Comparative Analysis of Instrumental Variables on the Assignment of Buprenorphine/Naloxone or Methadone for the Treatment of Opioid Use Disorder.

BACKGROUND: Instrumental variable (IV) analysis provides an alternative set of identification assumptions in the presence of uncontrolled confounding when attempting to estimate causal effects. Our objective was to evaluate the suitability of measures of prescriber preference and calendar time as potential IVs to evaluate the comparative effectiveness of buprenorphine/naloxone versus methadone for treatment of opioid use disorder (OUD). METHODS: Using linked population-level health administrative data, we constructed five IVs: prescribing preference at the individual, facility, and region levels (continuous and categorical variables), calendar time, and a binary prescriber's preference IV in analyzing the treatment assignment-treatment discontinuation association using both incident-user and prevalent-new-user designs. Using published guidelines, we assessed and compared each IV according to the four assumptions for IVs, employing both empirical assessment and content expertise. We evaluated the robustness of results using sensitivity analyses. RESULTS: The study sample included 35,904 incident users (43.3% on buprenorphine/naloxone) initiated on opioid agonist treatment by 1585 prescribers during the study period. While all candidate IVs were strong (A1) according to conventional criteria, by expert opinion, we found no evidence against assumptions of exclusion (A2), independence (A3), monotonicity (A4a), and homogeneity (A4b) for prescribing preference-based IV. Some criteria were violated for the calendar time-based IV. We determined that preference in provider-level prescribing, measured on a continuous scale, was the most suitable IV for comparative effectiveness of buprenorphine/naloxone and methadone for the treatment of OUD. CONCLUSIONS: Our results suggest that prescriber's preference measures are suitable IVs in comparative effectiveness studies of treatment for OUD.

The impact of relaxation of methadone take-home protocols on treatment outcomes in the COVID-19 era.

BACKGROUND: Background: In response to the COVID-19 pandemic, the US Substance Abuse and Mental Health Services Administration (SAMHSA) allowed for an increase in methadone take-home doses for the treatment of Opioid Use Disorder (OUD) in March 2020. OBJECTIVE: To evaluate the effects of the SAMSHA exemption on methadone adherence and OUD-related outcomes. METHODS: A convenience sample of 183 clients (58% female) were recruited from a methadone clinic in the fall of 2019 for a cross-sectional survey. Survey data was linked to clinical records, including urine drug testing (UDT) results for methadone and emergency department (ED) visits at the local hospital. Participants were on stable methadone dosing for 9 months prior to and following March 2020. Methadone adherence was assessed by UDTs; OUD-related outcomes were assessed by overdose events and ED visits. Logistic regression was used to assess the association between change in take-home methadone doses and outcomes. RESULTS: Mean take-home doses increased nearly 200% (11.4 doses/30 days pre-COVID-19 vs. 22.3 post-SAMHSA exemption). ED visits dropped from 74 (40.4%) pre-COVID-19 to 56 (30.6%) post-SAMHSA exemption (p = <0.001). No significant changes were observed in either the number of clients experiencing overdose or those who experienced one or more methadone negative UDTs in the post-SAMHSA exemption period. Adjusted models did not show a significant association between changes in take-home doses and associated outcomes. CONCLUSIONS: Despite a near-doubling of take-home methadone doses during the COVID-19 exemption period, the increase in take-home doses was not associated with negative treatment outcomes in methadone-adherent clients.

Longitudinal patterns of illicit drug use, antiretroviral therapy exposure and plasma HIV-1 RNA viral load among HIV-positive people who use illicit drugs.

OBJECTIVES: HIV-positive people who use illicit drugs (PWUD) experience elevated rates of HIV-associated morbidity and mortality compared with members of other key affected populations. Although suboptimal levels of access and adherence to antiretroviral therapy (ART) are common among HIV-positive PWUD, there is a need for studies investigating the possible biological impacts of noninjection illicit drug use among people living with HIV in real-world settings. METHODS: We accessed data from the ACCESS study, an ongoing prospective cohort of illicit drug users with systematic HIV viral load monitoring in a setting with universal care and ART dispensation records. We used multivariable generalized linear mixed models to estimate the longitudinal associations between noninjection use of crack cocaine, powder cocaine, opioids, methamphetamine, cannabis and alcohol on plasma HIV-1 RNA viral load, adjusted for ART exposure and relevant confounders. RESULTS: Between 2005 and 2018, 843 individuals from the ACCESS cohort were included and contributed to 8698 interviews. At baseline, the mean age was 43 years, 566 (67%) reported male sex and 659 (78%) used crack cocaine in the previous 6 months. In multivariable models adjusted for ART exposure, only crack cocaine use in the last 6 months was found to be significantly associated with higher HIV viral load. CONCLUSION: We observed significantly higher HIV viral load during periods of crack cocaine use independent of ART exposure. Our findings support further research to investigate the possible biological mechanisms of this effect.

