Outcomes of Antiretroviral Treatment
in Resource Limited and
Industrialized Countries
Matthias Egger MD
International epidemiological Databases to Evaluate AIDS (IeDEA)
ART Cohort Collaboration (ART-CC)
Swiss HIV Cohort Study (SHCS)
Universities of Bern and Cape Town
Switzerland and South Africa
Overview of talk
•
•
•
•
Sources of information
When do patients start ART?
What regimens are used?
What are the outcomes?
–
–
–
–
Loss to program
Virologic response
Opportunistic illnesses
All cause mortality
• Conclusions
CROI 2007 – Overview – 2
Sources of information
© Gideon Mendel/Corbis
CROI 2007 – Sources – 3
Antiretroviral Therapy (ART)
Cohort Collaboration
• France
• French Hospital Database on HIV
(FHDH)
• Aquitaine Cohort
• Germany
• 29 European countries
• Canada
• British Columbia Centre for Excellence
in HIV (BCCfE-HIV)
• South Alberta Clinic
• USA
• Italian Cohort of Antiretroviral-Naive
Patients (ICONA)
• Switzerland
• Swiss HIV Cohort Study
• Netherlands
• AIDS Therapy Evaluation project
Netherlands (ATHENA)
• Spain
• PISCIS, Catalonia and Balearic islands
• United Kingdom
• Royal Free Hospital Cohort, London
Cohort Collaboration
• The Multicenter Study Group on EuroSIDA
• Frankfurt HIV Cohort
• Köln / Bonn Cohort
• Italy
ART
• Collaborations in HIV Outcomes Research
US (CHORUS)
• 1917 Clinic Cohort, University of Alabama,
Birmingham
• University of Washington HIV Cohort,
Seattle
• Veterans Aging Cohort Study (VACS),
West Haven
www.art-cohort-collaboration.org
CROI 2007 – Sources – 4
International epidemiological
Databases to Evaluate AIDS
• 7 regional networks
• North America
• South America / Caribbean
• West Africa
• Central Africa
• East Africa
• Southern Africa
• Australia / Asia
• Resource limited countries networks
www.iedea-hiv.org
• ART-LINC Collaboration
www.art-linc.org
• Kids-ART-LINC Collaboration
www.anecca.org
• Treat Asia HIV Observational Database (TAHOD)
www.amfar.org
CROI 2007 – Sources – 5
Large, public scale up programs in
Sub-Saharan Africa
• Gugulethu township, Cape Town, RSA
• Khayelitsha township, Cape Town, RSA
• Centre de Prise en Charge de Recherche
et de Formation (CEPREF), Abidjan, Côte
d‘Ivoire
• Lighthouse Clinic, Lilongwe,
Malawi
CROI 2007 – Sources – 6
When do patients start antiretroviral
treatment?
© Gideon Mendel/Corbis
CROI 2007 – CD4 at start – 7
CD4 count at start of ART, 2003-2005
42 countries, 176 sites
ART
Cohort Collaboration
CROI 2007 – CD4 at start – 8
CD4 count at start of ART, 2003-2005
33,008 treatment-naive patients
N=8300
N=1028
N=19967
N=1274
N=2439
CROI 2007 – CD4 at start – 9
CD4 count at start of ART, 2003-2005
42 countries, 176 sites, 33,008 patients
164
179
200
187
192
163
102
157
123
103
86
125
159
95
53
134
122
100
206
72
97
97
239
87
181
Numbers are median CD4 counts
CROI 2007 – CD4 at start – 10
Median CD4 counts at start of ART
Trends over time
350
Europe & North America
CD4 cell count at start of ART
300
250
200
150
100
50
MSM
HET
IDU
Sub-Saharan Africa
0
1994
1996
1998
2000
2002
2004
2006
Year
CROI 2007 – CD4 at start – 11
What treatment regimens are used?
