Expanding access to healthcare for people who use drugs and sex workers: hepatitis C elimination implications from a qualitative study of healthcare experiences in British Columbia, Canada.

BACKGROUND: Hepatitis C virus (HCV) is a major health threat in Canada. In British Columbia (BC) province, 1.6% of the population had been exposed to HCV by 2012. Prevalence and incidence of HCV are very high in populations of people who use drugs (PWUD) and sex workers (SW), who may experience unique barriers to healthcare. Consequently, they are less likely to be treated for HCV. Overcoming these barriers is critical for HCV elimination. This research sought to explore the healthcare experiences of PWUD and SW and how these experiences impact their willingness to engage in healthcare in the future, including HCV care. METHODS: Interpretive Description guided this qualitative study of healthcare experiences in BC, underpinned by the Health Stigma and Discrimination framework. The study team included people with living/lived experience of drug use, sex work, and HCV. Twenty-five participants completed in-depth semi-structured interviews on their previous healthcare and HCV-related experiences. Thematic analysis was used to identify common themes. RESULTS: Three major themes were identified in our analysis. First, participants reported common experiences of delay and refusal of care by healthcare providers, with many negative healthcare encounters perceived as rooted in institutional culture reflecting societal stigma. Second, participants discussed their choice to engage in or avoid healthcare. Many avoided all but emergency care following negative experiences in any kind of healthcare. Third, participants described the roles of respect, stigma, dignity, fear, and trust in communication in healthcare relationships. CONCLUSIONS: Healthcare experiences shared by participants pointed to ways that better understanding and communication by healthcare providers could support positive change in healthcare encounters of PWUD and SW, who are at high risk of HCV infection. More positive healthcare encounters could lead to increased healthcare engagement which is essential for HCV elimination.

CD4 Count at Entry into Care and at Antiretroviral Therapy Prescription among Adults with Human Immunodeficiency Virus in the United States, 2005-2018.

From 2005 to 2018, among 32013 adults with human immunodeficiency virus entering care, median time to antiretroviral therapy (ART) prescription declined from 69 to 6 days, CD4 count at entry into care increased from 300 to 362 cells/µL, and CD4 count at ART prescription increased from 160 to 364 cells/µL.

Transmission of hepatitis C virus infection among younger and older people who inject drugs in Vancouver, Canada.

BACKGROUND & AIMS: Understanding HCV transmission among people who inject drugs (PWID) is important for designing prevention strategies. This study investigated whether HCV infection among younger injectors occurs from few or many transmission events from older injectors to younger injectors among PWID in Vancouver, Canada. METHODS: HCV antibody positive participants at enrolment or follow-up (1996-2012) were tested for HCV RNA and sequenced (Core-E2). Time-stamped phylogenetic trees were inferred using Bayesian Evolutionary Analysis Sampling Trees (BEAST). Association of age with phylogeny was tested using statistics implemented in the software Bayesian Tip Significance (BaTS) testing. Factors associated with clustering (maximum cluster age: five years) were identified using logistic regression. RESULTS: Among 699 participants with HCV subtype 1a, 1b, 2b and 3a infection (26% female, 24% HIV+): 21% were younger (<27years), and 10% had recent HCV seroconversion. When inferred cluster age was limited to <5years, 15% (n=108) were in clusters/pairs. Although a moderate degree of segregation was observed between younger and older participants, there was also transmission between age groups. Younger age (<27 vs. >40, AOR: 3.14; 95% CI: 1.54, 6.39), HIV (AOR: 1.97; 95% CI: 1.22, 3.18) and subtype 3a (AOR: 2.12; 95% CI: 1.33, 3.38) were independently associated with clustering. CONCLUSIONS: In this population of PWID from Vancouver, HCV among young injectors was seeded from many transmission events between HCV-infected older and younger injectors. Phylogenetic clustering was associated with younger age and HIV. These data suggest that HCV transmission among PWID is complex, with transmission occurring between and among older and younger PWID.

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.

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.

The effect of history of injection drug use and alcoholism on HIV disease progression.

