Abstract
A robust evidence-base describes the beneficial association between opioid agonist therapy (OAT) and HIV-related outcomes among people living with HIV and opioid use disorder. While some evidence suggests the stabilizing effect of OAT on antiretroviral therapy (ART) treatment engagement, less is understood about the potential for an inverse relationship. We sought to examine the relationship between transitions in ART engagement and transitions onto OAT. We used data from a prospective cohort of people living with HIV who use drugs in Vancouver, Canada—a setting with no-cost access to ART and low or no-cost access to OAT among low-income residents. Restricting the sample to those who reported daily or greater opioid use, we used generalized linear mixed-effects models to estimate the relationships between our primary outcome of transitions onto OAT (methadone or buprenorphine/naloxone) and transitions (1) onto ART and (2) into ART adherence. Subsequent analyses assessed the temporal sequencing of transitions. Between 2005 and 2017, among 433 participants, 48.3% reported transitioning onto OAT at least once. In concurrent analyses, transitions onto ART were positively and significantly associated with transitions onto OAT. Temporal sequencing revealed that transitions into OAT were also positively and significantly associated with subsequent transitions onto ART. OAT’s potential to facilitate the uptake of ART points to the continued need to scale-up low-threshold, client-centered substance use services integrated alongside HIV care.
INTRODUCTION
The use of antiretroviral therapy (ART) has led to substantial improvements in survival and quality of life for people living with HIV [1]. Following initiation of ART, subsequent optimal ART adherence leads to HIV viral suppression, resulting in delayed disease progression, reductions in rates of HIV-related co-morbidities and mortality, and declines in onward community viral transmission [1, 2].
People who use drugs (PWUD)—in particular, people who inject drugs (PWID)—are a key affected population at elevated risk for HIV infection. Globally and in Canada, approximately 18% and 11% of PWID, respectively, are living with HIV [3, 4]. PWID experience swifter rates of HIV disease progression and mortality, largely attributed to increased rates of co-morbidities, inconsistent access to ART, and socio-structural barriers to ART [5]. For example, data from the province of British Columbia (BC) illustrates that despite no-cost universal HIV treatment and care, among diagnosed HIV-positive PWID, 57% were virally suppressed compared to a virologic suppression rate of 69% among non-PWID [6]. Nonetheless, PWID who achieve viral suppression experience the same benefits from ART as other HIV-positive groups [2].
As the leading evidence-based treatment option for opioid use disorder, opioid agonist therapy (OAT), including buprenorphine/naloxone and methadone, play a crucial role in addressing the health and social harms associated with drug use, as well as represent an opportunity for effective engagement with systems of care. In Canada, buprenorphine/naloxone is the preferred first-line OAT, whereas methadone is considered the first-line alternative when buprenorphine/naloxone is contraindicated or not feasible for patients [7]. Across Canadian provinces, OAT is prescribed by community- or clinic-based physicians and nurse practitioners and is typically dispensed in community-based pharmacies.
Evidence suggests that long-term use of OAT is associated with numerous health and social benefits, including decreased frequency of drug use and improved mental health, physical health and social functioning [8, 9]. Among PWUD living with HIV and concurrent OUD, OAT use is associated with earlier initiation of ART, improved ART adherence and reduced risk of ART discontinuation [10,11,12]. These benefits suggest that engagement with OAT may provide a unique opportunity to engage PWUD with ART. While there is a well-established evidence-base documenting the beneficial effects of OAT on ART engagement and HIV-related outcomes, with some studies inferring a causal relationship between OAT and improvements across ART indicators [13], there is a limited understanding of the potential impact of ART on substance use treatment patterns. A small number of studies have considered the implications of ART beyond clinical outcomes, finding that use of ART may lead to improved quality of life, employment and other social indicators [14,15,16,17,18,19]. However, these studies are predominantly based in low-income settings and to our knowledge none have investigated the impact of transitions in ART engagement on substance use-specific treatment outcomes. Transitions of potential relevance for long-term ART engagement include transitions onto ART (i.e., initiating ART for the first time or re-initiating after a period of not using any ART) and transitions into ART adherence (i.e., taking ≥ 95% of medications after a period of using ART inconsistently).
