The ‘Expanded HIV care in opioid substitution treatment’ (EHOST) cluster-randomized, stepped-wedge trial: A study protocol

    The ‘Expanded HIV care in opioid substitution treatment’ (EHOST) clusterrandomized, stepped-wedge trial: A study protocol B. Nosyk, E. Krebs, J.E. Min, K. Ahamed, J. Buxton, C. Goldsmith, M. Hull, R. Joe, M. Krajden, V.D. Lima, M. Olding, E. Wood, J.S.G. Montaner PII: DOI: Reference:

S1551-7144(15)30077-X doi: 10.1016/j.cct.2015.08.020 CONCLI 1266

To appear in:

Contemporary Clinical Trials

Received date: Revised date: Accepted date:

29 May 2015 28 August 2015 30 August 2015

Please cite this article as: Nosyk B, Krebs E, Min JE, Ahamed K, Buxton J, Goldsmith C, Hull M, Joe R, Krajden M, Lima VD, Olding M, Wood E, Montaner JSG, The ‘Expanded HIV care in opioid substitution treatment’ (EHOST) clusterrandomized, stepped-wedge trial: A study protocol, Contemporary Clinical Trials (2015), doi: 10.1016/j.cct.2015.08.020

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ACCEPTED MANUSCRIPT The ‘Expanded HIV care in opioid substitution treatment’ (EHOST) cluster-randomized, stepped-wedge trial: A study protocol

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Nosyk B [1,2], Krebs E [1], Min JE [1], Ahamed K[1], Buxton J[3,4], Goldsmith C[2], Hull M[1,5], Joe R[5], Krajden M[3], Lima VD[1,6], Olding M[1], Wood E[1,6], Montaner JSG[1,6]

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1. BC Centre for Excellence in HIV/AIDS; 2. Faculty of Health Sciences, Simon Fraser University. 3. BC Centre for Disease Control and Prevention; 4. School of Population and Public Health, University of British Columbia; 5. Vancouver Coastal Health Authority; 6. Division of AIDS, Faculty of Medicine, University of British Columbia.

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Corresponding Author: Bohdan Nosyk, PhD 613-1081 Burrard Street Vancouver, BC V6Z 1Y6 E: [email protected] P: 604-806-8649

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Word Count: 5,692

Figures: 2

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Tables: 3

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Last Update: August 27th, 2015

Trial Registration: NCT02440256

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ACCEPTED MANUSCRIPT Abstract The public health response to HIV/AIDS has turned its focus onto optimizing health care system delivery to maximize case identification, access and sustained engagement in antiretroviral

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treatment (ART). Opioid Agonist Treatment (OAT) provides a critical opportunity for HIV testing and linkage to ART. The EHOST study is a cluster-randomized, stepped-wedge trial to evaluate

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a prescriber-focused intervention to increase HIV testing rates, and optimize ART engagement and retention outcomes among individuals engaged in OAT. The study will encompass all drug

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treatment clinics currently admitting patients for the treatment of opioid use disorder across the province of British Columbia, encompassing an estimated 90% of the OAT caseload. The trial

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will be executed over a 24-month period, with groups of clinics receiving the intervention in 6month intervals. Evaluation of the proposed intervention’s effectiveness will focus on three

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primary outcomes: (i) the HIV testing rate among those not known to be HIV positive; (ii) the rate of ART) initiation among those not on ART; and (iii) the rate of ART continuation among those on ART. A difference-in-differences analytical framework will be applied to estimate the

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intervention’s effect. This approach will assess site-specific changes in primary outcomes

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across clusters while adjusting for potential residual heterogeneity in patient case mix, volume, and quality of care across clinics. Statistical analysis of outcomes will be conducted entirely with

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linked population-level administrative health datasets. Facilitated by established collaborations between key stakeholders across the province, the EHOST intervention promises to optimize HIV testing and care within a marginalized and hard-to-reach population. Keywords: HIV; Opioid Agonist Treatment; antiretroviral treatment; stepped-wedge; clusterrandomized. Word Count: 269

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ACCEPTED MANUSCRIPT Abbreviations Opioid Agonist Treatment

ART

Combination Antiretroviral Therapy

PLHIV

People living with HIV

PWID

People who inject drugs

CHC

Community Health Clinic

BCMP

British Columbia Methadone Program

ICC

Inter-cluster correlation coefficient

DIN

Drug Identification Number

STOP HIV/AIDS

Seek and Treat for Optimal Prevention of

PTA SUR QALY

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PO

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British Columbia Centre for Excellence in HIV/AIDS

BC CDC

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HIV/AIDS BC-CfE

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OAT

BC Centre for Disease Control Primary Outcome Parallel trends assumption Seemingly unrelated regression Quality Adjusted Life Years

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ACCEPTED MANUSCRIPT 1.0 Introduction With accumulating evidence supporting the secondary preventative benefits of combination antiretroviral treatment (ART) (1-4), the public health response to the HIV/AIDS epidemic has

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turned its focus to optimizing health care delivery systems to maximize case identification, access and sustained engagement in HIV care (5). The HIV care cascade(6-10) illustrates the

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fact that control of the HIV epidemic hinges on health care systems’ performance in delivering

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care to people living with HIV (PLHIV). Maximizing viral suppression among PLHIV requires a multi-dimensional strategy simultaneously seeking out undiagnosed PLHIV, ensuring linkage to

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HIV care among those tested, retaining individuals on ART and ensuring the highest possible quality of care to ensure ART adherence and virologic suppression.