The effectiveness of highly active antiretroviral therapy (HAART) in preventing disease progression can be negatively influenced by the high prevalence of substance use among patients. Here, we quantify the effect of history of injection drug use and alcoholism on virologic and immunologic response to HAART. Clinical and survey data, collected at the start of HAART and at the interview date, were based on the study Longitudinal Investigations into Supportive and Ancillary Health Services (LISA) in British Columbia, Canada. Substance use was a three-level categorical variable, combining information on history of alcohol dependence and of injection drug use, defined as: no history of alcohol and injection drug use; history of alcohol or injection drug use; and history of both alcohol and injection drug use. Virologic response (pVL) was defined by ≥ 2 log10 copy/mL drop in a viral load. Immunologic response was defined as an increase in CD4 cell count percent of ≥ 100%. We used cumulative logit modeling for ordinal responses to address our objective. Of the 537 HIV-infected patients, 112 (21%) were characterized as having a history of both alcohol and injection drug use, 173 (32%) were nonadherent (<95%), 196 (36%) had a CD4⁺/pVL⁺ (Best) response, 180 (34%) a CD4⁺/pVL⁻ or a CD4⁻ /pVL⁺ (Incomplete) response, and 161 (30%) a CD4⁻ /pVL⁻ (Worst) response. For individuals with history of both alcohol and injection drug use, the estimated probability of non-adherence was 0.61, and (0.15, 0.25, 0.60) of Best, Incomplete and Worse responses, respectively. Screening and detection of substance dependence will identify individuals at high-risk for nonadherence and ideally prevent their HIV disease from progressing to advanced stages where HIV disease can become difficult to manage.

Characterizing durations of heroin abstinence in the California Civil Addict Program: results from a 33-year observational cohort study.

In accordance with the chronic disease model of opioid dependence, cessation is often observed as a longitudinal process rather than a discrete endpoint. We aimed to characterize and identify predictors of periods of heroin abstinence in the natural history of recovery from opioid dependence. Data were collected on participants from California who were enrolled in the Civil Addict Program from 1962 onward by use of a natural history interview. Multivariate regression using proportional hazards frailty models was applied to identify independent predictors and correlates of repeated abstinence episode durations. Among 471 heroin-dependent males, 387 (82.2%) reported 932 abstinence episodes, 60.3% of which lasted at least 1 year. Multivariate analysis revealed several important findings. First, demographic factors such as age and ethnicity did not explain variation in durations of abstinence episodes. However, employment and lower drug use severity predicted longer episodes. Second, abstinence durations were longer following sustained treatment versus incarceration. Third, individuals with multiple abstinence episodes remained abstinent for longer durations in successive episodes. Finally, abstinence episodes initiated >10 and ≤20 years after first use lasted longer than others. Public policy facilitating engagement of opioid-dependent individuals in maintenance-oriented drug treatment and employment is recommended to achieve and sustain opioid abstinence.

A 20-year population-based study of all-cause and cause-specific mortality among people with concurrent HIV and psychotic disorders.

OBJECTIVE: We aimed to characterize mortality among people with HIV (PWH) and psychotic disorders (PWH/psychosis+) vs. PWH alone (PWH/psychosis-). METHOD: A population-based analysis of mortality in PWH (age ≥19) in British Columbia (BC) from April 1996 to March 2017 was conducted using data from the Seek and Treat for Optimal Prevention of HIV/AIDS (STOP HIV/AIDS) study. Deaths were identified from the Vital Statistics Data (classified as HIV vs. non-HIV causes). Mortality trends across all fiscal years were examined. Cox models assessed the hazard of psychotic disorders on mortality; possible differences between schizophrenia and nonschizophrenia types of psychotic disorders were also evaluated. RESULTS: Among 13 410 PWH included in the analysis, 1572 (11.7%) met the case definition for at least one psychotic disorder. Over the study period, 3274 deaths (PWH/psychosis-: n  = 2785, PWH/psychosis+: n  = 489) occurred. A decline over time in all-cause mortality and HIV-related mortality was observed in both PWH/psychosis+ and PWH/psychosis- ( P value <0.0001). A decline in non-HIV mortality was observed among PWH/psychosis- ( P value = 0.003), but not PWH/psychosis+ ( P value = 0.3). Nonschizophrenia psychotic disorders were associated with increased risk of mortality; adjusted hazard ratios with (95% confidence intervals): all-cause 1.75 (1.46-2.09), HIV-related 2.08 (1.60-2.69), non-HIV-related 1.45 (1.11-1.90). Similar associations between schizophrenia and mortality were not observed. CONCLUSION: People with co-occurring HIV and nonschizophrenia psychotic disorders experienced a significantly higher risk of mortality vs. PWH without any psychotic disorder. Implementing care according to syndemic models considering interactions between HIV and particularly episodic psychotic disorders could help manage mortality risk more effectively among PWH/psychosis+.

