The opioid crisis is driving mortality among under-served people living with HIV in British Columbia, Canada.

INTRODUCTION: Universal provision of effective antiretroviral medication has been essential to reduce mortality, increase longevity, and reduce onward transmission of HIV. This study aims to illuminate persistent threats to the health and longevity of under-served PLWH in British Columbia (BC), Canada. METHODS: Between 2007 and 2010, 1000 PLWH across BC were enrolled in the Longitudinal Investigation into Supportive and Ancillary health services (LISA) study and completed a cross-sectional survey on their HIV-care experiences and healthcare engagement. The sample generally reflects an under-served population of PLWH. A linkage to the provincial Vital Statistics registry is used in this analysis in order to examine overall mortality and cause-specific mortality trends; probability of death was modeled using logistic regression for participants with ongoing clinical monitoring (n = 910). RESULTS: By June 2017, 208 (20.8%) participants had died. The majority of deaths 57 (27.4%) were attributed to drug-related complications or overdoses, 39 (18.8%) were attributed to HIV-related complications, and 36 (17.3%) to non-AIDS-defining malignancies. We observed elevated odds of death among PLWH who smoked tobacco (aOR: 2.11, 95% CI: 1.38, 3.23), were older (aOR: 1.06 per one-year increase, 95% CI: 1.04, 1.08), indicated heavy alcohol consumption (aOR: 1.57, 95% CI: 1.11, 2.22), and reported unstable housing (aOR: 1.96, 95% CI: 1.37, 2.80); while higher CD4 cell count was protective (aOR: 0.87 per 100-unit increase, 95% CI: 0.79, 0.94) as was male gender), though non-significant (aOR: 0.73, 95% CI: 0.49, 1.07). CONCLUSIONS: Overdose is - the leading cause of mortality among a cohort of under-served PLWH in BC, Canada. Public health efforts to end the HIV epidemic and support the health and well-being of PLWH are being thwarted by persistent health inequities and the enormous and persistent risks facing people who use drugs. Integrated low-barrier primary care is essential for supporting under-served PLWH, and safe drug supply is needed to support PLWH who use drugs.

HIV, schizophrenia, and all-cause mortality: A population-based cohort study of individuals accessing universal medical care from 1998 to 2012 in British Columbia, Canada.

Schizophrenia is a severe mental illness with important implications for morbidity and mortality. This population-based cohort study examined the impact of schizophrenia diagnoses on all-cause mortality among a sample of people living with HIV (PLHIV) and a 10% random sample of individuals living without HIV (HIV-) in British Columbia (BC), through a data linkage between the BC Centre for Excellence in HIV/AIDS and Population Data BC's data holdings. Schizophrenia diagnoses were identified via International Classification of Diseases version 9 and version 10 codes. Age- and sex-adjusted all-cause mortality rates from January 1st, 1998 to December 31st, 2012 were calculated. Multivariable logistic models assessed (1) HIV status and mortality among individuals diagnosed with schizophrenia, (2) schizophrenia diagnosis and mortality among PLHIV, and (3) correlates of mortality among PLHIV concurrently diagnosed with schizophrenia (HIV+/SZO+). From 1998 to 2012, 6.3% of those with HIV had a schizophrenia diagnosis, compared to 1.1% of those without HIV. While significant declines in mortality rates were observed throughout the study period, mortality rates were highest among HIV+/SZO+. After adjustment for substance use disorder and age at baseline, HIV+/SZO+ had a 2.64 times greater odds of mortality (95% confidence interval [CI] = 2.14-3.25) compared to HIV-/SZO+. For PLHIV, a schizophrenia diagnosis was not associated with mortality after controlling for potential confounders (adjusted odds ratio [aOR] = 0.90, 95%CI = 0.74-1.09). Among HIV+/SZO+, age, history of injection drug use, ever having an AIDS-defining illness, and never being on anti-psychotic medication or accessing psychiatric services were associated with mortality. Efforts should be made to identify and link to care individuals disproportionately affected by schizophrenia and excess mortality, including those living with HIV.

Prevalence of Human Immunodeficiency Virus-1 Integrase Strand Transfer Inhibitor Resistance in British Columbia, Canada Between 2009 and 2016: A Longitudinal Analysis.

BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are highly efficacious and well tolerated antiretrovirals with fewer adverse side-effects relative to other classes of antiretrovirals. The use of INSTIs raltegravir, elvitegravir, and dolutegravir has increased dramatically over recent years. However, there is limited information about the evolution and prevalence of INSTI resistance mutations in clinical human immunodeficiency virus populations. METHODS: Human immunodeficiency virus-1-positive individuals ≥19 years were included if they received ≥1 dispensed prescription of antiretroviral therapy (ART) in British Columbia between 2009 and 2016 (N = 9358). Physician-ordered drug resistance tests were analyzed and protease inhibitor (PI), reverse-transcriptase inhibitor (RT), and INSTI resistance were defined as having ≥1 sample with a combined, cumulative score ≥30 by Stanford HIV Drug Resistance Algorithm version 7.0.1. RESULTS: Although most ART-treated individuals were tested for PI and RT resistance, INSTI resistance testing lagged behind the uptake of INSTIs among INSTI-treated individuals (11% in 2009; 34% in 2016). The prevalence of INSTI resistance was relatively low, but it increased from 1 to 7 per 1000 ART-treated individuals between 2009 and 2016 (P < .0001, R2 = 0.98). Integrase strand transfer inhibitor resistance mutations increased at integrase codons 66, 97, 140, 148, 155, and 263. CONCLUSIONS: The prevalence of INSTI resistance remains low compared with PI and RT resistance in ART-treated populations but is expanding with increased INSTI use.

Trends in discharges from the HIV/AIDS ward at a tertiary Canadian Hospital from 2005 to 2014.

Advances in HIV therapies have transformed HIV infection into a manageable chronic disease. Accordingly, hospital admission trends among people living with HIV may have evolved over time. This study describes discharge diagnoses from the dedicated HIV/AIDS ward at St. Paul's Hospital in Vancouver, Canada. A retrospective database review of admissions to the HIV/AIDS ward between 1 July 2005 and 30 June 2014 was conducted. Primary discharge diagnoses were manually categorized by condition and reviewed by two physicians. Data were analysed in 12-month intervals. Trends were fitted using generalized estimating equations. A total of 1595 individuals with 3919 admissions were included. The median age was 46 years, 77.1% identified as male, 63.6% had a history of injection drug use (IDU) and 61.8% had a history of hepatitis C virus exposure. The most common reasons for admission included non-opportunistic respiratory tract infections (18.2%), cellulitis (7.3%), gastroenteritis (6.0%), endocarditis/bacteremia (4.9%) and bone/joint infections (3.5%). The proportion of admissions attributable to opportunistic infections declined from 16.2% in 2005 to 5.5% in 2014. Over this period, the proportion of individuals on antiretroviral therapy and with virologic suppression increased (odds ratio 1.19 [95% confidence interval 1.16, 1.23] and 1.22 [95% confidence interval 1.17, 1.26], respectively). These results demonstrate a decline in admissions related to opportunistic infections but increased admissions due to other infections among people living with HIV. Preventive and outpatient care for respiratory infections and complications of IDU may further improve health care outcomes and decrease hospital admissions in this setting.

Long-term effectiveness of initiating non-nucleoside reverse transcriptase inhibitor- versus ritonavir-boosted protease inhibitor-based antiretroviral therapy: implications for first-line therapy choice in resource-limited settings.

INTRODUCTION: In many resource-limited settings, combination antiretroviral therapy (cART) failure is diagnosed clinically or immunologically. As such, there is a high likelihood that patients may stay on a virologically failing regimen for a substantial period of time. Here, we compared the long-term impact of initiating non-nucleoside reverse transcriptase inhibitor (NNRTI)- versus boosted protease inhibitor (bPI)-based cART in British Columbia (BC), Canada. METHODS: We followed prospectively 3925 ART-naïve patients who started NNRTIs (N=1963, 50%) or bPIs (N=1962; 50%) from 1 January 2000 until 30 June 2013 in BC. At six months, we assessed whether patients virologically failed therapy (a plasma viral load (pVL) >50 copies/mL), and we stratified them based on the pVL at the time of failure ≤500 versus >500 copies/mL. We then followed these patients for another six months and calculated their probability of achieving subsequent viral suppression (pVL <50 copies/mL twice consecutively) and of developing drug resistance. These probabilities were adjusted for fixed and time-varying factors, including cART adherence. RESULTS: At six months, virologic failure rates were 9.5 and 14.3 cases per 100 person-months for NNRTI and bPI initiators, respectively. NNRTI initiators who failed with a pVL ≤500 copies/mL had a 16% higher probability of achieving subsequent suppression at 12 months than bPI initiators (0.81 (25th-75th percentile 0.75-0.83) vs. 0.72 (0.61-0.75)). However, if failing NNRTI initiators had a pVL >500 copies/mL, they had a 20% lower probability of suppressing at 12 months than pVL-matched bPI initiators (0.37 (0.29-0.45) vs. 0.46 (0.38-0.54)). In terms of evolving HIV drug resistance, those who failed on NNRTI performed worse than bPI in all scenarios, especially if they failed with a viral load >500 copies/mL. CONCLUSIONS: Our results show that patients who virologically failed at six months on NNRTI and continued on the same regimen had a lower probability of subsequently achieving viral suppression and a higher chance of evolving HIV drug resistance. These results suggest that improving access to regular virologic monitoring is critically important, especially if NNRTI-based cART is to remain a preferred choice for first-line therapy in resource-limited settings.

