The effect of a methadone reformulation on opioid agonist treatment outcomes: A population-based study in British Columbia, Canada, 2013-14.

INTRODUCTION: The province of British Columbia, Canada, changed the existing oral anhydrous methadone solution to a 10-times more concentrated pre-mixed solution, Methadose®, on February 1, 2014. We aimed to assess the immediate effects of the methadone reformulation on missed doses, days off methadone, changes in medication dosing and dispensations of opioids for pain, and hospitalizations and mortality among all people receiving treatment at or near the time of the change. METHODS: We conducted a population-based retrospective cohort study including all individuals receiving at least one methadone dispensation in the 12 months prior to the study period. We executed a difference-in-differences analysis by estimating a multivariate regression model to compare outcomes in the three months before and after the reformulation (November 1, 2013 to April 30, 2014) versus a time-lagged control cohort with similar characteristics observed during an equivalent nonoverlapping interval. We used daily individual-level linked health administrative data capturing missed doses, days off methadone, changes in methadone dosing, concurrent dispensations of opioids for pain, hospitalizations, and mortality. We stratified the cohorts into three subgroups: (i) those receiving OAT for ≥12 months; (ii) those receiving OAT for <12 months; and (iii) those not receiving OAT at the start of the study period. We conducted sensitivity analyses and placebo tests to assess the robustness of our results. RESULTS: Among the 16,339 individuals receiving methadone during the study period, the reformulation was associated with more instances of methadone dose increases (34.5% [95% Confidence Interval (CI): 27.4%, 41.5%]). For those retained in treatment ≥12 months prior to the study period (n = 7449), the reformulation was associated with more instances of methadone dose increases (50.2% [39.5%, 60.8%]) and dispensations of opioids for pain (62.2% [40.8%, 83.5%]), as well as an increase in missed doses (41.9% [29.1%, 54.7%]) and days off methadone (62.6% [39.7%, 85.4%]). We found no statistically significant change in risk of hospitalization or mortality. Sensitivity analyses supported our results. CONCLUSION: Our results reinforce the need expressed by people receiving methadone for greater client involvement in the planning and implementation of regulatory changes that may impact client care, especially those patients with a relatively long treatment history.

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.

Characterizing opioid agonist treatment discontinuation trends in British Columbia, Canada, 2012-2018.

BACKGROUND: Given the elevated risk of mortality immediately following opioid agonist treatment (OAT) discontinuation, determining the frequency and timing of OAT discontinuation can help guide the planning of services to facilitate uninterrupted OAT. We sought to describe weekly and monthly trends in OAT episode discontinuations in British Columbia to determine the potential resource needs for implementing support services. METHODS: This population-based retrospective study utilized a provincial-level linkage of health administrative databases to identify all people with opioid use disorder (PWOUD) who received OAT between 01/2012-08/2018. We defined OAT episodes as continuous medication dispensations without interruptions in prescribed doses lasting ≥5 days for methadone and ≥6 days for buprenorphine/naloxone. We derived the percentage of PWOUD discontinuing OAT every month and we considered weekly discontinuations between 09/2017-08/2018, accounting for weeks during which monthly income assistance payments from social service programs occurred. RESULTS: Our study included 37,207 PWOUD discontinuing 158,027 OAT episodes. Discontinuations were relatively stable month-to-month, increasing from 10.6 % to 14.9 % (2012-2018). The monthly percentage of discontinuations was 21.2 % for buprenorphine/naloxone and 10.0 % for methadone. Weekly discontinuations were greater in income disbursement weeks (816; IQR: 752, 901) compared to other weeks (655; IQR: 615, 683; p < 0.01). CONCLUSIONS: We identified a high, and stable rate of monthly OAT discontinuations and a consistently higher rate of discontinuing treatment among PWOUD accessing buprenorphine/naloxone. There is an urgent need to develop the evidence base for interventions to support OAT engagement and to improve clinical management of OUD to address the opioid-related overdose crisis.

The cascade of care for opioid use disorder among youth in British Columbia, 2018.

