Julio Montaner MD, FRCPC, FCCP

1
When to Start?

• Julio Montaner MD, FRCPC, FCCP
• Director, BC-Centre for Excellence on HIV/AIDS
• Professor of Medicine and Chair, AIDS Research
• Providence Health Care - University of British
  Columbia
• President, International AIDS Society

2
Integrating HIV Prevention and Treatment from
Slogans to Impact
J Salomon1, D Hogan1, J Stover2, K Stanecki3,
NWalker3-4, P Ghys3, B Schwartländer5 PLoS
Medicine, http//www.plosmedicine.org January
2005, Volume 2, Issue 1, e16
3

The Power of HAART Demographic Model
Treat 30
Cost of treatment
Treat all
Treat 30
Treat all
Montaner et al, Lancet 2006
4
V D Lima, et al JID July 1st 2008
5
50
50
75
CD4 350/mm3 Adh lt40
75
CD4 200/mm3 Adh lt40
90
90
100
100
50
50
CD4 350/mm3 Adh 40 - 80
CD4 200/mm3 Adh 40 - 80
75
75
90
90
100
100
50
50
CD4 350/mm3 Adh 80 - 95
CD4 200/mm3 Adh 80 - 95
75
75
90
90
100
100
50
50
CD4 350/mm3 Adh 95 - 100
CD4 200/mm3 Adh 95 - 100
75
75
90
90
100
100
V D Lima, et al JID July 1st 2008
6
Expected Impact of an Increase in HAART Coverage
from current 50 to 75 of Medically Eligible on
New HIV Infections in BC
V D Lima, et al JID July 1st 2008
7
Transmission model Incremental net benefit
(Millions of CDN ) over 30 years
Baseline Status Quo Scenario I Incremental
Benefit going from Baseline to 50 coverage with
Expanded Eligibility (n761) Scenario II Added
Incremental Benefit going from Scenario I to 75
coverage Expanded Eligibility (n1187)
Net benefit is an economic measure that
incorporates survival and QoL 1 Quality
adjusted life year (QALY) valued at 50K All
Values discounted at 3 per year, using 2005 CDN
Scenario II
Scenario I
10/22/2008 - Provisional
K Johnston et al, in progress, 2009
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And now back to When to Start
9
AIDS Death Rate in British Columbia
Eric Druyts, et al. BC-CfE, in preparation, 2009
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HAART Safety
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Survival on HAART by CD4 count
Hogg et al. JAMA 2001 Wood et al. AIDS 2003
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Continuous HAART
Cont Int
PVL U/D Int
CD4 High OK
Cost
Deaths 0 0
OI/Ca 0 0
Non-ADI Events Toxicity
QoL
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Continuous vs Intermittent HAART
Cont Int
PVL U/D Int
CD4 High OK
Cost
Deaths 0 0
OI/Ca 0 0
Non-ADI Events Toxicity
QoL
14
Continuous vs Intermittent HAART
Q Could Intermittent HAART preserve clinical
benefit and minimize ADEs/Cost?
15
SMART Endpoints
Primary and Major Secondary End Points Primary and Major Secondary End Points Primary and Major Secondary End Points Primary and Major Secondary End Points Primary and Major Secondary End Points Primary and Major Secondary End Points Primary and Major Secondary End Points
Hazard Ratio for Drug Conservation Group vs. Viral Suppression Group (95 CI)
End Point Drug Conservation Group (N2720) Drug Conservation Group (N2720) Viral Suppression Group (N2752) Viral Suppression Group (N2752) Hazard Ratio for Drug Conservation Group vs. Viral Suppression Group (95 CI) P Value
No. of Participants with Events Event Rate (per 100 Pers-Yr) No. of Participants with Event Event Rate (per 100 Pers-Yr)
Primary end point 120 3.3 47 1.3 2.6 (1.9-3.7) lt0.001
Death from any cause 55 1.5 30 0.8 1.8 (1.2-2.9) 0.007
Opportunistic disease
Serious 13 0.4 2 0.1 6.6 (1.5-29.1) 0.01
Non-serious 63 1.7 18 0.5 3.6 (2.1-6.1) lt0.001
Major cardiovascular, renal, or hepatic disease 65 1.8 39 1.1 1.7 (1.1-2.5) 0.009
Fatal or nonfatal cardiovascular disease 48 1.3 31 0.8 1.6 (1.0-2.5) 0.05
