Julio Montaner MD, FRCPC, FCCP Director, BC-Centre for Excellence on HIV/AIDS Professor of Medicine...

Julio Montaner MD, FRCPC, FCCPDirector, BC-Centre for Excellence on HIV/AIDS Professor of Medicine and Chair, AIDS Research

Providence Health Care - University of British ColumbiaPresident, International AIDS Society

When to Start?

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

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2006 2010 2014 2018 2022 2026 2030 2034 2038 2042 2046 2050

Year

HIV

infe

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000

popu

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Treat all Treat 30%

HIV prevalence

Montaner et al, Lancet 2006

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Treat all

Treat 30%

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ost (

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Treat all Treat 30%

Cost of treatment

Treat all

Treat 30%

The Power of HAART: Demographic Model

V D Lima, et al JID July 1st 2008

Adherence: 0% - <40%Guideline: ≤200 cells/mm 3

100

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1995 2000 2005 2010 2015 2020 2025 2030 2035

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Current Adherence: 78.5%Guideline: ≤200 cells/mm 3

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1995 2000 2005 2010 2015 2020 2025 2030 2035

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1995 2000 2005 2010 2015 2020 2025 2030 2035

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Adherence: 95% - 100%Guideline: ≤200 cells/mm 3

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1995 2000 2005 2010 2015 2020 2025 2030 2035

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50% 75% 90% 100%Coverage:


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150

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300

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1995 2000 2005 2010 2015 2020 2025 2030 2035

Year

Num

ber

of N

ew

Infe

ctio

ns

50% 75% 90% 100%Coverage:

Current Adherence: 78.5%Guideline: ≤350 cells/mm 3

100

150

200

250

300

350

400

450

500

550

1995 2000 2005 2010 2015 2020 2025 2030 2035

Year

Num

ber

of N

ew

Infe

ctio

ns

50% 75% 90% 100%Coverage:


100

150

200

250

300

350

400

450

500

550

1995 2000 2005 2010 2015 2020 2025 2030 2035

Year

Num

ber

of N

ew

Infe

ctio

ns

50% 75% 90% 100%Coverage:

Adherence: 95% - 100%Guideline: ≤350 cells/mm 3

100

150

200

250

300

350

400

450

500

550

1995 2000 2005 2010 2015 2020 2025 2030 2035

Year

Num

ber

of N

ew

Infe

ctio

ns

50% 75% 90% 100%Coverage:

CD4 200/mm3Adh <40%

CD4 200/mm3Adh 40 - 80%

CD4 200/mm3Adh 80 - 95%

CD4 200/mm3Adh 95 - 100%

CD4 350/mm3Adh <40%

CD4 350/mm3Adh 40 - 80%

CD4 350/mm3Adh 80 - 95%

CD4 350/mm3Adh 95 - 100%

50%

75%90%

100%

50%

75%90%

100%

50%

75%90%

100%

50%

75%90%

100%

50%

75%90%

100%

50%

75%90%

100%

50%

75%90%

100%

50%

75%90%

100% V D Lima, et al JID July 1st 2008

250

300

350

400

450

500

1995 2005 2015 2025 2035Year

Nu

mb

er

of

Ne

w In

fec

tio

ns

N o intervention Immediate uptake 3 years uptake 6 years uptake

Expected Impact of an Increase in HAART Coverage from current 50 to 75% of Medically

Eligible on New HIV Infections in BC


• 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$5 10 15 20 25 30

02

00

40

06

00

80

01

00

01

20

0

Time (years)

Ne

t Be

ne

fit (

mill

ion

$ C

an

20

05

)

Scenario 2 relative to Scenario 1Scenario 3 relative to Scenario 2

10/22/2008 - Provisional

Transmission modelIncremental net benefit (Millions of CDN $) over 30 years

Baseline = Status Quo

Scenario I = Incremental Benefit going from Baseline to 50% coverage with Expanded Eligibility (n=761)

Scenario II = Added Incremental Benefit going from Scenario I to 75% coverage Expanded Eligibility (n=1187)

Scenario I

Scenario II

K Johnston et al, in progress, 2009

And now back to When to Start…

AIDS Death Rate in British Columbia

Eric Druyts, et al. BC-CfE, in preparation, 2009

HAART: Safety

Survival on HAART by CD4 count

Hogg et al. JAMA 2001Wood et al. AIDS 2003

70

75

80

85

90

95

100

0 6 12 18 24 30 36 42

> 200 cells/mm3

50 - 199 cells/mm3

< 50 cells/mm3

Continuous HAART

0

200

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1200 Int CD4, CD4, cells/mm3

Int pVL, Kcopies/mL

0

200

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1200 Cont CD4, cells/mm3

Cont pVL, Kcopies/mL

Time

Time

Cont Int

PVL U/D Int

CD4 High OK

Cost +++ +

Deaths 0 0

OI/Ca 0 0

Non-ADI Events

+++

Toxicity

+

QoL + +++

Continuous vs Intermittent HAART

0

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Int pVL, Kcopies/mL

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Time

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Cont Int

PVL U/D Int

CD4 High OK

Cost +++ +

Deaths 0 0

OI/Ca 0 0

Non-ADI Events

+++

Toxicity

+

QoL + +++

Continuous vs Intermittent HAART

0

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Int pVL, Kcopies/mL

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Time

Time

Q: Could Intermittent

HAART preserve

clinical benefit and

minimize ADEs/Cost?