BACKGROUND: Medication for opioid use disorder (MOUD) is associated with substantial reductions in the risk of mortality, and American and Canadian guidelines recommend it as part of the full range of available treatments for youth with opioid use disorder (OUD). We estimated the OUD cascade of care for all adolescents (ages 12-18) and young adults (19-24) with OUD in British Columbia, Canada (BC) in 2018. METHODS: Using a provincial-level linkage of six health administrative databases, we classified youth with OUD as adolescents (ages 12-18) or young adults (19-24) to compare with older adults (≥25) and described key factors known to influence engagement in health care. The eight-stage cascade of care included diagnosed with OUD, ever engaged in MOUD, recently in MOUD, currently in MOUD, and retained in MOUD for ≥1 month, ≥3 months, ≥12 months, ≥24 months. RESULTS: We identified 4048 youth diagnosed with OUD as of September 30, 2018 (6.3% of all people with OUD). Most were young adults, aged 19-24 (n = 3602; 89.0% of all youth), a majority of whom were males (n = 1984; 55.1%). In contrast, adolescents diagnosed with OUD (n = 446; 11.0% of all youth) were mostly females (n = 287; 64.4%). Compared to adolescents, there were more young adults diagnosed with OUD ever engaged in MOUD (71.4% v. 36.5%), currently on MOUD (29.3% v. 16.8%), and retained in care for ≥1 year (8.6% v. 2.0%). CONCLUSIONS: A high proportion of youth aged 12-24 diagnosed with OUD in a health care setting in British Columbia received MOUD yet continued engagement is infrequent, particularly for adolescents. Long-term treatment plans for youth need to consider including MOUD when appropriate as part of tailored, youth-friendly services.

Attributing health benefits to preventing HIV infections versus improving health outcomes among people living with HIV: an analysis in six US cities.

OBJECTIVE: Combination strategies generate health benefits through improved health outcomes among people living with HIV (PLHIV) and prevention of new infections. We aimed to determine health benefits attributable to improved health among PLHIV versus HIV prevention for a set of combination strategies in six US cities. DESIGN: A dynamic HIV transmission model. METHODS: Using a model calibrated for Atlanta, Baltimore, Los Angeles, Miami, New York City (NYC) and Seattle, we assessed the health benefits of city-specific optimal combinations of evidence-based interventions implemented at publicly documented levels and at ideal (90% coverage) scale-up (2020-2030 implementation, 20-year study period). We calculated the proportion of health benefit gains (measured as quality-adjusted life-years) resulting from averted and delayed HIV infections; improved health outcomes among PLHIV; and improved health outcomes due to medication for opioid use disorder (MOUD). RESULTS: The HIV-specific proportion of total benefits ranged from 68.3% (95% credible interval: 55.3-80.0) in Seattle to 98.5% (97.5-99.3) in Miami, with the rest attributable to MOUD. The majority of HIV-specific health benefits in five of six cities were attributable HIV prevention, and ranged from 33.1% (26.1-41.1) in NYC to 83.1% (79.6-86.6) in Atlanta. Scaling up to ideal service levels resulted in three to seven-fold increases in additional health benefits, mostly from MOUD, with HIV-specific health gains primarily driven by HIV prevention. CONCLUSION: Optimal combination strategies generated a larger proportion of health benefits attributable to HIV prevention in five of six cities, underlining the substantial benefits of antiretroviral therapy engagement for the prevention of HIV transmission through viral suppression. Understanding to whom benefits accrue may be important in assessing the equity and impact of HIV investments.

Evaluation of risk mitigation measures for people with substance use disorders to address the dual public health crises of COVID-19 and overdose in British Columbia: a mixed-method study protocol.

