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Similar times to virologic suppression and switching or stopping for abacavir (ABC)/3TC and tenofovir (TDF)/FTC in antiretroviral-naive
HIV-positive patients starting therapy
M Loutfy, J Raboud, D Tan, S Blitz, K Chan, C Cooper, N Machouf, M Klein, D Moore, C Tsoukas, S Rourke, A Palmer, J Montaner, R Hogg, and the CANOC Collaboration
Overview
CANOC (Canadian Observational Cohort Collaboration) Key purpose is to evaluate the impact of antiretroviral care on the health
and well being of persons infected with HIV/AIDS across various regions of Canada. Participating cohorts
• BC Centre for Excellence in HIV/AIDS
• Clinique Medicale L’Actuel
• Canadian Co-infection Cohort Study
• EARTH
• Maple Leaf Medical Clinic
• Montreal Chest Institute IDS
• Ontario HIV Treatment Network
• Toronto General Hospital
• University of Ottawa
Background
Both ABC/3TC and TDF/FTC are commonly used NRTI backbones for first-line therapy
BHIVA, EACS guidelines recommend both as first-line HEAT trial
DHHS (US) considers ABC/3TC an “alternative” option ACTG A5202 trial- greater hazard of virologic failure
and safety/tolerability events if baseline VL>100000 Association with myocardial infarction in some studies
Objectives
To compare the time to
Virologic Suppression Switch / Stop of any part of cART regimen Switch / Stop of NRTI backbone
in ARV-naïve adults initiating ABC/3TC- and TDF/FTC- containing cART in CANOC
Methods
Criteria for inclusion in CANOC: HIV+ adults ≥ 18 years residing in Canada ARV-naïve prior to cART First cART date ≥ Jan 1st, 2000 CD4 and VL within 6 mo. prior to starting cART
Criteria for inclusion in this analysis: cART containing ABC/3TC or TDF/FTC with EFV,
NVP, LPV/r or ATV/r ≥ 2 follow-up VL tests available
Methods
Multivariable Weibull proportional hazards regression used to model Time to virologic suppression (VL<50 on 2
consecutive occasions ≥1 month apart) Time to switch / stop of any part of cART regimen Time to switch / stop of NRTI backbone
Primary predictor variable: ABC/3TC vs. TDF/FTC Covariates: age, sex, baseline CD4, baseline VL, 3rd
ARV, IDU, HCV, province, calendar year of initiating cART
Results: Patient characteristicsVariable Total (N=713) ABC/3TC (N=442) TDF/FTC (N=271) p-value
Age (years) 41 (35-46) 41 (34-47) 0.97
MaleFemale
62489
380 (86)62 (14)
244 (90)27 (10)
0.13
British Columbia Ontario Quebec
106326281
100 (22.6)202 (45.7)140 (31.7)
6 (2.2)124 (45.8)141 (52)
<0.001
Injection drug use – Yes (10.5%) No Unknown
47403263
35 (7.9)232 (52.5)175 (39.6)
12 (4.4)171 (63.1)88 (32.5)
0.01
HCV co-infection – Yes (12.2%) No Unknown
75538100
49 (11.1)334 (75.6)59 (13.3)
26 (9.6)204 (75.3)41 (15.1)
0.71
Prior AIDS-defining illness - Yes No
37676
26 (5.9)416 (94.1)
11 (4.1)260 (95.9)
0.39
Baseline CD4 (cells/mm3) 210 (140-290) 240 (160-310) 0.05
Baseline HIV VL (log10 copies/mL) 5.0 (4.4-5.0) 4.8 (4.3-5.0) 0.09
Atazanavir/ritonavirEfavirenzLopinavir/ritonavirNevirapine
23524916960
182 (41.2)133 (30.1)96 (21.7)31 (7)
53 (19.6)116 (42.8)73 (26.9)29 (10.7)
<0.001
Calendar year of starting cART 2006 (2005-2007) 2007 (2007-2008) <0.001
Results: Follow-up and Outcomes
