Treatment as Prevention - WHO

British ColumbiaCentre for Excellencein HIV/AIDS

Julio Montaner MD, FRCPC, FCCP, FRSCDirector, BC-Centre for Excellence on HIV/AIDS, Providence Health Care

Professor of Medicine and Head, Division of AIDS, University of British ColumbiaPresident, International AIDS Society

UNAIDS, Geneva, March 24th 2010

Treatment as Prevention:HAART Expansion - A Powerful Strategy to Reduce

AIDS Morbidity and Mortality and HIV Incidence

05

10152025303540

82 84 86 88 90 92 94Year

Dea

ths

per 1

00,0

00 P

opul

atio

n UnintentionalinjuryCancer

HeartdiseaseSuicide

HIV infection

Homicide

Chronic liverdiseaseStroke

Diabetes

USA - Trends in Annual Rates of DeathAges 25 to 44

Announced Oct 6th 2008

Harald zur Hausen Harald zur Hausen Françoise Françoise Barré-Sinoussi Barré-Sinoussi Luc Luc MontagnierMontagnier

Vancouver 1996“One World One Hope”

J Mellors et al. Annals 1997

00

20

40

60

80

100> 750501-750351-500201-350< 200

> 30 10-30 3-10 0.5-3 < 0.5

CD4+cells/µL

Plasma HIV RNA (thousand copies/mL)

% Progression to AIDS in 3 yrs


Plasma Viral Load, a strong Predictor of outcome in HIV Infected Individuals

High Plasma Viral Load: Poor PrognosisLow Plasma Viral Load: Good Prognosis

Montaner et al JAMA, March 25th 1998

Triple Therapy: AZT + ddI + NVP

AZT + ddI

AZT + NVP

Study Weeks0

0

-1

-2

-3

Dual Therapy Regimens

Triple Therapy: AZT+3TC+IDV

Gulick et al; JAMA, July 1, 1998

52

J Mellors et al. Annals 1997

00

20

40

60

80

100> 750501-750351-500201-350< 200

> 30 10-30 3-10 0.5-3 < 0.5

CD4+cells/µL

Plasma HIV RNA (thousand copies/mL)

% Progression to AIDS in 3 yrs


Cha

nge

in V

iral L

oad

Impact of HAART in BC-CfE

0

20

40

60

80

100

120

140

1993-94 1995-96 1997-98 1999-00 2001-02 2003-04

Death Rate per 1000

Modified from Hogg et al, Lancet. 2009

Greater than 85% reduction in death rate among those

engaged in care

Impact of HAART in BC-CfE

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20

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60

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120

140

1993-94 1995-96 1997-98 1999-00 2001-02 2003-04

Death Rate per 1000

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15

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25

30

35

1993-94 1995-96 1997-98 1999-00 2001-02 2003-04

Life Expectancy at age 20

Modified from Hogg et al, Lancet. 2009

HAART Can Reduce HIV Transmission

HAART stops HIV replication↓

HIV levels fall to undetectable in blood

as well as in sexual fluids↓

Sharp reduction in HIV transmission

Prevention Strategies

- Education- Change in behavoir- Harm reduction- New strategies/technology- Vaccines

Existing strategies have failedto contain the global HIV pandemic

Modified from Alimenti et al CAHR, 2009

VerticalTransmission

Canada, 1990 to 2008

Discordant Couples

S Attia, M Egger, M Muller, M Zwahlen and N Lowa. AIDS. 2009 Jul 17;23(11):1397-404

Discordant Couples

S Attia, M Egger, M Muller, M Zwahlen and N Lowa. AIDS. 2009 Jul 17;23(11):1397-404

Studies of heterosexual discordant couples observed notransmission in patients treated with ART and with viral load

below 400 c/ml, but data were compatible with onetransmission per 79 person-years.

B&M Gates Fdn: HIV Transmission Risk inHeterosexual Serodiscordant Couples

3,400 couples In 7 African countries

All counseled and given free condoms

HAART initiated based on CD4 count eligibility

Over the next 1 to 3 years, 103 new HIV infections

All but 1 infection occurred in the untreated couples Estimated 92% reduction of HIV transmission by HAART

Unadjusted relative risk: 0.17 (95% CI: 0.004-0.94; P = .037)

Adjusted relative risk: 0.08 (95% CI: 0.002-0.57; P = .004)

Adjusted for visit and CD4+ cell count at initiation

Donnell D, et al. CROI 2010. Abstract 136.