INTRODUCTION: The COVID-19 pandemic was preceded by an ongoing overdose crisis and linked to escalating drug overdose deaths in British Columbia (BC). At the outset of these dual public health emergencies, the BC government announced interim Risk Mitigation Guidance (RMG) that permitted prescribing medication alternatives to substances, including opioids, alcohol, stimulants and benzodiazepines, an intervention sometimes referred to as 'safe supply'. This protocol outlines the approach for a study of the implementation of RMG and its impacts on COVID-19 infection, drug-related and systemic harms, continuity of care for people with substance use disorder (SUD), as well as their behavioural, psychosocial and well-being outcomes. METHODS AND ANALYSIS: We conducted a parallel mixed-method study that involved both analysis of population-level administrative health data and primary data collection, including a 10-week longitudinal observational study (target n=200), a cross-sectional survey (target n=200) and qualitative interviews (target n=60). We implemented a participatory approach to this evaluation, partnering with people with lived or living expertise of drug use, and researchers and public health decision-makers across the province. Linked population-level administrative databases will analyse data from a cohort of BC residents with an indication of SUD between 1996 and 2020. We will execute high-dimensional propensity score matching and marginal structural modelling to construct a control group and to assess the impact of RMG dispensation receipt on a collaboratively determined set of primary and secondary outcomes. ETHICS AND DISSEMINATION: Study activities were developed to adhere to the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans, recommended COVID-19 research practices, and guided by the Truth and Reconciliation Commission's Calls to Action for public health, data governance and research ethics related to Indigenous people. Results will be disseminated incrementally, on an ongoing basis, through the consortium established for this study, then published in peer-reviewed journals.

Diagnosis of Opioid Use Disorder by Youths Assessed in Acute Care Settings in British Columbia, Canada.

OBJECTIVES: To describe trends in the number of youths diagnosed with opioid use disorder (OUD) and to identify factors associated with OUD diagnosis in acute care settings. STUDY DESIGN: Data from a population-based retrospective cohort study with linkage of 6 health administrative databases for 13 009 youth age 12-24 years identified with OUD between 2001 and 2018 in British Columbia, Canada were used to describe annual diagnoses. Using a multiple logistic regression model, we estimated the association between past-year health care utilization and OUD diagnosis in acute settings, controlling for sociodemographic and OUD-related comorbid conditions. RESULTS: Annual OUD diagnoses quadrupled between 2003 and 2017 (from 326 to 1473). Among the 6579 youth diagnosed with OUD between April 1, 2013 and September 30, 2018, 88.1% had past-year health system contacts. Youth age 12-18 had higher odds of OUD diagnosis in acute care (aOR 2.04; 95% CI 1.78, 2.34). Compared with no health care contact, youth receiving outpatient care only were less likely to be diagnosed with OUD in acute care (aOR 0.69; 95% CI 0.56, 0.84) and those with >1 urgent hospitalization were more likely to be diagnosed with OUD in acute care (aOR 1.87; 95% CI 1.40,2.49). CONCLUSIONS: More than 88% of youth had past-year health system contacts prior to diagnosis. Those age 12-18 years and with urgent hospitalizations in the year prior to diagnosis were more likely to have OUD diagnosed in acute care settings. Establishing an effective evidence-based system for early detection and intervention among youth with OUD must be a priority.

Estimates of opioid use disorder prevalence from a regression-based multi-sample stratified capture-recapture analysis.

BACKGROUND: An epidemic of opioid overdose has spread across North America, with illicit drug-related overdose emerging as a leading cause of death in recent years. Estimates of opioid use disorder (OUD) prevalence at the level of the public health service delivery area are needed to project resource needs and identify priority areas for targeted intervention. Our objective is to estimate the annual prevalence of OUD in British Columbia (BC), Canada, from 2000 to 2017. METHODS: We performed a multi-sample stratified capture-recapture analysis to estimate OUD prevalence in BC. The analysis included individuals identified from 3 administrative databases for 2000-2011 and 4 databases for 2012-2017, linked at the individual level. Negative binomial regression models on the counts of individuals within these strata were used to estimate prevalence, adjusting for dependency between databases. RESULTS: OUD prevalence in BC among people aged 12 years or older was 1.00 % (N = 34,663 individuals) in 2000 and increased to 1.54 % (N = 61,080) in 2011. Between 2013 and 2017 prevalence increased from 1.57 % (95 % confidence interval: 1.56-1.58) to 1.92 % (1.89-1.95; N = 83,760; 82,492-84,855). The greatest increases in prevalence were observed among males 12-30 years old and 31-44 years old, with 43.2 % and 40.2 % increases from 2013 to 2017. CONCLUSIONS: In BC, the OUD prevalence was 1.92 % among people 12 years or older in 2017. We estimated that prevalence has nearly doubled since 2000, with the highest increases in prevalence observed among males under 45.

Ending the HIV Epidemic Among Persons Who Inject Drugs: A Cost-Effectiveness Analysis in Six US Cities.