© Gideon Mendel/Corbis
CROI 2007 – regimens – 12
First line regimens, 2003-2005
3 most common regimens by region
3TC D4T EFV
3TC D4T EFV
3TC AZT LPV/r
40
3TC AZT EFV
3TC AZT NVP
EFV ETC TNV
20
60
80
100 0
20
Western Europe
40
60
20
% of patients
80
100
0
20
40
60
80
100
3TC D4T EFV
3TC D4T NVP
3TC AZT EFV
3TC AZT NVP
60
40
Southern Africa
3TC D4T EFV
3TC EFV TNV
40
100 0
3TC D4T NVP
3TC AZT EFV
20
80
Asia
3TC AZT LPV/r
0
3TC D4T NVP
3TC AZT EFV
3TC AZT EFV
0
West, Central & East Africa
South America
North America
60
% of patients
80
100
0
20
40
60
80
100
% of patients
CROI 2007 – regimens – 13
First line regimens, 2003-2005
No. of regimens used to treat 90% of patients
North America
South America
West, Central & East Africa
59
11
3
Western Europe
Asia
Southern Africa
47
3
3
CROI 2007 – regimens – 14
Loss to program
© Gideon Mendel/Corbis
CROI 2007 – loss – 15
Loss to program
• 16 treatment programs in Africa, Asia and Latin
America
– 12 with active tracing of patients (home visits,
telephone, reminder letters)
– 4 with no tracing
• 5,575 adult patients starting ART
– Median age 35 years, 46% women
– Median baseline CD4 cell count 105 cells/µL
CROI 2007 – loss – 16
Loss to program
• No follow up after initial visit
– 4% (0% to 9%)
• Loss to follow up during first 6 months
– 17% (0% to 57%)
CROI 2007 – loss – 17
Loss to program
Calendar period
≤ 2000
2001-2002
2003-2004
No follow up
Loss to follow up
Odds ratio
(95% CI)
Hazard ratio
(95% CI)
1
4.46 (1.26-15.7)
5.01 (1.27-19.8)
1
2.77 (1.69-4.55)
7.86 (4.71-13.1)
CROI 2007 – loss – 18
Loss to program
CD4 cell count (cells/µl)
≥ 50
25-49
< 25
No follow up
Loss to follow up
Odds ratio
(95% CI)
Hazard ratio
(95% CI)
1
2.76 (1.69-4.52)
2.50 (1.43-4.37)
1
1.04 (0.82-1.31)
1.47 (1.23-1.75)
CROI 2007 – loss – 19
Tracing of patients and mortality
8
Cumulative mortality (%)
Active tracing of patients
6
4
2
No tracing
0
0
3
6
9
12
Months after starting ART
Lancet 2006; 367: 817–24
CROI 2007 – loss – 20
Virologic response
© Gideon Mendel/Corbis
CROI 2007 – response – 21
Study population
• 1856 patients from Gugulethu and
Khayelitsha, Cape Town
– Median CD4 count 81 cells/µL, median age
33 years, 70% women
• 967 patients from Swiss HIV Cohort
– Median CD4 count 212 cells/µL, median age
38 years, 33% women
CROI 2007 – response – 22
Standardized
frequency
of viral load
measurement
Standardized
measurement
frequency
(% of total *100'000)
Frequency of viral load measurements
100
South Africa
South
Africa
50
0
100
Swiss
Switzerland
50
0
3
6
9
12
15
18
21
Months
fromafter
HAART
initiation
Months
starting
ART
24
CROI 2007 – response – 23
Initial virologic response
% with viral load <500 copies/ml
(<500 copies/ml)
100
South Africa
80
Switzerland
60
40
20
0
0
6
12
18
24
Months after starting ART
CROI 2007 – response – 24
Viral rebound
(>500 copies/ml)
100
% with viral rebound
80
South Africa
60
Switzerland
40
20
0
0
6
12
18
24
Months after first viral load <500 copies/ml
CROI 2007 – response – 25
Treatment change
(any change, including switching, substitution)
% with treatment change
60
Switzerland
40
20
South Africa
0
0
6
12
18
24
Months after starting ART
CROI 2007 – response – 26
Opportunistic illnesses
© Gideon Mendel/Corbis
CROI 2007 – OIs – 27
Most common OIs in first 3 months
TB (pulmonary / extrap.)
Herpes simplex disease
Cryptococcal meningits
Pneumocystis pneumonia
Oesophagial candidiasis
Kaposi‘s sarcoma
Toxoplasmosis of the brain
Bacterial pneumonia, recurrent
Sub-Saharan Africa
Europe & North America
TB (pulmonary / extrap.)