A co-interaction model of HIV and syphilis infection among gay, bisexual and other men who have sex with men.

We developed a mathematical model to study the co-interaction of HIV and syphilis infection among gay, bisexual and other men who have sex with men (gbMSM). We qualitatively analysed the model and established necessary conditions under which disease-free and endemic equilibria are asymptotically stable. We gave analytical expressions for the reproduction number, and showed that whenever the reproduction numbers of sub-models and co-interaction model are less than unity, the epidemics die out, while epidemics persist when they are greater than unity. We presented numerical simulations of the full model and showed qualitative changes of the dynamics of the full model to changes in the transmission rates. Our numerical simulations using a set of reasonable parameter values showed that: (a) both diseases die out or co-exist whenever their reproduction number is less than or exceed unity. (b) HIV infection impacts syphilis prevalence negatively and vice versa. (c) one possibility of lowering the co-infection of HIV and syphilis among gbMSM is to increase both testing and treatment rates for syphilis and HIV infection, and decrease the rate at which HIV infected individuals go off treatment.

The WHOMEN's scale (Women's HAART Optimism Monitoring and EvaluatioN Scale v.1) and the association with fertility intentions and sexual behaviours among HIV-positive women in Uganda.

The objective of this study was to develop a reliable HAART optimism scale among HIV-positive women in Uganda and to test the scale's validity against measures of fertility intentions, sexual activity, and unprotected sexual intercourse. We used cross-sectional survey data of 540 women (18-50 years) attending Mbarara University's HIV clinic in Uganda. Women were asked how much they agreed or disagreed with 23 statements about HAART. Data were subjected to a principal components and factor analyses. Subsequently, we tested the association between the scale and fertility intentions and sexual behaviour using Wilcoxon rank sum test. Factor analysis yielded three factors, one of which was an eight-item HAART optimism scale with moderately high internal consistency (alpha = 0.70). Women who reported that they intended to have (more) children had significantly higher HAART optimism scores (median = 13.5 [IQR: 12-16]) than women who did not intend to have (more) children (median = 10.5 [IQR: 8-12]; P < 0.0001). Similarly, women who were sexually active and who reported practicing unprotected sexual intercourse had significantly higher HAART optimism scores than women who were sexually abstinent or who practiced protected sexual intercourse. Our reliable and valid scale, termed the Women's HAART Optimism Monitoring and EvaluatioN scale (WHOMEN's scale), may be valuable to broader studies investigating the role of HAART optimism on reproductive intentions and sexual behaviours of HIV-positive women in high HIV prevalence settings.

Retention in care and mortality trends among patients receiving comprehensive care for HIV infection: a retrospective cohort study.

BACKGROUND: Studies examining the relation between comprehensive care and health outcomes associated with comorbidities unrelated to HIV infection have focused mainly on the health outcomes of HIV-infected people and comorbid substance use disorders. We aimed to assess the impact of retention in comprehensive HIV infection care on overall, AIDS-related and non-AIDS-related mortality. METHODS: Using a retrospective cohort design, we collected data for HIV-infected patients aged 19 years or more who first visited a comprehensive HIV infection clinic in Vancouver between Jan. 1, 2004, and Dec. 31, 2014. We defined retention in care as visit constancy (whether the patient attended the clinic at least once per given period) of 75% or greater. We used Poisson regression modelling to examine mortality trends. We performed Cox proportional hazards modelling to assess survival by retention during the first year of follow-up and identify factors associated with death. RESULTS: A total of 2101 patients were included in the study. Of the 2101, 1340 (63.8%) were retained in the first year of care, and 271 (12.9%) died during the study period. Among the 264 cases in which the cause of death was known, although the primary underlying cause of death (74 [28.0%]) was AIDS-related, half of all AIDS-related deaths (37/74 [50%]) occurred early in the study (2004-2007). In later years, most deaths (147/184 [79.9%]) were non-AIDS-related. Overall mortality was significantly reduced among patients with higher retention in care during the first year of follow-up (per 20% increase in visit constancy; adjusted hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.79-0.96). Higher retention was also associated with reduced risk of AIDS-related death (adjusted HR 0.79, 95% CI 0.64-0.97). INTERPRETATION: Although there was an overall trend toward decreased AIDS-related mortality over time, retention in care markedly decreased the likelihood of death. Maintaining patient engagement in comprehensive ancillary care is a patient-centred way of decreasing mortality rates among HIV-infected people.