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British Columbia (BC), Canada, has made considerable progress in decreasing the burden of HIV among people who inject drugs (PWID). Despite increasing testing rates(11), the number of new HIV diagnoses among PWID has fallen drastically in BC, from a high of 352 new

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diagnoses in 1996 to only 25 new diagnoses in 2013(11-14). While this decline was no doubt

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facilitated by multiple factors including ART scale-up(1, 3), population-level shifts from injection to non-injection drug use (1, 15) and expansion of harm reduction programs(16, 17), it is clear

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that increased access to Opioid Agonist Treatment (OAT)1 played a critical role in the decline of the HIV/AIDS epidemic(18). During the same period (1996-2012), OAT enrollment in BC increased from 2,800 clients to an estimated 13,000 (19). Holding OAT enrollment constant in a hypothetical modeling scenario resulted in an increase in the scale of the HIV epidemic in BC (18). These findings have been corroborated by an observational study which found that, among a prospective cohort of injection drug users in Vancouver, OAT with methadone was independently associated with a reduced hazard of HIV infection(20).

Aside from reducing the risk of HIV transmission directly through reduced drug injection(21, 22), OAT entry and regular follow-up provides critical opportunities for HIV testing, ART initiation and retention(23-26).

A recent BC-based population-level study demonstrated that, through the

provision of strengthened linkage to health care services(27) and the stability clients experience with alleviation of opioid withdrawal and craving(28), engagement in OAT increases the odds of

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We use the medical term Opioid Agonist Treatment (OAT) hereafter in the text to refer to treatment of opioid use disorder with methadone, buprenorphine and buprenorphine-naloxone. In recognition of a shift away from the terminology Opioid Substitution Treatment (OST), we limit use of “OST” to the study title.

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ACCEPTED MANUSCRIPT ART adherence by 68%(25). Furthermore, OAT engagement reduced the hazard of all-cause mortality by 66% alone, and by 84% when used in combination with ART(29).

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Despite the successes of OAT and ART expansion in BC, large deficits in HIV care remain for HIV-positive PWID. In particular, an estimated 2,100 PLHIV (9) are undiagnosed, while 2,144

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PWID are diagnosed but not on ART, and another 987 PWID are accessing ART but not virologic suppressed(30). Fragmented medical care for PWID likely contributes to these deficits,

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but has not been explicitly studied in BC. At least one prior study demonstrated that many OAT clients received medication prescriptions from multiple sources(31). Qualitative reviews of the

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BC OAT system(32-34) have further highlighted concerns amongst patients and providers about the separation of some OAT provision from other social and health services, a model of care

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which may be problematic for OATpatients who commonly present with multiple comorbidities requiring specialized care (35, 36).

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The Expanded HIV Care in Opioid Substitution Treatment Trial (EHOST) seeks to determine the

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causal effect of an OAT prescriber-focused intervention on HIV testing rates, treatment reengagement and retention outcomes among individuals engaged in OAT. An existing linkage of population-level data sources will then be used to evaluate the intervention and to determine its

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cost-effectiveness.

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ACCEPTED MANUSCRIPT 2.0 Methods 2.1 Study Design

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The EHOST intervention will be delivered as a stepped wedge cluster-randomized trial, a type of unidirectional crossover design in which clusters cross over from control to intervention.

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Clusters initiate the intervention at different time points, with every cluster receiving the intervention by the end of the study period. Clustering is done at the OAT site level as a smaller

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randomization unit (either at the individual or prescriber-level) is infeasible due to the fact that clients often receive OAT from multiple prescribers over time, particularly in the context of

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specialized drug treatment centers (37, 38). Both the delivery of the intervention and analysis of its effect is thus at the OAT site-level. The implications of this design are twofold: first, OAT sites

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within a cluster are correlated and second, given the unidirectional crossover, the effectiveness of the intervention is no longer compared solely within-cluster. As discussed in greater details hereafter, both of these implications have been incorporated into our analysis, which was

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designed with between-cluster and within-cluster considerations as well as to allow us to control

correlation.

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for temporal trends. Furthermore, our power calculations also account for intracluster

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The study will encompass all drug treatment clinics currently admitting patients for the treatment of opioid use disorder across the province of BC (see Figure 1 for a map of OAT sites). OAT can be prescribed in three types of sites: community health clinics (CHCs), private drug treatment clinics and office-based physician practices. As information on individual physicians prescribing OAT in office-based settings is not in the public domain, our focus is on the former two site types, which are thought to treat 90% of the OAT caseload in BC (39).

INSERT FIGURE 1 HERE A total of 51 identified OAT sites(40) will be randomized to EHOST in one of three possible clusters comprised of 17 sites. Among these 51 sites, there are 7 CHCs and 44 private facilities, with 10 sites providing Point of Care HIV testing. Randomization will be stratified by site type and availability of point of care HIV testing to ensure an equal mix of sites within each randomized step, as the probability of a client receiving HIV testing or HIV care may differ across these strata. Information on the provision of point-of-care testing was provided by the BC Centre for Disease Control (BC CDC)(41). 6

ACCEPTED MANUSCRIPT The trial will be executed over a 24-month period, with clusters of sites receiving the intervention in 6-month intervals. Site clusters will go from control to intervention, and delivery of the intervention to other OAT site clusters will be delayed until the following 6-month period. We

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have chosen to deliver the intervention in 6-month time intervals to allow sufficient time for the intervention to be implemented within the respective sites. The first interval will be used for

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baseline measurement; therefore none of the clusters will receive the intervention during this

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period. This stepped wedge design is illustrated in Figure 2.

