing strategies, even incrementally; 5) bang for the incremental buck (efficiency) vs. previous impact; and 6) community values. Conclusion and relevance: To optimise acceptance and use of results from economic models, researchers should engage with local community members and public health decision makers early to understand budgetary and community priorities. Participants prioritised evidence that supports their existing strategies, considers budgets and funding streams, and improves health equity; however, real-world budget constraints and conflicting interests serve as barriers to implementing model recommendations and reaching national goals.

Higher Hospitalization Rates in Children Born HIV-exposed Uninfected in British Columbia, Canada, Between 1990 and 2012.

BACKGROUND: Compared with children who are HIV-unexposed and uninfected (CHUU), children who are HIV-exposed and uninfected (CHEU) experience more clinical complications. We investigated hospitalizations among CHEU by antenatal antiretroviral therapy (ART) exposure, in British Columbia, Canada. METHODS: This retrospective controlled cohort study used administrative health data from 1990 to 2012. CHEU and CHUU were matched 1:3 for age, sex and maternal geographical area of residence. We determined adjusted odds ratios (aORs) via conditional logistic regression, adjusting for maternal risk factors. RESULTS: A total of 446 CHEU and 1333 CHUU were included. Compared with CHUU, more CHEU experienced one or more lifetime hospitalization (47.3% vs. 29.8%), one or more neonatal hospitalization (40.4% vs. 27.6%), and any intensive care unit admission (28.5% vs. 9.2%). In adjusted analyses, CHEU experienced higher odds of any lifetime hospitalization (aOR 2.30, 95% confidence interval 1.81-2.91) and neonatal hospitalization (aOR 2.14, 95% confidence interval 1.68-2.73), compared with CHUU. There was, however, no difference in infection-related hospitalizations (9.0% vs. 7.5%), which were primarily respiratory tract infections among both CHEU and CHUU. CHEU whose mothers-initiated ART preconception showed lower odds of infection-related hospitalizations than children whose mothers initiated ART during pregnancy or received no ART. CONCLUSIONS: CHEU experienced increased odds of hospitalization relative to CHUU. A substantial number of CHEU hospitalizations occurred within the neonatal period and were ICU admissions. Initiating ART preconception may reduce the risk of infection-related hospitalizations. These findings reinforce the benefit of ART in pregnancy and the need for ongoing pediatric care to reduce hospitalizations.

Validation and endorsement of health system performance measures for opioid use disorder in British Columbia, Canada: A Delphi panel study.

Background: Limited data exists on the performance of the healthcare system in opioid use disorder (OUD). We evaluated the face validity and potential risks of a set of health system performance measures for OUD collaboratively with clinicians, policymakers and people with lived experience of opioid use (PWLE) in the interest of establishing an endorsed set of measures for public reporting. Methods: Through a two-stage Delphi-panel approach, a panel of clinical and policy experts validated and considered 102 previously constructed OUD performance measures for endorsement using information on measurement construction, sensitivity analyses, quality of evidence, predictive validity, and feedback from local PWLE. We collected quantitative and qualitative survey responses from 49 clinicians and policymakers, and 11 PWLE. We conducted inductive and deductive thematic analysis to present qualitative responses. Results: A total of 37 measures of 102 were strongly endorsed (9/13 cascade of care, 2/27 clinical guideline compliance, 17/44 healthcare integration, and 9/18 healthcare utilization measures). Thematic analysis of responses revealed several themes regarding measurement validity, unintended consequences, and key contextual considerations. Overall, measures related to the cascade of care (excluding opioid agonist treatment dose tapering) received strong endorsements. PWLE highlighted barriers to accessing treatment, undignified aspects of treatment, and lack of a full continuum of care as their concerns. Conclusion: We defined 37 endorsed health system performance measures for OUD and presented a range of perspectives on their validity and use. These measures provide critical considerations for health system improvement in the care of people with OUD.

Opioid Use Disorder and Perinatal Outcomes.