Density of low-barrier opioid agonist clinics and risk of non-fatal overdose during a community-wide overdose crisis: A spatial analysis.

OBJECTIVES: In recent years, North America has witnessed a spike in the number of overdoses (OD) and OD-related deaths. The aim of this study was to assess spatial correlates of OD risk in Vancouver, Canada. METHODS: Data utilized for this study was from three open and ongoing prospective cohorts of people who use drugs (PWUDs) in Vancouver, Canada. Logistic regression analyses with generalized linear mixed-effects models (GLMM) was used to examine correlates of residing in areas characterized by high OD rates. Mapping was used to examine areas showing OD clusters. RESULTS: We included 1336 PWUDs who resided in the downtown area. In multivariable analysis, higher availability of methadone clinics within walking distance, daily cocaine injectors and daily crack users had independent decreased odds of living within an OD cluster. CONCLUSION: This study found that higher availability of methadone clinics was associated with decreased odds of living within OD clusters.

Prevalence and Correlates of Reporting Difficulty Taking Antiretroviral Treatment Among HIV-Positive Illicit Drug Users in Vancouver, Canada: A Longitudinal Analysis.

People living with HIV who use illicit drugs continue to experience high rates of suboptimal treatment outcomes from antiretroviral therapy (ART). Although previous studies have identified important behavioural, social and structural barriers to ART adherence, the effects of patient-level factors have not been fully evaluated. Thus, we sought to investigate the prevalence and correlates of reporting ART was difficult to take among a cohort of illicit drug users in Vancouver, Canada. We accessed data from the AIDS Care Cohort to evaluate Exposure to Survival Services (ACCESS), an ongoing prospective cohort of HIV-positive illicit drug users linked to comprehensive HIV clinical monitoring records. We used generalized linear mixed-effects modeling to identify factors longitudinally associated with periods in which individuals reported they found ART difficult to take. Between December 2005 and May 2014, 746 ART-exposed illicit drug users were recruited and contributed at least one study interview. Finding ART hard to take was reported by 209 (28.0%) participants at baseline, and 460 (61.7%) participants throughout the study period. Patients ingesting a greater daily pill count (adjusted odds ratio [AOR] = 1.12 per pill, 95% confidence interval [CI] 1.08-1.17) and experiencing barriers to healthcare (AOR = 1.64, 95% CI 1.34-2.01) were more likely to report difficulty taking ART. Patients less likely to report satisfaction with their HIV physician (AOR = 0.76, 95% CI 0.58-1.00) and achieve a non-detectable HIV viral load (AOR = 0.62, 95% CI 0.51-0.74) were more likely to report finding ART hard to take. In this community-recruited cohort of ART-exposed illicit drug users, a substantial proportion reported they found HIV treatment hard to take, which was clearly linked to higher dissatisfaction with healthcare experiences and, most importantly, a lower likelihood of experiencing optimal virologic outcomes. Our findings reveal a number of opportunities to improve HIV treatment experiences and outcomes for people who use illicit drugs, including the use of treatment regimens with lower pill burdens, as well as reducing barriers to healthcare access.

Substance use patterns and HIV-1 RNA viral load rebound among HIV-positive illicit drug users in a Canadian setting.

BACKGROUND: Active illicit drug use can present a barrier to the medical management of HIV infection by complicating adherence to antiretroviral therapy (ART). Plasma HIV-1 RNA viral load (VL) rebound, defined as a period of detectable HIV VL following ART and VL suppression, can lead to the generation of viral resistance and potential treatment failure. We sought to investigate the contribution of substance use patterns on rates of VL rebound. METHODS: We used data from the ACCESS study, a long-running community-recruited prospective cohort of HIV-positive people who use illicit drugs in Vancouver, Canada, a setting of universal no-cost HIV treatment. We analysed time to VL rebound (that is, two consecutive observations ≥1,000 copies/ml) after ART initiation and sustained viral suppression (that is, two consecutive observations <50 copies/ml) using extended Cox regression models with a recurrent events framework. RESULTS: Between May 1996 and November 2013, 564 ART-exposed participants achieved at least one instance of VL suppression and contributed 1,893.8 person-years of observation. Over follow-up, 198 (35.1%) participants experienced ≥ one instance of VL rebound. In adjusted analyses, VL rebound was associated with younger age (adjusted hazard ratio [AHR] =0.97, 95% CI: 0.95, 0.98), heroin injection (≥ daily versus < daily, AHR =1.52, 95% CI: 1.01, 2.30), crack use (≥ daily versus < daily, AHR = 1.73, 95% CI: 1.08, 1.92) and heavy alcohol use (≥ four versus < four drinks/day, AHR =1.97, 95% CI: 1.17, 3.31). CONCLUSIONS: The present study suggests that in addition to heavy alcohol use, high-intensity illicit drug use, particularly ≥ daily heroin injection and ≥ daily crack smoking are risk factors for VL rebound. In addition to the impact of high-intensity drug use on health-care engagement and ART adherence, some evidence exists on the direct impact of psychoactive substances on ART metabolism and the natural progression of HIV disease. At-risk individuals should be provided additional supports to preserve virological control and maintain the benefits of ART.