2.2 Description of the Intervention

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2.2.1 Local Health Care Delivery Context

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INSERT FIGURE 2 HERE

The Canada Health Act (42) provides universal coverage for all hospital and outpatient care. Prescription medications fall outside the scope of the Canada Health Act, though provinces

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provide varying degrees of coverage and co-payments according to ability to pay. HIV care has

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exceptional status in BC alone, where all medical care, HIV testing, antiretroviral treatment and laboratory monitoring is fully subsidized by the provincial government (43). OAT is covered for reimbursement under standard provincial drug benefit formularies and may be subject to co-

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payment, according to ability to pay (44). OAT with methadone is the first line treatment for opioid use disorder in BC, while buprenorphine and buprenorphine-naloxone (suboxone®) are also available (45, 46).

In BC and throughout Canada, accreditation is required to allow physicians to prescribe methadone and buprenorphine for opioid use disorder; a weekend course and follow-up evaluation is run by the British Columbia Methadone Program (BCMP) to educate physicians on best practices in OAT prescription, and to familiarize physicians with OAT clinical guidelines (47).

HIV treatment does not require similar certification, however supplemental training is

provided to physicians in the form of an ‘HIV module’, offered by the BC Provincial Health Services Authority.

In addition, an HIV/Antiretroviral treatment update is provided on a bi-

annual basis (48), and 18 integrated HIV care teams situated throughout the province were recently formed to promote HIV testing and best practices in HIV care. (49)

A number of policy changes pertaining to the delivery of HIV testing and care have been implemented within the province in recent years, including eliminating the need for pre-test 7

ACCEPTED MANUSCRIPT counseling for HIV testing, streamlined treatment and treatment initiation protocols, and an expanded set of Medical Service Plan codes offering financial incentives for not only HIV-related care visits, but also phone consultations with the HIV care team (50, 51) Each of these policies

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was implemented or modified to streamline HIV care and facilitate its delivery in primary care

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settings, by non-specialists, in the interest of making HIV testing and HIV care more accessible.

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2.2.2 Content of the EHOST Intervention

Details of the EHOST intervention are provided in Table 1.

The intervention distinguishes

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between three mutually exclusive categories of clients: (i) those not previously known to be HIVpositive; (ii) those who are known to be HIV-positive but not on ART; (iii) those who are known

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to be HIV-positive and on ART. HIV status will be determined via physician screening at the point of OAT initiation. Further, the EHOST intervention is intended to be delivered at three distinct times: (i) at the point of OAT entry; (ii) following a period of non-adherence and (iii) at

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regular bi-annual intervals.

INSERT TABLE 1 HERE

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The delivery of the EHOST intervention entails three main components. First, aided by a scripted communication guide, the project coordinator will communicate directly with the clinic manager to introduce the study procedures and determine support needs in scaling up HIV testing and treatment.

Second, again aided by a scripted communication guide, an addictions and HIV specialist will deliver an HIV care and billing consultation session to the Medical Director of the OAT clinic in the form of a phone conversation. This session will provide a brief background on the epidemiology of HIV among individuals with opioid use disorder and identified gaps in the HIV care continuum; outline the objectives and specific action items of the intervention; provide guidance on managing positive HIV cases; and inform physicians of the financial incentives, and the elimination of disincentives to provide HIV testing and care. Sites will also have the option of receiving an in-person Continuing Medical Education (CME)-accredited presentation and consultation session, to be led by the principal investigator and a clinical lead. This 30 minute presentation, delivered to physicians on-site, will similarly outline the rationale and evidence for HIV testing, early treatment and the secondary preventative benefits of treatment among people 8

ACCEPTED MANUSCRIPT who inject drugs; describe the evidence for the therapeutic benefits of HIV treatment alongside OAT; describe the new BC guidelines for HIV testing and billing codes; and share resources to

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support routine HIV testing and treatment.

Third, all sites will receive an information package that provides posters, physician reminder

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cards and other HIV care resources to support physicians unfamiliar with HIV care. These resources include drug treatment enrollment forms, billing codes for HIV care, and contact

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information for regional public health nurses, infectious disease specialists and a 1-800 number

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for Rapid Expert Advice and Consultation for HIV (REACH).

All materials developed for the EHOST intervention –including the scripted communication

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guides, the information package and the CME-accredited presentation—were developed over nine months through consultation with an advisory group of professionals involved in HIV care and OAT, including HIV care and addictions physicians affiliated with the BC Centre for

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Excellence in HIV/AIDS (BC-CfE), Vancouver Coastal Health, the BC CDC, the BC College of

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Family Physicians and Surgeons and the Portland Hotel Society; a senior epidemiologist at the BC CDC specializing in harm reduction and injection drug use; a clinical educator and a quality improvement coordinator at the BC CfE; and an OAT site manager based in Vancouver’s

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Downtown Eastside. The project coordinator for this project, who coordinated the intervention development and will oversee its implementation, holds a master’s degree in public health and brings previous experience coordinating quality improvement research with health care providers.

2.3 Evaluation

2.3.1 Databases Evaluation of the effectiveness of the proposed intervention will be conducted entirely through routinely collected health administrative data in BC, thus minimizing the costs of data collection, eliminating the possibility of non-response bias and maximizing the feasibility of the evaluation. The available linked population-level datasets are detailed in Table 2. We note that these datasets cover the vast majority of the spectrum of health services provided in BC, and will allow for accurate definition of the cohort, attribution of HIV status and measurement of each of the primary outcome measures and other critical covariates detailed below.

