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