Factors associated with discontinuation of methadone maintenance therapy (MMT) among persons who use alcohol in Vancouver, Canada.

BACKGROUND: We sought to examine the factors associated with discontinuation of MMT among persons on methadone who use alcohol. METHODS: We evaluated the impact of drug-related and other factors on discontinuation of MMT among persons enrolled in MMT and who reported any use of alcohol versus those who were enrolled in two community-recruited prospective cohorts of people who use illicit drugs (PWUD). Extended Cox models with time-dependent variables identified factors independently associated with time to first MMT discontinuation. RESULTS: Between December 2005 and 2015, 823 individuals on MMT who also reported using alcohol at least once were included in these analyses. During the study period, 391 (47.5%) discontinued methadone. Daily heroin injection (Adjusted Hazard Ratio [AHR] = 2.67, 95% Confidence Interval [CI]: 2.10-3.40) and homelessness (AHR = 1.42, 95% CI: 1.10-1.83) were positively associated with MMT discontinuation, whereas receiving other concurrent addiction treatment in addition to MMT (AHR = 0.07, 95% CI: 0.05-0.08), as well as >60 mg methadone dose (AHR = 0.48, 95% CI: 0.39-0.60), Hepatitis C virus seropositivity (AHR = 0.65, 95% CI: 0.47-0.90), and HIV seropositivity (AHR = 0.72, 95% CI: 0.57-0.91) were negatively associated with MMT discontinuation. Any/heavy alcohol use was not independently associated with MMT discontinuation. CONCLUSIONS: This study reinforces the known risks of continued heroin injection and homelessness for MMT discontinuation among individuals who also consume alcohol and highlights the protective effect of both MMT dose and receipt of concurrent addiction treatment.

Eligibility for heroin-assisted treatment (HAT) among people who inject opioids and are living with HIV in a Canadian setting.

OBJECTIVES: A growing body of evidence supports the effectiveness of injectable diacetylmorphine (i.e., heroin) for individuals with treatment-refractory opioid use disorder. Despite this evidence, and the increasing toll of opioid-associated morbidity and mortality, it remains controversial in some settings. To investigate the possible contribution of heroin-assisted treatment (HAT) to HIV treatment-related outcomes, we sought to estimate the proportion and characteristics of HIV-positive people who inject opioids that might be eligible for HAT in Vancouver, Canada. METHODS: We used data from a prospective cohort of people living with HIV who use illicit drugs in Vancouver, Canada. Using generalized estimating equations (GEE), we assessed the longitudinal relationships between eligibility for HAT, using criteria from previous clinical trials and guidelines, with behavioural, social, and clinical characteristics. RESULTS: Between 2005 and 2014, 478 participants were included in these analyses, contributing 1927 person-years of observation. Of those, 94 (19.7%) met eligibility for HAT at least once during the study period. In a multivariable GEE model, after adjusting for clinical characteristics, being eligible for HAT was positively associated with homelessness, female gender, high-intensity illicit drug use, drug dealing and higher CD4 count. CONCLUSIONS: In our study of HIV-positive people with a history of injection drug use, approximately 20% of participants were eligible for HAT at ≥ 1 follow-up period. Eligibility was linked to risk factors for sub-optimal HIV/AIDS treatment outcomes, such as homelessness and involvement in the local illicit drug trade, suggesting that scaling-up access to HAT might contribute to achieving optimal HIV treatment in this setting.

Dual sexual and drug-related predictors of hepatitis C incidence among sex workers in a Canadian setting: gaps and opportunities for scale-up of hepatitis C virus prevention, treatment, and care.

