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Objectives: To determine the time to CD4 : CD8 ratio normalization among Canadian adults living with HIV in the modern ART era. To identify characteristics associated with ratio normalization., Patients and Methods: Retrospective analysis of the Canadian Observational Cohort (CANOC), an interprovincial cohort of ART-naive adults living with HIV, recruited from 11 treatment centres across Canada. We studied participants initiating ART between 1 January 2011 and 31 December 2016 with baseline CD4 : CD8 ratio <1.0 and ≥2 follow-up measurements. Normalization was defined as two consecutive CD4 : CD8 ratios ≥1.0. Kaplan-Meier estimates and log-rank tests described time to normalization. Univariable and multivariable proportional hazards (PH) models identified factors associated with ratio normalization., Results: Among 3218 participants, 909 (28%) normalized during a median 2.6 years of follow-up. Participants with higher baseline CD4+ T-cell count were more likely to achieve normalization; the probability of normalization by 5 years was 0.68 (95% CI 0.62-0.74) for those with baseline CD4+ T-cell count >500 cells/mm3 compared with 0.16 (95% CI 0.11-0.21) for those with ≤200 cells/mm3 (P < 0.0001). In a multivariable PH model, baseline CD4+ T-cell count was associated with a higher likelihood of achieving ratio normalization (adjusted HR = 1.5, 95% CI 1.5-1.6 per 100 cells/mm3, P < 0.0001). After adjusting for baseline characteristics, time-dependent ART class was not associated with ratio normalization., Conclusions: Early ART initiation, at higher baseline CD4+ T-cell counts, has the greatest impact on CD4 : CD8 ratio normalization. Our study supports current treatment guidelines recommending immediate ART start, with no difference in ratio normalization observed based on ART class used., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To determine the impact of valaciclovir on HIV disease progression in treatment-naive HIV-positive adults., Methods: In this fully blind, multicentre, 1:1 randomized placebo-controlled trial, treatment-naive HIV-1-positive adults with CD4 counts 400-900 cells/mm3 and not meeting contemporaneous recommendations for combination ART (cART) were randomized to valaciclovir 500 mg or placebo twice daily, and followed quarterly until having two consecutive CD4 counts ≤350 cells/mm3 or initiating cART for any reason. The primary analysis compared the rate of CD4 count decline by study arm after adjusting for baseline CD4 count and viral load (VL). Secondary analyses compared the rate of CD4 percentage decline, HIV VL, herpes simplex virus (HSV) recurrences and drug-related adverse events. The trial closed after release of the START trial results in August 2015., Results: We enrolled 198 participants in Canada, Brazil, Argentina and the UK. Median (IQR) age was 35 (30-43) years. Baseline CD4 count was 592 (491-694) cells/mm3 and VL was 4.04 (3.5-4.5) log10 copies/mL. Over 276 person-years of follow-up, CD4 counts declined by 49 cells/mm3/year in the valaciclovir arm versus 58 cells/mm3/year in the placebo arm (P = 0.65). No differences were seen in the rate of change in CD4 percentage (-1.2%/year versus -1.7%/year, P = 0.34). VL was 0.27 log10 copies/mL lower in valaciclovir participants overall (P<0.001). Placebo participants had more HSV recurrences (62 versus 21/100 person-years, P < 0.0001) but similar rates of grade ≥2 drug-related adverse events., Conclusions: Unlike prior trials using aciclovir, we found that valaciclovir did not slow CD4 count decline in cART-untreated adults, although power was limited due to premature study discontinuation. Valaciclovir modestly lowered HIV VL.

Poor retention in HIV care is associated with poor clinical outcomes and mortality. Previous studies of predictors of poor retention have been conducted with a wide variety of populations, using different measures of retention, and occasionally have conflicting results. We studied demographic and psychosocial factors associated with inter-visit interval length in a setting of universal health care and modern cART. Patients attending ≥2 appointments with an HIV specialist at the Toronto General Hospital Immunodeficiency Clinic from 2004 to 2013 were studied. A sub-analysis included psychosocial measures from annual questionnaires for Ontario HIV Treatment Network Cohort Study (OCS) participants. Median inter-visit interval and constancy (percentage of 4-month intervals with ≥1 visit) were calculated by patient. Multivariable generalized estimating equation models identified factors associated with inter-visit interval length and intervals ≥12 months. 1591 patients were included. 615 patients completed an OCS questionnaire and were more likely to be older white MSM from Canada with a viral load (VL) <50 copies/ml. The median (IQR) of patients' median inter-visit intervals was 3.15 (2.78, 3.84) months and median (IQR) constancy was 90% (71%, 100%). Two percent of inter-visit intervals were ≥12 months and 25% of patients had ≥1 interval ≥12 months. Longer inter-visit intervals were associated with younger age, white race, earlier calendar year, longer duration of HIV, VL < 50 copies/mL and higher CD4 counts. Patients who were younger, white, had injection drug use as a risk factor, had a longer duration of HIV, and had VL ≥50 copies/mL were more likely to have an inter-visit interval ≥12 months. In the OCS sub-analysis including psychosocial variables, lower levels of depression were associated with longer inter-visit intervals. Retention at this tertiary care centre was high. Efforts to maximize attendance should focus on younger patients and those with substance abuse issues.

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.