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.

Physicians' patient base composition and mortality among people living with HIV who initiated antiretroviral therapy in a universal care setting.

OBJECTIVES: To assess the impact of physicians' patient base composition on all-cause mortality among people living with HIV (PLHIV) who initiated highly active antiretroviral therapy (HAART) in British Columbia (BC), Canada. DESIGN: Observational cohort study from 1 January 2000 to 31 December 2013. SETTING: BC Centre for Excellence in HIV/AIDS' (BC-CfE) Drug Treatment Program, where HAART is available at no cost. PARTICIPANTS: PLHIV aged ≥ 19 who initiated HAART in BC in the HAART Observational Medical Evaluation and Research (HOMER) Study. OUTCOME MEASURES: All-cause mortality as determined through monthly linkages to the BC Vital Statistics Agency. STATISTICAL ANALYSIS: We examined the relationships between patient characteristics, physicians' patient base composition, the location of the practice, and physicians' experience with PLHIV and all-cause mortality using unadjusted and adjusted Cox proportional hazards models. RESULTS: A total of 4 445 PLHIV (median age = 42, Q1, Q3 = 34-49; 80% male) were eligible for our study. Patients were seen by 683 prescribing physicians with a median experience of 77 previously treated PLHIV in the past 2 years (Q1, Q3 = 23-170). A multivariable Cox model indicated that the following factors were associated with all-cause mortality: age (aHR = 1.05 per 1-year increase, 95% CI = 1.04 to 1.06), year of HAART initiation (2004-2007: aHR = 0.65, 95% CI = 0.53 to 0.81, 2008-2011: aHR = 0.46, 95% CI = 0.35 to 0.61, Ref: 2000-2003), CD4 cell count at baseline (aHR = 0.88 per 100-unit increase in cells/mm3, 95% CI = 0.82 to 0.94), and < 95% adherence in first year on HAART (aHR = 2.28, 95% CI = 1.88 to 2.76). In addition, physicians' patient base composition, specifically, the proportion of patients who have a history of injection drug use (aHR = 1.11 per 10% increase in the proportion of patients, 95% CI = 1.07 to 1.15) or Indigenous ancestry (aHR = 1.07 per 10% increase , 95% CI = 1.03-1.11) and being a patient of a physician who primarily serves individuals outside of the Vancouver Coastal Health Authority region (aHR = 1.22, 95% CI = 1.01 to 1.47) were associated with mortality. CONCLUSIONS: Our findings suggest that physicians with a higher proportion of individuals who face potential barriers to care may need additional supports to decrease mortality among their patients. Future research is required to examine these relationships in other settings and to determine strategies that may mitigate the associations between the composition of physicians' patient bases and survival.

Highly active antiretroviral therapy and survival in HIV-infected injection drug users.

