The impact of ART for HIV on TB

Brian Williams

South African Centre for Epidemiological Modelling and Analysis

Basic model

Increase of TB with decline in CD4

10

1

0.1

450

275

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450

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450

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100

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.

Time since infection/CD4 cell count

Inci

denc

e of

TB

2x

Rate of increase:0.36 per 100 CD4 cells/µL

Decrease of Disease Duration with Increase in

Incidence

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.

0 0

i iD ID I

δ⎛ ⎞= ⎜ ⎟

⎝ ⎠

−

δ = 0.6 (0.2 to 0.8)

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

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600

1980 1990 2000 2010 2020 2030 2040

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tions

/yr

200

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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

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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

Reduction in TB when on ART

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

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600

1980 1990 2000 2010 2020 2030 2040

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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

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200/µL

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500/µL

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200

Immediate

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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

Predicted and observed CD4+ cell counts

IR

R

IR

R

TB notifications/100k HIV prevalence in adults

Zambia

SwazilandSouth Africa

Tanzania

Malawi

Lesotho

Ghana

Gabon

Botswana

Ivory Coast

Zimbabwe

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0 50 100 150 200 250

Zambia

Swaziland

South Africa

Tanzania

Malawi

Lesotho

Ghana

Gabon

Botswana

Ivory Coast

Zimbabwe

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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

0.30 ± 0.16 per 100 CD4/μL

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

Thank you

Time to death (years)

CD

4 ce

ll co

unts

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050

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0015

0020

0025

00

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0 10 20 30

ART drives CD4 back up

0

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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.

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Angola

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Botswana

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Botswana

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1980 1990 2000 2010 2020 2030 20400.0000.0010.0020.0030.0040.0050.0060.0070.008

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ce

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e an

d m

orta

lity/

yrGabon

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/yr

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dds

ratio

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s ra

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Angola

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Odd

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tio

Botswana

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1980 1990 2000 2010 2020 2030 20400.0000.0010.0020.0030.0040.0050.0060.0070.008

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ce

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e an

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orta

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tio

Ivory Coast

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tio

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1980 1990 2000 2010 2020 2030 2040

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s ra

tio

Malawi 1

0.00

0.02

0.04

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1980 1990 2000 2010 2020 2030 20400.000

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0.010

0.015

Pre

vale

nce

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d m

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tio

Tanzania

0.00

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1980 1990 2000 2010 2020 2030 20400.000

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Pre

vale

nce

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denc

e an

d m

orta

lity/

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Zambia

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1980 1990 2000 2010 2020 2030 2040

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Zambia

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1980 1990 2000 2010 2020 2030 2040

Odd

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tio

Zambia

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0.35

1980 1990 2000 2010 2020 2030 20400.000

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1980 1990 2000 2010 2020 2030 2040

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Zimbabwe

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tio

Zimbabwe

HIV TB IRR

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