The lack of evidence on the potential effects of transitions in ART engagement on OAT is considerable given the possibly important clinical implications of different pathways to optimally promote treatment and manage care for co-morbid conditions. PWUD living with HIV experience a range of health care challenges, including navigating siloed systems of care and overlapping forms of stigma and discrimination associated with disclosure of HIV-status or drug use in health care settings [20]. Investigating whether transitions in ART engagement are associated with transitions onto OAT could provide valuable insight into how either form of treatment may affect the other and highlight conditions needed for optimal treatment uptake and adherence. To further elucidate this relationship, the present study aims to examine the effects of transitioning: 1) onto ART and 2) into ART adherence with transitions onto OAT in a sample of people living with HIV who report daily or greater opioid use. In subsequent analyses exploring the sequential ordering of engagement in these two types of care, we further examine whether it is possible to identify whether transitions in ART engagement tended to occur before or after transitions onto OAT.
METHODS
Study Participants and Design
The present study draws on data from the AIDS Care Cohort to Evaluate exposure to Survival Services (ACCESS), an ongoing prospective cohort of HIV-positive PWUD based in Vancouver, Canada’s Downtown Eastside—a low-income neighbourhood characterized by high levels of drug use in the context of longstanding criminalization and marginalization. Participants are continually recruited through self-referral and community-based outreach in a range of settings including single-room occupancy hotels, low-barrier harm reduction services, and the open drug scene. Full cohort details have been described in detail elsewhere [21]. Participants are eligible to participate in the cohort if they are: 1) over the age of 18 years old; 2) HIV-seropositive; and 3) have used illegal drugs other than cannabis (which was considered illegal during the study period prior to cannabis legalization in October 2018) in the month prior to enrollment. At the baseline interview and subsequent follow-ups, participants answered interviewer-administered questionnaires obtaining data on demographic characteristics, socio-structural exposures, drug use behaviours, and other relevant exposures and outcomes. Participants provided blood samples for HIV clinical monitoring and HCV antibody testing. All participants provided written informed consent and received an honorarium of $40 at each study visit. This study was approved by the Providence Health Care/University of British Columbia Research Ethics Boards.
Data elicited through behavioural interviews was supplemented through the confidential linkage of HIV treatment data and relevant clinical measures from the BC Centre for Excellence in HIV/AIDS’ Drug Treatment Programme (DTP), a province-wide, centralized HIV registry and ART dispensary that provides ART to all HIV-positive individuals in BC. This data provides a comprehensive clinical profile for each ACCESS participant, including CD4 cell counts and HIV viral loads [22] conducted through the study or in the course of regular clinical care. The DTP also contains the details of all ART medications dispensed to all HIV-seropositive residents in the province. ART is dispensed at no cost through the province’s universal healthcare system.
For all analyses, we restricted the study sample to include all participants with ≥ 1 CD4 and ≥ 1 plasma HIV-1 RNA viral load measurement within ± 180 days of their baseline interview. Based on a previous approach [23], we further restricted the sample to include participants who reported daily or more frequent non-medical opioid use (e.g. use of heroin, and street obtained methadone, fentanyl or oxycodone) in the past six months prior to their baseline interview to include only those individuals indicated for OUD treatment. Participants with no baseline daily opioid use who reported subsequent daily non-medical opioid use during the study period were included from that point forward.
Measures
The primary outcome of interest was transitions onto OAT (i.e., initiating OAT for the first time or re-initiating after a period of not using any OAT) and was defined as self-reporting receipt of either methadone or bupenorphrine/naloxone with no use of these medications in the previous follow-up period. The primary independent variables of interest were 1) transitions onto ART (i.e., initiating ART for the first time or re-initiating after a period of not using any ART) and 2) transitions into ART adherence (i.e., taking ≥ 95% of medications after a period of using ART inconsistently). Transitioning onto ART was defined as receiving ≥ 1 day of ART in the past six months, with no ART receipt in the previous follow-up period vs. no ART receipt in both the current and previous follow-up period. Transitioning into ART adherence was defined as filling ≥ 95% pharmacy refills in the past six months, with filling < 95% refills in the previous follow-up period vs. ART non-adherence which was defined as filling < 95% refills in both the current and previous follow-up period.
In multivariable analyses, we adjusted for known or hypothesized confounders. Demographic characteristics included: age (per 10 years older), self-identified gender (man vs. woman, with transgender individuals grouped according to their self-identified gender identity), ethnicity (White vs. Indigenous or non-Indigenous Racialized ethnicity), and education attainment (high school or greater vs. less than high school). Socio-structural factors, drug use behaviours and health-related outcomes were assessed for the preceding six months and included: recent incarceration (yes vs. no), homelessness (yes vs. no), regular employment (regular, temporary, or self-employment; yes vs. no), informal or illegal income generation (e.g., street-based activities, sex work, drug dealing, theft and other illegal activities; yes vs. no), public injecting (yes vs. no), binge drug use (yes vs. no), syringe sharing (yes vs. no), pipe sharing (yes vs. no), injecting alone (yes vs. no), and CD4 cell counts (per 100 cell/mm3 increase). For CD4 cell counts, we used the mean of all measures in the previous six months or, if none, the most recent measure, as in previous analyses [24].