BACKGROUND: Persons who inject drugs (PWID) are at a disproportionately high risk of HIV infection. We aimed to determine the highest-valued combination implementation strategies to reduce the burden of HIV among PWID in 6 US cities. METHODS: Using a dynamic HIV transmission model calibrated for Atlanta, Baltimore, Los Angeles, Miami, New York City, and Seattle, we assessed the value of implementing combinations of evidence-based interventions at optimistic (drawn from best available evidence) or ideal (90% coverage) scale-up. We estimated reduction in HIV incidence among PWID, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) for each city (10-year implementation; 20-year horizon; 2018 $ US). RESULTS: Combinations that maximized health benefits contained between 6 (Atlanta and Seattle) and 12 (Miami) interventions with ICER values ranging from $94 069/QALY in Los Angeles to $146 256/QALY in Miami. These strategies reduced HIV incidence by 8.1% (credible interval [CI], 2.8%-13.2%) in Seattle and 54.4% (CI, 37.6%-73.9%) in Miami. Incidence reduction reached 16.1%-75.5% at ideal scale. CONCLUSIONS: Evidence-based interventions targeted to PWID can deliver considerable value; however, ending the HIV epidemic among PWID will require innovative implementation strategies and supporting programs to reduce social and structural barriers to care.

Can the 'Ending the HIV Epidemic' initiative transition the USA towards HIV/AIDS epidemic control?

: Using a dynamic HIV transmission model calibrated for six USA cities, we projected HIV incidence from 2020 to 2040 and estimated whether an established UNAIDS HIV epidemic control target could be met under ideal implementation of optimal combination strategies previously defined for each city. Four of six cities (Atlanta, Baltimore, New York City and Seattle) were projected to achieve epidemic control by 2040 and we identified differences in reaching epidemic control across racial/ethnic groups.

"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]).

Ending the HIV epidemic in the USA: an economic modelling study in six cities.

BACKGROUND: The HIV epidemic in the USA is a collection of diverse local microepidemics. We aimed to identify optimal combination implementation strategies of evidence-based interventions to reach 90% reduction of incidence in 10 years, in six US cities that comprise 24·1% of people living with HIV in the USA. METHODS: In this economic modelling study, we used a dynamic HIV transmission model calibrated with the best available evidence on epidemiological and structural conditions for six US cities: Atlanta (GA), Baltimore (MD), Los Angeles (CA), Miami (FL), New York City (NY), and Seattle (WA). We assessed 23 040 combinations of 16 evidence-based interventions (ie, HIV prevention, testing, treatment, engagement, and re-engagement) to identify combination strategies providing the greatest health benefit while remaining cost-effective. Main outcomes included averted HIV infections, quality-adjusted life-years (QALYs), total cost (in 2018 US$), and incremental cost-effectiveness ratio (ICER; from the health-care sector perspective, 3% annual discount rate). Interventions were implemented at previously documented and ideal (90% coverage or adoption) scale-up, and sustained from 2020 to 2030, with outcomes evaluated until 2040. FINDINGS: Optimal combination strategies providing health benefit and cost-effectiveness contained between nine (Seattle) and 13 (Miami) individual interventions. If implemented at previously documented scale-up, these strategies could reduce incidence by between 30·7% (95% credible interval 19·1-43·7; Seattle) and 50·1% (41·5-58·0; New York City) by 2030, at ICERs ranging from cost-saving in Atlanta, Baltimore, and Miami, to $95 416 per QALY in Seattle. Incidence reductions reached between 39·5% (26·3-53·8) in Seattle and 83·6% (70·8-87·0) in Baltimore at ideal implementation. Total costs of implementing strategies across the cities at previously documented scale-up reached $559 million per year in 2024; however, costs were offset by long-term reductions in new infections and delayed disease progression, with Atlanta, Baltimore, and Miami projecting cost savings over the 20 year study period. INTERPRETATION: Evidence-based interventions can deliver substantial public health and economic value; however, complementary strategies to overcome social and structural barriers to HIV care will be required to reach national targets of the ending the HIV epidemic initiative by 2030. FUNDING: National Institutes of Health.

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.

Development and Calibration of a Dynamic HIV Transmission Model for 6 US Cities.

