Download Mortality in the Highly Active Antiretroviral Therapy Era

PEN.012.1092
CLINICAL SCIENCE
Mortality in the Highly Active Antiretroviral Therapy Era
Changing Causes of Death and Disease in the HIV Outpatient Study
Frank J. Palella, Jr., MD,* Rose K. Baker, MA,Þ Anne C. Moorman, BSN, MPH,þ Joan S. Chmiel, PhD,*
Kathleen C. Wood, BSN,Þ John T. Brooks, MD,þ Scott D. Holmberg, MD, MPH,þ
and HIV Outpatient Study Investigators
Background: AIDS-related death and disease rates have declined in
the highly active antiretroviral therapy (HAART) era and remain
low; however, current causes of death in HAART-treated patients
remain ill defined.
Objective: To describe mortality trends and causes of death among
HIV-infected patients in the HAART era.
Design: Prospective, multicenter, observational cohort study of
participants in the HIV Outpatient Study who were treated from
January 1996 through December 2004.
Measurements: Rates of death, opportunistic disease, and other
nonYAIDS-defining illnesses (NADIs) determined to be primary or
secondary causes of death.
Results: Among 6945 HIV-infected patients followed for a median of
39.2 months, death rates fell from 7.0 deaths/100 person-years of
observation in 1996 to 1.3 deaths/100 person-years in 2004 (P = 0.008
for trend). Deaths that included AIDS-related causes decreased from
3.79/100 person-years in 1996 to 0.32/100 person-years in 2004 (P =
0.008). Proportional increases in deaths involving liver disease,
bacteremia/sepsis, gastrointestinal disease, non-AIDS malignancies,
and renal disease also occurred (P = G0.001, 0.017, 0.006, G0.001, and
0.037, respectively.) Hepatic disease was the only reported cause of
death for which absolute rates increased over time, albeit not significantly, from 0.09/100 person-years in 1996 to 0.16/100 personyears in 2004 (P = 0.10). The percentage of deaths due exclusively to
NADI rose from 13.1% in 1996 to 42.5% in 2004 (P G 0.001 for trend),
the most frequent of which were cardiovascular, hepatic, and
pulmonary disease, and non-AIDS malignancies in 2004. Mean CD4
cell counts closest to death (n = 486 deaths) increased from 59 cells/KL
in 1996 to 287 cells/KL in 2004 (P G 0.001 for trend). Patients dying of
NADI causes were more HAART experienced and initiated HAART at
higher CD4 cell counts than those who died with AIDS (34.5% vs
16.8%, respectively, received HAART for 4 of more years, P G 0.0001;
22.4% vs 7.8%, respectively, initiated HAART with CD4 cell counts
of more than 350 cells/KL, P G 0.001).
Received for publication January 20, 2006; accepted June 9, 2006.
From the *Feinberg School of Medicine, Northwestern University, Chicago,
IL; †Cerner Corporation, Vienna, VA; and ‡Division of HIV/AIDS
Prevention, National Center for HIV, STD, and TB Prevention, Centers
for Disease Control and Prevention, Atlanta, GA.
This work was supported by Centers for Disease Control and Prevention.
The HIV Outpatient Study investigators are listed in Appendix A.
Reprints: Frank Palella, Jr., MD, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Suite 200, 676 North
Saint Clair, Chicago, IL 60611 (e-mail: [email protected]).
J Acquir Immune Defic Syndr
Conclusions: Although overall death rates remained low through
2004, the proportion of deaths attributable to non-AIDS diseases
increased and prominently included hepatic, cardiovascular, and
pulmonary diseases, as well as non-AIDS malignancies. Longer time
spent receiving HAART and higher CD4 cell counts at HAART
initiation were associated with death from non-AIDS causes. CD4
cell count at time of death increased over time.
Key Words: mortality, opportunistic infection, liver, cause of
death, trends, HAART
(J Acquir Immune Defic Syndr 2006;43:27Y34)
M
arked and sustained reductions in AIDS-related death and
opportunistic disease have been observed as a consequence of the extensive use of highly active antiretroviral
therapy (HAART) since 1996 in the United States and
Europe.1Y7 These benefits have been observed across diverse
patient populations and have resulted in prolonged disease-free
survival, durable HIV virologic suppression, immunologic
(CD4 cell) repletion, and reductions in hospitalization rates.8
During this time, new morbidities have been observed among
HAART-treated persons that have been variably ascribed to
specific antiretroviral therapy (ART) received9,10 and to factors
other than treatment such as stage of underlying HIV disease,
baseline host (patient age, race, and sex), and other factors.11,12
Although AIDS-related death and opportunistic disease rates
have remained low, increased attention has been paid to the
treatment and consequences of important comorbidities such as
lipoatrophy, lipoaccumulation, insulin resistance with consequent hyperglycemia, hyperlipidemia, cardiovascular disease,
osteopenia, and, less commonly, symptomatic hyperlactatemia.11Y18 Another consequence of improved long-term
management of HIV infection has been recognition of the
increased importance of providing effective treatment of
chronic coinfections such as hepatitis B and C.19Y21
Detailed descriptions of the spectrum of illnesses
encountered among HAART-treated persons whose HIV
infection is under control and of the conditions that are likely
to result in death in such persons are lacking, although there are
some reports profiling causes of death among person-withAIDS diagnoses early in the HAART era,22 among non-US
populations that were less extensively HAART-treated,23,24 and
among women only.25 We sought to evaluate the most recent
trends in mortality and morbidity among mostly HAARTtreated persons in the HIV Outpatient Study (HOPS), a large
& Volume 43, Number 1, September 2006
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27
PEN.012.1093
J Acquir Immune Defic Syndr
Palella et al
geographically and ethnically diverse cohort of HIV-infected
persons in the United States. We present data profiling rates and
causes of death and disease (both opportunistic and nonopportunistic) over time among HOPS participants treated since 1996.