Statistical Analyses
We stratified baseline participant characteristics by status of transitioning onto OAT at any point during the study period and included all unique study participants eligible for any of our analyses. To assess differences between groups, we used Chi-square tests to analyze categorical variables and Mann–Whitney-U tests to analyze continuous variables.
Among people living with HIV who reported daily or greater opioid use, we estimated associations between transitioning onto ART and into ART adherence with transitions onto OAT. We also conducted subanalyses using lagged and forward-lagged ART uptake and ART adherence variables to examine the temporal sequencing. Analyses with lagged ART variables were used to assess whether the transitions in ART engagement in one six-month period occurred before transitions onto OAT in the subsequent six-month follow-up period. Conversely, analyses using forward-lagged ART variables were used to assess whether transitions in ART engagement one six-month follow-up period occurred after transitions onto OAT in the preceding follow-up period.
For analyses assessing the effect of transitions onto ART, all ACCESS participants were eligible. For analyses assessing the effect transitions into ART adherence, we included all observation periods from ACCESS participants following their earliest date of ART dispensation, i.e., all ART-exposed periods.
To estimate bivariable and multivariable relationships, we used generalized linear mixed models (GLMM). For multivariable models, we adjusted for known or hypothesized confounder variables in relation to the association of interest. For each variable, we fit a multivariable model containing all variables found to be significantly associated with transitioning onto OAT at the bivariate level (p < 0.10). Confounders were removed one at a time in a step-wise fashion to construct reduced models. Coefficient values associated with the ART variables in the full model were compared to the reduced models. Variables with the smallest relative change were removed sequentially and this process was continued until the maximum change from the full model exceeded 5%. This approach has been previously and widely used [25, 26]. The GLMM modeling approach described above was also used to conduct lagged and forward-lagged analyses to assess the temporal relationship between the independent and outcome variables. All p-values were two-sided. All statistical analyses were preformed using the SAS version 9.4.
RESULTS
Between December 2005 and December 2017, 959 HIV-positive individuals provided at least one interview during the study period, 45% (n = 433) of whom reported daily or greater opioid use and were included in the final sample. Of these individuals, 176 (42%) identified as women and the median age at baseline was 42 years (interquartile range: 36–49). At least once during the follow-up period, 209 (48%) study participants transitioned onto OAT, 148 (34%) transitioned onto ART and 244 (56%) transitioned into ART adherence. Those who transitioned onto OAT at any point during the study period were more likely to be younger, identify as an Indigenous or non-Indigenous racialized person, experience homelessness and report public injecting. Baseline characteristics are shown in Table 1.
Table 1.
Baseline characteristics of HIV-positive people reporting daily or more frequent opioid use included across all analyses, stratified by transitions onto OAT at any point during the follow-up period (2005–2017; N = 433)
| Characteristic | Total N = 433 N (%) |
Transitions onto OAT |
Odds ratio (95% CI) | p-value | |
|---|---|---|---|---|---|
| Yes n = 209 48.3% n (%) |
No n = 224 51.7% n (%) |
||||
|
| |||||
| Median age (IQR) | 42 (36–49) | 40 (34–47) | 44 (37–51) | 0.58 (0.46–0.73) | <0.0001 |