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ACCEPTED MANUSCRIPT

INSERT TABLE 2 HERE

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The study cohort will be identified within the population of individuals prescribed methadone, buprenorphine or buprenorphine-naloxone for opioid use disorder in the province of BC. An up-

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to-date set of drug identification numbers capturing all OAT observed in the PharmaNet database (52) will be used to identify the cohort at the point of analysis. These codes will

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encompass current and past identification numbers used for the medications in question and are specific to indications for opioid use disorder (as opposed to pain). Previous studies have

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defined methods to clean and process PharmaNet data to construct OAT episodes(37), as well as correct errors in the key fields used to create OAT episodes. Our prior experience with this

corrected.

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methodology yielded an error rate below 4%, with less than 1% of identified errors unable to be Furthermore, HIV status will be defined according to a previously-applied

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methodology using validated case-finding algorithms (53).

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The evaluation of the study will be at the OAT site-level. For researchers accessing PharmaNet data, de-identified physician IDs are available for individual OAT prescriptions. For this project we have requested an additional de-identified site ID, as well as a randomization step identifier.

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This additional requested information is readily available within PharmaNet and maintains confidentiality of individuals, prescribing physicians and OAT sites.

2.3.2 Key Measures

Primary Outcome Measures: We have defined three primary outcome measures: (i) the HIV testing rate among those not known to be HIV positive; (ii) the rate of ART initiation among those not on ART; and (iii) the rate of ART continuation among those on ART. The components and construction of each of these outcomes are detailed in Table 3.

INSERT TABLE 3 HERE

The temporal stages of delivery of the EHOST intervention (OAT entry, drop-out, and bi-annual follow-up) will be identified using our previously-established framework for OAT episode construction. (38) Date of prescription and length of prescription were used to construct OAT episodes where continuous treatment entailed no interruptions in prescribed doses lasting 10

ACCEPTED MANUSCRIPT longer than 30 days. HIV status will be established using the aforementioned case-finding algorithms, while ART receipt at the start of the quarterly follow-up period will be ascertained from BC-CfE drug treatment program records; these figures will be used to define the

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denominators for each of the three identified patient groups.

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2.4 Analysis

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2.4.1 Primary Analysis

The staggered-initiation of the intervention is designed specifically with the analytic framework in mind, providing a temporal control group in the middle stages of the trial (between months 6 and

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18 in Figure 2). Despite the randomized delivery of the intervention, it may be hypothesized that heterogeneity in patient case mix, volume, and the quality of care across OAT sites may result

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in diverging trends in outcomes across OAT sites over the study period. In our case, the key consideration is that individuals, nested within OAT sites and site clusters,

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are selected to receive the intervention based on an exogenous and observable policy change;

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as we are assigning receipt of the intervention, selection is based on an observable factor. Further, as discussed above in detail, the intervention is assigned in a stepwise manner over a 24 month period. Difference-in-differences (DID) estimators are used in natural and quasi-

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experimental settings in which treatment delivery undergoes a change that can be viewed as exogenous to the outcomes, and when data are available both before and after the change for those who receive and do not receive the intervention (54). As such, a DID analysis will be applied to determine the causal effect of the EHOST intervention on the primary outcomes. We will have 8 quarters of follow-up data for the three randomization steps receiving EHOST at staggered intervals. The effect of EHOST on each primary outcome (PO) can be estimated using pooled ordinary least squares in a regression model with the following form:

where

represents the primary outcome for OAT site i at time period t,

represents

the intervention for OAT site i at time t, X is a matrix of other covariates potentially correlated with changes in both PO and EHOST (discussed in section 2.4.2 below), and

represents the

random error term.

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ACCEPTED MANUSCRIPT However, other policy changes or events could occur around the same time as the EHOST intervention, and there could be unobservable time-varying factors correlated to

and

is a period-specific intercept,

is an OAT site-specific effect which captures time-

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where

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. As such, the error term can be represented as follows:

invariant unobservable factors that may be correlated with EHOST status,

is an idiosyncratic error term, which is independently and

identically distributed over i and t.

gives us the random trend DID model (55)

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=

Substituting equation (2) into (1), and taking the first

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difference (eg.

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site to have a different trend and

allows each OAT

estimated using linear mixed effects (or random intercept) estimation. Note that because , the term representing site-specific time-invariant unobservable factors (such

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as availability of counseling or other factors influencing the quality of care) drops out of the

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equation.

A key consideration in estimating DID models is the parallel trends assumption (PTA); that the

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do not depend on the value of EHOST, and therefore that all OAT sites within a site-cluster exhibit the same underlying trend in PO regardless of EHOST introduction. randomization scheme should ensure this, in which case we would have

Our stratified . It is possible,

however, that there may be time-varying unobservables that are correlated with both

and

EHOST status, such as changes in the underlying quality of care within an OAT site over time. The random trend model relaxes the parallel trends assumption by allowing different OAT sites to have different trends,

. Further, the PTA can be tested explicitly in this formulation through

a single-variable, generalized version of the Hausman test of fixed versus random effects (56), which takes into account the clustered nature of the data (55), and intuitively testing whether are correlated with

(57).

It is critical to note that the absolute differences between the OAT sites receiving and not receiving the EHOST intervention are not important. It is the difference in differences, or the differences in the changes in outcomes that are the measures subject to analysis. Unobserved confounders that are fixed over time (the term

above) are thus eliminated. As noted, the

random effects methodology also tests, explicitly, differences in time-varying factors across OAT sites. The emphasison changes in trends across OAT sites informed the decision to employ the 12

ACCEPTED MANUSCRIPT delayed-start design; in essence, this design feature provides control groups in the first two stages of implementation, while also delaying implementation differentially across clusters, thus minimizing the potential effect of the PTA, which should otherwise be eliminated by stratified

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randomization of OAT sites. Nonetheless we have considered a number of additional timevarying covariates to control for potential time-varying confounders (section 2.4.2).

