Switching from first ART regimen while virologically suppressed is common in the

CANOC cohort and is associated with increased risk of subsequent virologic failure

M Hull, A Cescon, JM Raboud, MB Klein, S Walmsley, E Ding, W Zhang, S Shurgold, N Machouf, AN Burchell, C Cooper, MR Loutfy, JSG Montaner, C Tsoukas, RS Hogg,

CANOC Collaboration

20th International AIDS ConferenceMelbourne Australia

July 2014

Disclosures

Supported by a Chercheur Nationaux award from the Fonds de Recherche Sante, Quebec (FRQ-S)

Received honoraria and acted as a consultant: ViiV, Gilead, Janssen and Merck

Research funding from: Merck and ViiV

Background Current first-line ART regimens are well-tolerated and

associated with long-term virologic suppression Switching or modifying regimens is common for

tolerability and convenience reasons In the early ART era 44% of individuals were found to

modify their regimen at a single site1

Approximately 40% of individuals in the ART-CC analysis modified first-line ART between 2002-20092

1Mocroft A. AIDS 2001;15: 185. 2Abgrall S. AIDS 2013;27:803.

Rationale & Objectives

Outcomes after switching for tolerability are presumed to be similar to those who remain on first-line regimens

We aimed to evaluate the risk of virologic failure in people who switch for reasons other than virologic failure Describe factors associated with regimen switch for

reasons other than virologic failure

Cohort CANOC is Canada’s largest pan-provincial HIV treatment cohort study This collaboration focuses on evaluating the impact of antiretroviral care

on the health of persons living with HIV across various regions of Canada Participating cohorts (approx 10,000 pts):

• BC Centre for Excellence in HIV/AIDS

• Clinique Medicale l’Actuel

• Immune Deficiency Treatment Centre (IDTC)

• Maple Leaf Medical Clinic

• Montreal Chest Institute IDS

• OHTN Cohort Study (OCS)

• Toronto General Hospital

• University of Ottawa

BC

ONQC

Inclusion Criteria

CANOC: ≥ 18 years old with first ART date ≥ January 1st, 2000 Started ART with at least 3 individual agents while

naive (i.e., no prior antiretroviral experience) Available baseline CD4 and viral load results within six

months prior to starting therapy

Inclusion Criteria

For this analysis: Started ART January 1, 2005 – June 30, 2012 Achieved virologic suppression on ART

Defined as 2 plasma viral loads (pVL) < 50 copies/mL > 1 month apart

Subsequent regimen switch while suppressed Within same class of ART To different class of ART

Outcomes

Factors associated with regimen switch

Time to virologic failure (from first suppression) Virologic failure defined as pVL > 1000 copies/mL

Statistical Methods Multinomial logistic regression model to assess

factors associated with first and subsequent regimen switches

Marginal Structural Model for risk of virologic failure after switch Time-varying switch as the primary variable of interest Time-varying CD4 cell count as time-dependent

confounder Time fixed covariates: age, gender, IDU status, baseline

CD4 count, province and calendar year of ART initiation

Baseline demographic and clinical characteristics (n=2807) Overall*

Never Switch 1804 (64)

Switched Regimen 1003 (36)

Switch regimen x1 391 (14)

Switch regimen ≥2 times 612 (22)

Time to first switch (years) 0.8 (0.4 – 1.7)

Age at regimen switch 42 (35 – 48)

Female 363 (13)

Province

• British Columbia 986 (35)

• Ontario 1128 (40)

• Quebec 700 (25)

Aboriginal ancestry 47 (2)

IDU history 340 (12)

HCV co-infection 425 (15)

Baseline CD4 count (cells/mm3) 260 (180 - 353)CD4 count at time of switch 450 (320 - 580)*Results are

median (Q1-Q3) or n (%).

