Transcript Causes of death in patients treated with ART 1996-2006: Collaborative analysis of 13 Cohort Studies Poster 708 ART Cohort Collaboration John Gill, Margaret May, Charlotte.

Causes of death in patients treated with ART 1996-2006:
Collaborative analysis of 13 Cohort Studies
Poster 708
ART
Cohort Collaboration
John Gill, Margaret May, Charlotte Lewden, Michael S. Saag, Ross Harris, Matthias Egger, Peter Reiss, Bruno Ledergerber, Amanda Mocroft and
Jonathan A.C. Sterne on behalf of the Antiretroviral Therapy Cohort Collaboration (ART-CC)
Abstract
Background
Background: An increasing proportion of deaths in patients on
ART are from causes not classified as AIDS-related.
Methods: Data were combined from 13 cohort studies in
Europe and N America (ART Cohort Collaboration). We reviewed
available information (ICD codes, characteristics at the time of
death) on 1876 deaths among 39,272 patients aged >15years,
who started triple ART during 1996-2006. Two or more
reviewers classified causes according to the CoDe classification,
with disagreements resolved after discussion.
Results: The table shows specific causes, which could be
assigned for 1,597 (85%) deaths. AIDS deaths (46% infection,
30% malignancy, 24% unspecified) were 63% of deaths in the
first year of ART, 43% thereafter. The table also shows hazard
ratios (HR) (adjusted for sex, age, viral load, AIDS, year of
starting ART and cohort) comparing those with lower with
higher baseline CD4 and patients infected via IDU with others.
Median baseline CD4 was 217 cells/L (IQR 94-343) in
survivors and 110 (33-247) in those who died. Median time to
death was 1.8 (0.6-3.8) years.
AIDS
Non-AIDS infection
Liver-related
Non-AIDS malignancy
CVD
Renal failure
Violent
Heart/vascular
Respiratory
Other
No (%)
deaths
791 (50)
128 (8.0)
113 (7.1)
189 (12)
76 (4.8)
24 (1.5)
124 (7.8)
56 (3.5)
22 (1.4)
74 (4.6)
Corresponding author:
John Gill
[email protected]
HR CD4
<100 v >350 (cells/mm3)
4.07 (3.01-5.50)
1.44 (0.80-2.59)
1.36 (0.76-2.45)
1.68 (1.06-2.66)
1.34 (0.65-2.80)
10.78 (1.31-89.00)
0.47 (0.26-0.85)
1.61 (0.70-3.69)
1.96 (0.39-9.87)
3.74 (1.61-8.70)
HR
IDU v non-IDU
1.60 (1.32-1.93)
3.67 (2.43-5.56)
6.33 (4.22-9.50)
2.53 (1.71-3.75)
1.59 (0.81-3.15)
1.26 (0.36-4.45)
3.68 (2.47-5.47)
3.84 (2.09-7.08)
5.20 (2.03-13.3)
2.22 (1.24-3.98)
Methods
• ART has dramatically improved life expectancy for HIVinfected patients.
• ART-related reductions in rates of mortality result
primarily from reductions in deaths from AIDS- or HIVrelated conditions.
• Mortality still remains higher than that of the general
population and an increasing number of deaths are
from causes not conventionally considered HIV-related.
 Large clinical endpoint trials such as SMART and
START now incorporate non-AIDS events as
endpoints.
• With HIV-infected persons living substantially longer,
and the introduction of even more effective and
tolerable drugs, it is important both to monitor causes
of death and to assess risk factors for different causes.
Objective
Results
Figure 1: Bar graph showing crude cause-specific
mortality rate according to length of time since start
of ART
Cause of death according to time since start of cART
In addition to AIDS, non-AIDS malignancy and renal failure
appeared associated with immunodeficiency at baseline. Rates
of non-AIDS infection, liver-related, non-AIDS malignancy,
violent, heart/vascular and respiratory deaths were markedly
elevated in patients infected via IDU. Rates of liver-related
death declined (p = 0.03) with year of starting ART: 0.83 (95%
CI 0.59-1.16) per 1000 years in 1996-7 declining to 0.42 (0.141.32) in 2004-6. Overall mortality rates increased with age, with
very strong associations of older age with non-AIDS malignancy
and CVD death.
Conclusions: To achieve further declines in mortality rates
among patients treated with ART, causes of non-AIDS death
must be addressed. Such causes are of particular importance in
patients infected via IDU.