B&M Gates Fdn: HIV Transmission Risk inHeterosexual Serodiscordant Couples

3,400 couples In 7 African countries

All counseled and given free condoms

HAART initiated based on CD4 count eligibility

Over the next 1 to 3 years, 103 new HIV infections

All but 1 infection occurred in the untreated couples Estimated 92% reduction of HIV transmission by HAART

Unadjusted relative risk: 0.17 (95% CI: 0.004-0.94; P = .037)

Adjusted relative risk: 0.08 (95% CI: 0.002-0.57; P = .004)

Adjusted for visit and CD4+ cell count at initiation

Donnell D, et al. CROI 2010. Abstract 136.

More recently an email has been circulated saying that: More recently an email has been circulated saying that: ““The single case of transmission involved a man The single case of transmission involved a man who initiated who initiated ARVs ARVs 18 days before his 12-month 18 days before his 12-month

study visit. At this visit his partner tested positive for HIV, study visit. At this visit his partner tested positive for HIV, having been negative at month 9.having been negative at month 9.””

Wood et al, BMJ, 2009

Wood et al, BMJ, 2009

Whiskers represent 95% confidence intervals.

Wood et al, BMJ, May 16, 2009

6 months Baseline

Plasma Viral Load (log10 copies/mL) Distribution

Modified from Anema et al. EIDJ 2009

Impact of HAART in BC-CfEFr

eque

ncy

of p

eopl

e

24 months Baseline

Plasma Viral Load (log10 copies/mL) Distribution

Impact of HAART in BC-CfEFr

eque

ncy

of p

eopl

e

Modified from Anema et al. EIDJ 2009

New HIV and Syphilis in BC

M REKART, BC-CDC, 2006

Rat

e pe

r 100

,000

pop

ulat

ion

New HIV and Syphilis in BCR

ate

per 1

00,0

00 p

opul

atio

n

M REKART, BC-CDC, 2006

Cost of Medical Management of 1 HIV infection over alifetime = $250,000

“HIV deficit” in BC in 2005: 400

Cost-Effectiveness of HAARTBC-DTP

Averted lifetime Rx cost up to 2001 US $96.4MA total of 3,963 pts were on HAART in BC in 2005

Total actual drug cost (using patented drugs) in 2005 $49 million US

800 cases per year

400 cases per year

Cost of Medical Management of 1 HIV infection over alifetime = $250,000

“HIV deficit” in BC in 2005: 400

Cost-Effectiveness of HAARTBC-DTP

Averted lifetime Rx cost up to U$A 100MA total of 3,963 pts were on HAART in BC in 2005

Total actual drug cost (using patented drugs) in 2005

U$A 50M

The Bc-CfE Mathematical ModelViviane D. Lima et al

JID 2008

Adherence: 0% - <40%

Guideline: !200 cells /mm 3

100

150

200

250

300

350

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450

500

550

1995 2000 2005 2010 2015 2020 2025 2030 2035

Year

Num

ber

of N

ew I

nfec

tions

50% 75% 90% 100%Coverage:

Current Adherence: 78.5%


100

150

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300

350

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450

500

550

1995 2000 2005 2010 2015 2020 2025 2030 2035

Year

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ber

of N

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nfec

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50% 75% 90% 100%Coverage:



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500

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1995 2000 2005 2010 2015 2020 2025 2030 2035

Year

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of N

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nfec

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50% 75% 90% 100%Coverage:

Adherence: 95% - 100%


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1995 2000 2005 2010 2015 2020 2025 2030 2035

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of N

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50% 75% 90% 100%Coverage:



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450

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1995 2000 2005 2010 2015 2020 2025 2030 2035

Year

Num

ber

of N

ew I

nfec

tions

50% 75% 90% 100%Coverage:

Current Adherence: 78.5%


100

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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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1995 2000 2005 2010 2015 2020 2025 2030 2035

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nfec

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50% 75% 90% 100%Coverage:

Adherence: 95% - 100%


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1995 2000 2005 2010 2015 2020 2025 2030 2035

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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 2008

Incremental net benefit (Millionsof CDN $) over 30 years

K Johnston et al, submitted, 2010

0 5 10 15 20 25 30

020

040

060

080

0

Time (years)

Net

Ben

efit

(milli

on $

Can

200

5)

Overall PopulationPatient-Centered

Overall population and

patient-centered

incremental net benefit of

increasing uptake of

HAART from 50% to 75%

over 30 years, based on a

willingness-to-pay

thresholds of $50,000 per

quality-adjusted life year.