Background. Heterogeneity in HIV microepidemics across US cities necessitates locally oriented, combination implementation strategies to prioritize resources. We calibrated and validated a dynamic, compartmental HIV transmission model to establish a status quo treatment scenario, holding constant current levels of care for 6 US cities. Methods. Built off a comprehensive evidence synthesis, we adapted and extended a previously published model to replicate the transmission, progression, and clinical care for each microepidemic. We identified a common set of 17 calibration targets between 2012 and 2015 and used the Morris method to select the most influential parameters for calibration. We then applied the Nelder-Mead algorithm to iteratively calibrate the model to generate 2000 best-fitting parameter sets. Finally, model projections were internally validated with a series of robustness checks and externally validated against published estimates of HIV incidence, while the face validity of 25-year projections was assessed by a Scientific Advisory Committee (SAC). Results. We documented our process for model development, calibration, and validation to maximize its transparency and reproducibility. The projected outcomes demonstrated a good fit to calibration targets, with a mean goodness-of-fit ranging from 0.0174 (New York City [NYC]) to 0.0861 (Atlanta). Most of the incidence predictions were within the uncertainty range for 5 of the 6 cities (ranging from 21% [Miami] to 100% [NYC]), demonstrating good external validity. The face validity of the long-term projections was confirmed by our SAC, showing that the incidence would decrease or remain stable in Atlanta, Los Angeles, NYC, and Seattle while increasing in Baltimore and Miami. Discussion. This exercise provides a basis for assessing the incremental value of further investments in HIV combination implementation strategies tailored to urban HIV microepidemics.

The impact of localized implementation: determining the cost-effectiveness of HIV prevention and care interventions across six United States cities.

OBJECTIVE: Effective interventions to reduce the public health burden of HIV/AIDS can vary in their ability to deliver value at different levels of scale and in different epidemiological contexts. Our objective was to determine the cost-effectiveness of HIV treatment and prevention interventions implemented at previously documented scales of delivery in six US cities with diverse HIV microepidemics. DESIGN: Dynamic HIV transmission model-based cost-effectiveness analysis. METHODS: We identified and estimated previously documented scale of delivery and costs for 16 evidence-based interventions from the US CDC's Compendium of Evidence-Based Interventions and Best Practices for HIV Prevention. Using a model calibrated for Atlanta, Baltimore, Los Angeles, Miami, New York City and Seattle, we estimated averted HIV infections, quality-adjusted life years (QALY) gained and incremental cost-effectiveness ratios (healthcare perspective; 3% discount rate, 2018$US), for each intervention and city (10-year implementation) compared with the status quo over a 20-year time horizon. RESULTS: Increased HIV testing was cost-saving or cost-effective across cities. Targeted preexposure prophylaxis for high-risk MSM was cost-saving in Miami and cost-effective in Atlanta ($6123/QALY), Baltimore ($18 333/QALY) and Los Angeles ($86 117/QALY). Interventions designed to improve antiretroviral therapy initiation provided greater value than other treatment engagement interventions. No single intervention was projected to reduce HIV incidence by more than 10.1% in any city. CONCLUSION: Combination implementation strategies should be tailored to local epidemiological contexts to provide the most value. Complementary strategies addressing factors hindering access to HIV care will be necessary to meet targets for HIV elimination in the United States.

Combined estimation of disease progression and retention on antiretroviral therapy among treated individuals with HIV in the USA: a modelling study.