CONTEXT: Highly active antiretroviral therapy (HAART) is often withheld from injection drug users (IDUs) infected with the human immunodeficiency virus (HIV) based on the belief that their unstable lifestyles may predetermine a markedly inferior outcome with HAART. However, long-term evaluations of HIV treatment outcomes among IDUs in comparison with other risk groups are not available. OBJECTIVE: To compare survival rates among HIV-infected patients initiating HAART with and without a history of injection drug use. DESIGN, SETTING, AND PATIENTS: Population-based, prospective cohort study (HAART Observational Medical Evaluation and Research [HOMER]) of 3116 antiretroviral-naive HIV-infected patients in a province-wide HIV/AIDS treatment program in British Columbia, Canada. Of the 3116 patients, 915 were IDUs (29.4%), 579 were female (18.6%), and the median age was 39.4 years (interquartile range, 33.3-46.4 years). Treatment with HAART was initiated between August 1, 1996, and June 30, 2006. The median duration of follow-up was 5.3 years (interquartile range, 2.8-8.3 years) for IDUs and 4.3 years (interquartile range, 2.0-7.6 years) for non-IDUs. Patients were followed up until June 30, 2007. Data were analyzed between November 1, 2007, and May 26, 2008. MAIN OUTCOME MEASURE: All-cause mortality. RESULTS: Overall, 622 individuals died (20.0%) during the study period (232 IDUs and 390 non-IDUs), for a crude mortality rate of 20.0% (95% confidence interval [CI], 18.4%-21.5%). At 84 months after the initiation of HAART, the product limit estimate of the cumulative all-cause mortality rate was similar between the 915 IDUs (26.5%; 95% CI, 23.2%-29.8%) and 2201 non-IDUs (21.6%; 95% CI, 16.9%-26.2%) (Wilcoxon P = .47). In multivariate time-updated Cox regression, the hazard ratio of mortality was similar between IDUs and non-IDUs (1.09; 95% CI, 0.92-1.29). CONCLUSION: In this study population, injection drug use was not associated with decreased survival among HIV-infected patients initiating HAART.

Innovative Multimodal Training Program for Family Physicians Leads to Positive Outcomes Among Their HIV-Positive Patients.

CME programs can increase physicians' uptake and adherence to clinical guidelines for chronic diseases. We developed an intensive multimodal training program for family physicians to increase their competency in the management and treatment of HIV, through group learning and via close interactions with expert clinicians in HIV. We trained 51 physicians from September 2010 to June 2015 and compared their adherence to clinical guidelines 1 year before and 1 year after the program. We observed significant increases in the physicians' HIV-related clinical competencies, in accordance with clinical guidelines, and an increase in the number of HIV-positive patients seen by these physicians and the number of combination antiretroviral therapies prescribed by these physicians. By combining various pedagogical approaches, as well as creating and encouraging communities of practice, we were able to make a durable impact on physician performance and patient-specific outcomes.

Adverse drug reactions to integrase strand transfer inhibitors.

OBJECTIVES: To describe and compare integrase strand transfer inhibitor (INSTI) adverse drug reactions (ADRs) for raltegravir, elvitegravir-cobicistat, and dolutegravir. DESIGN: Population-based, retrospective cohort. METHODS: Antiretroviral-experienced and naive persons at least 19 years old were included if they received their first prescription for raltegravir, elvitegravir-cobicistat, or dolutegravir in British Columbia, Canada, in 2012-2014, and were followed for 2 years until 31 December 2016. The primary outcome was an ADR resulting in INSTI discontinuation. ADR rates and 95% confidence intervals (95% CIs) were calculated by Poisson method. Cox proportional-hazards regression estimated the hazard ratio for ADR-related INSTI discontinuation, adjusted for confounders. ADR symptoms were compared across INSTIs. RESULTS: There were 1344 persons contributing 1464 person-INSTI exposures. The cohort was predominantly male (79%) and antiretroviral therapy-experienced (85%). ADR events and unadjusted ADR rates (95% CI) per 100 person-years were raltegravir 24 of 551 (4.4%), 2.91 (1.95, 4.35); elvitegravir-cobicistat 38 of 394 (9.6%), 5.94 (4.32, 8.16); and dolutegravir 27 of 519 (5.2%), 2.96 (2.03, 4.31). The ADR rate for elvitegravir-cobicistat was double that of dolutegravir (adjusted hazard ratio 2.24, 95% CI 1.13, 4.44), but not significantly different for either dolutegravir or elvitegravir versus raltegravir. Elvitegravir-cobicistat-treated persons had a significantly higher proportion of gastrointestinal and general (fatigue, malaise) ADRs. Neuropsychiatric ADRs were more frequent with dolutegravir, but not significantly different between INSTIs. Among those switching between INSTIs, there was no apparent relationship between experiencing an ADR to one INSTI and subsequent intolerance to another. CONCLUSIONS: This study affirms INSTIs are well tolerated during routine clinical use. Consideration of differences in side effect profiles can inform antiretroviral therapy individualization.

N348I in the connection domain of HIV-1 reverse transcriptase confers zidovudine and nevirapine resistance.

