Mina Hosseinipour, M.D., M.P.H

Lilongwe Malawi

� Overview of Early Mortality in ART programs

in Resource Poor Settings� Predictors of Mortality

� Causes of Mortality

� Cohort studies

� Autopsy studies

� The role of TB in mortality

� 27 clinics in Africa, South America, and

Asia

� >40,000 patients on HAART

� Principal Investigators

� François Dabis

� Matthias Egger

� Mauro Schechter

� Funding: ANRS & NIH

6.4% (5.1-7.7)

1.8% (1.5-2.2)

Braitstein et al; Lancet 2006.

���� HR unadjusted

���� HR adjusted

*Adjusted for cohort, sex, age,

baseline CD4, HAART regimen,

stage of diseaseMonths from starting HAART

0 3 6 9 12

Hazard

ratio (

95

% C

I)

0.5

1

2

4

8

16

Braitstein et al. Lancet 2006; 367: 817–24

Mortality in the first year of HAART(ART-LINC)

Months after starting ART

0 12 24 36 48

Cu

mu

lati

ve

mo

rta

lity

(%

)

0

5

10

15

20

25

30

0 12 24 36 48

< 25 cells/µL

25-49 cells/µL

50-99 cells/µL

100-199 cells/µL

> 200 cells/µL

Sub-Saharan Africa Europe & North America

Mortality by baseline CD4 cell count(ART-LINC and ART-CC)

Survival proportion over 21 months among patients (n=1235) from the time of entering a community-based

antiretroviral treatment programme in South Africa.

Lawn AIDS 2008

910 patients:

� 10% deaths at 12 months

- 85% deaths in

the first 6

months

Severe P et al New Eng. J. Med 2005 353:22-2325-2334

� Vast majority of 1st-year deaths occur early after HAART initiation

� Many in the first months

� Most by 6 months� Vast majority of 1st-year deaths occur among those with

advanced disease

� Lower CD4 counts associated with increased risk of death

Bisson et al, PLoS ONE 2008. Stringer, J. S. A. et al. JAMA 2006;296:782-793. Braitstein et al. Lancet 2006; 367: 817–24

� Many Government Programs do not have

active follow-up of clients� Loss to follow-up rates in scale up programs

range from 1 to 30%

� What is the status of LTFU patients?

Copyright restrictions may apply.

Stringer, J. S. A. et al. JAMA 2006;296:782-793.

Outcomes in the Antiretroviral Therapy Program,

Lusaka, Zambia (April 2004-November 2005)

7 % dead 21% lost

319

69

22

On HAART (78%)

Dead (17%)

Lost (5%)

Infectious Disease Care Clinic (n=410)

B. Definitive Outcomes as Determined by Active Follow-up

313

29

68

On HAART (76%)

Dead (7%)

Lost (17%)

Infectious Disease Care Clinic (n=410)

A. Initial Outcomes as Determined by Passive Follow-up

.8

.85

.9

.95

1

Surviva

l

0 100 200 300 400days

Active Follow-up Passive Follow-up

Kaplan Meier Survival

Bisson et al. PLoS ONE 2008.

59% of those lost to follow-up had died

High Rates of Death Among those Lost

to Follow-up

Hochgesang M, et al. 2006 XVI

International AIDS Conference.

Abstract TUPE0119

Months after starting ART

0 12 24 36 48

Cu

mu

lati

ve

mo

rta

lity

(%

)

0

5

10

15

20

25

30

0 12 24 36 48

< 25 cells/µL

25-49 cells/µL

50-99 cells/µL

100-199 cells/µL

> 200 cells/µL

Sub-Saharan Africa Europe & North America

Mortality by baseline CD4 cell count(ART-LINC and ART-CC)

Cohort 3 month

Mortality

(%)

Risk Factors

BMI Total

lymphocyte

count

CD4

count

WHO

stage

III/IV

HB

Ethiopia 16.7 <18.5 <750/ml NA IV <10.0g

%

Senegal ?? 18.5 <1200/ml <200 NA NA

Tanzania 19.2 <16 NA NA NA <8.0g

%

Dream 16.3 <18 NA <200 III/IV <10.4g%

� Causes of Death Less Consistently reported

� Loss to Follow-up issues� Reported Causes of Death often Non-specific

� Few Autopsy Studies to confirm causes of

Death

� 6 Cohort Studies (5 SSA, 1 Haiti)

� TB was among the leading cause of death in 5/6

cohorts

� TB likely under-reported due to difficulty in

making diagnosis and LTFU rates

Lawn CID 2006:43:770-776, Etard AIDS 2006:20: 1181-1189, Zachariah 2006: 20:2355-2360,

Moore CROI 2007 Abs 34, Kambugu IAS 2007 WEPEBO55; Severe, NEJM 2005

Cause of Death “Dream”

N=260

Kenya

N=15

Botswana

N=24

Cameroon

N=19

South Africa

N=205

India

N=155

Tuberculosis 23 4 4 1 42 29

Cryptococcal

Meningitis

N.R. 2 1 18 6

Pneumonia N.R. 2 N.R. 1 12 22

Sepsis N.R. N.R. N.R 2

Wasting/GE

Advanced HIV

Poor

Health/FUO

Unknown

122 5 4 14 76 86

Malaria 39 N.R. N.R. 1 N.R. N.R.