METHODS
The HIV Outpatient Study
The HOPS is an ongoing prospective observational
cohort study into which patients have been continuously
recruited and followed since 1993.26 Study sites are 12 clinics
(7 university, 3 public, and 2 private) in 10 US cities that
provide care for about 3000 HIV-infected patients per year.
More than 8000 HOPS patients have been seen in more than
30,000 person-years of observation since 1993. All HOPS
clinicians have extensive experience treating HIV-infected
patients. Information is abstracted from outpatient charts at
each visit and entered electronically by trained staff,
compiled centrally, then reviewed and edited before being
analyzed. Information abstracted includes demographic
characteristics and risk factors for HIV infection, symptoms,
diagnosed diseases (both definitive and presumptive), medications prescribed, including dose and duration, and laboratory values, including CD4 cell counts and measurements
of plasma HIV-1 RNA (viral load).
Since 2000, HOPS sites have used a standardized
mortality data entry template designed to capture patient
information near the time of death, including primary,
secondary, and contributing causes of death, hospitalization
chart information, and antiretroviral drug use. This mortality
data template was used to collect information for deaths that
occurred from January 1, 1996, to the end of the observation
& Volume 43, Number 1, September 2006
period (December 31, 2004) analyzed. As sites identified and
recorded known deaths among their HIV-infected patient
population, trained data abstractors completed the mortality
form using data available from sources, including one or
more of the following: death certificates, medical charts,
discharge summaries, autopsy reports, and direct discussion
with clinicians who had cared for the deceased. Whenever
possible, any additional information available from clinicians
(physicians and nurses) involved with the care of the
deceased was used.
Selection of Patients for Analysis
We analyzed data from 6945 participants in the HOPS
who were seen at least twice from January 1, 1996, to
December 31, 2004, using HOPS data updated as of
December 31, 2005. Data were censored at the end of 2004
to allow adequate time for data entry lag that occurs in the
identification and documentation of deaths. End of follow-up
was defined as the date of first occurrence of the following:
(1) last patient contact (physician/clinic visit, hospitalization,
home nursing visit, or telephone contact) plus 180 days,
(2) date of death, or (3) December 31, 2004. Only deaths that
occurred during follow-up were included in this analysis.
Analysis
We calculated the annual number of deaths per 100
person-years between 1996 and 2004. Up to 5 primary
and secondary causes of death could be entered for each
patient, and all documented death causes were analyzed. Causes
of death that were nonYAIDS-defining illnesses (NADIs) were
classified by the first author into the following disease
categories for analysis: bacteremia/sepsis, central nervous
system disorders, pulmonary diseases, hepatic diseases, renal
FIGURE 1. Mortality and HAART use over time.
28
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PEN.012.1094
J Acquir Immune Defic Syndr
& Volume 43, Number 1, September 2006
diseases, cardiovascular diseases, gastrointestinal diseases, and
nonopportunistic malignancies. We calculated annual death
rates that involved at least one of these disease categories and
annual death rates involving AIDS.
We also evaluated HAART use over time in relation to
death rates. The HAART definition used for this analysis
included antiretroviral regimens that fell into one of the
following categories: (a) 3 antiretrovirals, one of which was
either a protease inhibitor (PI) or a nonnucleoside reversetransciptase inhibitor; (b) 3 nucleoside reverse-transciptase
inhibitors, one of which was abacavir or tenofovir (TDF)
(except for the regimens abacavir + TDF + lamivudine (3TC)
and didanosine + TDF + 3TC; (c) 2 full-dose PIs; and (d) a
boosted PI with an nonnucleoside reverse-transciptase inhibitor.
We evaluated CD4 cell counts within 6 months of death
by year of death, by duration of time spent receiving HAART,
and by CD4 cell count at HAART initiation, all stratified by
cause of death. If a patient’s ART discontinuation date was not
known at the time of death, this date was imputed to be 90 days
after the last visit with a HOPS clinician.