Summary

HAART is widely regarded as a cost effective, life-saving strategy

↓ Mortality of treated HIV/AIDS patients↓ Morbidity of treated HIV/AIDS patients↓ Health Resource utilization↓ Vertical Transmission of HIV infection

Furthermore, when the impact of HAART on HIVtransmission is considered, HAART expansionbecomes a cost-averting strategy

The third approach, though, is the most intriguing. This is to do nothingmore than press ahead faster with the treatment program. Since treatmentreduces viral load, it should, in theory, make those being treated lessinfectious. Of course, theory is one thing and practice another. But studiesin Taiwan and British Columbia (the latter by Julio Montaner, the incomingpresident of the International AIDS Society, which organizes the conference)have shown big falls in transmission rates as ARVs have been rolled out.

HIV prevalence

Montaner et al, Lancet 2006

Number of infectionsprevented

Treat all

Treat 30%

Cost of treatment

Treat all

Treat 30%

The Power of HAART: Demographic Model

R Granich, C Gilks, C Dye, K De Cock, B Williams. The Lancet Nov 26th 2008

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

Illustration by Peter Schrank

Thank you

An Alternative Approach

Preliminary Results

Methods Prospective ecological study in BC, Canada

Used administrative records to evaluate the associationbetween expansion of HAART coverage, population levelplasma HIV-1-viral load and new HIV diagnoses

HIV testing, CD4 & viral load testing and HAARTdistribution are centralized and free in BC

Data for second half of 2009 is preliminary due to delayedreporting, therefore only the first half of 2009 was used forstatistical analyses

Montaner et al, CROI 2010

January 2004

The second expansion of HAARToccurred prior to the new 2008

IAS-USA Guidelines, which wereadopted in BC at the end of 2008

The first expansion of HAARToccurred as a result of the new 1996

IAS-USA Guidelines, which wereadopted in BC in the summer of

1996

Summer of 1996

Year Montaner et al, CROI 2010

0.01

0.10

1.00

1995 2000 2005 2010

0.20

0.02

0.04

0.01

0.10

1.00

1995 2000 2005 2010

0.20

0.02

0.04

90

80

70

60

Inci

denc

e/yr

Vira

l loa

d <

50/

mL

(%)

Acquired resistancefalling

Plasma viral loadsuppression rising

Num

ber of New

HIV+ D

iagnosesNum

ber o

f Act

ive

HA

AR

T Pa

rtic

ipan

ts

Year

New HIV+ Diagnoses (All)

New HIV+ Diagnoses (IDU)

Active on HAART

Number of Active HAARTParticipants and Number of New

HIV+ Diagnoses per Year

p=0.015


Number of Active HAARTParticipants and Number of New

HIV+ Diagnoses per Year

New HIV+ Diagnoses (All)

New HIV+ Diagnoses (IDU)

Active on HAART

Num

ber of New

HIV+ D

iagnoses

Year

Num

ber o

f Act

ive

HA

AR

T Pa

rtic

ipan

ts

p=0.015

p=0.085

p=0.026


“True” New Yearly HIV Diagnoses in BC

BC-CDC Updated March 2010

Jan 2004

Year Year # of HIV Tests # of HIV Tests

BC-CDC Report, 2009

HIV testing in BC, 1985 to 2008

Hepatitis C, 1999-2008 Infectious Syphilis, 1999-2008

Genital Chlamydia, 1999-2008 Gonorrhea, 1999-2008

• BC

x Canada

• BC

x Canada

• BC

x Canada• BC

x Canada

2004

2004 2004

2004

HighestHIV-1- PlasmaViral load per

Year

Ever on Treatment&

Censoring at the time ofDeath or Move

IDUIDU

The proportion of HIV infected IDUs engaged in care in BC with plasma viralload >1500 c/mL, as a surrogate for “high” community HIV-1-viral load,

decreased from ~50% in 2000-04 to ~20% in 2009 (p<0.001)

Non IDUNon IDU


“Provincial Viral Load”All Patients Ever Tested for Plasma HIV-1-Viral Load in BC

Censoring at the time of Death or MoveCensoring at the time of Death or Move

New Data: Pre HAART CD4 Count

Montaner et al, 2010, Preliminary Data

Community pVL and New HIV DiagnosesSan Francisco

Das-Douglas M, et al. CROI 2010. Abstract 33.