Anemia 35 N.R. 1 N.R. N.R. N.R.

KS N.R. 1 2 N.R. 11 N.R.

Hepatotoxicity/

Drug Toxicity

N.R. N.R. 3 ?1 6 N.R.

Marazzi, AIDS Res Human Retrovirus 2008; Karcher TMIH 2007, Wester Epid &

Social Science 2005, Mzileni 2008, Kamarasamy Int J Infect Dis 2009

� Tuberculosis (16-51%)

� Invasive Bacterial Infections (8-49%)� Wasting (13-43%)

� Cryptococcal Meningitis

� Kaposi’s Sarcoma

“Unknown” is the most common cause

� Even in resource rich settings, Autopsies

change the Cause of Death

� Primary diagnosis changed in 70%

� 36% of all opportunistic infections were missed.

▪ six of nine cytomegalovirus

▪ all tuberculosis

▪ 75% of Kaposi's sarcoma.

Beadsworth Int J STD AIDS 20(2): 84-86.

� HIV wasting syndrome (93 patients)

� Disseminated TB was found in 41/93 (44%)

� Linear Trend between degree of wasting and

prevalence of Tuberculosis.

Lucas et al, BMJ 1994.

� 75 HIV-1 positive inpatient deaths in Kenya

� Tuberculosis, Pneumonia 96% of all deaths

� Tuberculosis >50%, Disseminated in 80%

� 104 HIV positive inpatient deaths in Botswana

� TB (40%), bacterial pneumonia (23%),

Pneumocystis carinii pneumonia (11%), and

Kaposi's sarcoma (11%)

Rana, et al. JAIDS 2000, Ansari, et al Int J Tuberc Lung Dis 6(1): 55-63.

� Inpatient Pulmonary Unit in Cote d'Ivoire

� 44% of deaths due to Tuberculosis

� High rates of disseminated TB

� South Africa HIV positive Gold Miners

� 35% of deaths due to TB

� 47% of all deaths had evidence of TB

� Clinical vs. Autopsy diagnosis for TB

▪ 43% Sensitivity and 67% Specificity

Domoua, K. et al. (1995). Med Trop (Mars) 55(3): 252-254., Murray J. et al. (2007)

AIDS: 21: S97-S104.

� 47 HIV-infected patients with premortem diagnosis of TB (none on ART)� 79% Confirmed the diagnosis, 21% no TB� 53% of patients the autopsy and clinical cause were

concordant.� Immediate or contributory causes of death were:

� extensive pulmonary tuberculosis, 32 (68%); � disseminated tuberculosis, 28 (60%); � bacterial pneumonia, 13 (26%); � cytomegalovirus pneumonitis in seven (15%); � Pneumocystis pneumonia was found in five cadavers

(11%). � Salmonella spp. was cultured from 11 splenic specimens.

Martinson, AIDS 2007

Stringer, J. S. A. et al. JAMA 2006;296:782-793.

Do prevalent severe OIs increase risk of death

early after HAART initiation?

� Pulmonary TB ranged from 4.8/100 py in Cameroon to 17.7/100py in Kenya

� Of the TB cases, TB occurred within the first 3 months of ART� 76.3% Cambodia

� 52.5% Thailand

� 51.9% Kenya

� 66.7% Malawi

� 80.0% Cameroon

Bonnet,et al. AIDS 2006, 20: 1275-1279

Lawn Am J Respir Crit Care Med Vol 177. pp 680–685, 2008

Survival among patients with AIDS and TB

and initiation of ART at GHESKIO-Haiti

Koenig S, Fitzgerald JW, Pape JW CID 2009

� High Early mortality in ART programs

� Risk Factors for Death well described � Causes of death less well described

� TB is major player based on ART cohort,Pre-ART

autopsy studies, and TB incidence trends

� Tuberculosis is a common incident infection

post ART initiation associated with increased mortality

� Do community deaths have a similar pattern

to inpatients death?� Do ART treated patients have the same

spectrum of deaths?

� Could more aggressive screening for TB or

empiric TB treatment in high risk patients

modify mortality risk?