A tale of two countries:all-cause mortality among people living with HIV and receiving combination antiretroviral therapy in the UK and Canada

Objectives We sought to compare all-cause mortality of people living with HIV and accessing care in Canada and the UK. Methods Individuals from the Canadian Observational Cohort (CANOC) collaboration and UK Collaborative HIV Cohort (UK CHIC) study who were aged ≥ 18 years, had initiated antiretroviral therapy (ART) for the first time between 2000 and 2012 and who had acquired HIV through sexual transmission were included in the analysis. Cox regression was used to investigate the difference in mortality risk between the two cohort collaborations, accounting for loss to follow-up as a competing risk. Results A total of 19 960 participants were included in the analysis (CANOC, 4137; UK CHIC, 15 823). CANOC participants were more likely to be older [median age 39 years (interquartile range (IQR): 33, 46 years) vs. 36 years (IQR: 31, 43 years) for UK CHIC participants], to be male (86 vs. 73%, respectively), and to report men who have sex with men (MSM) sexual transmission risk (72 vs. 56%, respectively) (all P < 0.001). Overall, 762 deaths occurred during 98 798 person-years (PY) of follow-up, giving a crude mortality rate of 7.7 per 1000 PY [95% confidence interval (CI): 7.1, 8.3 per 1000 PY]. The crude mortality rates were 8.6 (95% CI: 7.4, 10.0) and 7.5 (95% CI: 6.9, 8.1) per 1000 PY among CANOC and UK CHIC study participants, respectively. No statistically significant difference in mortality risk was observed between the cohort collaborations in Cox regression accounting for loss to follow-up as a competing risk (adjusted hazard ratio 0.86; 95% CI: 0.72–1.03). Conclusions Despite differences in national HIV care provision and treatment guidelines, mortality risk did not differ between CANOC and UK CHIC study participants who acquired HIV through sexual transmission

Predictors of CD4:CD8 ratio normalization and its effect on health outcomes in the era of combination antiretroviral therapy.

HIV leads to CD4:CD8 ratio inversion as immune dysregulation progresses. We examined the predictors of CD4:CD8 normalization after combination antiretroviral therapy (cART) and determined whether normalization is associated with reduced progression to AIDS-defining illnesses (ADI) and death.A Canadian cohort of HIV-positive adults with CD4:CD830 days apart, and (2) ADI and death from all causes were assessed using adjusted proportional hazards models.4206 patients were studied for a median of 2.77 years and 306 (7.2%) normalized their CD4:CD8 ratio. Factors associated with achieving a normal CD4:CD8 ratio were: baseline CD4+ T-cells >350 cells/mm(3), baseline CD8+ T-cells <500 cells/mm(3), time-updated HIV RNA suppression, and not reporting sex with other men as a risk factor. There were 213 ADIs and 214 deaths in 13476 person-years of follow-up. Achieving a normal CD4:CD8 ratio was not associated with time to ADI/death.In our study, few individuals normalized their CD4:CD8 ratios within the first few years of initiating modern cART. This large study showed no additional short-term predictive value of the CD4:CD8 ratio for clinical outcomes after accounting for other risk factors including age and HIV RNA

Cohort profile: the Canadian Observational Cohort collaboration

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Comparison of atazanavir/ritonavir and darunavir/ritonavir based antiretroviral therapy for antiretroviral naïve patients

Background: Atazanavir/ritonavir and darunavir/ritonavir are common protease inhibitor-based regimens for treating patients with HIV. Studies comparing these drugs in clinical practice are lacking. Methods: We conducted a retrospective cohort study of antiretroviral naïve participants in the Canadian Observational Cohort (CANOC) collaboration initiating atazanavir/ritonavir- or darunavir/ritonavir-based treatment. We used separate Fine and Gray competing risk regression models to compare times to regimen failure (composite of virologic failure or discontinuation for any reason). Additional endpoints included virologic failure, discontinuation due to virologic failure, discontinuation for other reasons, and virologic suppression. Results: We studied 222 patients treated with darunavir/ritonavir and 1791 patients treated with atazanavir/ritonavir. Following multivariable adjustment, there was no difference between darunavir/ritonavir and atazanavir-ritonavir in the risk of regimen failure (adjusted hazard ratio 0.76, 95% CI 0.56 to 1.03) Darunavir/ritonavir-treated patients were at lower risk of virologic failure relative to atazanavir/ritonavir treated patients (aHR 0.50, 95% CI 0.28 to 0.91), findings driven largely by high rates of virologic failure among atazanavir/ritonavir-treated patients in the province of British Columbia. Of 108 discontinuations due to virologic failure, all occurred in patients starting atazanavir/ritonavir. There was no difference between regimens in time to discontinuation for reasons other than virologic failure (aHR 0.93; 95% CI 0.65 to 1.33) or virologic suppression (aHR 0.99, 95% CI 0.82 to 1.21). Conclusions: The risk of regimen failure was similar between patients treated with darunavir/ritonavir and atazanavir/ritonavir. Although darunavir/ritonavir was associated with a lower risk of virologic failure relative to atazanavir/ritonavir, this difference varied substantially by Canadian province and likely reflects regional variation in prescribing practices and patient characteristics.Other UBCNon UBCReviewedFacult