BACKGROUND: The catalytically active 66-kDa subunit of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) consists of DNA polymerase, connection, and ribonuclease H (RNase H) domains. Almost all known RT inhibitor resistance mutations identified to date map to the polymerase domain of the enzyme. However, the connection and RNase H domains are not routinely analysed in clinical samples and none of the genotyping assays available for patient management sequence the entire RT coding region. The British Columbia Centre for Excellence in HIV/AIDS (the Centre) genotypes clinical isolates up to codon 400 in RT, and our retrospective statistical analyses of the Centre's database have identified an N348I mutation in the RT connection domain in treatment-experienced individuals. The objective of this multidisciplinary study was to establish the in vivo relevance of this mutation and its role in drug resistance. METHODS AND FINDINGS: The prevalence of N348I in clinical isolates, the time taken for it to emerge under selective drug pressure, and its association with changes in viral load, specific drug treatment, and known drug resistance mutations was analysed from genotypes, viral loads, and treatment histories from the Centre's database. N348I increased in prevalence from below 1% in 368 treatment-naïve individuals to 12.1% in 1,009 treatment-experienced patients (p = 7.7 x 10(-12)). N348I appeared early in therapy and was highly associated with thymidine analogue mutations (TAMs) M41L and T215Y/F (p < 0.001), the lamivudine resistance mutations M184V/I (p < 0.001), and non-nucleoside RTI (NNRTI) resistance mutations K103N and Y181C/I (p < 0.001). The association with TAMs and NNRTI resistance mutations was consistent with the selection of N348I in patients treated with regimens that included both zidovudine and nevirapine (odds ratio 2.62, 95% confidence interval 1.43-4.81). The appearance of N348I was associated with a significant increase in viral load (p < 0.001), which was as large as the viral load increases observed for any of the TAMs. However, this analysis did not account for the simultaneous selection of other RT or protease inhibitor resistance mutations on viral load. To delineate the role of this mutation in RT inhibitor resistance, N348I was introduced into HIV-1 molecular clones containing different genetic backbones. N348I decreased zidovudine susceptibility 2- to 4-fold in the context of wild-type HIV-1 or when combined with TAMs. N348I also decreased susceptibility to nevirapine (7.4-fold) and efavirenz (2.5-fold) and significantly potentiated resistance to these drugs when combined with K103N. Biochemical analyses of recombinant RT containing N348I provide supporting evidence for the role of this mutation in zidovudine and NNRTI resistance and give some insight into the molecular mechanism of resistance. CONCLUSIONS: This study provides the first in vivo evidence that treatment with RT inhibitors can select a mutation (i.e., N348I) outside the polymerase domain of the HIV-1 RT that confers dual-class resistance. Its emergence, which can happen early during therapy, may significantly impact on a patient's response to antiretroviral therapies containing zidovudine and nevirapine. This study also provides compelling evidence for investigating the role of other mutations in the connection and RNase H domains in virological failure.

Health-adjusted life expectancy in HIV-positive and HIV-negative men and women in British Columbia, Canada: a population-based observational cohort study.

BACKGROUND: We sought to understand whether people living with HIV (PLHIV) ever on highly active antiretroviral therapy (ART) follow a pattern where morbidity is compressed into the last years of life or lessened as people age. We aimed to estimate health-adjusted life expectancy (HALE) among adults living with and without HIV, and examine dependency between causes of comorbidities. METHODS: The Comparative Outcomes and Service Utilization Trends (COAST) study is a retrospective cohort of adults (≥20 years) including all known PLHIV and a 10% random sample of the general population of British Columbia, and with longitudinal data spanning from April 1, 1996, to Dec 31, 2012. We determined the prevalence of select comorbidities (cardiovascular, respiratory, liver, and renal diseases, and non-AIDS defining cancers because of their high prevalence among PLHIV) by age and sex by use of case-finding algorithms. Deaths were obtained from a vital event registry from British Columbia, Canada. Comorbid-specific HALE was estimated from 20 years of age by HIV status and sex. For each comorbidity, a healthy state was defined as the proportion of life expectancy comorbid-free, and was adjusted on the probability of occurrence of other different comorbidities. The sensitivity of HALE estimates was assessed to the sequencing of select comorbidities for the dependent comorbidity adjustments. FINDINGS: Our sample consisted of electronic health records from 9310 HIV-infected and 510 313 uninfected adults over the period April 1, 1996, to Dec 31, 2012. These individuals contributed 49 605 deaths and 5 576 841 person-years over the study period. At exactly age 20 years, HALE was about 31 years (SD 0·16) among men living with HIV and 27 years (0·16) among women living with HIV. In the HIV-negative population, HALE was around 58 years (SD 0·02) for men and 63 years (0·02) for women. These results seem independent of ordering. However, PLHIV, particularly women living with HIV, had much shorter overall life expectancies than did their HIV-negative counterparts in the general population [29·1 years (SD 0·1) vs 65·4 years (0·1)], and thus spent less time in a healthy state. INTERPRETATION: Although we noted little differences in the levels of morbidity compression by HIV status, PLHIV-especially women living with HIV-spent less time in a healthy state. Expanded service delivery interventions to address complex care needs of ageing PLHIV are crucial to address shorter life expectancies, and improve their healthy states. FUNDING: Canadian Institutes of Health Research.