Fatal or nonfatal renal disease 9 0.2 2 0.1 4.5 (1.0-20.9) 0.05
Fatal or nonfatal liver disease 10 0.3 7 0.2 1.4 (0.6-3.8) 0.46
Grade 4 event 173 5.0 148 4.2 1.2 (1.0-1.5) 0.13
Grade 4 event or death from any cause 205 5.9 164 4.7 1.3 (1.0-1.6) 0.03
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SMART Endpoints
Primary and Major Secondary End Points Primary and Major Secondary End Points Primary and Major Secondary End Points Primary and Major Secondary End Points Primary and Major Secondary End Points Primary and Major Secondary End Points Primary and Major Secondary End Points
Hazard Ratio for Drug Conservation Group vs. Viral Suppression Group (95 CI)
End Point Drug Conservation Group (N2720) Drug Conservation Group (N2720) Viral Suppression Group (N2752) Viral Suppression Group (N2752) Hazard Ratio for Drug Conservation Group vs. Viral Suppression Group (95 CI) P Value
No. of Participants with Events Event Rate (per 100 Pers-Yr) No. of Participants with Event Event Rate (per 100 Pers-Yr)
Primary end point 120 3.3 47 1.3 2.6 (1.9-3.7) lt0.001
Death from any cause 55 1.5 30 0.8 1.8 (1.2-2.9) 0.007
Opportunistic disease
Serious 13 0.4 2 0.1 6.6 (1.5-29.1) 0.01
Non-serious 63 1.7 18 0.5 3.6 (2.1-6.1) lt0.001
Major cardiovascular, renal, or hepatic disease 65 1.8 39 1.1 1.7 (1.1-2.5) 0.009
Fatal or nonfatal cardiovascular disease 48 1.3 31 0.8 1.6 (1.0-2.5) 0.05
Fatal or nonfatal renal disease 9 0.2 2 0.1 4.5 (1.0-20.9) 0.05
Fatal or nonfatal liver disease 10 0.3 7 0.2 1.4 (0.6-3.8) 0.46
Grade 4 event 173 5.0 148 4.2 1.2 (1.0-1.5) 0.13
Grade 4 event or death from any cause 205 5.9 164 4.7 1.3 (1.0-1.6) 0.03
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SMART Endpoints
Primary and Major Secondary End Points Primary and Major Secondary End Points Primary and Major Secondary End Points Primary and Major Secondary End Points Primary and Major Secondary End Points Primary and Major Secondary End Points Primary and Major Secondary End Points
Hazard Ratio for Drug Conservation Group vs. Viral Suppression Group (95 CI)
End Point Drug Conservation Group (N2720) Drug Conservation Group (N2720) Viral Suppression Group (N2752) Viral Suppression Group (N2752) Hazard Ratio for Drug Conservation Group vs. Viral Suppression Group (95 CI) P Value
No. of Participants with Events Event Rate (per 100 Pers-Yr) No. of Participants with Event Event Rate (per 100 Pers-Yr)
Primary end point 120 3.3 47 1.3 2.6 (1.9-3.7) lt0.001
Death from any cause 55 1.5 30 0.8 1.8 (1.2-2.9) 0.007
Opportunistic disease
Serious 13 0.4 2 0.1 6.6 (1.5-29.1) 0.01
Non-serious 63 1.7 18 0.5 3.6 (2.1-6.1) lt0.001
Major cardiovascular, renal, or hepatic disease 65 1.8 39 1.1 1.7 (1.1-2.5) 0.009
Fatal or nonfatal cardiovascular disease 48 1.3 31 0.8 1.6 (1.0-2.5) 0.05
Fatal or nonfatal renal disease 9 0.2 2 0.1 4.5 (1.0-20.9) 0.05
Fatal or nonfatal liver disease 10 0.3 7 0.2 1.4 (0.6-3.8) 0.46
Grade 4 event 173 5.0 148 4.2 1.2 (1.0-1.5) 0.13
Grade 4 event or death from any cause 205 5.9 164 4.7 1.3 (1.0-1.6) 0.03
Of 85 deaths in SMART, only 7 (8) were from ADIs
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SMART Immediate vs Deferred HAART
Emery S, et al. IAS 2007. Abst WEPEB018
19
SMART Immediate vs Deferred HAART
Emery S, et al. IAS 2007. Abst WEPEB018
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SMART Summary

• Continued HAART better than Intermittent HAART
• Survival
• AIDS and non AIDS events
• Adverse effects
• Quality of life
• Differences remained when HAART was re-started
• What is driving the excess morbidity and
  mortality?