All analyses were done using a standard statistical
package (SAS version 8.2, SAS Institute, Cary, NC). Tests for
trend in death rates were done using log-linear modeling of
death rates over time assuming a Poisson distribution where
rates were calculated based upon numbers of deaths divided
by 100 person-years.27 Tests for trend by age over time were
done using general linear modeling. Reported P values are
not adjusted for multiple comparisons.
HIV Mortality in the HAART Era
RESULTS
The 6945 patients analyzed had a median follow-up of
39.2 months. From 1996 through 2004, we identified 702
deaths. Death rates declined from 7.0 deaths per 100 personyears in 1996 to 1.3 deaths per 100 person-years in 2004 (P =
0.008 for trend; Fig. 1) and stabilized at approximately 2.0
deaths per 100 person-years between 1999 and 2002, after
which little further decline was noted. Over this same period,
HAART utilization rates rose from 43% of patients in 1996 to
82% in 2004. Since 1999, about 78% of HOPS participants
received HAART.
Characterization of those who died by age, sex, race,
HIV risk, and insurance status (Table 1) revealed that death
rates dropped for all groups of patients. However, death rates
were higher among African Americans, those who were publicly insured, and those with a history of injection drug use.
Median age at death increased from 39 years in 1996 to 49 years
in 2004 (P G 0.001), as did the median age of HOPS participants overall (from 38 to 44 years), although not as steeply.
We were able to obtain at least one primary and/or
secondary cause of death for 554 (79%) of the 702 deaths. We
compared patients for whom causes of death were known
versus not known. We found no significant differences with
respect to sex, age, HIV risk behavior, months of HAART use,
CD4 cell counts, or plasma HIV viral loads within 6 months
of death. Persons for whom no cause of death information
was available were more likely to be African American (P =
0.011), have public insurance (P = 0.011), and have had
TABLE 1. Demographics of HIV Outpatient Study Patient Deaths Between 1996 and 2004
Year of Death
Total patients
Total deaths
Sex
Female
Male
Race
African American
White, non-Hispanic
Other/unknown
Insurance
Private
Public
Other/unknown
HIV risk
High-risk heterosexual
Intravenous drug use
Male sex with male
Other/unknown
Age at death
Age of patients at end of
observation in the year
1996
1997
1998
1999
2000
2001
2002
2003
2004
Total
2783
153
3156
91
3233
85
3316
65
3517
73
3601
61
3630
79
3602
55
3414
40
6945
702
444 (3.2)
2339 (5.9)
604 (2.1)
2552 (3.1)
657 (2.0)
2576 (2.8)
675 (2.2)
2641 (1.9)
696 (2.0)
2821 (2.1)
738 (1.6)
2863 (1.7)
751 (2.3)
2879 (2.2)
734 (1.8)
2868 (1.5)
703 (1.0)
2711 (1.2)
1375 (8.6)
5570 (10.5)
593 (4.4)
1914 (6.0)
276 (4.4)
806 (3.7)
1965 (2.5)
385 (2.9)
903 (2.4)
1920 (2.9)
410 (1.7)
982 (2.8)
1896 (1.6)
438 (1.4)
1042 (2.5)
1989 (2.0)
486 (1.4)
1082 (2.3)
2007 (1.5)
512 (1.2)
1102 (2.6)
2012 (1.8)
517 (2.7)
1060 (1.4)
2025 (1.6)
517 (1.6)
999 (2.7)
1931 (0.6)
484 (0.2)
2096 (10.9)
3894 (10.3)
955 (7.5)
1336 (5.0)
1121 (7.0)
326 (2.4)
1486 (2.7)
1321 (3.6)
349 (1.2)
1499 (2.5)
1359 (3.2)
375 (1.1)
1561 (1.2)
1374 (3.1)
381 (1.0)
1687 (1.5)
1409 (3.1)
421 (0.7)
1776 (1.1)
1398 (2.6)
427 (1.4)
1828 (1.0)
1385 (4.1)
417 (1.0)
1849 (1.1)
1363 (2.3)
390 (0.8)
1739 (0.8)
1319 (1.9)
356 (0.3)
3202 (8.1)
2845 (14.2)
898 (4.1)
422 (2.6)
641 (1.4)
733 (2.2)
783 (1.9)
835 (2.2)
883 (1.6)
904 (2.0)
900 (2.1)
828 (1.3)
416 (5.8)
474 (4.8)
474 (3.0)
465 (2.6)
472 (3.8)
449 (3.6)
430 (5.1)
386 (2.3)
356 (2.2)
1770 (6.2) 1860 (2.8) 1850 (2.8) 1894 (1.7) 2018 (1.6) 2073 (1.4) 2088 (1.6) 2096 (1.2) 2013 (0.9)
175 (5.1)
181 (3.9)
176 (2.3)
174 (3.4)
192 (2.6)
196 (0.5)
208 (2.9)
220 (0.4)
217 (0.9)
39 [35Y45] 41 [36Y47] 41 [37Y47] 41 [36Y48] 44 [40Y52] 45 [41Y52] 44 [39Y49] 50 [43Y54] 49 [43Y52.5]
38 [34Y45] 39 [34Y45] 40 [35Y46] 41 [36Y47] 41 [36Y47] 42 [37Y48] 43 [38Y49] 44 [38Y50] 44 [39Y50]
1595 (8.2)
973 (15.0)
3963 (9.7)
414 (9.9)
43 [38Y49]
42 [37Y48]
Values are given as n (%) of active patients who died or median [q1Yq3].
