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 Conference
Melbourne 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
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
Results

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)
Age at regimen switch
Female
0.8 (0.4 – 1.7)
42 (35 – 48)
363 (13)
Province
• British Columbia
986 (35)
• Ontario
1128 (40)
• Quebec
700 (25)
Aboriginal ancestry
*Results are
median (Q1-Q3)
or n (%).
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)
Characteristics of Individuals
with ART switch
Characteristic
Never Switch
(n= 1804)
Switch Once
(n=391)
Switch ≥2
(n=612)
1602 (66)
202 (11)
337 (86)
54 (14)
505 (84)
107 (18)
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
280 (190 - 370)
252 (187 – 350)
220 (131 – 302)
<0.001
Gender
Male
Female
Age at first ART
Baseline CD4
Province
P value
<0.001
<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
Gender
Male
Switch Once
Switch ≥2
0.84 (0.59-1.18)
0.53 (0.39-0.71)
0.31
<0.001
Age (per 10 years)
Switch Once
Switch ≥2
0.88 (0.78-0.99)
0.99 (0.89-1.11)
0.04
0.90
IDU
Switch Once
Switch ≥2
0.82 (0.53-1.26)
1.11 (0.81-1.52)
0.36
0.54
Baseline CD4 cell count
(per 100 cells)
Switch Once
Switch ≥2
1.07 (0.99-1.15)
0.99 (0.92-1.07)
0.09
0.79
Ontario
Switch Once
Switch ≥2
2.84 (2.05-3.95)
0.32 (0.25-0.42)
<0.001
Quebec
Switch Once
Switch ≥2
2.86 (1.99-4.10)
0.48 (0.36-0.64)
< 0.001
Year of ART initiation
(before vs. after 2008)
Switch Once
Switch ≥2
0.86 (0.60-1.23)
0.69 (0.49-0.95)
0.53
0.03
Duration of ART
(per year)
Switch Once
Switch ≥2
1.45 (1.32-1.60)
1.72 (1.57-1.88)
<0.001
Province (ref. BC)
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)
<0.001
Age (per 10 yrs)
0.98 (0.71 – 1.35)
0.884
IDU
2.85 (1.70 – 4.80)
<0.001
Baseline 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)
www.canoc.ca
Thank you
@CANOCresearch
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).