TRENDS, PREDICTORS AND OUTCOMES ASSOCIATED WITH UNSTRUCTURED TREATMENT INTERRUPTIONS AMONG HIV-POSITIVE INDIVIDUALS ON ANTIRETROVIRAL THERAPY IN CANADA

Background The expanded use of combination antiretroviral therapy (cART) has dramatically enhanced the quality of care and life expectancy of HIV-positive individuals. However, incomplete adherence and treatment interruptions (TIs) due to treatment fatigue, side effects and cART toxicities have emerged as major challenges to the full realization of the therapeutic promise of cART. Despite the relatively high frequency of TIs, their determinants and outcomes are still not well-characterized. Methods Trends, predictors and consequences of treatment interruption (TI) and resumption in two study populations were estimated. First, the Longitudinal Investigations into Supportive and Ancillary health services (LISA) is a cross-sectional study of hard-to-reach individuals on cART in British Columbia. Between 2007 and 2010, 1000 participants were interviewed about sociodemographic and clinical factors. Using pharmacy recording, TIs were defined as a patient-initiated interruption in treatment of at least 90 days during the 12 months preceding or following the study interview. Multivariable logistic regression was used to identify factors associated with treatment interruption. The second study, the Canadian Observational Cohort (CANOC) collaboration, is composed of treatment-naïve HIV-positive individuals who initiated cART between 2000-2011. TIs were defined as interruptions in cART for a period of at least 90 days. Cox proportional hazards regression was used to identify determinants and consequences of cART interruption and resumption. Results Of 768 participants included in the LISA study, 15% had a TI recorded during the study window. In multivariable analysis, TIs were significantly associated with current illicit drug use (adjusted odds ratio (aOR): 1.68, 95% confidence interval [CI] Of 768 participants included in the LISA study, 15% had a TI recorded during the study window. In multivariable analysis, TIs were significantly associated with current illicit drug use (adjusted odds ratio (aOR): 1.68, 95% confidence interval [CI: 1.05-2.68); <95% adherence in the first year of treatment (aOR: 2.68, 95% CI: 1.67-4.12); living with more than one person (aOR: 1.95; 95% CI: 1.22-3.14) or on the street (aOR: 5.08, 95% CI: 1.72-14.99) compared to living alone; poor perception of overall health (aOR: 1.64 95% CI: 1.05-2.55); being unemployed (aOR: 2.22, 95% CI: 1.16-4.23); and younger age at interview (aOR: 0.57, 95% CI: 0.44-0.75, per 10 year increment). A total of 7,633 CANOC participants initiating cART between 2000 and 2011, of whom 1,860 (24.5%) had at least one TI ≥90 days. The prevalence of TI in the first calendar year of cART decreased by half over the study period. Predictors of a first TI were female sex (adjusted hazard ratio (aHR): 1.59, 95% CI: 1.33-1.92), Aboriginal ancestry (aHR: 1.67, 1.27-2.20), a history of injecting drug use (aHR: 1.43, CI: 1.09-1.89), hepatitis C antibody seropositivity (aHR: 2.17, CI: 1.68-2.79), a baseline CD4 cell count above 350 cells/mm3 versus less than 200 cells/mm3 (aHR: 1.46, CI: 1.17-1.81) and use of zidovudine versus tenofovir in the initial cART regimen (aHR: 2.47, CI: 1.92-3.20). Factors protective against TI were older age (aHR: 0.79, CI: 0.73-0.87), higher HIV plasma viral load (log10) (aHR: 0.87, CI: 0.78-0.97) and residence in Ontario (aHR: 0.55, CI: 0.43-0.70) or Quebec (aHR: 0.42, CI: 0.31-0.57) versus British Columbia (BC). Factors predicting resumption of treatment after a first TI included male sex, residence in BC, older age, more recent cART initiation and a CD4 cell count <200 cells/mm3 at cART initiation (all p<0.05). TIs were associated with increased risk of mortality (aHR: 1.79, CI: (1.49-2.16)) after adjusting for socio-demographic and clinical factors. Conclusions Despite significant improvements in cART since its advent and the decreasing prevalence of TIs, gaps in treatment remain relatively common. As cART is propagated at increasing levels globally, and the impetus to provide treatment earlier in the course of HIV infection for individual and public health benefits gains momentum, ensuring continuity of treatment becomes even more vital. Strategies to support continuous HIV treatment are needed to maximize the benefits of cART