The impact of scaling-up combination antiretroviral therapy on patterns of mortality among HIV-positive persons in British Columbia, Canada.

INTRODUCTION: Despite the tremendous improvements in survival, some groups of people living with HIV (PLHIV) continue to have lower survival rates than the overall HIV-positive population. Here, we characterize the evolving pattern of mortality among PLHIV in British Columbia since the beginning of the expansion of antiretroviral treatment in 2003. METHODS: This retrospective cohort study included 3653 individuals ≥20 years old, who enrolled on treatment between January 1, 2003, and December 31, 2012, and were followed until December 31, 2013. All-cause mortality rates and standardized mortality ratios (SMRs) were calculated to compare mortality outcomes of PLHIV to the general population. Abridged life tables were constructed to estimate the life expectancy at age 20 years for PLHIV. RESULTS: The overall crude mortality rate was 28.57 per 1000 person-years, the SMR was 3.22 and the life expectancy was 34.53 years. Interestingly, if we considered only individuals alive after the first year, the life expectancy increased to 48.70 years (41% increase). The SMRs for males and females decreased over time. Although females had higher SMRs in 2003 to 2008, this difference no longer existed in 2009 to 2011. There were also important differences in mortality outcomes for different clinical and demographical characteristics. CONCLUSIONS: Mortality outcomes of PLHIV who initiated antiretroviral treatment have dramatically improved over the last decade. However, there is still room for improvement and multilateral efforts should continue to promote early, sustained engagement of PLHIV on treatment so that the impact of treatment can be fully realized.

Virologic suppression and mortality of patients who migrate for HIV care in the province of British Columbia, Canada, from 2003 to 2012: a retrospective cohort study.

BACKGROUND: Migration among persons living with HIV (PLWH) seeking HIV care is common; however its effect on health outcomes in resource-rich settings is not well understood. We conducted a retrospective cohort study to quantify the extent to which PLWH are migrating for care within British Columbia (BC) and its association with virologic suppression and mortality. METHODS: Eligible PLWH first initiated treatment in BC between 2003 and 2012 (N = 3653). Analyses were performed at the regional Health Authority (HA) level (N = 5). For privacy reasons, we kept the name of these HAs anonymous and we re-named these five regions as 1 to 5. PLWH were classified according to the HA where they resided and received HIV care. We calculated all-cause mortality rates, life expectancies (at age of 20 years), and in, out and net migration rates across HAs using different demographic methods. Virologic suppression (<50 copies/mL) was based on the last viral load available for each PLWH. We also calculated per-capita rates (per 100 PLWH ever on cART) for each HA by dividing the number of PLWH by the number of physicians attending this population. RESULTS: There is considerable heterogeneity in physician availability across all HAs, with per-capita rates (per 100 PLWH ever on cART) ranging from 2.2 (HA 1) to 12.7 (HA 3) based on the HA PLWH received care. We observed that in HAs 1, 4, and 5, between 4 and 10% of PLWH migrated to HA 3 (i.e. the largest urban center) to receive care, and for HA 2 this proportion increased to 21%. In HA 3, 77% of its PLWH residents remained in the same HA for their care. Migrating to a larger center for HIV care was not associated with higher rates of viral load suppression; it was significantly associated with lower mortality rates and higher life expectancies. CONCLUSIONS: A thorough understanding of the reason(s) for these significant migration rates across BC will be critical to inform resource allocation and optimize the impact of HIV treatment.

Initiation of antiretroviral therapy at high CD4+ cell counts is associated with positive treatment outcomes.

OBJECTIVE: There is limited research investigating the possible mechanisms of how starting combination antiretroviral therapy (cART) at a higher CD4 cell count decreases mortality. This study investigated the association between initiating cART with short-term and long-term achievement of viral suppression; emergence of any drug resistance and of an AIDS-defining illness (ADI); long-term treatment adherence; and all-cause mortality. METHODS: This retrospective cohort study included 4120 naive patients who initiated cART between 2000 and 2012. Patients were followed until 2013, death or until the last contact date (varied by outcome). The main exposure was the interaction between period of cART initiation (2000-2006 and 2007-2012) and CD4 cell count at cART initiation (<500 versus ≥500 cells/µl). We considered both baseline and longitudinal covariates. We fitted different multivariable models using cross-sectional and longitudinal statistical methods, depending on the outcome. RESULTS: Patients who initiated cART with a CD4 cell count at least 500 cells/µl in 2007-2012 had an increased likelihood of achieving viral suppression at 9 months and of maintaining an adherence level of at least 95% over time, and the lowest probability of developing any resistance and an ADI during follow-up. These patients were not the ones with the highest likelihood of maintaining viral suppression over time, most likely due to viral load blips experienced during the follow-up. CONCLUSION: The outcomes in this study likely play an important role in explaining the positive impact of early cART initiation on mortality. These results should alleviate some of the concerns clinicians may have when initiating cART in patients with high CD4s as recommended by current treatment guidelines.