29
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PEN.012.1095
J Acquir Immune Defic Syndr
Palella et al
& Volume 43, Number 1, September 2006
TABLE 2. Cause of Death Rates and Distribution of Causes of Death Among HOPS Patients, 1996Y2004
A. Cause of Death Rates Among HOPS Patients, 1996Y2004
Year of Death
1996
1997
1998
1999
2000
2001
2002
Total patients
2783
3156
3233
3316
3517
3601
3630
Person-years of observation
2189
2503
2629
2818
3041
3180
3203
Primary or secondary cause
AIDS
83 [3.79] 47 [1.88] 50 [1.89]
42 [1.49] 34 [1.12] 29 [0.91] 39 [1.22]
All non-AIDS
20 [0.91] 25 [1.0]
23 [0.87]
10 [0.35] 25 [0.82] 22 [0.69] 31 [0.97]
Unknown
50 [2.28] 19 [0.76] 12 [0.45]
13 [0.46] 14 [0.46] 10 [0.31]
9 [0.28]
Total
153 [7.0]
91 [3.64] 85 [3.22]
65 [2.31] 73 [2.40] 61 [1.92] 79 [2.47]
Deaths with at least 1 non-AIDS primary and secondary cause* (regardless of an existing AIDS cause)
Bacteremia/sepsis
6 [0.27]
4 [0.16]
4 [0.15]
4 [0.14]
9 [0.30]
4 [0.13]
14 [0.44]
Neurologic disorders
8 [0.37]
9 [0.36]
6 [0.23]
6 [0.21]
5 [0.16]
4 [0.13]
6 [0.19]
Cardiovascular disease
16 [0.73] 17 [0.68] 18 [0.68] 14 [0.50]
9 [0.30]
9 [0.28]
16 [0.50]
Gastrointestinal disease
6 [0.27]
5 [0.20]
9 [0.34]
4 [0.14]
4 [0.13]
8 [0.25]
12 [0.37]
Hepatic disease
2 [0.09]
9 [0.36]
7 [0.26]
2 [0.07] 11 [0.36] 13 [0.41]
17 [0.53]
Non-AIDS malignancy
4 [0.18]
2 [0.08]
4 [0.15]
4 [0.14]
6 [0.20]
3 [0.09]
4 [0.12]
Pulmonary disease
22 [1.00] 16 [0.64] 12 [0.45] 13 [0.46]
9 [0.30] 10 [0.31]
16 [0.50]
Renal disease
11 [0.50]
5 [0.20]
8 [0.30]
6 [0.21]
8 [0.26]
6 [0.19]
11 [0.34]
Any non-AIDS disorder
62 [2.83] 48 [1.92] 48 [1.82] 37 [1.31] 46 [1.51] 40 [1.26]
60 [1.87]
Deaths with at least 1 non-AIDS primary and secondary cause* (in the absence of an AIDS cause)
Bacteremia/sepsis
3 [0.14]
3 [0.12]
0 [0.0]
2 [0.07]
5 [0.16]
2 [0.06]
7 [0.22]
Neurologic disorders
3 [0.14]
4 [0.16]
3 [0.11]
1 [0.04]
4 [0.13]
1 [0.03]
2 [0.06]
Cardiovascular disease
7 [0.32] 11 [0.44]
8 [0.30]
3 [0.11]
7 [0.23]
5 [0.16]
9 [0.28]
Gastrointestinal disease
2 [0.09]
4 [0.16]
5 [0.19]
1 [0.04]
2 [0.07]
6 [0.19]
5 [0.16]
Hepatic disease
1 [0.09]
8 [0.36]
5 [0.27]
1 [0.07]
7 [0.36]
9 [0.41] 12 [0.53]
Non-AIDS malignancy
3 [0.14]
1 [0.04]
4 [0.15]
2 [0.07]
3 [0.10]
2 [0.06]
1 [0.03]
Pulmonary disease
8 [0.37] 11 [0.44]
6 [0.23]
3 [0.11]
3 [0.10]
5 [0.16]
9 [0.28]
Renal disease
5 [0.23]
2 [0.08]
3 [0.11]
2 [0.07]
6 [0.20]
4 [0.13]
5 [0.16]
2003
2004
P (test for trend)
3602
3183
3414
3075
27 [0.85]
20 [0.63]
8 [0.25]
55 [1.73]
10 [0.32]
17 [0.55]
13 [0.42]
40 [1.30]
G0.0001
0.524
G.0001
G.0001
3 [0.09] 2 [0.06]
2 [0.06] 3 [0.10]
14 [0.44] 6 [0.20]
7 [0.22] 3 [0.10]
10 [0.31] 5 [0.16]
6 [0.19] 7 [0.23]
8 [0.25] 6 [0.20]
8 [0.25] 4 [0.13]
40 [1.26] 27 [0.88]
0.777
0.007
0.010
0.874
0.100
0.264
0.0004
0.311
0.0003
1 [0.03]
1 [0.03]
7 [0.22]
5 [0.16]
5 [0.31]
1 [0.03]
3 [0.09]
3 [0.09]
1 [0.03]
3 [0.10]
4 [0.13]
3 [0.10]
4 [0.16]
4 [0.13]
4 [0.13]
3 [0.10]
0.476
0.256