Mortality According to CD4 Count at Start of Combination Antiretroviral Therapy Among HIV-infected Patients Followed for up to 15 Years After Start of Treatment: Collaborative Cohort Study.

BACKGROUND: CD4 count at start of combination antiretroviral therapy (ART) is strongly associated with short-term survival, but its association with longer-term survival is less well characterized. METHODS: We estimated mortality rates (MRs) by time since start of ART (&lt;0.5, 0.5-0.9, 1-2.9, 3-4.9, 5-9.9, and ≥10 years) among patients from 18 European and North American cohorts who started ART during 1996-2001. Piecewise exponential models stratified by cohort were used to estimate crude and adjusted (for sex, age, transmission risk, period of starting ART [1996-1997, 1998-1999, 2000-2001], and AIDS and human immunodeficiency virus type 1 RNA at baseline) mortality rate ratios (MRRs) by CD4 count at start of ART (0-49, 50-99, 100-199, 200-349, 350-499, ≥500 cells/µL) overall and separately according to time since start of ART. RESULTS: A total of 6344 of 37 496 patients died during 359 219 years of follow-up. The MR per 1000 person-years was 32.8 (95% confidence interval [CI], 30.2-35.5) during the first 6 months, declining to 16.0 (95% CI, 15.4-16.8) during 5-9.9 years and 14.2 (95% CI, 13.3-15.1) after 10 years' duration of ART. During the first year of ART, there was a strong inverse association of CD4 count at start of ART with mortality. This diminished over the next 4 years. The adjusted MRR per CD4 group was 0.97 (95% CI, .94-1.00; P = .054) and 1.02 (95% CI, .98-1.07; P = .32) among patients followed for 5-9.9 and ≥10 years, respectively. CONCLUSIONS: After surviving 5 years of ART, the mortality of patients who started ART with low baseline CD4 count converged with mortality of patients with intermediate and high baseline CD4 counts

First occurrence of diabetes, chronic kidney disease, and hypertension among North American HIV-infected adults, 2000-2013

Background: There remains concern regarding the occurrence of noncommunicable diseases (NCDs) among individuals aging with human immunodeficiency virus (HIV), but few studies have described whether disparities between demographic subgroups are present among individuals on antiretroviral therapy (ART) with access to care. Methods: We assessed the first documented occurrence of type 2 diabetes mellitus (DM), chronic kidney disease (CKD), and treated hypertension (HTN) by age, sex, and race within the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). HIV-infected adults (≥18 years) who initiated ART were observed for first NCD occurrence between 1 January 2000 and 31 December 2013. Cumulative incidences as of age 70 were estimated accounting for the competing risk of death; Poisson regression was used to compare rates of NCD occurrence by demographic subgroup. Results: We included >50000 persons with >250000 person-years of follow-up. Median follow-up was 4.7 (interquartile range, 2.4–8.1) years. Rates of first occurrence (per 100 person-years) were 1.2 for DM, 0.6 for CKD, and 2.6 for HTN. Relative to non-black women, the cumulative incidences were increased in black women (68% vs 51% for HTN, 52% vs 41% for DM, and 38% vs 35% for CKD; all P < .001); this disparity was also found among men (73% vs 60% for HTN, 44% vs 34% for DM, and 30% vs 25% for CKD; all P < .001). Conclusions: Racial disparities in the occurrence of DM, CKD, and HTN emphasize the need for prevention and treatment options for these HIV populations receiving care in North America