| Gender | |||||
| Man | 246 (58.3) | 112 (54.6) | 134 (61.8) | 0.75 (0.51–1.10) | 0.1384 |
| Woman | 176 (41.7) | 93 (45.4) | 83 (38.2) | ||
| White ethnicity | |||||
| Yes | 221 (51.4) | 93 (44.7) | 128 (57.7) | 0.59 (0.41–0.87) | 0.0073 |
| No | 209 (48.6) | 115 (55.3) | 94 (42.3) | ||
| Education | |||||
| High school or greater | 179 (42.3) | 87 (42.4) | 92 (42.2) | 1.01 (0.69–1.49) | 0.9606 |
| Less than high school | 244 (57.7) | 118 (57.6) | 126 (57.8) | ||
| Incarcerationa | |||||
| Yes | 63 (14.6) | 36 (17.3) | 27 (12.1) | 1.52 (0.89–2.61) | 0.1268 |
| No | 368 (85.4) | 172 (82.7) | 196 (87.9) | ||
| Homelessnessa | |||||
| Yes | 142 (32.9) | 79 (38.0) | 63 (28.3) | 1.56 (1.04–2.33) | 0.0318 |
| No | 289 (67.1) | 129 (60.0) | 160 (71.7) | ||
| Regular employmenta | |||||
| Yes | 45 (10.4) | 20 (9.6) | 25 (11.2) | 0.84 (0.45–1.57) | 0.5877 |
| No | 388 (89.6) | 189 (90.4) | 199 (88.8) | ||
| Informal or illegal income generationa | |||||
| Yes | 254 (58.7) | 131 (62.7) | 123 (54.9) | 1.38 (0.94–2.03) | 0.1009 |
| No | 179 (41.3) | 78 (37.3) | 101 (45.1) | ||
| Public injectinga | |||||
| Yes | 192 (45.7) | 104 (51.2) | 88 (40.6) | 1.54 (1.05–2.27) | 0.0281 |
| No | 228 (54.3) | 99 (48.8) | 129 (59.4) | ||
| Binge drug usea | |||||
| Yes | 198 (47.0) | 86 (42.2) | 112 (51.6) | 0.68 (0.46–1.00) | 0.0520 |
| No | 223 (53.0) | 118 (57.8) | 105 (48.4) | ||
| Syringe sharinga | |||||
| Yes | 33 (7.9) | 15 (7.4) | 18 (8.4) | 0.87 (0.43–1.77) | 0.6987 |
| No | 386 (92.1) | 189 (92.6) | 197 (91.6) | ||
| Pipe sharinga | |||||
| Yes | 183 (43.3) | 91 (44.4) | 92 (42.4) | 1.09 (0.74–1.61) | 0.6498 |
| No | 240 (56.7) | 114 (55.6) | 126 (57.8) | ||
| Injecting alonea | |||||
| Yes | 300 (71.8) | 149 (73.4) | 151 (70.2) | 1.17 (0.76–1.79) | 0.4722 |
| No | 118 (28.2) | 54 (26.6) | 64 (29.8) | ||
| Median baseline CD4 cell count (IQR) | 340 (220–520) | 340 (230–480) | 340 (200–540) | 0.97 (0.90–1.06) | 0.9315 |
95% CI: 95% confidence interval, HIV: human immunodeficiency virus, IQR: interquartile range, OAT: opioid agonist therapy
Describes behaviours or exposures in the past 6 prior to interview
In multivariable GLMM, transitions onto ART remained positively and significantly associated with transitions onto OAT (Adjusted OR (AOR) = 2.33; 95% confidence interval (CI): 1.50–3.62). Analyses assessing temporal sequencing revealed a positive and significant association when transitions onto ART occurred after transitions onto OAT (AOR = 2.51; 95% CI 1.49–4.22), indicating that starting OAT increased the likelihood of subsequent ART uptake. However, there was no association between transitions onto ART prior to transitions onto OAT, indicating that starting ART does not increase the likelihood of subsequent OAT uptake. Associations between transitions onto ART and OAT are displayed in Table 2.
Table 2.
Generalized linear mixed models of associations between transitions onto ART and OAT among HIV-positive people reporting daily or more frequent opioid use in Vancouver, Canada (2005–2017; N = number of observations)
| Characteristic | Concurrent transitions onto ART N = 3785 |
Lagged† transitions onto ART N = 2789 |
Forward-lagged‡ transitions onto ART N = 2770 |
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|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
|
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| Bivariable cOR (95% CI) | Multivariable aOR (95% CI) | Bivariable cOR (95% CI) | Multivariable aOR (95% CI) | Bivariable cOR (95% CI) | Multivariable aOR (95% CI) | |||||||
|
| ||||||||||||
| Transitions onto ART | 2.72 (1.78–4.16) | *** | 2.33 (1.50–3.62) | *** | 1.32 (0.69–2.51) | 1.09 (0.57–2.09) | 4.04 (2.51–6.49) | *** | 2.51 (1.49–4.22) | *** | ||