Effects of a switch from tenofovir- to abacavir-based antiretroviral therapy, with or without atazanavir, on renal function.

INTRODUCTION: Tenofovir disoproxil fumarate (TDF)-associated renal dysfunction may abate when TDF is replaced with abacavir (ABC). The extent to which the third drug atazanavir contributes to renal dysfunction is unclear. METHODS: A retrospective analysis was conducted on adults who had plasma viral load (pVL)<200 copies/mL for≥six months while receiving TDF/lamivudine (3TC) - or TDF/emtricitabine (FTC)-based antiretroviral therapy (ART), then switched to ABC/3TC while retaining the third drug in the ART regimen. CD4, pVL, creatinine, estimated glomerular filtration rate (eGFR), serum phosphorus, urine albumin to creatinine ratio and serum lipids were compared between pre-switch baseline and 3, 6 and 12 months after the switch to ABC. RESULTS: A total of 286 patients switched from TDF to ABC between 2004 and 2014: 232 (81%) male, median age 48 years (interquartile range (IQR) 42, 56). The third drug was atazanavir (± ritonavir) in 141 (49%) cases. The pVL was<50 copies/mL in 93 to 96% at all time points. Median serum creatinine was 93 µmol/L (IQR 80-111) at baseline and decreased to 88 µmol/L (IQR 78-98) at 12 months after the switch to ABC. Median eGFR increased from 74 (IQR 60-88) mL/min at baseline to 80 mL/min (IQR 69-89) at 12 months. Results were not significantly different between patients on atazanavir versus those on another third drug. CONCLUSIONS: Viral suppression was maintained among patients who switched from TDF/3TC or TDF/FTC to ABC/3TC. Serum creatinine and eGFR improved up to 12 months after switching to ABC/3TC, irrespective of whether or not patients were also receiving atazanavir±ritonavir.

Quantifying the effect of health status on health care utilization using a preference-based health measure.

The purpose of this study was to quantify the effect of health status on current and future payments and number of visits to health professionals in a large, representative community sample in British Columbia, Canada. The study population was comprised of all respondents to the 1994/5 cycle of the Canadian National Population Health Survey (NPHS) who were 12 years of age or older and residing in the province of British Columbia (N = 2084). Health status was measured with the Health Utilities Index (HUI). Two outcomes were defined for each subject: (a) the sum of all healthcare costs covered by the Medical Services Plan, incurred during a given fiscal year, and (b) the total number of visits to all health practitioners during the same year. Outcome data were obtained for a period 1994-1998. We examined the relationship between the HUI and healthcare use in a multivariate log-linear model. In the full sample, better health in 1994-1995 was associated with lower healthcare cost and lower number of visits from 1994 through 1998. The overall adjusted cost ratio was 0.89 (99% CI = 0.85, 0.94) and the overall adjusted visit ratio was 0.91 (99% CI + 0.87, 0.95). The effect of health status on the costs of care and on the number of visits was similar in men and women, was stronger in persons less than 45 years of age compared to those 45+, and was not different according to place of residence. We conclude that the HUI is a strong predictor of health services use over 5 years. A 0.1 improvement in health utility is associated with a 10% reduction in the costs of care and number of visits to health professionals.