Results

Characteristics of Individuals with ART switchCharacteristic Never Switch

(n= 1804)Switch Once

(n=391)Switch ≥2(n=612)

P value

Gender Male Female

1602 (66)202 (11)

337 (86)54 (14)

505 (84)107 (18)

<0.001

Age at first ART 41 (33 – 47) 38 (32 – 45) 42 (35 – 48) <0.001

IDU 206 (11) 29 (8) 105 (25) 0.008

HCV 258 (14) 43 (11) 124 (20) 0.002

Baseline CD4 280 (190 - 370) 252 (187 – 350) 220 (131 – 302) <0.001

Province <0.001

BC 569 (32) 58 (15) 359 (59)

Ontario 779 (43) 210 (54) 139 (23)

Quebec 463 (25) 123 (31) 114 (19)

*Results are median (Q1-Q3) or n (%).

Multinomial Logistic Regression Analysis - Factors associated with single or multiple regimen switches

Characteristic Outcome Adjusted Odds Ratio (95% Confidence Interval)

P value

GenderMale

Switch OnceSwitch ≥2

0.84 (0.59-1.18)0.53 (0.39-0.71)

0.31<0.001

Age (per 10 years) Switch OnceSwitch ≥2

0.88 (0.78-0.99)0.99 (0.89-1.11)

0.040.90

IDU Switch OnceSwitch ≥2

0.82 (0.53-1.26)1.11 (0.81-1.52)

0.360.54

Baseline CD4 cell count (per 100 cells)

Switch OnceSwitch ≥2

1.07 (0.99-1.15)0.99 (0.92-1.07)

0.090.79

Province (ref. BC)

Ontario Switch OnceSwitch ≥2

2.84 (2.05-3.95)0.32 (0.25-0.42) <0.001

Quebec Switch OnceSwitch ≥2

2.86 (1.99-4.10)0.48 (0.36-0.64) < 0.001

Year of ART initiation(before vs. after 2008)

Switch OnceSwitch ≥2

0.86 (0.60-1.23)0.69 (0.49-0.95)

0.530.03

Duration of ART (per year)

Switch OnceSwitch ≥2 1.45 (1.32-1.60)

1.72 (1.57-1.88) <0.001

Results – Marginal Structural Model for regimen switch and risk of virologic failure

Characteristic Adjusted Odds Ratio (95% Confidence Interval)

P value

Regimen Switch 1.35 (1.18 – 1.53) <0.001

Male gender 0.35 (0.21 – 0.58) <0.001Age (per 10 yrs) 0.98 (0.71 – 1.35) 0.884IDU 2.85 (1.70 – 4.80) <0.001Baseline CD4 (per 100 cells/mm3) 1.08 (0.93 – 1.26) 0.30

Province (ref. BC) 0.260 Ontario 1.11 (0.63 – 1.95) Quebec 1.33 (0.78 – 2.26)Year of ART initiation(before vs. after 2008) 1.17 (0.70 – 1.93) 0.55

Discussion Even with modern ART, regimen switch while virologically

suppressed was common, occurring in 36% of individuals Presumed toxicity/tolerability/simplification/DDI

Switching was associated with longer duration of ART Switching ≥ 2 times was female gender Provincial differences in rates of switching (BC having

more persons switching ≥2 times) Switching from first ART regimen while virologically

suppressed was associated with subsequent virologic failure

Discussion Switching ART for “tolerability” reasons might represent

specific patient characteristics where ART intolerance is a marker for factors associated with poor adherence rather than with ART-agent specific concerns (e.g. IDU)

Women more likely to switch and to experience subsequent virologic failure-- may represent regimen changes around pregnancies

Limitations We could not identify specific reasons for switch We were unable to assess role of adherence We did not evaluate specific components of regimens

being switched Virologic failure was defined by virologic rebound

Development of associated resistance mutations has not yet been assessed

Conclusions

Regimen switching while virologically suppressed may not be completely benign

Closer follow up among patients switching for non-virologic reasons may be warranted as such switches may serve as a marker for problems with adherence or poorer tolerance of medications (e.g. women)

We would like to thank all of the participants for allowing their information to be a part of CANOC. CANOC is supported by the Canadian Institutes of Health Research (CIHR) and the

CIHR Canadian HIV Trials Network (CTN 242).

The CANOC Collaboration includes: 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), Angela Cescon (British Columbia Centre for

Excellence in HIV/AIDS), 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), Sean Hosein (CATIE), 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 (Queen’s University, Contributes to the Ontario HIV Treatment Network).

Thank you www.canoc.ca

@CANOCresearch