OBJECTIVES: Evidence on the perinatal health of mother-infant dyads affected by opioids is limited. Elevated risks of opioid-related harms for people with opioid use disorder (OUD) increase the urgency to identify protective factors for mothers and infants. Our objectives were to determine perinatal outcomes after an OUD diagnosis and associations between opioid agonist treatment and birth outcomes. METHODS: We conducted a population-based retrospective study among all women with diagnosed OUD before delivery and within the puerperium period in British Columbia, Canada, between 2000 and 2019 from provincial health administrative data. Controlling for demographic and clinical characteristics, we determined associations of opioid agonist treatment on birth weight, gestational age, infant disorders related to gestational age and birth weight, and neonatal abstinence syndrome via logistic regression. RESULTS: The population included 4574 women and 6720 live births. Incidence of perinatal OUD increased from 166 in 2000 to 513 in 2019. Compared with discontinuing opioid agonist treatment during pregnancy, continuous opioid agonist treatment reduced odds of preterm birth (adjusted odds ratio: 0.6; 95% confidence interval: 0.4-0.8) and low birth weight (adjusted odds ratio: 0.4; 95% confidence interval: 0.2-0.7). Treatment with buprenorphine-naloxone (compared with methadone) reduced odds of each outcome including neonatal abstinence syndrome (adjusted odds ratio: 0.6; 95% confidence interval: 0.4-0.9). CONCLUSIONS: Perinatal OUD in British Columbia tripled in incidence over a 20-year period. Sustained opioid agonist treatment during pregnancy reduced the risk of adverse birth outcomes, highlighting the need for expanded services, including opioid agonist treatment to support mothers and infants.

Preterm Birth and Antiretroviral Exposure in Infants HIV-exposed Uninfected.

BACKGROUND: Infants HIV-exposed and uninfected (IHEU) who are born to women living with HIV are at an increased risk of preterm birth (PTB). Antenatal exposure to certain maternal antiretroviral therapy (ART) regimens has been associated with PTB, although existing studies in this domain are limited and report discordant findings. We determined odds of PTB among IHEU by antenatal ART regimens and timing of exposure, adjusting for maternal risk factors. METHODS: We retrospectively studied IHEU born in British Columbia (BC), Canada between 1990 and 2012 utilizing provincial health administrative databases. We included data from a control group of infants HIV-unexposed and uninfected (IHUU) matched ~3:1 for each IHEU on age, sex and geocode. RESULTS: A total of 411 IHEU and 1224 IHUU were included in univariable analysis. PTB was more frequent among IHEU (20%) compared with IHUU (7%). IHEU were more often antenatally exposed to alcohol, tobacco, as well as prescription, nonprescription, and illicit drugs (IHEU: 36%, 8% and 35%; vs. IHUU: 3%, 1% and 9%, respectively). After adjusting for maternal substance use and smoking exposure, IHEU remained at increased odds of PTB [adjusted odds ratio (aOR) (95% CI): 2.66; (1.73, 4.08)] compared with matched IHUU controls. ART-exposed IHEU (excluding those with NRTIs only ART) had lower adjusted odds of PTB compared with IHEU with no maternal ART exposure, regardless of regimen [aOR range: 0.16-0.29 (0.02-0.95)]. Odds of PTB between IHEU exposed to ART from conception compared with IHEU exposed to ART postconception did not differ [aOR: 0.91 (0.47, 1.76)]; however, both groups experienced lower odds of PTB compared with IHEU with no maternal ART [preconception: aOR: 0.28 (0.08, 0.89); postconception: aOR 0.30 (0.11, 0.83)]. CONCLUSIONS: BC IHEU were over twice as likely to be born preterm compared with demographically matched controls. Maternal substance use in pregnancy modulated this risk; however, we found no adverse associations of PTB with exposure to antenatal ART.

The Potential Epidemiological Impact of Coronavirus Disease 2019 (COVID-19) on the Human Immunodeficiency Virus (HIV) Epidemic and the Cost-effectiveness of Linked, Opt-out HIV Testing: A Modeling Study in 6 US Cities.

BACKGROUND: Widespread viral and serological testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may present a unique opportunity to also test for human immunodeficiency virus (HIV) infection. We estimated the potential impact of adding linked, opt-out HIV testing alongside SARS-CoV-2 testing on the HIV incidence and the cost-effectiveness of this strategy in 6 US cities. METHODS: Using a previously calibrated dynamic HIV transmission model, we constructed 3 sets of scenarios for each city: (1) sustained current levels of HIV-related treatment and prevention services (status quo); (2) temporary disruptions in health services and changes in sexual and injection risk behaviors at discrete levels between 0%-50%; and (3) linked HIV and SARS-CoV-2 testing offered to 10%-90% of the adult population in addition to Scenario 2. We estimated the cumulative number of HIV infections between 2020-2025 and the incremental cost-effectiveness ratios of linked HIV testing over 20 years. RESULTS: In the absence of linked, opt-out HIV testing, we estimated a total of a 16.5% decrease in HIV infections between 2020-2025 in the best-case scenario (50% reduction in risk behaviors and no service disruptions), and a 9.0% increase in the worst-case scenario (no behavioral change and 50% reduction in service access). We estimated that HIV testing (offered at 10%-90% levels) could avert a total of 576-7225 (1.6%-17.2%) new infections. The intervention would require an initial investment of $20.6M-$220.7M across cities; however, the intervention would ultimately result in savings in health-care costs in each city. CONCLUSIONS: A campaign in which HIV testing is linked with SARS-CoV-2 testing could substantially reduce the HIV incidence and reduce direct and indirect health care costs attributable to HIV.