Mean CVL

0

5000

10,000

15,000

20,000

25,000

30,000

2004 2005 2006 2007 2008

Mea

n C

omm

unity

Vira

l Loa

d (c

opie

s/m

L)

Newly diagnosed andreported HIV cases

0

200

400

600

800

1000

1200

Num

ber of New

ly Diagnosed H

IV Cases

P = .005 forassociation*

798

642523 518

434

*Data insufficient to prove significant association with reduced HIV incidence.

A Formidable Challenge

A Unique Opportunity

When to Start HAART?A matter of Perspective

years

Viral Load

CD4 Count


years

years

Viral Load

CD4 Count


years

years

years

Viral Load

CD4 Count

Cost: 2010 to 2050

Granich. CROI 2010

0

10

20

30

40

50

60

70

0 1 2 3 4 5 60

1

2

3

4

5

6

7

0

10

20

30

40

50

60

70

0 1 2 3 4 5 60

1

2

3

4

5

6

7

0

10

20

30

40

50

60

70

0 1 2 3 4 5 60

1

2

3

4

5

6

7

Pers

on y

ears

on

ART

(M)

Dea

ths

(M)

Cos

t (B

n$)

Economics of ART up to 2050 in South AfricaCurrent policy vs. Universal Access at different CD4 counts

Current 200 350 500 Immediate

STOP HIV & AIDSSTOP HIV & AIDS: Seek and Treat toOptimally Prevent HIV & AIDS*

* Supported through a $2.5M five year Avant Garde Award by theNational Institute for Drug Abuse (NIDA) at the NIH in 2008 and$48M (+ drugs) four year outreach grant by BC Govt in 2010

Prospectively Evaluate the Impact of HAART Expansionon AIDS Morbidity and Mortality and HIV Incidence in BC

Intervention Primary Endpoint HAART Expansion HIV Incidence within medical guidelines at years 3 to 5

Secondary Endpoints:

MORBIDITY AND MORTALITY, CD4 COUNTS, HIV-1-RNA LEVELS,

RESISTANCE, ADVERSE EVENTS, SAFETY, ADHERENCE,

HOSPITALIZATIONS, RESOURCE UTILIZATION

STOP HIV & AIDSSTOP HIV & AIDS: Seek and Treat toOptimally Prevent HIV & AIDS*

* Supported through a $2.5M five year Avant Garde Award by theNational Institute for Drug Abuse (NIDA) at the NIH in 2008 and$48M (+ drugs) four year outreach grant by BC Govt in 2010

HAART has a substantial added preventive value

The magnitude of this effect is not yet fully characterized, and

may well vary in different settings

Seek and Treat among those who have a medical indication for

HAART cannot wait for the above to be resolved

Many lives will be saved and much insight will be gained from

closely monitoring a more “aggressive”roll out of HAART within Rx

Guidelines

Seek and Treat outside the range where treatment is medically

indicated remains a research question

However, Rx Guidelines leave few outside the “treatment

envelope”

TAP should serve to re-energize Universal Access

HAART Expansion to Reduce AIDSMorbidity & Mortality, and HIV Incidence

Combination prevention

CommunityInterventions

BiomedicalInterventions

StructuralInterventions

HIV testing,linkage to careand expanded

HAARTcoverage

Individualand small

groupbehavioral

interventions

HIVHIVPreventionPrevention

Modified from T. Coates

All scientific work is incomplete - whether it beobservational or experimental. All scientific work isliable to be upset or modified by advancingknowledge. That does not confer upon us a freedomto ignore the knowledge we already have, or topostpone the action that it appears to demand at agiven time.

Bradford-Hill, A. 1965 The environment and disease: Association orCausation? President address at January 14 meeting. Proceedings of the

Royal Society of Medicine 163 (seriesB): 295-300

A Statistician’s Opinion


Seek and Treat to OptimallyPrevent HIV & AIDS

STOP HIV & AIDSSTOP HIV & AIDS

R Hogg, E Wood, T Kerr, M Tyndall, A Levy, PR Harrigan,Viviane Lima, Aranka Anema, Stephen Smith, Warren O’Brien

Pedro Cahn, Jose Esparza, Craig Mc Clure, Robin GornaJacques Normand, Nora Volkow

IAS - USA ART Guidelines Panel, IAS, WHO and UNAIDS

BC-MoH and MHL&SSPH Foundation

Merck, Gilead, ViiVMSHRF, CIHR, NIDA and NIH

H&W, Ottawa

Research Staff and Study Participants

Thank You


Treatment as Prevention - WHO

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