Median follow-up time was ABC/3TC-12 months (IQR 5,23) TDF/FTC- 6 months (IQR 4,12)
Virologic suppression rates at 6 and 12 months 69% and 93% for ABC/3TC 63% and 89% for TDF/FTC
Status of initial cART N ABC/3TC (n=442) TDF/FTC (n=271) P-value
Ongoing Switched 3rd drug only Switched backbone Stopped
4721055680
265 (60)73 (16.5)36 (8.1)68 (15.4)
207 (76.4)32 (11.8)20 (7.4)12 (4.4)
<0.001
Results: Time to virologic suppression, multivariable modelVariable Adjusted Hazard Ratio (95% CI) p-value
Nucleoside backbone: TDF/FTC ABC/3TC
1.001.21 (0.92,1.59) 0.17
Baseline HIV viral load: Below 100000 copies/mL Above 100000 copies/mL
1.000.75 (0.54, 1.04) 0.09
Interaction of ABC/3TC and VL>100000 0.86 (0.58,1.26) 0.44
Age (per 10-year increment) 1.09 (0.99,1.21) 0.08
Province: British Columbia Ontario Quebec
1.000.69 (0.51,0.92)0.51 (0.36,0.72)
0.01<0.001
History of injection drug use: No Yes Unknown
1.000.60 (0.39, 0.90)0.78 (0.62, 0.99)
0.010.04
Baseline CD4 count (per 100 cells/mm3) 1.06 (0.99,1.14) 0.08
3rd antiretroviral agent: Efavirenz Nevirapine Atazanavir/ritonavir Lopinavir/ritonavir
1.000.73 (0.49,1.09)0.83 (0.64,1.06)1.02 (0.80,1.29)
0.120.130.88
Calendar year (per year) 1.10 (1.03,1.17) 0.004
Results: Time to virologic suppression
Results: Time to switch/stop of cART, multivariable model
Variable Adjusted Hazard Ratio (95% CI) p-value
Nucleoside backbone: TDF/FTC ABC/3TC
1.001.08 (0.69,1.68) 0.75
Baseline HIV viral load: Below 100000 copies/mL Above 100000
copies/mL
1.001.22 (0.75, 2.01) 0.43
Interaction of ABC/3TC and VL>100000 0.99 (0.56, 1.77) 0.98
Sex: Female Male
1.000.58 (0.41,0.81) 0.001
Province: British Columbia Ontario Quebec
1.000.53 (0.38, 0.75)0.51 (0.34, 0.75)
<0.001<0.001
3rd antiretroviral agent: Efavirenz Nevirapine Atazanavir/ritonavir Lopinavir/ritonavir
1.001.10 (0.63, 1.91)0.95 (0.66, 1.35)1.78 (1.29, 2.45)
0.750.76
<0.001
Calendar year (per year) 1.18 (1.07, 1.30) 0.001
Results: Time to switch/stop of cART
Results: Time to NRTI switch/stop, multivariable model
Variable Adjusted Hazard Ratio (95% CI) p-value
Nucleoside backbone: TDF/FTC ABC/3TC
1.001.30 (0.68,2.48) 0.43
Baseline HIV viral load: Below 100000 copies/mL Above 100000 copies/mL
1.001.70 (0.84,3.43)
0.14
Interaction of ABC/3TC and VL>100000 0.67 (0.30,1.49) 0.32
Province: British Columbia Ontario Quebec
1.000.68 (0.43,1.09)0.80 (0.44,1.46)
0.110.47
History of injection drug use: No Yes Unknown
1.002.76 (1.55,4.92)1.58 (0.99,2.52)
<0.0010.06
3rd antiretroviral agent: Efavirenz Nevirapine Atazanavir/ritonavir Lopinavir/ritonavir
1.001.26 (0.59,2.67)1.63 (1.04,2.55)1.05 (0.65,1.71)
0.550.030.84
Calendar year (per year) 1.10 (0.96,1.26) 0.17
Results: Time to switch/stop of NRTIs
Results: Time to Virologic Failure (ACTG Def’n)
Limitations
ABC/3TC arm included Once-daily & twice-daily dosing Separate & fixed dose combination tablets
Reasons for switching / stopping therapy not available in CANOC database
Observational design means that allocation to ART was not random
Conclusions
Among ART-naïve HIV+ adults in CANOC, no difference observed between ABC/3TC and TDF/FTC in time to Virologic Suppression Switch / Stop of any part of cART regimen Switch / Stop of NRTI backbone
Findings support use of either ABC/3TC or TDF/FTC as reasonable first-line NRTI backbone choices