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Each PO can be evaluated individually or jointly in a seemingly unrelated regression (SUR)

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modeling framework that accounts for the correlation in error terms across models on each PO. That is, the SUR model is a system of linear equations with errors that are correlated across equations for a given OAT site, but are uncorrelated across OAT sites. This is intuitive, as we

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would expect, for example, testing and treatment uptake rates to be correlated within OAT sites, but not necessarily across OAT sites. The Breusch-Pagan test for error independence can be

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used to formally test this hypothesis (58). All data management and econometric analysis will be conducted with SAS version 9.3 and Stata version 13.1.

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2.4.2 Time-varying covariates

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Our focus will be on differences, or changes in factors that may confound the EHOST → PO relationship. Changes in: (i) the demographic mix of clients enrolled in OAT across study sites,

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including age, gender, medical comorbidity (as defined by the Charlson Comorbidity Index(59)and Chronic Disease Score(60) composite scores), aboriginal ethnicity, (ii) the mix of client OAT experience, including the mean cumulative past treatment experience of clients by site, and the mean number of past OAT episodes by site; (iii) the OAT client volume by site; (iv) the number of physicians licensed to offer OAT by site.

Each of these covariates will be

constructed from the available data. We further emphasize that all covariates are measured at the OAT site-level, according to the unit of analysis within this study. 2.5 Secondary Analyses First, we will modify our existing population-level HIV transmission model (18) to estimate the incremental effect of the observed changes in HIV testing, treatment uptake and retention among OAT clients versus the status quo, over a 20-year time horizon. To calculate the incremental cost-effectiveness of an intervention, analyses must consider the added efficacy (generally measured in QALYs) and the additional costs of the intervention.

The cost-

effectiveness ratio is then calculated with incremental costs in the numerator and incremental benefits in the denominator. 13

ACCEPTED MANUSCRIPT In our dynamic, compartmental transmission model that simulates the HIV/AIDS epidemic in BC, the adult population of BC aged 15-64 are partitioned into compartments on the basis of HIV risk behavior (men who have sex with men (MSM), injection drug users (IDU), MSM-IDU,

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and heterosexual), screening status (screened in past 12 months or not) and HIV infection status. Among those HIV-infected, individuals were further classified as infected, diagnosed,

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and on ART, and partitioned according to CD4 cell count strata (CD4≥500 ppm3, 350-499, 200349, <200). Health state transitions occurred at monthly intervals and we incorporated HIV

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transmission through heterosexual contact, homosexual contact and needle sharing associated with injection drug use. The probability of HIV transmission between two persons depended on

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the infected person’s HIV risk behavior classification, disease status and treatment status and the uninfected person’s HIV risk behavior classification. The model captures HIV transmission

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through needle sharing as a function of the annual number of injections, average needle-sharing rates and probability of transmission per shared needle. Further, these probabilities are allowed to change over time according to proxies of injection and sexual risk behavior – specifically,

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rates of OAT uptake (38)and non-HIV sexually transmitted disease (61)during the study period.

counseling.

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The model also accounts for changes in risky behavior due to effective HIV screening and

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The results of the EHOST intervention will be incorporated into the model explicitly through three mechanisms to determine its estimated long-term cost and public health benefits. First, the anticipated increased HIV screening rate can be inputted directly; second, we anticipated an increased rate of ART initiation due to linkage to HIV care in OAT which can, again, be altered directly; third, an anticipated decreased rate of ART discontinuation will be implemented by updating a previously-published population-level analysis (62) to estimate rates of transitioning out of ART for HIV-infected PWID. Second, we will employ multiple regression analysis to define the determinants of ART adherence in the EHOST intervention. The analysis will employ extant linked provincial data sources as well as ongoing prospective cohort studies from the Urban Health Research Initiative (UHRI) at the British Columbia Centre for Excellence in HIV/AIDS which has since 1996 recruited and retained under follow-up approximately 2,300 individuals who are actively using illicit drugs from Vancouver. At recruitment and every six months thereafter, each cohort participant answers a comprehensive interviewer-administered semi-structured questionnaire. Information gathered during the baseline and follow-up interviews includes: socio-demographic information (age, gender, ethnic background, migration, education, income); drug-using 14

ACCEPTED MANUSCRIPT behaviors (injection and non-injection drug use frequency, drug type, public and binge use); and social,

policy,

economic,

and

physical

exposures

(including

unstable

housing

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homelessness, incarceration and criminal justice system contacts, engagement in methadone,

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access to treatment for alcohol and drug use, sex work participation and environments, health and social service use) The determinants of adherence we will explore can be summarized into

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three distinct groups: individual-level determinants of HIV care in OAT (eg. other illicit drug use and comorbid mental health conditions) as well as structural determinants of treatment delivery

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(eg. office-based vs. specialized drug treatment centers) and policies (eg. OAT co-payment).

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2.6 Power calculation

Past analyses suggest that approximately 4000 OAT clients will be observed in each

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randomization step annually, with 250 new clients enter each randomization step each year and expectations for continued growth in enrollment.(38) Further, interruptions in treatment lasting > 7 days are commonplace among individuals in OAT, with a mean of 0.64 per episode

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(min-max: 1-30).(37) These figures are large enough to provide stable numerators and

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denominators in the key indicators used in the primary outcome at the quarterly level.

As noted earlier, a total of 8 quarterly measurements across 51 sites with 230 clients per site

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are the basis of the proposed analysis. Assuming the baseline proportion of any of the given outcome measures is 30%, a two-tailed test with an alpha level of 0.01 and an intracluster correlation of 0.04, the available sample size will provide a power of 0.95 to detect a difference in proportion of 2.5% (ie. from 30% to 27.5%) (63). While a minimally important difference in proportions tested, re-engaged in care or maintained in stable treatment as a result of the intervention is not known and may be considered arbitrary, the study is clearly powered to detect even minimal differences.