Geographic Variations in Retention in Care among HIV-Infected Adults in the United States

ObjectiveTo understand geographic variations in clinical retention, a central component of the HIV care continuum and key to improving individual- and population-level HIV outcomes.DesignWe evaluated retention by US region in a retrospective observational study.MethodsAdults receiving care from 2000–2010 in 12 clinical cohorts of the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) contributed data. Individuals were assigned to Centers for Disease Control and Prevention (CDC)-defined regions by residential data (10 cohorts) and clinic location as proxy (2 cohorts). Retention was ≥2 primary HIV outpatient visits within a calendar year, >90 days apart. Trends and regional differences were analyzed using modified Poisson regression with clustering, adjusting for time in care, age, sex, race/ethnicity, and HIV risk, and stratified by baseline CD4+ count.ResultsAmong 78,993 adults with 444,212 person-years of follow-up, median time in care was 7 years (Interquartile Range: 4–9). Retention increased from 2000 to 2010: from 73% (5,000/6,875) to 85% (7,189/8,462) in the Northeast, 75% (1,778/2,356) to 87% (1,630/1,880) in the Midwest, 68% (8,451/12,417) to 80% (9,892/12,304) in the South, and 68% (5,147/7,520) to 72% (6,401/8,895) in the West. In adjusted analyses, retention improved over time in all regions (p<0.01, trend), although the average percent retained lagged in the West and South vs. the Northeast (p<0.01).ConclusionsIn our population, retention improved, though regional differences persisted even after adjusting for demographic and HIV risk factors. These data demonstrate regional differences in the US which may affect patient care, despite national care recommendations

Laboratory Measures as Proxies for Primary Care Encounters: Implications for Quantifying Clinical Retention Among HIV-Infected Adults in North America

Because of limitations in the availability of data on primary care encounters, patient retention in human immunodeficiency virus (HIV) care is often estimated using laboratory measurement dates as proxies for clinical encounters, leading to possible outcome misclassification. This study included 83,041 HIV-infected adults from 14 clinical cohorts in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) who had ≥1 HIV primary care encounters during 2000–2010, contributing 468,816 person-years of follow-up. Encounter-based retention (REB) was defined as ≥2 encounters in a calendar year, ≥90 days apart. Laboratory-based retention (RLB) was defined similarly, using the dates of CD4-positive cell counts or HIV-1 RNA measurements. Percentage of agreement and the κ statistic were used to characterize agreement between RLB and REB. Logistic regression with generalized estimating equations and stabilized inverse-probability-of-selection weights was used to elucidate temporal trends and the discriminatory power of RLB as a predictor of REB, accounting for age, sex, race/ethnicity, primary HIV risk factor, and cohort site as potential confounders. Both REB and RLB increased from 2000 to 2010 (from 67% to 78% and from 65% to 77%, respectively), though REB was higher than RLB throughout (P < 0.01). RLB agreed well with REB (80%–86% agreement; κ = 0.55–0.62, P < 0.01) and had a strong, imperfect ability to discriminate between persons retained and not retained in care by REB (C statistic: C = 0.81, P < 0.05). As a proxy for REB, RLB had a sensitivity and specificity of 84% and 77%, respectively, with misclassification error of 18%

Impact of Age on Retention in Care and Viral Suppression

Retention in care is important for all HIV-infected persons and is strongly associated with initiation of antiretroviral therapy and viral suppression. However, it is unclear how retention in care and age interact to effect viral suppression. We evaluated whether the association between retention and viral suppression differed by age at entry into care

Association between U.S. State AIDS Drug Assistance Program (ADAP) Features and HIV Antiretroviral Therapy Initiation, 2001–2009