0.170
0.588
0.100
0.696
0.038
0.836
2003
2004
P (test for trend)
B. Distribution of Causes of Death Among HOPS Patients, 1996Y2004
Year of Death
1996
1997
1998
1999
2000
2001
2002
Total deaths
153
91
85
65
73
61
79
55
Primary or secondary cause
AIDS
83 (54.2) 47 (51.6)
50 (58.8) 42 (64.6) 34 (46.6) 29 (47.5) 39 (49.4) 27 (49.1)
All non-AIDS
20 (13.1) 25 (27.5)
23 (27.1) 10 (15.4) 25 (34.2) 22 (36.1) 31 (39.2) 20 (36.4)
Unknown
50 (32.7) 19 (20.9)
12 (14.1) 13 (20.0) 14 (19.2) 10 (16.4)
9 (11.4)
8 (14.5)
Deaths with at least 1 non-AIDS primary and secondary cause† (regardless of an existing AIDS cause)
Bacteremia/sepsis
6 (3.92)
4 (4.40)
4 (4.71)
4 (6.15) 9 (12.33) 4 (6.56) 14 (17.72) 3 (5.45)
Neurologic disorders
8 (5.23)
9 (9.89)
6 (7.06)
6 (9.23) 5 (6.85)
4 (6.56)
6 (7.59) 2 (3.64)
Cardiovascular disease
16 (10.46) 17 (18.68) 18 (21.18) 14 (21.54) 9 (12.33) 9 (14.75) 16 (20.25) 14 (25.45)
Gastrointestinal disease
6 (3.92)
5 (5.49)
9 (10.59) 4 (6.15) 4 (5.48)
8 (13.11) 12 (15.19) 7 (12.73)
Hepatic disease
2 (1.31)
9 (9.89)
7 (8.24)
2 (3.08) 11 (15.07) 13 (21.31) 17 (21.52) 10 (18.18)
Non-AIDS malignancy
4 (2.61)
2 (2.20)
4 (4.71)
4 (6.15) 6 (8.22)
3 (4.92)
4 (5.06) 6 (10.91)
Pulmonary disease
22 (14.38) 16 (17.58) 12 (14.12) 13 (20.0) 9 (12.33) 10 (16.39) 16 (20.25) 8 (14.54)
Renal disease
11 (7.19)
5 (5.49)
8 (9.41)
6 (9.23) 8 (10.96) 6 (9.84) 11 (13.92) 8 (14.54)
Any non-AIDS disorder
62 (40.52) 48 (52.75) 48 (56.47) 37 (56.92) 46 (63.01) 40 (65.57) 60 (75.95) 40 (72.73)
Deaths with at least 1 non-AIDS primary and secondary cause† (in the absence of an AIDS cause)
Bacteremia/sepsis
3 {15.0} 3 {12.0} 0 {0.0}
2 {20.0} 5 {20.0} 2 {9.09}
7 {22.58} 1 {5.0}
Neurologic disorders
3 {15.0} 4 {16.0} 3 {13.04} 1 {10.0} 4 {16.0} 1 {4.55}
2 {6.45} 1 {5.0}
Cardiovascular disease
7 {35.0} 11 {44.0} 8 {34.78} 3 {30.0} 7 {28.0} 5 {22.73} 9 {29.03} 7 {35.0}
Gastrointestinal disease
2 {10.0} 4 {16.0} 5 {21.74} 1 {10.0} 2 {8.0} 6 {27.27} 5 {16.13} 5 {25.0}
Hepatic disease
1 {5.0}
8 {32.0} 5 {21.74} 1 {10.0} 7 {28.0} 9 {40.91} 12 {38.71} 5 {25.0}
Non-AIDS malignancy
3 {15.0} 1 {4.0}
4 {17.39} 2 {20.0} 3 {12.0} 2 {9.09}
1 {3.23} 1 {5.0}
40
10 (25.0)
17 (42.5)
13 (32.5)
0.008
G.0001
0.021
2 (5.00)
3 (7.50)
6 (15.00)
3 (7.50)
5 (12.50)
7 (17.50)
6 (15.00)
4 (10.00)
27 (67.50)
0.017
0.873
0.124
0.006
G.0001
0.0005
0.723
0.037
G.0001
1
3
4
3
4
4
{5.88}
{17.65}
{23.53}
{17.65}
{23.53}
{23.53}
30
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0.992
0.322
0.216
0.373
0.114
0.848
PEN.012.1096
J Acquir Immune Defic Syndr
& Volume 43, Number 1, September 2006
HIV Mortality in the HAART Era
TABLE 2. (continued)
Pulmonary
disease
Renal disease
8 {40.0}
11 {44.0}
6 {26.09}
3 {30.0}
3 {12.0}
5 {22.73}
9 {29.03}
3 {15.0}
4 {23.53}
0.039
5 {25.0}
2 {8.0}
3 {13.04}
2 {20.0}
6 {24.0}
4 {18.18}
5 {16.13}
3 {15.0}
3 {17.65}
0.950
Values are given as n [rate per 100 person-years], n (% of deaths), or n {% of deaths with all non-AIDS causes}.