SMART: EndpointsPrimary and Major Secondary End Points *

Hazard Ratio forDrug Conservation

Group vs. Viral

Suppression Group (95% CI)

End Point

Drug Conservation Group(N=2720)

Viral Suppression Group(N=2752)

P Value

No. of Participants with

Events

Event Rate(per 100 Pers-Yr)


Event


Primary end point 120 3.3 47 1.3 2.6 (1.9-3.7) <0.001

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) <0.001

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

QuickTime™ and a decompressor

are needed to see this picture.

SMART: Endpoints Primary and Major Secondary End Points *


Group vs. Viral


End Point



P Value


Events



Event





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) <0.001


65 1.8 39 1.1 1.7 (1.1-2.5) 0.009


48 1.3 31 0.8 1.6 (1.0-2.5) 0.05


9 0.2 2 0.1 4.5 (1.0-20.9) 0.05


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


205 5.9 164 4.7 1.3 (1.0-1.6) 0.03



SMART: Endpoints Primary and Major Secondary End Points *


Group vs. Viral


End Point



P Value


Events



Event





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) <0.001


65 1.8 39 1.1 1.7 (1.1-2.5) 0.009


48 1.3 31 0.8 1.6 (1.0-2.5) 0.05


9 0.2 2 0.1 4.5 (1.0-20.9) 0.05


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


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

Emery S, et al. IAS 2007. Abst WEPEB018

Virologic Suppression StrategyContinuous HAART

(n = 249 not receiving ART at Bsl)

Treatment Interruption StrategyDeferred HAART until CD4+ count

< 250/mm³; discontinue therapy when CD4+ cell count > 350/mm³(n = 228 not receiving ART at Bsl)

CD4 > 350/mm³ Antiretroviral naive

(n = 249) or not on ART for

≥ 6 mos (n = 228)

(N = 477)

Mean follow-up: 16 months

Study halted early

SMART: Immediate vs Deferred HAART

Opportunistic Disease/Death Opportunistic Disease Alone

Serious non ADI/non-OD-Death OD/Serious non ADI &All Cause Death

SMART: Immediate vs Deferred HAART

Emery S, et al. IAS 2007. Abst WEPEB018

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?

SMART: Consequences of Stopping HAART

Change in D-Dimer (µg/mL)From Baseline to 1 Month

Month 1 HIV-1 RNA Level (copies/mL)

0

0.2

0.3

D-D

imer

(µ

g/m

L)

> 50,00010,000-50,000

401-10,000

≤ 400

0.28

0.11

0.40

0

0.1

P = .0005 for trend

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

²400 400-10,000

10-50,000

>50,000

IL-6 (pg/ml)

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):

e203doi:10.1371/journal.pmed.0050203

Kuller L, et al. CROI 2008. Abstract 139.Modified from Kuller LH, et al. (2008). PLoS Med 5(10):

e203doi:10.1371/journal.pmed.0050203

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

SMART: Risk of Death and Biomarkers

New Evidence

ICAAC/IDSA 2008 & CROI 2009

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 < 350 l/mm3

Primary outcome: death from any cause

Kitahata MM, et al. ICAAC/IDSA 2008. Abstract H-896b.

Survival Benefit With Earlier vs Deferred HAART

Survival Benefit With Earlier vs Deferred HAART

Kitahata MM, et al. ICAAC/IDSA 2008. Abstract H-896b.

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

Parameter Associated With Risk of Death Relative Hazard (95% CI)

Older age (per 10 yrs)

BL CD4+ cell count (per 100 cells/mm3 increase)

1.6

1.0 2.50.1

Deferral of HAART until < 350 cells/mm3 (vs starting at 350-500 cells/mm3)

Female sex

0.9

1.7

1.1

P Value

< .001

.290

< .001

.083

M Kitahata for

CROI 2009

.51

24

Haz

ard

Rat

io f

or A

IDS

or

Dea

th

0 100 200 300 400 500CD4 threshold (cells/mm3)

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)

ART Cohort Collaboration

Jonathan A C Sterne CROI, 2009

When to Start ARTA Policy Evaluation While Awaiting Trial Results: South Africa

Walensky et al CROI 2009 Abstract 596b

• 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 <250/μL or severe opportunistic disease (OD)

• ART at CD4 <350/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.