| Older age (per 10 years older) | 0.66 (0.57–0.76) | *** | 0.66 (0.57–0.76) | *** | 0.66 (0.57–0.76) | *** | 0.77 (0.63–0.95) | * | 0.66 (0.57–0.76) | *** | 0.58 (0.49–0.70) | *** |
| Identifying as man | 0.87 (0.69–1.11) | – | 0.87 (0.69–1.11) | – | 0.87 (0.69–1.11) | – | ||||||
| White ethnicity | 0.71 (0.56–0.90) | ** | – | 0.71 (0.56–0.90) | ** | 0.62 (0.44–0.86) | ** | 0.71 (0.56–0.90) | ** | – | ||
| ≥ High school educationa | 0.92 (0.72–1.18) | – | 0.92 (0.72–1.18) | – | 0.92 (0.72–1.18) | – | ||||||
| Recent incarcerationa | 1.61 (1.08–2.40) | * | – | 1.61 (1.08–2.40) | * | – | 1.61 (1.08–2.40) | * | – | |||
| Homelessnessa | 2.17 (1.67–2.84) | *** | – | 2.17 (1.67–2.84) | *** | 1.78 (1.19–2.66) | ** | 2.17 (1.67–2.84) | *** | – | ||
| Regular employment | 0.73 (0.51–1.06) | – | 0.73 (0.51–1.06) | – | 0.73 (0.51–1.06) | – | ||||||
| Informal or illegal income generationa | 1.42 (1.12–1.81) | ** | – | 1.42 (1.12–1.81) | ** | – | 1.42 (1.12–1.81) | ** | – | |||
| Public injectinga | 1.50 (1.16–1.94) | ** | – | 1.50 (1.16–1.94) | ** | 0.83 (0.56–1.23) | 1.50 (1.16–1.94) | ** | – | |||
| Binge drug usea | 1.29 (1.02–1.64) | * | – | 1.29 (1.02–1.64) | * | – | 1.29 (1.02–1.64) | * | – | |||
| Syringe sharinga | 2.40 (1.37–4.22) | ** | – | 2.40 (1.37–4.22) | ** | – | 2.40 (1.37–4.22) | ** | – | |||
| Pipe sharinga | 1.37 (1.06–1.78) | * | – | 1.37 (1.06–1.78) | * | 1.24 (0.87–1.77) | 1.37 (1.06–1.78) | * | – | |||
| Injecting alonea | 1.17 (0.91–1.50) | – | (0.91–1.50) | 1.24 (0.89–1.73) | 1.17 (0.91–1.50) | – | ||||||
| CD4 cell counts (per 100 cell/mm3 increase) | 0.93 (0.88–0.98) | ** | 0.94 (0.89 –0.99) | * | 0.93 (0.88–0.98) | ** | 0.96 (0.89–1.02) | 0.93 (0.88–0.98) | ** | 0.93 (0.87–1.00) | ||
95% CI: 95% confidence interval, aOR: adjusted odds ratio, ART: antiretroviral therapy, cOR: crude odds ratio, HIV: human immunodeficiency virus, OAT: opioid agonist therapy
p < 0.05
p < 0.01
p < 0.001
ART engagement preceding transitions onto OAT
Transitions onto OAT preceding ART engagement
Describes behaviours or exposures in the past 6 prior to interview
In multivariable GLMM, transitioning into ART adherence was not associated with transitions onto OAT. In analyses testing temporal sequencing, neither transitions into ART adherence that occurred prior or subsequent to transitions onto OAT were significantly associated. Associations between transitions into ART adherence and OAT are displayed in Table 3.
Table 3.
Generalized linear mixed models of associations between transitions into ART adherence and transitions onto OAT among HIV-positive people reporting daily or more frequent opioid use in Vancouver, Canada (2005–2017; N = number of observations)
| Characteristic | Concurrent transitions into ART adherence N = 3378 |
Lagged† transitions into ART adherence N = 2471 |
Forward-lagged‡ transitions into ART adherence N = 2522 |
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|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
|
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| Bivariable cOR (95% CI) | Multivariable aOR (95% CI) | Bivariable cOR (95% CI) | Multivariable aOR (95% CI) | Bivariable cOR (95% CI) | Multivariable aOR (95% CI) | |||||||
|
| ||||||||||||
| Transitions into ART adherence | 0.75 (0.47–1.18) | 0.75 (0.47–1.20) | 1.45 (0.93–2.25) | 1.28 (0.81–2.04) | 1.33 (0.85–2.07) | 1.31 (0.84–2.06) | ||||||
| Older age (per 10 years older) | 0.66 (0.57–0.76) | *** | 0.71 (0.60–0.84) | *** | 0.66 (0.57–0.76) | *** | 0.73 (0.59–0.89) | ** | 0.66 (0.57–0.76) | *** | 0.59 (0.48–0.72) | *** |
| Male | 0.87 (0.69–1.11) | – | 0.87 (0.69–1.11) | – | 0.87 (0.69–1.11) | – | ||||||
| White ethnicity | 0.71 (0.56–0.90) | ** | – | 0.71 (0.56–0.90) | ** | – | 0.71 (0.56–0.90) | ** | – | |||
| ≥ High school educationa | 0.92 (0.72–1.18) | – | 0.92 (0.72–1.18) | – | 0.92 (0.72–1.18) | – | ||||||