*Rates by specific causes are not mutually exclusive because some deaths have multiple causes reported.
†Percentages by specific causes are not mutually exclusive because some deaths have multiple causes reported.
shorter lengths of follow-up (P = 0.0009) than those for
whom cause of death information was known.
Deaths for which AIDS-related causes were included
among reported death causes decreased from 3.79 per 100
person-years in 1996 to 0.32 per 100 person-years in 2004
(Table 2A). Deaths for which no primary or secondary causes
were available also significantly decreased over time from
2.28 per 100 person-years to 0.42 per 100 person-years (P G
0.0001). We observed significant reductions over time in
deaths for which neurologic, cardiovascular, and pulmonary
disorders were cited as death causes with or without a concurrent opportunistic infection (Table 2A). Hepatic disease
was the only reported cause of death that increased in rate over
time (albeit not significantly), from 0.09 per 100 person-years
in 1996 to 0.16 per 100 person-years in 2004 (P = 0.100),
peaking in 2002 (0.53 per 100 person-years). Among patients
dying of hepatic disease, the proportion who were coinfected
with hepatitis B or C increased from 50% in 1996 to 80% in
2004 (P = 0.079 for trend). If deaths that included an AIDSrelated cause were excluded, a significant decrease in NADIassociated deaths was observed for deaths associated with
pulmonary disease from 0.37 per 100 person-years in 1996 to
0.13 per 100 person-years in 2004 (P = 0.038).
Evaluation of cause-specific deaths as a proportion of
all deaths in a given year (Table 2B) revealed decreases over
time in the proportion of deaths due to AIDS (P = 0.008) and
unknown causes (P = 0.021), with concomitant increases in
the proportion of deaths associated exclusively with NADIs
from 13.1% in 1996 to 42.5% in 2004 (P G 0.001). More
specifically, proportional increases in deaths caused by
bacteremia/sepsis, gastrointestinal disease, hepatic disease,
non-AIDS malignancies, and renal disease were observed.
When specific NADI death causes were evaluated as a
proportion of deaths for which only NADI causes were
documented, we noted no significant trends except for a
decrease in pulmonary illnessYrelated deaths, decreasing
from 40% in 1996 to 23.5% in 2004 (P = 0.039 for trend). The
most frequently reported NADI causes in 2004 (regardless of
trend) were cardiovascular, hepatic and pulmonary disease,
and non-AIDS malignancies.
CD4 cell counts nearest to time of death were known
for 486 (69%) of deaths. Mean CD4 cell count values
increased over time from 59 cells/KL in 1996 to 287 cells/KL
in 2004 (P G 0.001 for trend) for all observed deaths. This
increase was greater for deaths due exclusively to NADI
causes (Fig. 2) for which mean CD4 cell counts closest to
death rose from 76 cells/KL in 1996 to 354 cells/KL in 2004
(P G 0.0001 for trend). In comparison, among AIDS-related
deaths, CD4 cell counts closest to death increased from
42 cells/KL in 1996 to 130 cells/KL in 2004 (P = 0.014 for
trend).
Complete ART history was known for 569 (81%) of the
702 deaths. CD4 cell counts at time of HAART initiation and
overall HAART use duration were significantly associated
with cause of death category (AIDS- vs NADI-associated
cause of death; Table 3). Among exclusively NADIassociated deaths, 34.7% had received HAART for 4 or
more years compared with 16.8% of patients dying with
FIGURE 2. Mean CD4 cell count within 6 months of death.