Comparative effectiveness of buprenorphine-naloxone versus methadone for treatment of opioid use disorder: a population-based observational study protocol in British Columbia, Canada.

INTRODUCTION: Despite a recent meta-analysis including 31 randomised controlled trials comparing methadone and buprenorphine for the treatment of opioid use disorder, important knowledge gaps remain regarding the long-term effectiveness of different treatment modalities across individuals, including rigorously collected data on retention rates and other treatment outcomes. Evidence from real-world data represents a valuable opportunity to improve personalised treatment and patient-centred guidelines for vulnerable populations and inform strategies to reduce opioid-related mortality. Our objective is to determine the comparative effectiveness of methadone versus buprenorphine/naloxone, both overall and within key populations, in a setting where both medications are simultaneously available in office-based practices and specialised clinics. METHODS AND ANALYSIS: We propose a retrospective cohort study of all adults living in British Columbia receiving opioid agonist treatment (OAT) with methadone or buprenorphine/naloxone between 1 January 2008 and 30 September 2018. The study will draw on seven linked population-level administrative databases. The primary outcomes include retention in OAT and all-cause mortality. We will determine the effectiveness of buprenorphine/naloxone vs methadone using intention-to-treat and per-protocol analyses-the former emulating flexible-dose trials and the latter focusing on the comparison of the two medication regimens offered at the optimal dose. Sensitivity analyses will be used to assess the robustness of results to heterogeneity in the patient population and threats to internal validity. ETHICS AND DISSEMINATION: The protocol, cohort creation and analysis plan have been approved and classified as a quality improvement initiative exempt from ethical review (Providence Health Care Research Institute and the Simon Fraser University Office of Research Ethics). Dissemination is planned via conferences and publications, and through direct engagement and collaboration with entities that issue clinical guidelines, such as professional medical societies and public health organisations.

"Ending the Epidemic" Will Not Happen Without Addressing Racial/Ethnic Disparities in the United States Human Immunodeficiency Virus Epidemic.

We estimated human immunodeficiency virus incidence and incidence rate ratios (IRRs) for black and Hispanic vs white populations in 6 cities in the United States (2020-2030). Large reductions in incidence are possible, but without elimination of disparities in healthcare access, we found that wide disparities persisted for black compared with white populations in particular (lowest IRR, 1.69 [95% credible interval, 1.19-2.30]).

Opioid agonist treatment and risk of mortality during opioid overdose public health emergency: population based retrospective cohort study.

OBJECTIVE: To compare the risk of mortality among people with opioid use disorder on and off opioid agonist treatment (OAT) in a setting with a high prevalence of illicitly manufactured fentanyl and other potent synthetic opioids in the illicit drug supply. DESIGN: Population based retrospective cohort study. SETTING: Individual level linkage of five health administrative datasets capturing drug dispensations, hospital admissions, physician billing records, ambulatory care reports, and deaths in British Columbia, Canada. PARTICIPANTS: 55 347 people with opioid use disorder who received OAT between 1 January 1996 and 30 September 2018. MAIN OUTCOME MEASURES: All cause and cause specific crude mortality rates (per 1000 person years) to determine absolute risk of mortality and all cause age and sex standardised mortality ratios to determine relative risk of mortality compared with the general population. Mortality risk was calculated according to treatment status (on OAT, off OAT), time since starting and stopping treatment (1, 2, 3-4, 5-12, >12 weeks), and medication type (methadone, buprenorphine/naloxone). Adjusted risk ratios compared the relative risk of mortality on and off OAT over time as fentanyl became more prevalent in the illicit drug supply. RESULTS: 7030 (12.7%) of 55 347 OAT recipients died during follow-up. The all cause standardised mortality ratio was substantially lower on OAT (4.6, 95% confidence interval 4.4 to 4.8) than off OAT (9.7, 9.5 to 10.0). In a period of increasing prevalence of fentanyl, the relative risk of mortality off OAT was 2.1 (95% confidence interval 1.8 to 2.4) times higher than on OAT before the introduction of fentanyl, increasing to 3.4 (2.8 to 4.3) at the end of the study period (65% increase in relative risk). CONCLUSIONS: Retention on OAT is associated with substantial reductions in the risk of mortality for people with opioid use disorder. The protective effect of OAT on mortality increased as fentanyl and other synthetic opioids became common in the illicit drug supply, whereas the risk of mortality remained high off OAT. As fentanyl becomes more widespread globally, these findings highlight the importance of interventions that improve retention on opioid agonist treatment and prevent recipients from stopping treatment.