| Recent incarcerationa | 1.61 (1.08–2.40) | * | – | 1.61 (1.08–2.40) | * | – | 1.61 (1.08–2.40) | * | – | |||
| Homelessnessa | 2.17 (1.67–2.84) | *** | 1.61 (1.13–2.28) | ** | 2.17 (1.67–2.84) | *** | – | 2.17 (1.67–2.84) | *** | – | ||
| Regular employmenta | 0.73 (0.51–1.06) | – | 0.73 (0.51–1.06) | – | 0.73 (0.51–1.06) | – | ||||||
| Informal or illegal income generationa | 1.42 (1.12–1.81) | ** | – | 1.42 (1.12–1.81) | ** | – | 1.42 (1.12–1.81) | ** | – | |||
| Public injectinga | 1.50 (1.16–1.94) | ** | – | 1.50 (1.16–1.94) | ** | – | 1.50 (1.16–1.94) | ** | – | |||
| Binge drug usea | 1.29 (1.02–1.64) | * | – | 1.29 (1.02–1.64) | * | – | 1.29 (1.02–1.64) | * | – | |||
| Syringe sharinga | 2.40 (1.37–4.22) | ** | – | 2.40 (1.37–4.22) | ** | – | 2.40 (1.37–4.22) | ** | – | |||
| Pipe sharinga | 1.37 (1.06–1.78) | * | – | 1.37 (1.06–1.78) | * | – | 1.37 (1.06–1.78) | * | – | |||
| Injecting alonea | 1.17 (0.91–1.50) | – | 1.17 (0.91–1.50) | – | 1.17 (0.91–1.50) | – | ||||||
| CD4 cell counts (per 100 cell/mm3 increase) | 0.93 (0.88–0.98) | ** | – | 0.93 (0.88–0.98) | ** | – | 0.93 (0.88–0.98) | ** | 0.90 (0.84–0.97) | ** | ||
95% CI: 95% confidence interval, aOR: adjusted odds ratio, ART: antiretroviral therapy, cOR: crude odds ratio, HIV: human immunodeficiency virus, OAT: opioid agonist therapy
p < 0.05
p < 0.01
p < 0.001
ART engagement preceding transitions onto OAT
Transitions onto OAT preceding ART engagement
Describes behaviours or exposures in the past 6 prior to interview
DISCUSSION
Using data from a prospective cohort of PWUD living with HIV linked to comprehensive HIV clinical measures including ART dispensation in a setting of no-cost medical care, we found that transitions onto ART, but not transitions into ART adherence were positively and significantly associated with transitions onto OAT within the same concurrent six-month follow-up period. Analyses assessing temporal sequencing further revealed that transitions onto OAT increased the likelihood of the subsequent uptake of ART, but not the likelihood of becoming ART adherent. Neither transitioning onto ART nor transitioning into ART adherence increased the likelihood of subsequent OAT uptake. While a substantial body of evidence suggests that OAT engagement can result in improved HIV-related treatment outcomes, to our knowledge this is the first study of its kind to investigate the effects of ART and OAT among PWUD using a modelling strategy that looks at transitions in both ART and OAT status, as well as the time sequencing of initiation processes into each treatment regimen. Contrary to our initial hypothesis, transitions in ART engagement did not demonstrate a role in supporting OAT uptake. However, our findings indicate that OAT may play a role in supporting the uptake of ART.
While the clinical benefits of ART for survival are clear, some prior research, predominantly from sub-Saharan Africa, has explored the beneficial effects of ART on the quality of life, mental health, and economic well-being of people living with HIV [15,16,17,18, 27]. These studies suggest that patients who remain on ART experience long-term physical and mental health benefits such as decreased pain and mobility concerns as well as reductions in anxiety and depression that result in improved socioeconomic-wellbeing through increased labour productivity and ability to complete daily tasks [15,16,17,18, 27]. Engagement with HIV treatment has been also shown to promote stability, renew motivation and hope in one’s life circumstances [28] and facilitate motivations to maintain good health and plan for the future [29, 30]. While our study did not demonstrate significant effects of ART engagement prior to OAT uptake, our findings do support a significant relationship between the initiation of OAT and subsequent uptake of HIV treatment.
