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The impact of ART for HIV on TB
Brian Williams
South African Centre for Epidemiological Modelling and Analysis
10
1
0.1
450
275
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Italy Italy Italy CapePPD-neg. Anergic PPD-pos. Town
CD4 cell counts/μL
Inci
denc
e of
TB
(%/y
ear)
Incidence of TB increases at 0.36 per 100 CD4/μL.
Antonucci JAMA 1995; Badri Lancet 2002
Lawn SD, Myer L, Edwards D, Bekker LG, Wood E. Abstract 788: CROI 2009
Rate of increase: 0.42 ± 0.17 per 100 CD4+ cell counts per μL.
9.4
1.11.11.0
5.9
2.2
0
2
4
6
8
10
1991-1994 1995-1997 1998-1999
Ann
ual i
ncid
ence
(%)
. HIV- HIV+
TB incidence among gold miners in SACorbett EL Stable incidence rates of tuberculosis (TB) among human immunodeficiency virus (HIV)-negative South African gold miners during a decade of epidemic HIV-associated TB. J Infect Dis. 2003;188: 1156-63.
To fix δ we used the model for South Africa to find the value of δ that fits the average disease duration ratio for South Africa
The model fits the data without ART
TB notification rates in South Africa
0
200
400
600
1980 1990 2000 2010 2020 2030 2040
Not
ifica
tions
/yr
200
Not
ifica
tions
/100
k/yr
Given the epidemic of HIV, we then have one global parameter (δ ) and two country specific parameters (I0 and C0).
C0 ≡ Rate of increase of TB incidence with time
0
200
400
600
1980 1990 2000 2010 2020 2030 2040 2050
Not
ifica
tions
/100
k/yr
0
200
400
600
1980 1990 2000 2010 2020 2030 2040 2050
Not
ifica
tions
/100
k/yr
0
200
400
600
1980 1990 2000 2010 2020 2030 2040 2050
Not
ifica
tions
/100
k/yr
0
200
400
600
1980 1990 2000 2010 2020 2030 2040 2050
Not
ifica
tions
/100
k/yr
0
200
400
600
1980 1990 2000 2010 2020 2030 2040 2050
Not
ifica
tions
/100
k/yr
0
200
400
600
1980 1990 2000 2010 2020 2030 2040 2050
Not
ifica
tions
/100
k/yr
A B C D E F
The TB epidemic in South Africa. A to C without ART; E to G with testing and immediate ART. A and D: d = 0; B and E; d = 0.60; C and F; d = 1.0.
CD4 cell counts/μL from published surveys and estimated in this study
Survey This model
Botswana 626 ± 26 666 ± 40South Africa 1179 ± 36 964 ± 35Tanzania 911 ± 38 1201 ± 28Zambia 840 ± 60 1189 ± 26
Study number
IRR
for T
B o
n an
d of
f AR
T
0.0
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 10 12 14 16
Incidence rate ratio for TB among people on ART and not on ART. Heavy red line: weighted geometric mean.
1. Low income countries; 2. High income countries; 3. South Africa 4. Europe; 5. Europe and North America; 6. Europe and North America; 7. Europe and North America; 8. Brazil; 9. Italy.23 10. Brazil; 11. Spain; 12. United States; 13. Europe; 14. Brazil.
0
200
400
600
1980 1990 2000 2010 2020 2030 2040
Not
ifica
tions
/yr
South Africa
HIV negativeHIV positive; not ARTHIV positive; ARTHIV positive; all
Not
ifica
tions
/100
k/yr
TB in South Africa: test and treat immediately
Impact on TB of testing people in South Africa once a year for HIV and starting them on ART at different CD4 levels
0
100
200
300
400
500
600
700
1980 1990 2000 2010 2020 2030 2040 2050
Not
ifica
tions
/100
k/yr
200
200/µL
0
100
200
300
400
500
600
700
1980 1990 2000 2010 2020 2030 2040 2050
Not
ifica
tions
/100
k/yr
200
350/µL
0
100
200
300
400
500
600
700
1980 1990 2000 2010 2020 2030 2040 2050
Not
ifica
tions
/100
k/yr
200
500/µL
0
100
200
300
400
500
600
700
1980 1990 2000 2010 2020 2030 2040 2050
Not
ifica
tions
/100
k/yr
200
Immediate
0
100
200
300
400
500
02468101214161820
100/μL200/μL
350/μL
500/μL
10 5 1
Time since seroconversion (years)
Inci
denc
e of
HIV
+TB
/100
k/ye
ar
2
2015
2050
AIDS related TB in South Africa
IR
R
IR
R
TB notifications/100k HIV prevalence in adults
Zambia
SwazilandSouth Africa
Tanzania
Malawi
Lesotho
Ghana
Gabon
Botswana
Ivory Coast
Zimbabwe
0
5
10
15
20
25
30
0 50 100 150 200 250
Zambia
Swaziland
South Africa
Tanzania
Malawi
Lesotho
Ghana
Gabon
Botswana
Ivory Coast
Zimbabwe
0
5
10
15
20
25
30
0.0 0.1 0.2 0.3
A B
H
IV p
reva
lenc
e in
adu
lts
TB notifications/100k
Ivory Coast
Botswana
Gabon
Ghana
Lesotho
Malawi
Tanzania
South Africa
Swaziland
Zambia
Zimbabwe
0.0
0.1
0.2
0.3
0 50 100 150 200 250
C
Need…• Models structured by age and gender
• Much better data on the extent to which ART reduces the incidence of TB
• Much better understanding of the role of CD4 cell counts in determining the risk of TB
• Data on the relative risk of latent breakdown and new infection
• Carefully monitor trends in TB incidence as ART coverage is increased
Time to death (years)
CD
4 ce
ll co
unts
0.00
0.05
0.10
0.15
050
010
0015
0020
0025
00
0
10
0 10 20 30
ART drives CD4 back up
0
200
400
600
0 1 2 3 4Years since start of treatment
CD
4 ce
ll co
unt/m
icro
L
Williams BG et al. J Infect Dis. 2006;194:1450-8.CASCADE Collaboration Lancet. 2000;355:1131-7.