9.70
AIDS
•Retrospective review of all deaths in 39,272 patients aged>15 years enrolled in 13 observational
cohorts who were (154,667 person years of follow up).
•Deaths were classified into the categories specified in the Cause of Death (CoDe) project protocol
(www.cphiv.dk), using both a computer algorithm and a team of clinicians and epidemiologists.
•CVD included myocardial infarction (MI), ischaemic heart disease (IHD), stroke, heart failure,
unspecified and other heart disease
•Violent deaths included suicide, overdose, accident and unspecified violent deaths
•Adjusted hazard ratios were estimated using Cox models
Results
Figure 2: Adjusted1 hazard ratio (95% CI) for risk factors at start of ART with specific causes of
death: CD4 cell count (per 100 cell decrease), transmission risk group (IDU v. non-IDU), viral
load (log HIV-1 RNA >5 v. <5 log copies) and prior AIDS diagnosis (v. no AIDS).
Cause of death
• To examine the distribution of causes of death among
HIV infected patients who initiated combination
antiretroviral therapy (ART) between 1996 and 2006,
and to quantify associations of prognostic factors with
cause-specific mortality.
HR per 100 cell decrease in CD4 count
1.43 (1.34-1.53)
AIDS
1.31 (1.12-1.53)
Malignancy
1.14 (1.02-1.27)
Malignancy
0.84 (0.62-1.13)
Infection
1.12 (0.97-1.28)
Infection
1.85 (1.25-2.73)
CVD
1.08 (0.95-1.23)
CVD
1.54 (1.05-2.27)
Violent
0.84 (0.74-0.95)
Violent
0.90 (0.61-1.31)
Liver related
1.05 (0.91-1.20)
Liver related
1.20 (0.80-1.80)
Respiratory
1.13 (0.82-1.55)
Respiratory
3.62 (1.30-10.09)
Renal failure
1.73 (1.18-2.55)
Renal failure
1.65 (0.66-4.14)
Other
1.37 (1.13-1.66)
Other
1.44 (0.86-2.42)
.5
1
2
4
8
Cause of death
HR IDU v. non-IDU
8
Cause of death
12
AIDS
1.58 (1.31-1.91)
AIDS
3.20 (2.71-3.78)
Malignancy
2.41 (1.62-3.58)
Malignancy
1.26 (0.89-1.78)
Infection
3.56 (2.35-5.39)
Infection
1.84 (1.23-2.74)
CVD
2.50 (1.58-3.94)
CVD
0.97 (0.63-1.50)
Violent
3.68 (2.47-5.49)
Violent
1.39 (0.89-2.18)
Respiratory
2.26 (0.94-5.45)
1.31
Renal failure
1.26 (0.35-4.47)
Renal failure
0.91 (0.36-2.30)
Other
2.27 (1.27-4.04)
Other
1.22 (0.71-2.09)
.5
1Models
< 1 year
1-2 years
>2 years
0.72
0.40
0.40
0
ART-CC 2006
2
4
6
8
Crude rate per 1000 person years
10
1
2
4
8
12
• 1,876 (4.8%) patients died: 1,597 (85%) of these
deaths were assigned a cause according to the CoDe
categories: table in abstract shows the number of
deaths in each of these categories.
• Rates of specific causes of death varied considerably
according to patients’ characteristics at initiation of ART
and the duration of therapy.
• Rates of AIDS, the leading cause of death, declined
with time on ART, but rates of non-AIDS causes of
deaths remained approx. constant with time on ART.
• Immunodeficiency was associated with deaths from
AIDS, non-AIDS malignancy and renal failure.
• A diagnosis of AIDS before starting ART was associated
with death from both AIDS and non-AIDS infections.
• IDU had higher mortality and an increased risk of all
specific causes of death, with a particularly high hazard
of deaths from liver-related disease and violence.
• Overall mortality rates increased with age, with very
strong associations of older age with non-AIDS
malignancy and CVD death.