BACKGROUND: Accurately estimating HIV disease progression and retention on antiretroviral therapy (ART) can help inform interventions to control HIV microepidemics and mathematical models used to inform health-resource allocation decisions. Our objective was to estimate the monthly probabilities of on-ART CD4 T-cell count progression, mortality, ART dropout, and ART reinitiation using a continuous-time multistate Markov model. We also aimed to validate health-state transition probability estimates to ensure they accurately reproduced the regional HIV microepidemics across the USA. METHODS: In our modelling study, we considered a cohort of patients from the HIV Research Network, a consortium of 17 adult and paediatric HIV-care providers located in the northeastern (n=8), southern (n=5), and western (n=4) regions of the USA. Individuals aged 15 years or older who were in HIV care (defined as one CD4 test and one HIV-care visit in a calendar year period) with at least one ART prescription between Jan 1, 2010, and Dec 31, 2015, were included in the analysis. We used continuous-time multistate Markov models to estimate transitions between CD4 strata and between on-ART and off-ART states. We examined and adjusted for differences in probability of transition by region, race or ethnicity, sex, HIV risk group, and other baseline clinical indicators. FINDINGS: The median age of the 32 242 individuals included in the analysis was 44 years (interquartile range 35-51). Over a median follow-up of 4·9 years (2·6-6·0), 8614 (26·7%) of 32 242 people interrupted ART and 1325 (4·1%) of 32 242 people died. Women, men who have sex with men, and individuals with no previous ART experience had greater increases in CD4 cell counts, whereas black people and people who inject drugs had increased probabilities of ART dropout and faster disease progression. Regardless of CD4 strata, individuals had increased hazard for ART dropout if they were from the south (adjusted hazard ratio [aHR] range from 1·91, 95% CI 1·71-2·13, to 2·45, 2·29-2·62) or the west (aHR range from 1·29, 1·10-1·51, to 1·66, 1·51-1·82) of the USA, compared with individuals from the northeast USA. INTERPRETATION: Our results show heterogeneities in disease progression during ART and probability of ART retention across race and ethnicity, HIV risk groups, and regions. These differences should be viewed as targets for intervention and should be incorporated in mathematical models of regional HIV microepidemics in the USA. FUNDING: US National Institutes of Health, Agency for Healthcare Research and Quality, and Health Resources and Services Administration.

The Cost-Effectiveness of Human Immunodeficiency Virus Testing and Treatment Engagement Initiatives in British Columbia, Canada: 2011-2013.

Background: Recognition of the secondary preventive benefits of antiretroviral therapy (ART) has mobilized global efforts to "seek, test, treat, and retain" people living with human immunodeficiency virus [HIV]/AIDS (PLHIV) in HIV care. We aimed to determine the cost-effectiveness of a set of HIV testing and treatment engagement interventions initiated in British Columbia, Canada, in 2011-2013. Methods: Using a previously validated dynamic HIV transmission model, linked individual-level health administrative data for PLHIV, and aggregate-level HIV testing data, we estimated the cost-effectiveness of primary care testing (hospital, emergency department [ED], outpatient), ART initiation, and ART retention initiatives vs a counterfactual scenario that approximated the status quo. HIV incidence, mortality, costs (in 2015$CDN), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios were estimated. Analyses were executed over 5- to 25-year time horizons from a government-payer perspective. Results: ED testing was the best value at $30216 per QALY gained and had the greatest impact on incidence and mortality among PLHIV, while ART initiation provided the greatest QALY gains. The ART retention initiative was not cost-effective. Delivered in combination at the observed scale and sustained throughout the study period, we estimated a 12.8% reduction in cumulative HIV incidence and a 4.7% reduction in deaths among PLHIV at $55258 per QALY gained. Results were most sensitive to uncertainty in the number of undiagnosed PLHIV. Conclusions: HIV testing and ART initiation interventions were cost-effective, while the ART retention intervention was not. Developing strategies to reengage PLHIV lost to care is a priority moving forward.

Informing Targeted Interventions to Optimize the Cascade of HIV Care Using Cluster Analyses of Health Resource Use Among People Living with HIV/AIDS.

Increased awareness of the secondary preventive benefits of antiretroviral treatment (ART) has strengthened the desire to optimize health care systems' response to HIV/AIDS. We identified clusters of health resource utilization (HRU) among people living with HIV (PLHIV) to inform targeted interventions aimed to optimize the cascade of HIV care. Using linked population-level health databases in British Columbia, Canada, we selected two analytic samples of PLHIV with 3 years of follow-up between 2006-2011 that were classified as intermittently retained in care or intermittently engaged in ART, and executed a probabilistic model-based clustering analysis for each sample with 5 and 9 quarterly HRU variables, respectively. We found clear HRU profile differences among both samples with similar HIV-related care: one featured active involvement in non-HIV care, the other little or no health care interaction following linkage to care. Differential reengagement intervention strategies capitalizing on missed opportunities in non-HIV care and further engaging physicians delivering HIV care are needed to optimize the response to the HIV epidemic.