Falling epidemic
Rising epidemic
SS+ TuberculosisPrevalence Incidence Disease Duration
(%) (%/yr) (yr)HIV+ 0.44 (0.02-1.05) 2.87 (1.94-4.25) 0.15 (0.05-0.48)HIV- 0.55 (0.14–0.95) 0.48 (0.27-0.84) 1.15 (0.48-1.13)
DDR = 0.13 (0.09–0.20)Gold miners in South Africa
We define disease duration as prevalence divided by incidence
But: Robin Wood finds 1.12.
Liz Corbett
Reduction in TB incidence over 20 years among HIV-positive people as a function of effective coverage and the CD4 count/µL at which people start ART. ART reduces the incidence of TB to the level immediately after sero-conversion.
0
100
200
300
400
1980 1990 2000 2010 2020 2030 2040
Not
ifica
tions
/yr
Angola
0
20
40
60
80
100
120
140
1980 1990 2000 2010 2020 2030 2040
Odd
s ra
tio
Angola
0.00
0.01
0.02
0.03
1980 1990 2000 2010 2020 2030 20400.000
0.001
0.002
0.003
Prev
alen
ce
Inci
denc
e an
d m
orta
lity/
yr
Angola
0.00
0.10
0.20
0.30
1980 1990 2000 2010 2020 2030 20400.000
0.010
0.020
0.030
0.040
0.050
Prev
alen
ce
Inci
denc
e an
d m
orta
lity/
yr
Botswana
0
100
200
300
400
500
600
700
1980 1990 2000 2010 2020 2030 2040
Not
ifica
tions
/yr
Botswana
0
5
10
1980 1990 2000 2010 2020 2030 2040
Odd
s ra
tio
Botswana
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
1980 1990 2000 2010 2020 2030 20400.0000.0010.0020.0030.0040.0050.0060.0070.008
Prev
alen
ce
Inci
denc
e an
d m
orta
lity/
yrGabon
0
100
200
300
1980 1990 2000 2010 2020 2030 2040
Not
ifica
tions
/yr
Gabon
0
5
10
15
20
25
30
1980 1990 2000 2010 2020 2030 2040
Odd
s ra
tio
Gabon
0.00
0.01
0.02
0.03
1980 1990 2000 2010 2020 2030 20400.000
0.001
0.002
0.003
0.004
Prev
alen
ce
Inci
denc
e an
d m
orta
lity/
yr
Ghana 1
0
10
20
30
40
50
60
70
1980 1990 2000 2010 2020 2030 2040
Not
ifica
tions
/yr
Ghana 1
0
5
10
15
20
25
1980 1990 2000 2010 2020 2030 2040O
dds
ratio
Ghana 1
0.00
0.02
0.04
0.06
0.08
1980 1990 2000 2010 2020 2030 20400.000
0.005
0.010
Prev
alen
ce
Inci
denc
e an
d m
orta
lity/
yr
Ivory Coast
0
20
40
60
80
100
120
1980 1990 2000 2010 2020 2030 2040
Not
ifica
tions
/yr
Ivory Coast
0
5
10
15
20
1980 1990 2000 2010 2020 2030 2040
Odd
s ra
tio
Ivory Coast
0.00
0.10
0.20
0.30
1980 1990 2000 2010 2020 2030 20400.000
0.010
0.020
0.030
0.040
0.050
Prev
alen
ce
Inci
denc
e an
d m
orta
lity/
yr
Lesotho
0
100
200
300
400
500
600
700
1980 1990 2000 2010 2020 2030 2040
Not
ifica
tions
/yr
Lesotho
0
5
10
1980 1990 2000 2010 2020 2030 2040
Odd
s ra
tio
Lesotho
0.00
0.05
0.10
0.15
1980 1990 2000 2010 2020 2030 20400.000
0.010
0.020
Prev
alen
ce
Inci
denc
e an
d m
orta
lity/
yr
Malawi 1
0
50
100
150
200
250
1980 1990 2000 2010 2020 2030 2040
Not
ifica
tions
/yr
Malawi 1
0
5
10
15
1980 1990 2000 2010 2020 2030 2040
Odd
s ra
tio
Malawi 1
0
100
200
300
400
1980 1990 2000 2010 2020 2030 2040
Not
ifica
tions
/yr
Angola
0
20
40
60
80
100
120
140
1980 1990 2000 2010 2020 2030 2040
Odd
s ra
tio
Angola
0.00
0.01
0.02
0.03
1980 1990 2000 2010 2020 2030 20400.000