Kaposi‘s sarcoma
CMV disease
Pneumocystis pneumonia
Other mycobacterial disease
Oesophagial candidiasis
Wasting
Encephalopathy
ART
Cohort Collaboration
0
Arch Intern Med. 2005;165:416-423
50
100
150
200
250
Incidence rate (cases / 1000 pyrs)
300
CROI 2007 – OIs – 28
Mortality
© Gideon Mendel/Corbis
CROI 2007 – mortality - 29
Study population
• Scale up programs in Sub-Saharan Africa
–
–
–
–
11,231patients
777 deaths
15,350 person years of follow up
Loss to follow up 13% over 2 years
• ART Cohort Collaboration
–
–
–
–
38,050 patients
2,026 deaths
144,994 person years of follow up
Loss to follow up 6% over 2 years
ART
Cohort Collaboration
CROI 2007 – mortality - 30
Cumulative mortality (%)
Mortality over four years
15
Sub-Saharan Africa
10
5
Europe & North America
0
0
12
24
36
48
Months after start of ART
CROI 2007 – mortality - 31
Mortality by baseline CD4 cell count
Sub-Saharan Africa
Europe & North America
Cumulative mortality (%)
30
< 25 cells/µL
25-49 cells/µL
50-99 cells/µL
100-199 cells/µL
> 200 cells/µL
25
20
15
10
5
0
0
12
24
36
48
0
12
24
36
48
Months after starting ART
CROI 2007 – mortality - 32
Relative mortality over time
Relative mortality rate (95% CI)
Sub-Saharan Africa vs. industrialized
countries
16
Adjusted for:
Age, sex, CD4 count,
8
clinical stage at baseline
4
2
Reference
(industrialized countries)
1
0.5
1 2
Lancet 2006; 367: 817–24
3-4
5-6
7-12
13-24 25-36 37-48
Months from starting ART
CROI 2007 – mortality - 33
Mortality by cohort
(unadjusted results)
ART
Europe & North America
Cohort Collaboration
Sub-Saharan Africa
0.25 0.5
1
2
4
8
16
Mortality in first year after ART initiation (%)
CROI 2007 – mortality - 34
Mortality by cohort
(adjusted for age, sex,
CD4 count, year, stage)
ART
Europe & North America
Cohort Collaboration
Sub-Saharan Africa
0.25 0.5
1
2
4
8
16
Mortality in first year after ART initiation (%)
CROI 2007 – mortality - 35
Conclusions
© Gideon Mendel/Corbis
CROI 2007 – conclusionis - 36
• Most patients in resource-limited and many
patients in industrialized countries start ART late
or very late
• In industrialized settings many different first-line
regimens are used and changes are frequent
• Few regimens are used in resource limited
settings and changes are less frequent
• Virologic and immunologic responses are very
similar
CROI 2007 – conclusions – 37
• In some resource-limited settings substantial
proportions of patients are lost to the program
early on
• TB is the most frequent complication in patients
starting ART
• Mortality is substantially higher in resourcelimited settings, particularly in the first months of
ART
• Taking into account differences in prognostic
factors, mortality in programs in sub-Saharan
Africa is comparable to that observed in
industrialized settings
CROI 2007 – conclusions – 38
Acknowledgements
• University of Bern
– Martin Brinkhof, Bea Fatzer, Claire Graber, Anke Huss, Olivia
Keiser
• University of Cape Town
– Andrew Boulle, Linda-Gail Bekker, Katherine Hilderbrand,
Landon Myer, Catherine Orrell, Robin Wood
• University of Bordeaux
– François Dabis, Elise Arrive, Eric Balestre
• University of Bristol
– Jonathan Sterne, Margaret May, Ross Harris
CROI 2007 – acknowledgements – 39
Steering groups
• ART-LINC collaboration of IeDEA
– F Ba-Gomis, D Bangsberg, A Boulle, J Chisanga, Eric Delaporte,
Diana Dickinson, Ernest Ekong, K Marhoum El Filali, P Miotti, C
Kabugo, S Kimaiyo, M Khongphatthanayothin, N Kumarasamy,
C Laurent, R Lüthy, J McIntyre, T Meade, E Messou, D Nash, A
Ndir, W Nyandiko Mokaya, M Pascoe, P Saliif Sow, S Phiri, M
Schechter, C Seyler, J Sidle, E Sprinz, S Touré, S Van der
Borght, R Weigel, R Wood,
• ART Cohort Collaboration
– J Casabona, G Chêne, D Costagliola, F Dabis, A d’Arminio
Monforte, F de Wolf, J Gill, R Hogg, A Justice, M Kitahata, B
Ledergerber, C Leport, J Lundgren, M May, A Phillips, P Reiss,
M Saag, C Sabin, N Schmeisser, S Staszewski, J Sterne, I
Weller
• IeDEA executive committee
– F Dabis, M Bacon, D Cooper, T Hartwell, M Law, R McCraig, R
Moore, R Huebner, S Gange, D Masys, R Ryder, C Yiannoutsos,
C Williams.
CROI 2007 – acknowledgements – 40
Funders
• Office of AIDS Research, NIH, USA
• National Institute of Allergy and Infectious
Disease (NIAID), USA
• Agence National de Recherches sur le SIDA
(ANRS), France
• Medical Research Council, UK
CROI 2007 – acknowledgements – 41
Thank you
© Gideon Mendel/Corbis
[email protected]
CROI 2007 – thank you – 42