Antiretroviral Treatment MAntiretroviral Treatment Monitoring: onitoring:

A Canadian CaA Canadian Case Examplese Example

Robert Hogg, PhDRobert Hogg, PhDBC Centre for Excellence in HIV/AIDSDept. of Health Care and Epidemiology

University of British Columbia

British Columbia

HIV/AIDS Drug Treatment Program

• In BC antiretrovirals have been centrally distributed free of charge to eligible HIV+ individuals since 1986

• In October 1992, the HIV/AIDS Drug Treatment Program became the responsibility of the BC Centre for Excellence

• Ever enrolled over 6,500 and 2,800 currently on therapy

Monitoring and Evaluation

• Patient, Physician and geographical characteristics

• Antiretroviral therapy dispensing information

• Sociodemographic and adherence-related data

• Clinical and laboratory data, including CD4 and plasma viral load

• Morbidity and mortality data updated through linkages

• Antiretroviral resistance

• Adherence measures

Percent of persons first starting antiretroviral therapy on NNRTIs (Aug 1998 to Jan 2003)

Nevirapine use in British Columbia (Jan 2002 to Jan 2003)

Percent frequency distribution of initial antiretroviral regimens in British Columbia (1993-2001)

Fre

qu

en

cy D

istr

ibu

tio

n (

%)

Therapy Start Time (year)

N

0102030405060708090

100

1993 1994 1995 1996 1997 1998 1999 2000 2001

1 ARV

2 ARV

3 ARV

4 ARV

614 317 398 963 764 456 397 291 284

Progression to AIDS/Death

0

5

10

15

20

25

30

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Months

% o

f pa

tien

ts p

rog

ress

ing

JAMA 1998 & CMAJ 1999

No therapyMono-therapy

Dual-therapy

Triple therapy

Deaths per 1,000 pts ever on therapy

0

20

40

60

80

100

120

140

19

94

-1

19

94

-3

19

95

-1

19

95

-3

19

96

-1

19

96

-3

19

97

-1

19

97

-3

19

98

-1

19

98

-3

19

99

-1

19

99

-3

20

00

-1

20

00

-3

20

01

-1

0 to 100

100 to 350

350 to 500

above 500

CD4 (/mm3)

Num

ber

of D

eath

s

YearBy Quarters

Updated from Hogg et al, Lancet, 1999

Drug Costs

Cost: 1992/93: $500,000 US

2003/3004: $30,000,000 US

Antiretroviral cohorts

International (PLATO, ART collaborative study)

First start (HOMER)

Mega HAART

Women

STI

IDU (BART)

HAART Observational Medical Evaluation and Research (HOMER) Study

• Population-based study of HIV+ men and women in the Drug Treatment Program

• Aged 18 years and over

• Antiretroviral naive

• First prescribed triple therapy (2 NRTIs and either a PI or an NNRTI) between August 1, 1996 and September 30, 1999

HOMER

D

isea

se T

ype

Dis

ease

Typ

e

Recommendations Recommendations

Cells/mm3Cells/mm3< 5 K< 5 K 5 to 30 K5 to 30 K > 30 K> 30 K

< 350< 350

350 to 500350 to 500

> 500> 500

RecommendRecommend

RecommendRecommend

Based on CD4 decline, high viral load, patient interest, Based on CD4 decline, high viral load, patient interest, adherence potential, and risk of side effectsadherence potential, and risk of side effects

Symptomatic

200 cells/mm3

> 200 cells/mm3

IAS-USA, JAMA, July 2002IAS-USA, JAMA, July 2002

When to start therapy in 2002

Combined CD4 & HIV-RNA groups Hogg et al JAMA, 2001P

rob

ablit

y o

f S

urv

ival

(%

)

Time from Start of ARVs (mths)

70

72

74

76

78

80

82

84

86

88

90

92

94

96

98

100

0 3 6 9 12 15 18 21 24

High HIV-RNA: >=100K c/mL (n=360)Low HIV-RNA: < 100K c/mL (n=416)

High HIV-RNA: >=100K c/mL (n=204)Low HIV-RNA: < 100K c/mL (n= 97)

High HIV-RNA: >=100K c/mL (n=114)Low HIV-RNA < 100K c/mL (n= 28)