Conclusions
HR AIDS v. no AIDS
4.94(1.96-12.45)
0.75
0.56
0.78
Other causes (N<20)
4
Respiratory
0.67
0.83
0.85
0.28
0.13
0.11
2
1.46 (0.94-2.28)
Violent deaths
Renal failure
1
Liver related
0.72
0.66
0.90
0.17
0.23
0.14
.5
6.05 (4.03-9.09)
CVD
Respiratory disease
12
Liver related
0.83
0.67
Liver related
HR Viral load >5 v. <5 log copies
1.11
0.93
1.37
3.34
Non-AIDS Infection
Cause of death
AIDS
4.88
Non-AIDS Malignancy
Results
.5
1
2
4
8
12
were mutually adjusted for age, sex, IDU, CD4, viral load, prior AIDS diagnosis, cohort and year of starting ART
ART-CC Contributing Cohorts
UAB 1917 Clinic Cohort (Birmingham, Alabama, USA), Aquitaine (France), ATHENA (AIDS Therapy Evaluation Project Netherlands), BCCfE-HIV (British Columbia Centre for Excellence in HIV/AIDS, Canada), CHORUS/Vanderbilt (Collaborations in HIV
Outcomes Research US), CoRIS (Cohorte de la Red de Investigacion en Sida RIS, Spain), EuroSIDA, Frankfurt: Klinikum der JW Goethe-Universität Frankfurt, Germany), FHDH (French Hospital Database on HIV), HAVACS (HIV Atlanta Veterans
Affairs Cohort Study, US), ICONA (Italian Cohort of Antiretroviral-Naive Patients), Köln/Bonn (Departments of Internal Medicine at University of Cologne and Bonn, Germany), PISCIS (Proyecto para la Informatización del Seguimiento Clínicoepidemiológico de la Infección por HIV y SIDA, Spain), Royal Free (Ian Charleson Centre at the Royal Free Hospital London, UK), SHCS (Swiss HIV Cohort Study), South Alberta (Southern Alberta Clinic, Canada), VACH, VACS (Observational cohort
study of HIV-positive and matched HIV-negative veterans based on the Veterans Health Administration, USA), Vancouver (St. Paul's Hospital in Vancouver, Canada), Washington (University of Washington Harborview Medical Center, USA).
ART-CC Steering Committee
Jordi Casabona (PISCIS), Geneviève Chêne (Aquitaine), Dominique Costagliola (FHDH), François Dabis (Aquitaine), Antonella D’Arminio Monforte (ICONA), Frank de Wolf (ATHENA), Matthias Egger (SHCS), Gerd Fatkenheuer (Köln/Bonn), John Gill
(South Alberta Clinic), Robert Hogg (BCCfE-HIV), Amy Justice (VACS), Mari Kitahata (Washington), Bruno Ledergerber (SHCS), Ole Kirk (EuroSIDA), Peter Reiss (ATHENA), Michael Saag (UAB 1917 Clinic Cohort), Fiona Lampe (Royal Free), HansReinhard Brodt (Frankfurt), Julia del Amo (CoRIS-MD), Myriam Garrido (VACH), Jodie Guest (HAVACS), Tim Sterling (Vanderbilt).
study of HIV-positive and matched HIV-negative veterans based on the Veterans Health Administration, USA), Vancouver (St. Paul's Hospital in Vancouver, Canada), Washington (University of Washington Harborview Medical Center, USA).
ART-CC Co-ordinating Team
Jonathan A. C. Sterne (PI), Margaret May.
ART-CC Sources of Funding
UK Medical Research Council (MRC), GlaxoSmithKline, Agence Nationale de Recherches sur le Sida (ANRS), Institut National de la Santé et de la Recherche Médicale (INSERM), French, Italian, Swiss Ministries of Health, Dutch Stichting HIV
Monitoring, European Commission, British Columbia and Alberta Governments, Michael Smith Foundation for Health Research, Canadian Institutes of Health Research, Roche, Boehringer-Ingelheim, St. Paul's Hospital Foundation, UAB CFAR Network
of Integrated Clinical Sciences (C-NICS), NA-ACCORD, NIH, FIPSE
• ART continues to have a dramatic impact in reducing
rates of mortality from HIV infection in high-income
countries.
• AIDS remains the most common cause of death.
• The strong inverse association of rates of AIDS death
with CD4 counts at the time of starting ART supports
arguments for earlier initiation of ART.
• Conditions associated with social and lifestyle factors
contribute the next most frequent causes of death, with
violence and liver related diseases (mainly due to
hepatitis) contributing 15% of all deaths.
• The importance of lifestyle is reinforced by the
observations that the malignancies were mainly lung
cancer and likely associated with smoking, and that
many endocarditis cases occurred in patients infected
via IDU.