The cascade of care for opioid use disorder: a retrospective study in British Columbia, Canada.

BACKGROUND AND AIMS: The 'cascade of care' framework, measuring attrition at various stages of care engagement, has been proposed to guide the public health response to the opioid overdose public health emergency in British Columbia, Canada. We estimated the cascade of care for opioid use disorder and identified factors associated with care engagement for people with opioid use disorder (PWOUD) provincially. DESIGN: Retrospective study using a provincial-level linkage of four health administrative databases. SETTING AND PARTICIPANTS: All PWOUD in BC from 1 January 1996 to 30 November 2017. MEASUREMENTS: The eight-stage cascade of care included diagnosed PWOUD, ever on opioid agonist treatment (OAT), recently on OAT, currently on OAT and retained on OAT: ≥ 1, ≥ 3, ≥ 12 and ≥ 24 months). Health-care use, homelessness and other demographics were obtained from physician billing records, hospitalizations, and drug dispensation records. Receipt of income assistance was indicated by enrollment in Pharmacare Plan C. FINDINGS: A total of 55 470 diagnosed PWOUD were alive at end of follow-up. As of 2017, a majority of the population (n = 39 456; 71%) received OAT during follow-up; however, only 33% (n = 18 519) were currently engaged in treatment and 16% (n = 8960) had been retained for at least 1 year. Compared with those never on OAT, those currently engaged in OAT were more likely to be aged under 45 years [adjusted odds ratio (aOR) = 1.75, 95% confidence interval (CI) = 1.64, 1.89], male (aOR = 1.72, 95% CI = 1.64, 1.82), with concurrent substance use disorders (aOR = 2.56, 95% CI = 2.44, 2.70), hepatitis C virus (HCV) (aOR = 1.22, 95% CI = 1.14, 1.33) and either homeless or receiving income-assistance (aOR = 4.35, 95% CI = 4.17, 4.55). Regular contact with the health-care system-either in out-patient or acute care settings-was common among PWOUD not engaged in OAT, regardless of time since diagnosis or treatment discontinuation. CONCLUSIONS: People with opioid use disorder in British Columbia, Canada show high levels of out-patient care prior to diagnosis. Younger age, male sex, urban residence, lower income level and homelessness appear to be independently associated with increased opioid agonist treatment engagement.

Exploring the live birth rates of women living with HIV in British Columbia, Canada.

OBJECTIVE: To evaluate the birth rates of women living with HIV (WLWH) compared to the general population in British Columbia (BC), Canada. METHODS: We retrospectively reviewed clinical and population level surveillance data from 1997 to 2015. Live birth rates from 1997 to 2015 among WLWH aged 15-49 years were compared with those of all BC women. Next, the number of live births among WLWH with a live birth between 1997-2012 and HIV-negative controls matched 1:3 by geocode were compared. RESULTS: WLWH had a lower birth rate compared to all BC women [31.4 (95%CI, 28.6-34.3) vs. 40.0 (39.3-40.1)/1000 person years]. Stratified by age, WLWH aged 15-24 years had a higher birth rate while WLWH aged 25-49 years had a lower birth rate than BC women (p<0.01). Between 1997 and 2015, birth rates for both populations decreased among women aged 15-24 years, and increased among women aged 25-49 years, most strikingly among WLWH 35-49 years (p<0.01). When comparing WLWH with a live birth to HIV-negative geocode matched controls, WLWH aged 15-24 years (p = 0.03) and aged 25-34 years (p<0.01) had more live births than controls while WLWH aged 35-49 years did not (p = 0.06). CONCLUSIONS: On a population level, WLWH have lower birth rates than the general population. However, this is not observed among WLWH who have ever given birth compared with matched controls, suggesting that sociodemographic factors may play an important role. WLWH are increasingly giving birth in their later reproductive years. Taken together, our data supports the integration of reproductive health and HIV care.

Neurodevelopmental outcomes and in-utero antiretroviral exposure in HIV-exposed uninfected children.