0.001
0.002
0.003
Prev
alen
ce
Inci
denc
e an
d m
orta
lity/
yr
Angola
0.00
0.10
0.20
0.30
1980 1990 2000 2010 2020 2030 20400.000
0.010
0.020
0.030
0.040
0.050
Prev
alen
ce
Inci
denc
e an
d m
orta
lity/
yr
Botswana
0
100
200
300
400
500
600
700
1980 1990 2000 2010 2020 2030 2040
Not
ifica
tions
/yr
Botswana
0
5
10
1980 1990 2000 2010 2020 2030 2040
Odd
s ra
tio
Botswana
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
1980 1990 2000 2010 2020 2030 20400.0000.0010.0020.0030.0040.0050.0060.0070.008
Prev
alen
ce
Inci
denc
e an
d m
orta
lity/
yr
Gabon
0
100
200
300
1980 1990 2000 2010 2020 2030 2040
Not
ifica
tions
/yr
Gabon
0
5
10
15
20
25
30
1980 1990 2000 2010 2020 2030 2040
Odd
s ra
tio
Gabon
0.00
0.01
0.02
0.03
1980 1990 2000 2010 2020 2030 20400.000
0.001
0.002
0.003
0.004
Prev
alen
ce
Inci
denc
e an
d m
orta
lity/
yr
Ghana 1
0
10
20
30
40
50
60
70
1980 1990 2000 2010 2020 2030 2040
Not
ifica
tions
/yr
Ghana 1
0
5
10
15
20
25
1980 1990 2000 2010 2020 2030 2040
Odd
s ra
tio
Ghana 1
0.00
0.02
0.04
0.06
0.08
1980 1990 2000 2010 2020 2030 20400.000
0.005
0.010
Prev
alen
ce
Inci
denc
e an
d m
orta
lity/
yr
Ivory Coast
0
20
40
60
80
100
120
1980 1990 2000 2010 2020 2030 2040
Not
ifica
tions
/yr
Ivory Coast
0
5
10
15
20
1980 1990 2000 2010 2020 2030 2040
Odd
s ra
tio
Ivory Coast
0.00
0.10
0.20
0.30
1980 1990 2000 2010 2020 2030 20400.000
0.010
0.020
0.030
0.040
0.050
Prev
alen
ce
Inci
denc
e an
d m
orta
lity/
yr
Lesotho
0
100
200
300
400
500
600
700
1980 1990 2000 2010 2020 2030 2040
Not
ifica
tions
/yr
Lesotho
0
5
10
1980 1990 2000 2010 2020 2030 2040
Odd
s ra
tio
Lesotho
0.00
0.05
0.10
0.15
1980 1990 2000 2010 2020 2030 20400.000
0.010
0.020
Prev
alen
ce
Inci
denc
e an
d m
orta
lity/
yr
Malawi 1
0
50
100
150
200
250
1980 1990 2000 2010 2020 2030 2040
Not
ifica
tions
/yr
Malawi 1
0
5
10
15
1980 1990 2000 2010 2020 2030 2040
Odd
s ra
tio
Malawi 1
0.00
0.02
0.04
0.06
0.08
1980 1990 2000 2010 2020 2030 20400.000
0.005
0.010
0.015
Pre
vale
nce
Inci
denc
e an
d m
orta
lity/
yr
Tanzania
0
50
100
150
200
1980 1990 2000 2010 2020 2030 2040
Not
ifica
tions
/yr
Tanzania
0
5
10
15
20
25
30
1980 1990 2000 2010 2020 2030 2040
Odd
s ra
tio
Tanzania
0.00
0.05
0.10
0.15
0.20
1980 1990 2000 2010 2020 2030 20400.000
0.010
0.020
0.030
0.040
Pre
vale
nce
Inci
denc
e an
d m
orta
lity/
yr
Zambia
0
100
200
300
400
500
600
1980 1990 2000 2010 2020 2030 2040
Not
ifica
tions
/yr
Zambia
0
5
10
15
20
1980 1990 2000 2010 2020 2030 2040
Odd
s ra
tio
Zambia
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
1980 1990 2000 2010 2020 2030 20400.000
0.010
0.020
0.030
0.040
0.050
Prev
alen
ce
Inci
denc
e an
d m
orta
lity/
yr
Zimbabwe
0
100
200
300
400
500
1980 1990 2000 2010 2020 2030 2040
Not
ifica
tions
/yr
Zimbabwe
0
5
10
15
20
25
30
1980 1990 2000 2010 2020 2030 2040
Odd
s ra
tio
Zimbabwe
HIV TB IRR
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