BACKGROUND: Hepatitis C virus (HCV) represents a significant cause of morbidity and mortality globally. While sex workers may face elevated HCV risks through both drug and sexual pathways, incidence data among sex workers are severely lacking. HCV incidence and predictors of HCV seroconversion among women sex workers in Vancouver, BC were characterized in this study. METHODS: Questionnaire and serological data were drawn from a community-based cohort of women sex workers (2010-2014). Kaplan-Meier methods and Cox regression were used to model HCV incidence and predictors of time to HCV seroconversion. RESULTS: Among 759 sex workers, HCV prevalence was 42.7%. Among 292 baseline-seronegative sex workers, HCV incidence density was 3.84/100 person-years (PY), with higher rates among women using injection drugs (23.30/100 PY) and non-injection crack (6.27/100 PY), and those living with HIV (13.27/100 PY) or acute sexually transmitted infections (STIs) (5.10/100 PY). In Cox analyses adjusted for injection drug use, age (hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.86-1.01), acute STI (HR 2.49, 95% CI 1.02-6.06), and non-injection crack use (HR 2.71, 95% CI 1.18-6.25) predicted time to HCV seroconversion. DISCUSSION: While HCV incidence was highest among women who inject drugs, STIs and the use of non-injection stimulants appear to be pathways to HCV infection, suggesting potential dual sexual/drug transmission. Integrated HCV services within sexual health and HIV/STI programs are recommended.

Switching to nevirapine-based regimens after undetectable viral load is not associated with increased risk of discontinuation due to toxicity.

INTRODUCTION: Due to its good tolerability, favourable cardiovascular risk-profile, low-pill burden and cost, nevirapine-based regimens are an attractive simplification strategy for patients with suppressed viral load (VL). However, current guidelines recommend caution if nevirapine (NVP) is prescribed in males and females with CD4 counts above 400 or 250 cells/µL, respectively. The aim of this study is to determine the prevalence and risk factors associated with development of toxicity or treatment discontinuation in patients switching to NVP-based regimens. MATERIALS AND METHODS: Retrospective chart review of HIV-infected patients with suppressed VL who switched from a PI-based regimen to a NVP-based regimen in four HIV clinics in Argentina, between 1997 and 2013. Bivariate and multivariate analyses were performed to explore factors associated with treatment discontinuation. High CD4 count was defined as CD4-cell count ≥400 or 250 cells/µL in males and females, respectively. RESULTS: Of 218 patients included, 165 (75.7%) were male; 21 (9.6%) were co-infected with HCV and/or HBV. Median baseline (BSL) CD4 count: 138 cells/µL (IQR: 64-276). At switch, patients had a median age of 38 years (IQR: 33.4-43.8) and had been suppressed for a median of 1.4 years (IQR: 0.6-2.2); 138 patients (63.3%) had high CD4-cell counts: among females, median CD4 count at switch was 462 (IQR: 330-709) cells/µL; among males, 433 (IQR: 305-595) cells/µL. Thirty-six patients (13.5%) presented NVP-related toxicity (30 skin toxicity, 6 hepatic toxicity), 29 (13.3%) discontinued NVP. Median time to development to toxicity: 32 days (IQR: 15-75). In bivariate analysis, chronic hepatitis was the only variable associated with development of toxicity (OR: 2.90, 95% CI 1.08-7.78). In multivariate analysis, no statistical significant associations were observed between either development of toxicity or treatment discontinuation and gender, chronic hepatitis, age or CD4-cell count at BSL or at switch (all p>0.05). CONCLUSIONS: In our study, switching to a NVP-based regimen in patients with undetectable VL was associated with a low incidence of skin or liver toxicity, and treatment discontinuation. Moreover, these were unrelated to the CD4-cell count. Our findings suggest that, in contrast with ART-naïve patients, switching to NVP-based regimens could be a safe strategy for patients with suppressed viremia regardless of the CD4-cell count.

A public health response against Strongyloides stercoralis: time to look at soil-transmitted helminthiasis in full.

Strongyloides stercoralis infections have a worldwide distribution with a global burden in terms of prevalence and morbidity that is largely ignored. A public health response against soil-transmitted helminth (STH) infections should broaden the strategy to include S. stercoralis and overcome the epidemiological, diagnostic, and therapeutic challenges that this parasite poses in comparison to Ascaris lumbricoides, Trichuris trichiura, and hookworms. The relatively poor sensitivity of single stool evaluations, which is further lowered when quantitative techniques aimed at detecting eggs are used, also complicates morbidity evaluations and adequate drug efficacy measurements, since S. stercoralis is eliminated in stools in a larval stage. Specific stool techniques for the detection of larvae of S. stercoralis, like Baermann's and Koga's agar plate, despite superiority over direct techniques are still suboptimal. New serologies using recombinant antigens and molecular-based techniques offer new hopes in those areas. The use of ivermectin rather than benzimidazoles for its treatment and the need to have curative regimens rather than lowering the parasite burden are also unique for S. stercoralis in comparison to the other STH due to its life cycle, which allows reproduction and amplification of the worm burden within the human host. The potential impact on STH of the benzimidazoles/ivermectin combinations, already used for control/elimination of lymphatic filariasis, should be further evaluated in public health settings. While waiting for more effective single-dose drug regimens and new sensitive diagnostics, the evidence and the tools already available warrant the planning of a common platform for STH and S. stercoralis control.