The CANOC Collaboration includes: Community Advisory Committee: Sean Hosein (Chair), Bruno Lemay, Shari Margolese, Evelyne Ssengendo; Investigators: Gloria Aykroyd (Ontario HIV Treatment Network), Louise Balfour (University of Ottawa, Contributes to the Ontario HIV Treatment
Network), Ahmed Bayoumi (University of Toronto, Contributes to the Ontario HIV Treatment Network), John Cairney (University of Toronto, Contributes to the Ontario HIV Treatment Network), Liviana Calzavara (University of Toronto, Contributes to the Ontario HIV Treatment Network), Curtis Cooper (University of Ottawa, Contributes to the Ontario HIV Treatment Network), Fred Crouzat (Maple Leaf Medical Clinic), Kevin Gough (University of Toronto, Contributes to the Ontario HIV Treatment Network), Silvia Guillemi (British Columbia Centre for Excellence in HIV/AIDS,
University of British Columbia), Richard Harrigan (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), Marianne Harris (British Columbia Centre for Excellence in HIV/AIDS), George Hatzakis (McGill University), Robert Hogg (British Columbia Centre for
Excellence in HIV/AIDS, Simon Fraser University), Don Kilby (University of Ottawa, Ontario HIV Treatment Network), Marina Klein (Montreal Chest Institute Immunodeficiency Service Cohort, McGill University), Richard Lalonde (The Montreal Chest Institute Immunodeficiency Service Cohort and McGill University), Viviane Lima (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), Mona Loutfy (University of
Toronto, Maple Leaf Medical Clinic), Nima Machouf (Clinique Medicale l’Actuel, University de Montreal), Ed Mills (British Columbia Centre for Excellence in HIV/AIDS, University of Ottawa), Peggy Millson (University of Toronto, Contributes to the Ontario HIV Treatment Network), Julio
Montaner (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), David Moore (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), Alexis Palmer (British Columbia Centre for Excellence in HIV/AIDS), Janet Raboud
(University of Toronto, University Health Network), Anita Rachlis (University of Toronto, Contributes to the Ontario HIV Treatment Network), Stanley Read (University of Toronto, Contributes to the Ontario HIV Treatment Network), Sean Rourke (Ontario HIV Treatment Network, University of
Toronto), Marek Smieja (McMaster University, Contributes to the Ontario HIV Treatment Network), Irving Salit (University of Toronto, Contributes to the Ontario HIV Treatment Network), Darien Taylor (Canadian AIDS Treatment Information Exchange Contributes to the Ontario HIV Treatment
Network), Benoit Trottier (Clinique Medicale l’Actuel, University de Montreal), Chris Tsoukas (McGill University), Sharon Walmsley (University of Toronto, Contributes to the Ontario HIV Treatment Network), and Wendy Wobeser (Queens University, Contributes to the Ontario HIV Treatment
Network).
Thank you
For more information about CANOC, please visit
www.canoc.ca
Comparisons and Interpretation
ACTG A5202 RCT ATZr and EFV 3rd agent Partially blinded
Primary End Point Time to Virological Failure
HIV ≥1000 16-24wk HIV ≥200 24wk+
HEAT RCT KLT 3rd agent
Primary End Point Proportion with HIV <50 at wk48