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SMART Consequences of Stopping HAART
Change in IL-6 (pg/ml)From Baseline to 1 Month
Kuller L, et al. CROI 2008. Abstract
139. Modified from Kuller LH, et al. (2008). PLoS
Med 5(10) e203doi10.1371/journal.pmed.0050203
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SMART Risk of Death and Biomarkers

• Risk of Death Associated with Biomarker Levels
  at Entry
• Risk of Death Associated with Latest Biomarker
  Level
• Risk of Death Associated with Change in
  Biomarker Levels

Kuller L, et al. CROI 2008. Abstract
139. Modified from Kuller LH, et al. (2008). PLoS
Med 5(10) e203doi10.1371/journal.pmed.0050203
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New Evidence

• ICAAC/IDSA 2008 CROI 2009

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Survival Benefit With Earlier vs Deferred HAART

• NA-ACCORD, established in 2006, includes 22 HIV
  cohorts
• Analysis includes patients with CD4 count
  351-500/mm3 at study visit between 1996-2006
• Compared outcomes based on Rx according to
• Immediate treatment initiated HAART within 1.5
  years of first CD4 count in 351-500/mm3 range
• Deferred treatment did not initiate HAART within
  1.5 years of first CD4 count in 351-500/mm3
  range. Included patients who did not initiate
  treatment after reaching CD4 count lt 350 l/mm3
• Primary outcome death from any cause

Kitahata MM, et al. ICAAC/IDSA 2008. Abstract
H-896b.
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Survival Benefit With Earlier vs Deferred HAART

• Increased relative hazard of death with deferral
  of HAART remained unchanged when adjusted for IDU
  or for HCV co-infection, which were both
  independent predictors of mortality

Kitahata MM, et al. ICAAC/IDSA 2008. Abstract
H-896b.
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M Kitahata for CROI 2009
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Hazard ratios for AIDS or death, adjusted for
lead times and unseen events
Comparison Hazard ratio (95 CI)
276-375 vs 376-475 1.19 (0.96 to 1.47)
251-350 vs 351-450 1.28 (1.04 to 1.57)
226-325 vs 326-425 1.21 (1.01 to 1.46)
Jonathan A C Sterne CROI, 2009
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When to Start ARTA Policy Evaluation While
Awaiting Trial Results South Africa

• Used a published mathematical model of
  HIV-infection in South Africa to simulate
  co-trimoxazole prophylaxis plus 3 alternative ART
  initiation strategies
• No ART (for comparison only)
• ART at CD4 lt250/µL or severe opportunistic
  disease (OD)
• ART at CD4 lt350/µL or severe OD
• Projected 5-year morbidity, mortality, and
  costs, in a South African cohort of HIV-infected
  persons with mean age 33 years.
• Natural history and healthcare utilization data
  derived from the Cape Town AIDS Cohort.
• Assumed 2 sequential ART regimens (NNRTI-based
  followed by PI-based), with published 48-week
  viral suppression rates of 84 and 71, and per
  person annual costs of 288 and 564.

Walensky et al CROI 2009 Abstract 596b
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When to Start ARTA Policy Evaluation While
Awaiting Trial Results South Africa

• Over a 5-year, 4.7 million HIV South Africans
  will become eligible to start ART in the CD4 250
  to 350/µL window.
• Assuming all eligible patients present for care
  and that ART is equally effective in the CD4 250
  to 350/µL range, initiation of ART at lt350/µL
  compared to lt250/µL would result in fewer total
  OD (730,272 vs 951,370) and fewer total deaths
  (244,249 vs 497,059).
• Starting at lt350/µL would also lead to
  additional (discounted) treatment costs of 1.4
  billion over the next 5 years.
• As long as the probability that the trial will
  confirm a survival benefit to earlier ART is
  judged to be greater than 17, a policy of
  initiating ART at CD4 lt350/µL is cost-effective
  and should be used over the next 5 years.
• Conclusions Earlier ART initiation in South
  Africa will reduce morbidity and mortality
  substantially, and will be cost-effective. In
  anticipation of trial results, treatment
  guidelines should be liberalized to allow for
  earlier ART initiation (CD4lt350/µL).