OBJECTIVES: To assess and compare neurodevelopmental disorders in HIV-exposed uninfected (HEU) and HIV-unexposed uninfected (HUU) children in British Columbia, Canada. To determine associations between these outcomes and in-utero exposure to antiretroviral drugs. DESIGN: Retrospective controlled cohort study. METHODS: Data were collected on 446 HEU children and 1323 HUU children (matched ∼1 : 3 for age, sex, and geocode) born between 1990 and 2012. Multivariable logistic regressions determined odds ratios of neurodevelopmental disorder diagnoses. RESULTS: HEUs had three times higher odds of being born preterm (P < 0.0001), and a more than two-fold increase in odds for autism, disturbance of emotions, hyperkinetic syndrome, and developmental delay compared with matched HUUs (P < 0.02) in unadjusted analysis. This association was reduced [adjusted neurodevelopmental disorder odds ratio (AOR) = 1.67; 95% confidence interval: 1.12-2.48; P = 0.011] after adjusting for maternal substance use and/or smoking (children born after April 2000). Regardless of antiretroviral exposure type (i.e. none, treatment with one or multiple drug classes), HEUs had higher odds of any neurodevelopmental disorders compared with matched HUUs; however, there was no evidence suggesting any specific classes of antiretroviral drugs or exposure durations increased their likelihood of neurodevelopmental disorders. CONCLUSION: The results suggest no adverse associations between antiretroviral drugs and neurodevelopmental disorders within antiretroviral-exposed HEU children in our cohort. Prevalence of neurodevelopmental disorders is higher in HEUs; however, maternal substance use plays a role, as could other environmental factors not captured. These findings highlight a need for holistic support for pregnant women as well as careful developmental monitoring of HEUs past infancy, and access to early interventions, particularly among those born preterm and those exposed to addictive substances.

Ywhaz/14-3-3ζ Deletion Improves Glucose Tolerance Through a GLP-1-Dependent Mechanism.

Multiple signaling pathways mediate the actions of metabolic hormones to control glucose homeostasis, but the proteins that coordinate such networks are poorly understood. We previously identified the molecular scaffold protein, 14-3-3ζ, as a critical regulator of in vitro ß-cell survival and adipogenesis, but its metabolic roles in glucose homeostasis have not been studied in depth. Herein, we report that Ywhaz gene knockout mice (14-3-3ζKO) exhibited elevated fasting insulin levels while maintaining normal ß-cell responsiveness to glucose when compared with wild-type littermate controls. In contrast with our observations after an ip glucose bolus, glucose tolerance was significantly improved in 14-3-3ζKO mice after an oral glucose gavage. This improvement in glucose tolerance was associated with significantly elevated fasting glucagon-like peptide-1 (GLP-1) levels. 14-3-3ζ knockdown in GLUTag L cells elevated GLP-1 synthesis and increased GLP-1 release. Systemic inhibition of the GLP-1 receptor attenuated the improvement in oral glucose tolerance that was seen in 14-3-3ζKO mice. When taken together these findings demonstrate novel roles of 14-3-3ζ in the regulation of glucose homeostasis and suggest that modulating 14-3-3ζ levels in intestinal L cells may have beneficial metabolic effects through GLP-1-dependent mechanisms.

Inter-domain tagging implicates caveolin-1 in insulin receptor trafficking and Erk signaling bias in pancreatic beta-cells.

OBJECTIVE: The role and mechanisms of insulin receptor internalization remain incompletely understood. Previous trafficking studies of insulin receptors involved fluorescent protein tagging at their termini, manipulations that may be expected to result in dysfunctional receptors. Our objective was to determine the trafficking route and molecular mechanisms of functional tagged insulin receptors and endogenous insulin receptors in pancreatic beta-cells. METHODS: We generated functional insulin receptors tagged with pH-resistant fluorescent proteins between domains. Confocal, TIRF and STED imaging revealed a trafficking pattern of inter-domain tagged insulin receptors and endogenous insulin receptors detected with antibodies. RESULTS: Surprisingly, interdomain-tagged and endogenous insulin receptors in beta-cells bypassed classical Rab5a- or Rab7-mediated endocytic routes. Instead, we found that removal of insulin receptors from the plasma membrane involved tyrosine-phosphorylated caveolin-1, prior to trafficking within flotillin-1-positive structures to lysosomes. Multiple methods of inhibiting caveolin-1 significantly reduced Erk activation in vitro or in vivo, while leaving Akt signaling mostly intact. CONCLUSIONS: We conclude that phosphorylated caveolin-1 plays a role in insulin receptor internalization towards lysosomes through flotillin-1-positive structures and that caveolin-1 helps bias physiological beta-cell insulin signaling towards Erk activation.