31
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PEN.012.1097
J Acquir Immune Defic Syndr
Palella et al
& Volume 43, Number 1, September 2006
TABLE 3. Highly Active Antiretroviral Therapy Use by Cause of Death Among HIV Outpatient Study Deaths (1996Y2004)
Cause of
Death
Category
CD4 at the Start of HAART, cells/KL
G50
AIDS
All non-AIDS
Unknown
Total
102 (56.7)
29 (29.6)
27 (48.2)
158 (47.3)
AIDS
All non-AIDS
Unknown
Total
AIDS
All non-AIDS
Total
50Y199
43
26
12
81
200Y349
(23.9)
21 (11.7)
(26.5)
21 (21.4)
(21.4)
10 (17.9)
(24.2)
52 (15.6)
Years of HAART Use
350+
P
14 (7.8)
22 (22.4)
7 (12.5)
43 (12.9)
G0.001
e1
2
3
4+
P
164 (56.2)
65 (38.9)
69 (62.7)
298 (52.4)
38 (13.0)
28 (16.8)
10 (9.1)
76 (13.4)
Patient on ART at Time of Death
41 (14.0)
16 (9.6)
15 (13.6)
72 (12.6)
49 (16.8)
58 (34.7)
16 (14.5)
123 (21.6)
G0.0001
No
Yes
Unknown
P
173 (47.9)
81 (42.0)
254 (42.8)
146 (40.4)
100 (51.8)
246 (44.4)
42 (11.6)
12 (6.2)
54 (9.8)
0.015
Values are given as n (%).
AIDS-related diseases (overall P G 0.0001). CD4 cell count
measurements documented within 6 months before HAART
initiation were available for 334 of the deceased. Evaluation
of these revealed that 22.4% of patients dying of NADI
causes versus 7.8% of patients dying of AIDS-related illness
initiated HAART with CD4 more than 350 cells/KL (P =
0.001). Patients who died exclusively from NADI causes
were also more likely to have been receiving ART at the
time of death (51.8%) compared with 40.4% of patients with
AIDS death causes (P = 0.015). However, knowledge of
ART receipt status at the time of death was known for more
persons with exclusively NADI causes of death than those
with AIDS-related death causes.
DISCUSSION
Our review of causes of death among a large and
demographically diverse population of HIV-infected persons
in the post-HAART era revealed several major findings. First,
while overall death rates remained quite low through the ninth
year of highly prevalent HAART use in the HOPS, the annual
percentage of deaths with at least one non-AIDS cause of
death increased progressively over time, accounting for well
over half of all deaths by the end of 2004. During the period
2000 to 2004, non-AIDS death causes prominently included
hepatic, pulmonary, and cardiovascular illnesses. Compared
with persons dying from AIDS-related conditions, persons
with exclusively non-AIDS death causes initiated ART at
higher CD4 cell counts, were more HAART experienced, and
were more likely to have received HAART near the time of
death. Consonant with these findings, mean CD4 cell counts
proximal to the time of death and age at death increased
significantly over time. Long-term HIV suppression, CD4
cell count stability or improvement, and clinical benefits
provided by ART increasingly allowed HOPS participants to
avoid AIDS-defining illnesses and delay death even if they
had a history of a prior AIDS-defining illness. As a result,
more prolonged survival allowed chronic underlying comorbid conditions or risks for such conditions to become more
clinically relevant, particularly liver disease (especially
chronic coinfection with viral hepatitis), hypertension,
diabetes, cardiovascular illness, pulmonary disease, and
non-AIDS malignancies.
HIV treatments themselves may have resulted in
conditions that contributed to an increased likelihood of certain
deaths. Our data can be interpreted to imply that the increased
proportion of nonYAIDS-related causes of death (from multiple
illness categories) can be attributed to longer ART treatment
(eg, PI use and myocardial infarctions as seen in this cohort),13
but those with longer ART treatment histories also were living
longer with comorbid illnesses and chronic risks for illnesses
other than AIDS. Likewise, recent reports from this cohort and
others demonstrate mortality benefits of initiating ART earlier
in the course of HIV infection (ie, at higher CD4 cell counts)28
and the survival benefits of maintaining continuous HAART
even when higher CD4 cell counts have been achieved.29 Thus,
while appreciating the shift in spectrum of illnesses contributing to death among those living longer in the HAART era, it is
important to emphasize that any contributions of ART to the
risk for NADIs are clearly outweighed by the benefits
consequent to HAART’s use in reducing overall mortality
and AIDS-related morbidity. These benefits are dramatic, durable, and unequivocal.1Y7
It is also possible that HAART-associated immune
reconstitution may have increased the risk for NADIs via
chronic immune activation and upregulation of proinflammatory
32
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PEN.012.1098
J Acquir Immune Defic Syndr
& Volume 43, Number 1, September 2006
cytokines. This has been suggested in recent analyses from this
cohort and others profiling increased rates of specific nonAIDS-related morbidities.30Y32
Given that our findings show increasing mean CD4
values at death among HIV-infected HAART-treated persons,
are CD4 cell counts losing their predictive value in the assessment of death risk in this population? Although this seems to
be true for both those dying with or those dying without
AIDS-defining illnesses, it needs to be interpreted in light of
our central findingsVthat AIDS-associated death rates
remained durably low among HAART-treated persons, and
such deaths are increasingly likely to occur as a consequence of NADIs, particularly among persons with higher
CD4 cell counts and those who were receiving HAART near
the time of death. There was no evidence that AIDSassociated opportunistic diseases occurred and contributed
to death despite increasing CD4 counts (particularly among
those with CD4 counts approximately 9150 cells/KL)
nearest to time of death, nor that there was an overt
dissociation between CD4 counts and opportunistic infection
risk. However, we did not undertake a formal predictor
analysis to assess the ability of CD4 cell counts measured
near the time of death to predict death risk. This has been
done in other studies.33
There are unavoidable limitations in an analysis of an
observational cohort of HIV-infected ambulatory outpatients.