BackgroundU.S. state AIDS Drug Assistance Programs (ADAPs) are federally funded to provide antiretroviral therapy (ART) as the payer of last resort to eligible persons with HIV infection. States differ regarding their financial contributions to and ways of implementing these programs, and it remains unclear how this interstate variability affects HIV treatment outcomes.MethodsWe analyzed data from HIV-infected individuals who were clinically-eligible for ART between 2001 and 2009 (i.e., a first reported CD4+ <350 cells/uL or AIDS-defining illness) from 14 U.S. cohorts of the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). Using propensity score matching and Cox regression, we assessed ART initiation (within 6 months following eligibility) and virologic suppression (within 1 year) based on differences in two state ADAP features: the amount of state funding in annual ADAP budgets and the implementation of waiting lists. We performed an a priori subgroup analysis in persons with a history of injection drug use (IDU).ResultsAmong 8,874 persons, 56% initiated ART within six months following eligibility. Persons living in states with no additional state contribution to the ADAP budget initiated ART on a less timely basis (hazard ratio [HR] 0.73, 95% CI 0.60–0.88). Living in a state with an ADAP waiting list was not associated with less timely initiation (HR 1.12, 95% CI 0.87–1.45). Neither additional state contributions nor waiting lists were significantly associated with virologic suppression. Persons with an IDU history initiated ART on a less timely basis (HR 0.67, 95% CI 0.47–0.95).ConclusionsWe found that living in states that did not contribute additionally to the ADAP budget was associated with delayed ART initiation when treatment was clinically indicated. Given the changing healthcare environment, continued assessment of the role of ADAPs and their features that facilitate prompt treatment is needed

Using observational data to emulate a randomized trial of dynamic treatment switching strategies

BACKGROUND: When a clinical treatment fails or shows suboptimal results, the question of when to switch to another treatment arises. Treatment switching strategies are often dynamic because the time of switching depends on the evolution of an individual's time-varying covariates. Dynamic strategies can be directly compared in randomized trials. For example, HIV-infected individuals receiving antiretroviral therapy could be randomized to switching therapy within 90 days of HIV-1 RNA crossing above a threshold of either 400 copies/ml (tight-control strategy) or 1000 copies/ml (loose-control strategy).METHODS: We review an approach to emulate a randomized trial of dynamic switching strategies using observational data from the Antiretroviral Therapy Cohort Collaboration, the Centers for AIDS Research Network of Integrated Clinical Systems and the HIV-CAUSAL Collaboration. We estimated the comparative effect of tight-control vs. loose-control strategies on death and AIDS or death via inverse-probability weighting.RESULTS: Of 43 803 individuals who initiated an eligible antiretroviral therapy regimen in 2002 or later, 2001 met the baseline inclusion criteria for the mortality analysis and 1641 for the AIDS or death analysis. There were 21 deaths and 33 AIDS or death events in the tight-control group, and 28 deaths and 41 AIDS or death events in the loose-control group. Compared with tight control, the adjusted hazard ratios (95% confidence interval) for loose control were 1.10 (0.73, 1.66) for death, and 1.04 (0.86, 1.27) for AIDS or death.CONCLUSIONS: Although our effective sample sizes were small and our estimates imprecise, the described methodological approach can serve as an example for future analyses

Incidence of AIDS-Defining Opportunistic Infections in a Multicohort Analysis of HIV-infected Persons in the United States and Canada, 2000–2010

Background. There are few recent data on the rates of AIDS-defining opportunistic infections (OIs) among human immunodeficiency virus (HIV)–infected patients in care in the United States and Canada

Trends and Disparities in Antiretroviral Therapy Initiation and Virologic Suppression Among Newly Treatment-Eligible HIV-Infected Individuals in North America, 2001–2009

Background. Since the mid-1990s, effective antiretroviral therapy (ART) regimens have improved in potency, tolerability, ease of use, and class diversity. We sought to examine trends in treatment initiation and resulting human immunodeficiency virus (HIV) virologic suppression in North America between 2001 and 2009, and demographic and geographic disparities in these outcomes