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ACCEPTED MANUSCRIPT 3.0 Discussion 3.1 Current Status of Trial

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The trial was funded by the Canadian Institutes of Health Research and received ethical approval from the Simon Fraser University Behavioural Research Ethics Board. The trial

Interventional Trials) practices when applicable(64).

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protocol addressed recommended SPIRIT (Standard Protocol Items: Recommendations for The EHOST study team is currently

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working with the BC Ministry of Health, the STOP HIV/AIDS steering committee, the College of Pharmacists of BC and the BC Methadone Program at the College of Physicians and Surgeons

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of BC to establish data linkage and finalize the content and delivery of the intervention. The trial is slated to begin in the fall of 2015.

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3.2 Implications

There is equipoise in each aspect of the EHOST intervention. First, it is unclear the extent and Paltiel et al. (65)

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frequency with which HIV testing among OAT entrants is cost-effective.

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examined a variety of retesting frequencies for the general population and various high-risk groups, and noted that, in high-risk populations (defined as a population in which the annual

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incidence of HIV infection is 1.2%), testing every 5 years was highly cost-effective, while annual testing, with an incremental cost-effectiveness ratio of $100,000 per quality-adjusted life-year gained, may also be considered cost-effective by standard thresholds of willingness to pay (66). As a result, the current US Centre for Disease Control and Prevention testing guidelines recommend annual screening for persons presumed to be at high risk for HIV infection, including PWID, men who have sex with men, persons who exchange sex for money, and the sex partners of these people (67). Given substantially higher rates of HIV infection observed among PWID in BC (observed to be 10-20% in prior experimental and non-experimental studies (68, 69), there may be considerable value in more frequent testing among OAT clients.

Even after enrollment in OAT, clients may remain at elevated risk of HIV via concurrent injection of non-opioids or continued injection of opioids as a result of poor treatment adherence and retention – a common observation in OAT outcome evaluation(70). As a result, we expect the optimal frequency of HIV testing will be substantially higher than in the general population. The EHOST intervention was designed to provide a minimum bi-annual HIV testing frequency for those with unknown HIV status.

Incorporating the results of the proposed study within a

population-level dynamic, compartmental model for the provincial HIV/AIDS epidemic(18) will 16

ACCEPTED MANUSCRIPT allow us to determine whether this more frequent HIV testing policy is not only effective, but also cost-effective use of scarce healthcare funding.

addressed by the EHOST intervention.

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Finally, there are clear gaps in engagement in HIV treatment among PWID that may be Aside from the raw numbers of individuals not

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diagnosed, on ART, or achieving virologic suppression, we know that ART adherence, although far more likely during OAT, is not guaranteed. Specifically, in the prior analysis identifying the

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impact of OAT on ART adherence, we found that HIV-positive PWID spent a median of 56% of the time they were in OAT receiving ART; when out of OAT individuals received ART only 38%

there is considerable room for improvement.

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of the time.(25) This tells us both that the benefits of engagement in OAT are clear, however

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Further, reducing fragmentation by targeting OAT sites to improve HIV care – as opposed to targeting HIV prescribers to offer OAT – is preferable for several reasons. First, our analysis on

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the effects of OAT on ART adherence identified some degree of ART on OAT engagement

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(controlled for using a marginal structural modeling analytic approach), but this effect was substantially weaker than the effect of OAT on ART adherence.(29)

As opposed to

antiretrovirals, certification is required to prescribe methadone or buprenorphine(47), making

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linkage to HIV care through OAT prescribers perhaps more plausible than the contrary, as ART prescribers without an OAT exemption would have to refer clients elsewhere. Furthermore, as we have hypothesized earlier, addressing opioid withdrawal and craving may provide the stability HIV-positive PWID need to successfully adhere to ART.(28)

While it is unclear whether an intervention targeting OAT prescribers can impact HIV testing and care among HIV-positive PWID, there are certainly well-defined incentives to provide such care and supports for potential prescribers, while policies surrounding testing and treatment initiation have been streamlined in recent years to facilitate uptake. Furthermore, at least one similarlydesigned intervention executed within the province, with a more passive form of delivery, demonstrated a positive effect attributable to the intervention(71). Finally, as the evaluation is based entirely on administrative data sources already linked and updated annually, our intervention can be executed rapidly, and at low cost. This will facilitate rapid communication of results to all stakeholders engaged in the care of people living with HIV/AIDS and opioid use disorders.

17

ACCEPTED MANUSCRIPT 3.3 Limitations Despite its unique advantages, there are several limitations to the internal and external validity of the study which we have considered carefully and addressed wherever possible. First, non-

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nominal testing is available in BC, and will result in outcome misclassification, an inherent limitation in our analysis for primary outcomes related to HIV testing. However, it may only bias

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the HIV test receipt primary outcome if the misclassification is differential; ie. if rates of non-

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nominal reporting are different across OAT site clusters. We anticipate the stratified randomization will balance this factor across OAT site clusters. Second, despite the stratified randomized design, the randomization units (OAT delivery sites) may be highly heterogeneous

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in terms of their client case-mix, volume and quality of care, which may change over time at different trajectories, thus potentially confounding the EHOST→PO relationship. In addition to

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controls via stratification on OAT site type and the analytic focus on differences rather than levels of covariates, we have also considered a variety of covariates to control for any residual confounding. We are confident that the proposed approach will provide an unbiased estimate of