Trends in Use of Combination Antiretroviral Therapy and Treatment Response from 2000 to 2016 in the Canadian Observational Cohort (CANOC): A Longitudinal Cohort Study

Background: Advances in treatment have turned HIV from a terminal illness to a more manageable condition. Over the past 20 years, there have been considerable changes to HIV treatment guidelines, including changes in preferred antiretrovirals and timing of initiation of combination antiretroviral therapy (cART). Objective: To examine real-world trends in cART utilization, viral control, and immune reconstitution among people living with HIV in Canada. Methods: Data were obtained from the Canadian Observational Cohort (CANOC). CANOC participants were eligible if they were antiretroviral therapy–naive at entry and initiated 3 or more antiretrovirals on or after January 1, 2000; if they were at least 18 years of age at treatment initiation; if they were residing in Canada; and if they had at least 1 viral load determination and CD4 count within 1 year of CANOC entry. Baseline and annual mean CD4 counts were categorized as less than 200, 200–350, 351–500, and more than 500 cells/mm3. Annual mean viral loads were reported as suppressed (&lt; 50 copies/mL), low (50–199 copies/mL), or high detectable (≥ 200 copies/mL). The cART regimens were reported yearly. Results: All CANOC participants were included (n = 13 040). Over the study period, the proportion of individuals with an annual mean CD4 count above 500 cells/mm3 increased from 16.3% to 65.8%, while the proportion of individuals with an undetectable mean viral load increased from 10.6% to 83.2%. As of 2007, the most commonly prescribed 2-agent nucleoside reverse transcriptase inhibitor backbone was tenofovir disoproxil fumarate and emtricitabine. In terms of third agents, non-nucleoside reverse transcriptase inhibitors were the most common class in the periods 2000–2003 and 2014–2015, protease inhibitors were most common in the period 2004–2013, and integrase inhibitors were most common in 2016. Conclusions: Concordance with treatment guidelines was demonstrated over time with respect to cART prescribing and immunologic and virologic response. RÉSUMÉ Contexte : Les progrès effectués dans le domaine des traitements ont transformé le VIH. Celui-ci est passé d’une maladie en phase terminale à une maladie plus gérable. Au cours des 20 dernières années, des changements considérables ont eu lieu dans les directives de traitement du VIH, y compris des changements dans les antirétroviraux privilégiés et le moment de l’initiation de la thérapie antirétrovirale combinée (TARc). Objectif : Examiner les tendances réelles de l’utilisation de la TARc, du contrôle viral et de la reconstitution immunitaire chez les personnes vivant avec le VIH au Canada. Méthodes : Les données ont été obtenues auprès de la Canadian Observational Cohort (CANOC). Les participants à la CANOC étaient admissibles s’ils n’avaient jamais reçu de traitement antirétroviral à l’entrée et avaient commencé la prise de 3 antirétroviraux ou plus le 1er janvier 2000 ou après cette date; s’ils avaient au moins 18 ans au moment du début du traitement; s’ils résidaient au Canada; et s’ils avaient au moins 1 charge virale et un nombre de CD4 dans l’année suivant l’entrée à la CANOC. Les numérations initiales et annuelles moyennes de CD4 ont été classées comme inférieures à 200, 200 à 350, 351 à 500, et supérieures à 500 cellules/mm3. Les charges virales moyennes annuelles ont été signalées comme supprimées (&lt; 50 copies/mL), faibles (50 à 199 copies/mL) ou élevées détectables (≥ 200 copies/mL). Les régimes de la TARc ont été rapportés chaque année. Résultats : Tous les participants à la CANOC ont été inclus (n = 13 040). Au cours de la période d’étude, la proportion de personnes ayant une numération CD4 moyenne annuelle supérieure à 500 cellules/mm3 est passée de 16,3 % à 65,8 %, tandis que la part de personnes ayant une charge virale moyenne indétectable est passée de 10,6 % à 83,2 %. En 2007, la bithérapie de base d’inhibiteurs nucléosidiques de la transcriptase inverse la plus couramment prescrite était le fumarate de ténofovir disoproxil et l’emtricitabine. En matière de troisièmes agents, la classe la plus courante dans les périodes 2000-2003 et 2014-2015 était les inhibiteurs non nucléosidiques de la transcriptase inverse; les plus courants dans la période 2004-2013 étaient les inhibiteurs de protéase; et les inhibiteurs de l’intégrase étaient les plus courants en 2016. Conclusions : La concordance avec les directives de traitement a été démontrée au fil du temps en ce qui concerne la prescription de la cART et la réponse immunologique et virologique