A large and expansive body of research indicates that OAT is associated with numerous health and socioeconomic benefits, including improved HIV treatment indicators [8,9,10,11,12]. Our research adds further empirical evidence in support of OAT’s beneficial effects, with temporal sequencing indicating that OAT may facilitate ART uptake through its potentially stabilizing effects. This is consistent with past research, suggesting that individuals on OAT are more likely to achieve physical and social stabilization, and as a result are more likely to overcome barriers to accessing medical care and beginning ART treatment [12, 31]. It is important to note that although our findings point to a lack of predictive power of high-risk drug use behaviours (e.g., public injecting, binge drug use) in the adjusted analyses, these activities remain important to consider during treatment initiation in clinical practice.
Furthermore, despite the individual and public health benefits achieved through optimal adherence and subsequent viral suppression, we did not find an association between transitions onto OAT and initiation into ART adherence. Nevertheless, numerous studies have indicated a positive and robust association between OAT and ART adherence. A 2018 systematic review of HIV-positive opioid dependent individuals found that being on OAT was associated with a twofold increase in ART adherence [12]. A study from the current setting, evaluating the causal effect between co-morbid treatment modalities further found that OAT increased the odds of HAART adherence [13]. Null findings in the present study may be explained by the operationalization of the primary outcome—transitions onto OAT—defined by initiating OAT for the first time or re-initiating after a period of not using any OAT. Individuals may not be able to achieve ART adherence without the longer-term use and steadying effects of OAT. In this way, it is possible that long-term retention of OAT may be associated with ART adherence, however future investigations to assess this potentiality are warranted.
Notwithstanding, our research has important implications for individuals with co-occurring conditions, specifically those who are ART-naïve or use ART inconsistently, suggesting that treatment plans may benefit from initially focusing on stabilization with OAT, and then subsequent uptake of ART. These findings highlight the need for the continued scale-up of integrated, low-threshold OAT treatment services alongside HIV treatment and care, with specific emphasis on OUD stabilization with OAT prior to engagement with ART. Integration of OAT and HIV treatment and care is a widely promoted approach to reducing barriers and meeting the treatment needs of people living with co-occurring conditions [28]. Predominant and preferred models of integration centre around co-dispensation and the co-location of services but may also include coordinated care offered through a single provider, referrals to services between clinics, and cross-disciplinary case management teams [20, 28, 32]. At the institutional level, approaches to integration may include policies of structure and accountability, and the creation of supportive environments across systems of care [28]. Evidence for the benefits of integration span a range of outcomes that include the increased uptake and adherence to both treatment regimens and improved HIV- and substance use-related health outcomes [20, 28].
Complementary to integrated models of OUD and HIV treatment and care, low-threshold approaches of OAT delivery are central to meeting the treatment needs of PWUD with co-occurring conditions. Despite varied consensus on low-threshold program characteristics, the overall approach prioritizes the reduction of drug-related harm over abstinence as the primary goal of treatment [33, 34]. In their most common form, low-threshold OAT programs feature flexible attendance and policies that do not penalize patients for ongoing drug use and treatment interruptions [33,34,35]. Compared to higher-threshold OAT programs, evaluations indicate that low-threshold programs have higher retention rates of vulnerable populations [36], and are associated with a reduction in a range of drug-related harms including decreases in heroin use [37], HIV risk behaviours [38], and injection-related mortality [39, 40]. Therefore, low-threshold integrated approaches may hold potential to support long-term treatment engagement for co-morbid conditions as individuals may choose to initiate or re-engage with OAT at their own discretion, while still being supported with HIV treatment and care [28].
Despite the potential wide-ranging benefits of low-threshold approaches to integration, challenges to implementation exist. Some individuals may choose to avoid integrated services as a means of avoiding stigma and discrimination associated with the disclosure of their HIV- or drug use status [41], thus important operational considerations include ensuring client privacy and confidentiality in discrete settings, as well as comprehensive staff training [28, 42]. Other reported barriers include providers’ low confidence or inexperience with treating co-occurring conditions, increased staff workloads, lack of institutional supports, and isolated systems of care [20, 43, 44]. Nonetheless, in light of our findings which indicate that the use of OAT may promote the uptake of ART, low-threshold, client-centred approaches to integrated care hold promise in facilitating treatment uptake for co-occurring conditions [20].