Relative effects of antiretroviral therapy and harm reduction initiatives on HIV incidence in British Columbia, Canada, 1996-2013: a modelling study.

BACKGROUND: Antiretroviral therapy (ART) and harm reduction services have been cited as key contributors to control of HIV epidemics; however, the specific contribution of ART has been questioned due to uncertainty of its true efficacy on HIV transmission through needle sharing. We aimed to isolate the independent effects of harm reduction services (opioid agonist treatment uptake and needle distribution volumes) and ART on HIV transmission via needle sharing in British Columbia, Canada, from 1996 to 2013. METHODS: We used comprehensive linked individual health administrative and registry data for the population of diagnosed people living with HIV in British Columbia to populate a dynamic, compartmental transmission model to simulate the HIV/AIDS epidemic in British Columbia from 1996 to 2013. We estimated HIV incidence, mortality, and quality-adjusted life-years (QALYs). We also estimated scenarios designed to isolate the independent effects of harm reduction services and ART, assuming 50% (10-90%) efficacy, in reducing HIV incidence through needle sharing, and we investigated structural and parameter uncertainty. FINDINGS: We estimate that 3204 (upper bound-lower bound 2402-4589) incident HIV cases were averted between 1996 and 2013 as a result of the combined effect of the expansion of harm reduction services and ART coverage on HIV transmission via needle sharing. In a hypothetical scenario assuming ART had zero effect on transmission through needle sharing, we estimated harm reduction services alone would have accounted for 77% (upper bound-lower bound 62-95%) of averted HIV incidence. In a separate hypothetical scenario where harm reduction services remained at 1996 levels, we estimated ART alone would have accounted for 44% (10-67%) of averted HIV incidence. As a result of high distribution volumes, needle distribution predominantly accounted for incidence reductions attributable to harm reduction but opioid agonist treatment provided substantially greater QALY gains. INTERPRETATION: If the true efficacy of ART in preventing HIV transmission through needle sharing is closer to its efficacy in sexual transmission, ART's effect on incident cases averted could be greater than that of harm reduction. Nonetheless, harm reduction services had a vital role in reducing HIV incidence in British Columbia, and should be viewed as essential and cost-effective tools in combination implementation strategies to reduce the public health and economic burden of HIV/AIDS. FUNDING: BC Ministry of Health; National Institutes of Health (R01DA041747); Genome Canada (142HIV).

Estimating State Transitions for Opioid Use Disorders.

AIM: The aim was to estimate transitions between periods in and out of treatment, incarceration, and legal supervision, for prescription opioid (PO) and heroin users. METHODS: We captured all individuals admitted for the first time for publicly funded treatment for opioid use disorder (OUD) in California (2006 to 2010) with linked mortality and criminal justice data. We used Cox proportional hazards and competing risks models to assess the effect of primary PO use (v. heroin) on the hazard of transitioning among 5 states: (1) opioid detoxification treatment; (2) opioid agonist treatment (OAT); (3) legal supervision (probation or parole); (4) incarceration (jail or prison); and (5) out-of-treatment. Transitions were conditional on survival, and death was modeled as an absorbing state. RESULTS: Both primary PO (n = 11,733) and heroin (n = 19,926) users spent most of their median 2.3 y of observation out of treatment. Primary PO users were significantly younger (median age 30 v. 34 y), and a higher percentage were female (43.1% v. 31.5%; P < 0.001), white (74.6% v. 63.1%; P < 0.001), and had completed high school (31.8% v. 18.9%; P < 0.001). When compared to primary heroin users, PO users had a higher hazard of transitioning from detoxification to OAT (Hazard Ratio (HR), 1.65; 95% CI, 1.54 to 1.77), and had a lower hazard of transitioning from out-of-treatment to either detoxification (0.75 [0.70, 0.81]) or OAT (0.90 [0.85, 0.96]). CONCLUSION: Our findings can be applied directly in state transition modeling to improve the validity of health economic evaluations. Although PO users tended to remain in treatment for longer durations than heroin users, they also tended to remain out of treatment for longer after transitioning to an out-of-treatment state. Despite the proven effectiveness of time-unlimited treatment, individuals with OUD spend most of their time out of treatment.