Predictors of viral suppression and rebound among HIV-positive men who have sex with men in a large multi-site Canadian cohort

Background: Gay, bisexual and other men who have sex with men (MSM) are disproportionately affected by HIV in Canada. Combination antiretroviral therapy has been shown to dramatically decrease progression to AIDS, premature death and HIV transmission. However, there are no comprehensive data regarding combination antiretroviral therapy outcomes among this population. We sought to identify socio-demographic and clinical correlates of viral suppression and rebound. Methods: Our analysis included MSM participants in the Canadian Observational Cohort, a multi-site cohort of HIV-positive adults from Canada’s three most populous provinces, aged ≥18 years who first initiated combination antiretroviral therapy between 2000 and 2011. We used accelerated failure time models to identify factors predicting time to suppression (2 measures 200 copies/mL ≥30 days apart). Results: Of 2,858 participants, 2,448 (86 %) achieved viral suppression in a median time of 5 months (Q1–Q3: 3–7 months). Viral suppression was significantly associated with later calendar year of antiretroviral therapy initiation, no history of injection drug use, lower baseline viral load, being on an initial regimen consisting of non-nucleoside reverse-transcriptase inhibitors, and older age. Among those who suppressed, 295 (12 %) experienced viral rebound. This was associated with earlier calendar year of antiretroviral therapy initiation, injection drug use history, younger age, higher baseline CD4 cell count, and living in British Columbia. Conclusions: Further strategies are required to optimize combination antiretroviral therapy outcomes in men who have sex with men in Canada, specifically targeting younger MSM and those with a history of injection drug use.Medicine, Faculty ofOther UBCNon UBCReviewedFacult

A CD4+ cell count <200 cells per cubic millimeter at 2 years after initiation of combination antiretroviral therapy is associated with increased mortality in HIV-infected individuals with viral suppression

OBJECTIVE To determine the long-term impact of immunologic discordance (viral load <50 copies/mL and CD4+ count <=200 cells/mm3) in antiretroviral-naive patients initiating combination antiretroviral therapy (cART). METHODS Our analysis included antiretroviral-naive individuals from a population-based Canadian Observational Cohort that initiated cART after January 1, 2000, and achieved virologic suppression. Multivariable Cox proportional hazards regression was used to examine the association between 1-year and 2-year immunologic discordance and time to death from all-causes. Correlates of immunologic discordance were assessed with logistic regression. RESULTS Immunologic discordance was observed in 19.9% (404 of 2028) and 10.2% (176 of 1721) of individuals at 1 and 2 years after cART initiation, respectively. Two-year immunologic discordance was associated with an increased risk of death [adjusted hazard ratio = 2.69; 95% confidence interval (CI): 1.26 to 5.78]. One-year immunologic discordance was not associated with death (adjusted hazard ratio = 1.12; 95% CI: 0.54 to 2.30). Two-year immunologic discordance was associated with older age (aOR per decade = 1.23; 95% CI: 1.03 to 1.48), male gender (aOR = 1.86; 95% CI: 1.09 to 3.16), injection drug use (aOR = 2.75; 95% CI: 1.81 to 4.17), and lower baseline CD4+ count (aOR per 100 cells = 0.24; 95% CI: 0.19 to 0.31) and viral load (aOR per log10 copies/mL = 0.46; 95% CI: 0.33 to 0.65). CONCLUSIONS Immunologic discordance after 2 years of cART in antiretroviral-naive individuals was significantly associated with an increased risk of mortality