High HIV-RNALow HIV-RNA

Low HIV-RNAHigh HIV-RNA

High CD4

Intermediate CD4

Low HIV-RNAHigh HIV-RNA

Low CD4

High CD4: >=200 cells/mm3

Intermediate CD4:>=50-199 cells/mm3

Low CD4:< 50 cells/mm3

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100

0 6 12 18 24 30 36 4230

35

40

45

50

55

60

65

70

75

80

85

90

95

100

0 6 12 18 24 30 36 42

> 200 cells/mm 3> 200 cells/mm 3

50 - 199 cells/mm 3

50 - 199 cells/mm 3

< 50 cells/mm 3

< 50 cells/mm 3

CD4 groups stratified by adherence

Time Since Start of ARVsTime Since Start of ARVs Time Since Start of ARVsTime Since Start of ARVs

Pro

bab

ility

of

Su

rviv

al (

%)

Pro

bab

ility

of

Su

rviv

al (

%)

Wood et al. AIDS, 2003

< 75% Adherent> 75% Adherent

Pro

bab

ility

of

Su

rviv

al (

%)

Pro

bab

ility

of

Su

rviv

al (

%)

Risk of Death by baseline CD4 cell count and adherence

Adherence CD4 Adjusted

Level Cell Count Relative Hazard (95% CI)

> 75% > 200 1.0 REF

< 75% > 200 3.6 (1.7, 7.4)

> 75% 50 - 199 4.5 (2.4, 8.7)

< 75% 50 - 199 9.8 (4.5, 21.3)

> 75% < 50 6.2 (3.0, 12.6)

< 75% < 50 35.7 (16.2, 78.9)

*Model was adjusted for physician experience, history of injection drug use, baseline plasma viral load, age, and AIDS at baseline.

Wood et al. AIDS, 2003

NNRTI vs. PI: Time to Death

70

72

74

76

78

80

82

84

86

88

90

92

94

96

98

100

0 6 12 18 24 30 36

PIPI

NNRTINNRTI

Initial RegimenInitial Regimen

Pro

bab

ility

of

Su

rviv

al (

%)

Pro

bab

ility

of

Su

rviv

al (

%)

p = 0.252p = 0.252Log-rankLog-rank

Time from Start of ARVs (months)Time from Start of ARVs (months)

Hogg et al., IAS, 2002

Time to Switching TherapyP

rob

abil

ity

of

Ad

din

g/S

wit

chin

g A

RV

(%

)

Time from Start of ARVs (months)

log rank p<0.001

0

10

20

30

40

50

60

70

80

0 6 12 18 24 30 36

2 Nuc + PI (N=983)2 Nuc + NNRTI (N=439)

Time to First Simultaneous Resistance to AntiretroviralsP

rob

abil

ity

of

Det

ecti

ng

Res

ista

nce

(%

)

4C>=3C>=2C>=1C N=

N=N=N= 1219 959 873 772 623

1219 954 861 752 602

1219 873 743 621 4881219 932 822 702 559

Time from Start of Antiretrovirals(months)

0

5

10

15

20

25

30

35

40

0 6 12 18 24

4 Classes

>=3 Classes

>=2 Classes

>=1 Class

Harrigan et al., IAS, 2003

Time to First Detection of Resistance to Each Class of Antiretrovirals

Pro

bab

ilit

y o

f D

etec

tin

g R

esis

tan

ce (

%)

(Lamiv)(NNRTI)

(NRTI)(PI)

N=N=N=N=

1219 899 783 662 5281219 937 826 712 570

1219 947 848 741 5911219 935 839 730 580

Time from Start of Antiretrovirals(months)

0

5

10

15

20

25

30

35

40

0 6 12 18 24

PI

NRTI (non-3TC)

NNRTI

Lamivudine

Harrigan et al., IAS, 2003

Donald RumsfeldClarifying US Policy on the war on terror

Newsweek, March 10, 2003

“There are known knows. These are things we know that we know. There are known unknowns. That is to say, there are things that we know we don’t know. But these are also unknown unknowns. There are things we don’t know we don’t know.”

Human security?

Based on E Wood and P Braitstein et al. Lancet 2000 June 17;vol 355:2095-2100

1999 2000 2001 2002 2003 2004 200546

47

48

49

50

YearYear

Lif

e E

xpec

tan

cy a

t B

irth

Lif

e E

xpec

tan

cy a

t B

irth

No Therapy

25% Antiretroviral Therapy Use

Impact of Various ART Strategies in South Africa

Acknowledgements

Michael O’ShaughnessyPaula BraitsteinRichard HarriganNada Gataric

Julio MontanerBenita YipKeith ChanEvan Wood

Michael Smith Foundation for Health Research The Canadian Institutes of Health Research

BC Centre for Excellence in HIV/AIDS