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the effect of the EHOST intervention on the primary outcomes we’ve defined. Third, given that

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our analysis is to be conducted at the OAT site-level, we can safeguard against contamination in cases when individual clients are managed by multiple physicians within the same OAT

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site(72), however physicians working out of multiple OAT sites assigned to different clusters may result in some degree of misclassification, which attenuates the estimate of the effect of the intervention towards the null hypothesis, making our results conservative.The analysis is executed at the OAT site-level, to mirror the site-level roll-out of the intervention. This latter point is the key consideration in judging this study design; in cases where ecological (ie. OAT site-level) data are used to investigate an individual-level phenomenon, the ecological fallacy applies – which is that the association observed between exposure and outcome need not reflect individual-level associations. Although both the elements of the outcomes and the exposure in our case are delivered at the individual-level, the intervention is designed as a programmatic implementation tool and communicated to physicians, rather than patients. Indeed, both the intervention and outcome are different across the different types of OAT clients, according to their HIV status. As such, we argue here that the analytic framework we’ve devised is appropriate, and will allow for unbiased assessment of the causal effect of the EHOST intervention.

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ACCEPTED MANUSCRIPT In terms of implementation, a potential concern is non-engagement or non-response of randomized sites. The intervention and analytic framework are designed to handle an intent-totreat approach. By focusing on site-specific differences during the study period, our analysis

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adjusts for site-level effectiveness, i.e. both engaged and non-engaged sites will be accounted for whereas only the effect of the intervention is captured, regardless of whether the site is

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engaged or not.

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Our focus on specialized drug treatment facilities is expected to capture 90% of the client population, thus providing a high level of external validity within the province of BC. However, the BC HIV and drug abuse treatment experience differs from other provinces within Canada First, all HIV-related care, including medication, is

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and internationally on several domains.

universally covered in BC, in contrast to other Canadian provinces where no exceptional funding

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status is placed on antiretroviral medications. Second, OAT provision is subject to provincial drug insurance coverage rules, which vary across provinces (73). Finally, it is well-known that is more accessible in BC than all provinces but Ontario(34).

These factors increase the

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likelihood of success of the EHOST intervention relative to other regions with poorer access to

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HIV and OAT. This point however does not diminish the scientific or public health value of the intervention, which we believe is high on both counts.

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3.4 Conclusion

Facilitated by established collaborations between key stakeholders across the province, the EHOST intervention promises to provide a significant public health benefit at a cost substantially lower than trials relying on primary data collection. Further, the trial’s aim is for health system re-engineering in the interest of optimizing HIV testing and care within a marginalized and hardto-reach population. It is our hope that this trial can serve as a template for future interventions to optimize health care delivery in HIV/AIDS and other disease areas. Acknowledgements: This trial is funded by an operating grant from the Canadian Institutes of Health Research (CIHR), and receives supplemental support from the BC Ministry of Health and the British Columbia Node of the CIHR-funded Canadian Research Initiative on Substance Misuse. The funding agreement ensured the authors’ independence in designing the study, interpreting the data, writing, and publishing the report. BN is a Michael Smith Foundation for Health Research Scholar. VDL is a CIHR and a Michael Smith Foundation for Health Research Scholar. We acknowledge the support of the Seek and Treat for Optimal Prevention of

19

ACCEPTED MANUSCRIPT HIV/AIDS Committee and the BC Methadone Program at the College of Physicians and

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Surgeons of BC for their input into the design and execution of the proposed trial.

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ACCEPTED MANUSCRIPT References Wood E, Kerr T, Marshall BDL, Li K, Zhang R, Hogg RS, et al. Longitudinal community plasma HIV-1-RNA concentrations and incidence of HIV-1 among injecting drug users: a prospective cohort study. BMJ. 2009;338:1191–4.

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69.

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70.

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Figure 1. Geographic Information Systems map for Opioid Agonist Treatment sites featured in the EHOST Intervention

Legend: DTC: private drug treatment centre; POC: available point-of-care HIV testing; CHC: Community Health Centre; Northern: Northern Health Authority; Interior: Interior Health Authority; Vancouver Island: Vancouver Island Health Authority; Vancouver Coastal: Vancouver Coastal Health Authority; Fraser: Fraser Health Authority.

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ACCEPTED MANUSCRIPT Figure 2. Cluster-randomized, stepped-wedge trial design

expanded HIV care intervention

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ACCEPTED MANUSCRIPT Table 1. The Expanded HIV care intervention for individuals in opioid agonist treatment

OAT interruption2

Bi-annual follow-up3

Intervention Offer HIV test

HIV+, not on HAART HIV+, on HAART

Offer CD4, pVL, resistance test4, HAART Offer CD4, pVL, resistance test

Unknown HIV status

Offer HIV test

HIV+, not on HAART HIV+, on HAART Unknown HIV status HIV+, not on HAART

Offer HAART HAART adherence assessment Offer HIV test Offer HAART

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OAT entry

Client status Unknown HIV status

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Offer CD4, pVL, resistance test; HAART adherence assessment 1. OAT: Opioid Agonist Treatment. 2. Defined an interruption in dose pick-ups ≥ 7 days. 3. Diagnostic tests and assessment of HAART adherence may be offered more frequently than every six months, where specified by BC HIV/AIDS Therapeutic Guidelines. 4. For those with no prior resistance test. HIV+, on HAART

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ACCEPTED MANUSCRIPT Table 2. Descriptions of databases employed in this proposal Description

BCCfE drug treatment program and laboratory disease registry

The treatment program and clinical databases held at the BC-CfE include information on all individuals who have ever received antiretroviral treatment for HIV, including complete historical antiretroviral treatment records, HIV-related laboratory test records (80% of all CD4 tests provincially, all pVL, drug resistance tests), as well as information on demographics and mode of HIV transmission.

