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