Walensky et al CROI 2009 Abstract 596b
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• Summary
• HIV is a chronic inflammatory disease
• Inflammation important driver of non-AIDS
  events
• heart, liver, kidney, etc
• malignancies
• Inflammation important driver of CD4 decline
• ADIs at a late stage of the disease

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• Summary
• HIV is a chronic inflammatory disease
• Inflammation important driver of non-AIDS
  events
• heart, liver, kidney, etc
• malignancies
• Inflammation important driver of CD4 decline
• ADIs at a late stage of the disease

32

• Summary
• HIV is a chronic inflammatory disease
• Inflammation important driver of non-AIDS
  events
• heart, liver, kidney, etc
• malignancies
• Inflammation important driver of CD4 decline
• ADIs at a late stage of the disease

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When to Start Antiretroviral Therapy
Measure Recommendation Comments
Symptomatic HIV disease Therapy recommended
Asymptomatic HIV disease
CD4 lt350/µL Therapy recommended Recommendation strengthened since 2006
CD4 gt350/µL Therapy should be considered and decision individualized Correlates of faster HIV disease progression High viral load (gt100,000 RNA copies/mL) Rapidly declining CD4 (gt100/µL per year) Coexistent conditions influenced by uncontrolled viremia Presence of, or high risk for, cardiovascular disease Active HBV or HCV HIV-associated nephropathy
Examples
Antiretroviral Treatment of Adult HIV
Infection2008 Recommendations of the
IAS-USA Hammer SM Eron JJ, Jr. Reiss P
Schooley RT Thompson MA Walmsley S Cahn P
Fischl MA Gatell JM Hirsch MS Jacobsen DM
Montaner JSG Richman DD Yeni P Volberding PA.
JAMA. 2008 300 (5) 555-570
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When to Start The Real World

• Review of data from 2003-2005 from 176 sites in
  42 countries (N 33,008)
• Since 2000, CD4 cell count at initiation in
  developed countries stable at approximately
  150-200 cells/mm3, increasing in sub-Saharan
  Africa from 50-100 cells/mm3

164
200
179
187
192
163
123
157
206
102
86
95
53
103
125
134
100
122
72
97
97
239
87
181
Egger M, et al. CROI 2007. Abstract 62.
35
AIDS Death Rate in British Columbia
BC
HA1
HA2
HA4
HA3
DTES
HA5
Eric Druyts, et al. BC-CfE, in preparation, 2009
36
AIDS Death Rate in British Columbia
Eric Druyts, et al. BC-CfE, in preparation, 2009
37
Expanded HAART Coverage an Aid to HIV Prevention

• Montaner et al, Lancet, IAS, Toronto, 2006

38
Expected Impact of an Increase in HAART Coverage
from current 50 of Medically Eligible to 75 on
New HIV Infections in BC
V D Lima, et al JID July 1st 2008
39
Transmission model Incremental net benefit
(Millions of CDN ) over 30 years
Baseline Status Quo Scenario I Incremental
Benefit going from Baseline to 50 coverage with
Expanded Eligibility (n761) Scenario II Added
Incremental Benefit going from Scenario I to 75
coverage Expanded Eligibility (n1187)
Net benefit is an economic measure that
incorporates survival and QoL 1 Quality
adjusted life year (QALY) valued at 50K All
Values discounted at 3 per year, using 2005 CDN
Scenario II
Scenario I
K Johnston et al, in progress, 2009
40
When to Start HAART?A matter of Perspective
Viral Load
CD4 Count
years
41
When to Start HAART?A matter of Perspective
Viral Load
CD4 Count
years
years
42
When to Start HAART?A matter of Perspective
Viral Load
CD4 Count
years
years
years
43
When to Start HAART?A matter of Perspective
Viral Load
CD4 Count
years
years
years
44
AIDS Nov 27th 2008, The Economist Deploying the
drugs used to treat AIDS may be the way to limit
its spread
45
Acknowledgements
L. Akagi A. Alimente A. Anis R. Barrios J.
Bishop G. Bondy K. Buchanan D. Burge I. Day J.
Forbes S. Guillemi R. Harrigan M. Harris S. Smith
R.S. Hogg E. Lun W. A. McLeod D. Money V.
Montessori P. Philips N. Pick N. Press P. M.
Sestak D. Shahvarani C. Sherlock G. Tsang M.
Tyndall W. OBriain
P. Cahn J.J. Eron M. A. Fischl J. M. Gatell S.M.
Hammer M. S. Hirsch D. M. Jacobsen P. Reiss D. D.
Richman R.T. Schooley M.A. Thompson P. A.
Volberding S. Walmsley P. Yeni
46
5th IAS Conference on HIV Pathogenesis,
Treatment and Prevention 19 - 22 July 2009
Abstratct Submission Deadline 25th February 2009
In partnership with Dira Sengwe
47

• Thank You