BCCDC HIV/AIDS Surveillance Database

The BC provincial HIV/AIDS surveillance database contains records of all individuals with a positive HIV test done in BC. It also captures information collected through an enhanced surveillance form for all persons with a newly diagnosed HIV infection.

Urban Health Research Initiative prospective cohort studies

Beginning in 1996, the Urban Health Research Initiative at the BCCfE has recruited and retained under follow-up approximately 2,500 individuals actively using illicit drugs from vulnerable and marginalized groups in downtown Vancouver. Using word-of-mouth, snowball sampling and other community-based methods, UHRI investigators have populated four long-term open observational prospective cohorts from public drug markets, single-room occupancy hotels, homeless shelters, low-barrier health and social service providers and other venues. The Vancouver Injection Drug User Study (VIDUS1) was started in 1996 and included approximately 1,500 HIV-seropositive and –seronegative individuals aged 18-years and older who had used illicit drug via injection in the previous month. In 2007, VIDUS1 was split into two cohorts, one containing HIV-negative PWID (VIDUS2) and one containing HIV-positive drug users (AIDS Care Cohort to evaluate Exposure to Survival Services (ACCESS)). The At-Risk Youth Survey (ARYS), an observational cohort of street-involved illicit-drug using youth, was subsequently added in 2008. Given the complementary inclusion criteria of VIDUS1, VIDUS2, ARYS and ACCESS and the use of harmonized research instruments and measures, this research platform allows for the analysis of a virtual cohort including approximately 2,500 illicit drug users.

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Database

BC Ministry of Health (BCMoH) Administrative Databases Medical Services Plan Database

The Medical Services Plan database includes records of all medical services provided by fee-for-service practitioners to individuals covered by British Columbia’s Medical Insurance Plan including laboratory and diagnostic procedures. It also includes encounter records for practitioners who are funded through areas such as Alternative Payment Branch or Primary care for the Population Based Funding sites and claims records for the fee for service payments processed by MSP for the Insurance Corporation of British Columbia and Worksafe BC. The dataset includes information on the dates, diagnoses, and types of outpatient care delivered throughout the study period, as well as the costs billed to the provincial Ministry of Health. Physician fee for service claims are reimbursed at the rates listed in the Medical Services Commission Payment Schedule in accordance with the Schedule’s Preamble rules. 30

ACCEPTED MANUSCRIPT Records for hospital discharges are included in the Discharge Abstract Database file from the BC Ministry of Health. The database contains demographic, administrative and clinical information for acute, rehabilitation and day surgery patients in acute care hospitals in BC.

BC PharmaNet Database

The BC PharmaNet database records all prescription drug dispensation in British Columbia. Data fields available included a de-identified patient ID, quantity dispensed (number of pills dispensed), de-identified prescriber code, cost of drugs dispensed, drug identification number, the date of the prescription, the length of the prescription (number of days supplied), drug dosage (quantity), de-identified prescriber code and the cost of drugs dispensed. Further information about the medication is also available including name of the active ingredient, name of the product, dosage of the product, form of the medication (pill, capsule, etc.), and codes for grouping similar medications.

BC Vital Statistics Database

The BC Vital Statistics database includes fields on the date of death (year and month) as well as ICD-9 and ICD-10 codes identifying probable cause of death.

Home and Community Care Database

This database includes information regarding use of home support and nursing services, adult day services, group homes, assisted living, community rehabilitation, long term care, respite care/hospice, residential care and convalescent care. These data will be used to form a complete picture of the range of services required by persons with HIV/AIDS and the costs associated with these services.

Mental Health Services

This database houses information on the use of mental health services including fee for service (general practitioners and psychiatrists), institutional care, community clinics, and acute care. Persons with a mental illness can access any or all of these services over time. It should be noted that reporting may not be complete, some providers are not captured and children under the mandate of the Ministry of Children and Family Development are not included.

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BC: British Columbia; BC-CfE: BC Centre for Excellence in HIV/AIDS; pVL: plasma viral load; PWID: people who inject drugs.

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Table 3. Construction of Primary Outcome Measures Variable

Construction Denominator

Unknown HIV status

OAT non-adherence

HIV test

Quarterly follow-up3

HIV test

No. of unknown HIV patients who entered OAT No. of unknown HIV patients with non-adherence OAT2 No. of unknown HIV patients who started OAT before

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OAT entry

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HIV+, not on HAART

Data Source

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Numerator

HAART dispensation

OAT non-adherence

HAART dispensation

Quarterly follow-up3

HAART dispensation

No. of HIV+ patients who entered OAT No. of HIV+ patients with non-adherence OAT2 No. of HIV+ patients who started OAT before

Case-finding algorithms status1; BCCfE drug tre laboratory disease regis database for HAART di

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Receipt of HAART in the previous period

AC CE P

TE

No. of HIV+ patients on HAART who entered OAT No. of HIV+ patients on Case-finding algorithms Receipt of HAART in OAT non-adherence HAART with non-adherence status1; BCCfE drug tre the previous period 2 OAT BC PharmaNet databas dispensation No. of HIV+ patients on Receipt of HAART in 3 Quarterly follow-up HAART who started OAT the previous period before 1. Data sources include BCCfE drug treatment program and laboratory disease registry, BCCDC HIV/AIDS surveillance database, DAD, MSP database, BC PharmaNet database; 2. Defined as two consecutive positive urine tests or interruption in dose pick-ups ≥ 7 days; 3. The follow-up interval includes a period of OAT non-adherence OAT entry

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