When to Start ARTA Policy Evaluation While Awaiting Trial Results: South Africa

Walensky et al CROI 2009 Abstract 596b

• 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 <350/μL compared to <250/μL would result in fewer total OD (730,272 vs 951,370) and fewer total deaths (244,249 vs 497,059).

• Starting at <350/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 <350/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 (CD4<350/μL).

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

Summary




Summary




When to Start Antiretroviral TherapyWhen to Start Antiretroviral Therapy

Measure Recommendation Comments

Symptomatic HIV disease Therapy recommended

Asymptomatic HIV disease

CD4 <350/µL Therapy recommended Recommendation strengthened since 2006

CD4 >350/µL Therapy should be considered and decision individualized

Correlates of faster HIV disease progression:

High viral load (>100,000 RNA copies/mL)

Rapidly declining CD4 (>100/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 InfectionAntiretroviral Treatment of Adult HIV Infection2008 Recommendations of the IAS-USA2008 Recommendations of the IAS-USAHammer SM; Eron JJ, Jr.; Reiss P; Schooley RT; Thompson MA; Walmsley S; 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; Cahn P; Fischl MA; Gatell JM; Hirsch MS; Jacobsen DM; Montaner JSG; Richman DD; Yeni P; Volberding PA. Richman DD; Yeni P; Volberding PA.

JAMA. JAMA. 2008; 300 (5) 555-5702008; 300 (5) 555-570

164

187

102

181

200192

87 239

163

97

134

179

97

100125

12386

122103 53

157 20695

72

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

When to Start: The Real World

Egger M, et al. CROI 2007. Abstract 62.





DTES

BCHA1

HA2

HA4

HA5


HA3

Eric Druyts, et al. BC-CfE, in preparation, 2009 Eric Druyts, et al. BC-CfE, in preparation, 2009


0

20

40

60

80

100

120

140

1601987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

year

rate

per

100,0

00 p

op

ula

tio

n

Vancouver Total (joinpoint) City Centre (joinpoint) Downtown Eastside (joinpoint)

Vancouver Total (observed) City Centre (observed) Downtown Eastside (observed)

Eric Druyts, et al. BC-CfE, in preparation, 2009

Expanded HAART Coverage: an Aid to HIV Prevention

Montaner et al, Lancet, IAS, Toronto, 2006

250

300

350

400

450

500

1995 2005 2015 2025 2035Year

Nu

mb

er

of

Ne

w In

fec

tio

ns

N o intervention Immediate uptake 3 years uptake 6 years uptake

Expected Impact of an Increase in HAART Coverage from current 50% of Medically Eligible

to 75% on New HIV Infections in BC


• 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$5 10 15 20 25 30

02

00

40

06

00

80

01

00

01

20

0

Time (years)

Ne

t Be

ne

fit (

mill

ion

$ C

an

20

05

)

Scenario 2 relative to Scenario 1Scenario 3 relative to Scenario 2

Transmission modelIncremental net benefit (Millions of CDN $) over 30 years

Baseline = Status Quo

Scenario I = Incremental Benefit going from Baseline to 50% coverage with Expanded Eligibility (n=761)

Scenario II = Added Incremental Benefit going from Scenario I to 75% coverage Expanded Eligibility (n=1187)

Scenario I

Scenario II

K Johnston et al, in progress, 2009

When to Start HAART?A matter of Perspective

years0

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Viral Load

CD4 Count


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years

years

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Viral Load

CD4 Count


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years

years

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Viral Load

CD4 Count


0

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years

years

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Viral Load

CD4 Count

AIDS Nov 27th 2008, The EconomistDeploying the drugs used to treat AIDS may be the way to limit its spread



Illustration by Peter Schrank

Acknowledgements

P. CahnP. Cahn

J.J. Eron J.J. Eron

M. A. FischlM. A. Fischl

J. M. GatellJ. M. Gatell

S.M. HammerS.M. Hammer

M. S. HirschM. S. Hirsch

D. M. JacobsenD. M. Jacobsen

P. ReissP. Reiss

D. D. RichmanD. D. Richman

R.T. Schooley R.T. Schooley

M.A. ThompsonM.A. Thompson

P. A. VolberdingP. A. Volberding

S. Walmsley S. Walmsley

P. YeniP. Yeni

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. O’Briain

In partnership withDira Sengwe

5th IAS Conference on HIV Pathogenesis, Treatment and Prevention

19 - 22 July 2009

Abstratct Submission DeadlineAbstratct Submission Deadline

25th February 200925th February 2009

Thank You

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Julio Montaner MD, FRCPC, FCCP Director, BC-Centre for Excellence on HIV/AIDS Professor of Medicine...

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