This study has limitations. Since the study sample was not randomly derived, our findings may not be generalizable to the wider population of HIV-positive people who use opioids frequently. This study was conducted in a setting of universal access to HIV treatment and care and widespread availability of OAT at low or no cost to low-income residents. Efforts to reduce the economic and structural barriers to accessing both forms of treatment are considerable in this setting, and therefore may not be generalizable to other contexts with different medical and prescription drug insurance coverage or treatment availability. It is likely that our associations of interest may be attenuated given that in settings where financial and institutional barriers exist, these constraints may hinder an individuals’ ability to engage with treatment. With respect to our subanalyses, given that transitions onto OAT and ART may be influenced by a multitude of behavioural, socioeconomic and structural factors that vary over time, it is possible that estimated effects of temporal relationships may have been affected by length of time between follow-up periods which may have ranged from one to eleven months across participants. In addition, the self-reported nature of non-clinical indicators may have contributed to social desirability and recall bias, due to the sensitivity and stigma associated with drug use. However, it should be noted that self-reported measures of drug use behaviours among PWUD are considered reliable and valid [45]. Study findings should likewise be interpreted with caution due to unobserved and unmeasured confounders not adjusted for in the analyses.
CONCLUSIONS
In conclusion, contrary to our initial hypothesis, transitions in ART engagement did not demonstrate a role in promoting OAT. Nonetheless, this study provides further evidence for the significant and positive association between OUD and HIV treatment. Examining the temporal sequencing of the two types of care revealed additional empirical support indicating that OAT may facilitate the uptake of ART through its potentially stabilizing effects and highlight the importance of treating OUD prior to, or concurrently alongside HIV. To meet the needs of PWUD living with HIV, our findings point to the continued scale-up of HIV and OUD treatment and care through a range of integrated, low-threshold, client-centered approaches. Future research should aim to examine the transition-related temporal effects of ART engagement on long-term OAT retention, as well as other forms of drug and alcohol treatment to best support the management of comorbid conditions in this key affected population.
Acknowledgements
We would like to thank the study participants for their contributions to the research, as well as past and current researchers and staff, especially Dr. Ekaterina Novosa, Christy Zonneveld, Steve Kain and Ana Prado for their research and administrative assistance. We gratefully acknowledge the British Columbia Centre for Excellence in HIV/AIDS’ contribution of data from the Drug Treatment Programme.
Funding
This study was supported by the US National Institutes of Health (NIH; R01DA021525). Sanjana Mitra is supported by a Frederick Banting and Charles Best CIHR Doctoral Award. Lindsey Richardson and M-J Milloy are supported by New Investigator Awards from the Canadian Institutes of Health Research and Scholar Awards from the Michael Smith Foundation for Health Research (CIHR; MSH 217672, MSH 360816). Lindsey Richardson’s research is additionally supported by a CIHR Foundation Grant (FDN-154320) and the Canada Research Chairs program through a Tier II Canada Research Chair in Social Inclusion and Health Equity. M-J Milloy is additionally supported in part by NIH (U01DA021525). Seonaid Nolan is supported by a Health Professional Award from the Michael Smith Foundation for Health Research and the University of British Columbia’s Steven Diamond Professorship in Addiction Care Innovation. No funding sources were involved in the study design, data collection, analysis, or interpretation.
Footnotes
DECLARATIONS
Conflict of Interest
M-J Milloy’s institution (the University of British Columbia) has received an unstructured gift from NG Biomed Ltd., a private firm seeking a government license to produce medical cannabis, to support him. M-JM is also the Canopy Growth professor of cannabis science at the University of British Columbia, a position established by arms’ length gifts from Canopy Growth, a licensed producer of cannabis, and the Government of British Columbia’s Ministry of Mental Health and Addictions. He has no personal financial relationships (e.g., employment, stock ownership, consulting, etc.) with the cannabis industry.
Ethical Approval
This study was approved by the Providence Health Care/University of British Columbia Research Ethics Boards.
Consent to Participate
All cohort participants provided written informed consent.
Availability of Data and Materials
Public sharing of data for this study is not permitted under the parameters of the research ethics approval, given potentially identifying and sensitive health and legal information. Requests for anonymized data can be made to the University of British Columbia/Providence Health Care Research Ethics Board by researchers who meet specific criteria set in the ethics approval. For further inquiries, please contact the research administration office of the British Columbia Centre on Substance Use: inquiries@bccsu.ubc.ca.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Public sharing of data for this study is not permitted under the parameters of the research ethics approval, given potentially identifying and sensitive health and legal information. Requests for anonymized data can be made to the University of British Columbia/Providence Health Care Research Ethics Board by researchers who meet specific criteria set in the ethics approval. For further inquiries, please contact the research administration office of the British Columbia Centre on Substance Use: inquiries@bccsu.ubc.ca.