Continuing professional development in HIV chronic disease management for primary care providers.

Primary care providers need continuing professional development (CPD) in order to improve their knowledge and confidence in the care of patients with chronic conditions. We developed an intensive modular CPD program in the chronic disease management of HIV for primary care providers. The program combines self-directed learning, interactive tutorials with experts, small group discussions, case studies, clinical training, one-on-one mentoring and individualized learning objectives. We trained 27 family physicians and 7 nurse practitioners between 2011 and 2013. The trainees reported high levels of satisfaction with the program. There was a 136.76% increase in the number of distinct HIV-positive patients receiving HIV-related medication refills that were prescribed by the trainees.

Temporal trends in the discontinuation of first-line antiretroviral therapy.

OBJECTIVES: The aim of this study was to describe the rates and predictors of discontinuing first-line antiretroviral therapy in the different eras of treatment over a nearly 20 year period initiated in British Columbia between 1992 and 2010. METHODS: All naive adults who started antiretroviral therapy (first-line antiretroviral therapy) at any hospital or clinic in British Columbia (Canada) in 1992-2010 were included in this population-based retrospective cohort study. We were primarily interested in whether the era of treatment (1992-95, 1996-2000, 2001-05 and 2006-10) was associated with discontinuation (stopping or switching of initial treatment) within 3 years of starting therapy. Weibull survival analysis was used to model the era of treatment and its association with time to discontinuation. RESULTS: The study included 7901 patients. Overall, the probability of discontinuing at 12, 24 and 36 months of treatment was 52%, 68% and 76%, respectively. In the adjusted model, variables associated with discontinuing were earlier treatment era, younger age, low adherence and lower baseline CD4 count. Regarding the 2006-10 period, the probability of discontinuing at 12, 24 and 36 months was 36%, 47% and 53%, respectively. In the adjusted model, the variables associated with discontinuation were younger age, female gender, AIDS-defining illnesses at baseline, low adherence and a protease inhibitor (PI)-based regimen. CONCLUSIONS: Discontinuation rates of first-line therapy have decreased over time, but are still quite high even for the latest drug combinations. In the most recent era, younger women on a PI regimen and those not achieving optimal adherence had the highest risk of discontinuing first-line antiretroviral therapy.

Gender inequities in quality of care among HIV-positive individuals initiating antiretroviral treatment in British Columbia, Canada (2000-2010).

OBJECTIVES: We measured gender differences in "Quality of Care" (QOC) during the first year after initiation of antiretroviral therapy and investigated factors associated with poorer QOC among women. DESIGN: QOC was estimated using the Programmatic Compliance Score (PCS), a validated metric associated with all-cause mortality, among all patients (≥19 years) who initiated ART in British Columbia, Canada (2000-2010). METHODS: PCS includes six indicators of non-compliance with treatment initiation guidelines at baseline (not having drug resistance testing before treatment; starting on a non-recommended regimen; starting therapy at CD4<200 cells/mm3) and during first-year follow-up (receiving <3 CD4 tests; receiving <3 viral load tests; not achieving viral suppression within six months). Summary scores range from 0-6; higher scores indicate poorer QOC. Multivariable ordinal logistic regression was used to measure if female gender was an independent predictor of poorer QOC and factors associated with poorer QOC among women. RESULTS: QOC was determined for 3,642 patients (20% women). At baseline: 42% of women (34% men) did not have resistance testing before treatment; 17% of women (9% men) started on a non-recommended regimen (all p<0.001). At follow-up: 17% of women (11% men) received <3 CD4; 17% of women (11% men) received <3 VL; 50% of women (41% men) did not achieve viral suppression (all p<0.001). Overall, QOC was better among men (mean PSC = 1.54 (SD = 1.30)) compared with women (mean = 1.89 (SD = 1.37); p<0.001). In the multivariable model, female gender (AOR = 1.16 [95% CI: 0.99-1.35]; p = 0.062) remained associated with poorer QOC after covariate adjustment. Among women, those with injection drug use history, of Aboriginal ancestry, from Vancouver Island, and who initiated ART in earlier years were more likely to have poorer QOC. CONCLUSIONS: Poorer QOC among women, especially from marginalized communities, demands that barriers undermining women's access to high-quality care be addressed to improve treatment and health for women with HIV.