First, we lack a readily available age- and risk-matched HIVseronegative population to whom we can easily compare our
death rates from nonYAIDS-related illnesses. As successfully
treated HIV patients survive longer with higher CD4 cell
counts, it is reasonable to anticipate that their diseases will
more closely resemble those of comparable nonYHIVinfected persons. Second, the HOPS is a dynamic cohort in
which all patients are not necessarily followed continuously
throughout the course of their HIV infection (ie, patients may
enter or leave the cohort any time during the observation
period). However, we believe that a major strength of this
analysis is that it profiles mortality rates and causes among a
heterogeneous and representative group of HIV-infected
persons who received care from their own HIV clinicians.
Third, discernment of precise causes of death is always a
challenge. We gathered cause of death information from
meticulous review of medical records with input from
clinicians caring for patients near the time of death.
Moreover, the proportion of deaths for which there was no
death cause information available decreased over time.
Because many of the deceased died while hospitalized, and
we were able to undertake systematic and careful review of
inpatient as well as outpatient records, we may have better
classification of death causes than other published reports.
Short of the routine performance of autopsies, we believe we
thoroughly accessed available clinical data from existing
sources. Finally, some recent reports have discussed the role
of more optimal medication adherence upon improved
survival among HAART-treated persons with advanced
HIV infection.34 Although we did not have precise measurements of medication adherence for all of the deceased profiled
in this report, a recent report from the HOPS suggests a very
high rate of HAART medication adherence in our cohort.35
HIV Mortality in the HAART Era
In conclusion, in an era during which HIV-infected
persons routinely live longer as a result of timely intervention
with HAART, it is important for clinicians to be aware that
other underlying, nontraditionally HIV-related conditions are
ever more likely to figure prominently in the risk for death and
disease. These conditions should be aggressively screened for,
monitored, and treated. Chronic liver disease (especially in
chronic viral hepatitisYcoinfected persons), cardiovascular
and pulmonary disease, and non-AIDS malignancies loom
particularly large among these nontraditionally HIV-related
morbidities that usually require specific ongoing targeted
therapy. Although HIV-infected persons are clearly living
longer as a consequence of effective HAART, they may be
dying earlier than those in the general population, albeit not
from traditionally HIV-associated conditions. These observations underscore the need for improved vigilance on the part of
clinicians in maintaining proactive and preventive medical
care and routine screening for all HIV-infected persons
receiving HAART.
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APPENDIX
The HOPS Investigators include the following investigators and sites: Anne C. Moorman, Tony Tong, Scott D.
Holmberg (currently at Research Triangle Institute, Atlanta),
John T. Brooks, and Kate Buchacz, Division of HIV/AIDS
Prevention, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta,
GA; Kathleen C. Wood, Rose K. Baker, and Carl Armon,
Cerner Corporation, Vienna, VA; Frank J. Palella, Joan S.
Chmiel, Katharine A. Kirby, Janet Cheley, and Tiffany
Murphy, Feinberg School of Medicine, Northwestern University, Chicago, IL; Kenneth A. Lichtenstein, University of
Colorado Health Sciences Center, Denver, CO; Kenneth S.
Greenberg, Benjamin Young, Barbara Widick, Cheryl
Stewart, and Peggy Zellner, Rose Medical Center, Denver,
CO; Bienvenido G. Yangco, Kalliope Halkias, and Arletis
Lay, Infectious Disease Research Institute, Tampa, FL;
Douglas J. Ward and Charles A. Owen, Dupont Circle
Physicians Group, Washington, DC; Jack Fuhrer, Linda
Ording-Bauer, Rita Kelly, and Jane Esteves, State University
of New York, Stony Brook, NY; Ellen M. Tedaldi, Ramona
A. Christian, and Linda Walker-Kornegay, Temple University School of Medicine, Philadelphia, PA; Joseph B.
Marzouk, Roger T. Phelps, and Mark Rachel, Adult Immunology Clinic, Oakland, CA; Silver Sisneros and Mark
Rachel, Fairmont Hospital, San Leandro, CA; Richard M.
Novak, Jonathan P. Uy, and Andrea Wendrow, University of
Illinois at Chicago, Chicago, IL.
34
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