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Trends and charateristics of causes of death among persons with AIDS in Los Angeles County, 1990-2002

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Trends and charateristics of causes of death among persons with AIDS in Los Angeles County, 1990-2002

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Content TRENDS AND CHARATERISTICS OF CAUSES OF DEATH AMONG
PERSONS WITH AIDS IN LOS ANGELES COUNTY, 1990-2002
by
Yihang Liu
____________________________________________________
A Thesis Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(APPLIED BIOSTATISTICS/EPIDEMIOLOGY)
December 2006
Copyright2006 Yihang Liu
ii
ACKNOWLEDGMENTS
I would like to express my sincerest appreciation to
Dr. Anny Xiang and Dr. Stanley Azen, co-chairmen of
my thesis committee, for their guidance and supports
throughout the development of this thesis. My
gratitude also extends to Professor Michael Cody for
his serving on my thesis committee. I also thank Dr.
Zhijuan Sheng from Los Angeles County Department of
Health Service HIV Epidemiology Program for
providing the dataset, and most importantly, for her
valuable suggestions.
iii
TABLE OF CONTENTS
Acknowledgements ii
List of Tables iv
List of Figures v
Abstract vi
Charter 1: Introduction 1
Charter 2: Materials and Methods 9
Charter 3: Results 18
Charter 4: Discussions 33
Charter 5: Limitations 45
Charter 6: Conclusions 48
References 50
iv
LIST OF TABLES
Table 1: Annual death rates (per 10,000
population) of AIDS cases in Los
Angeles County population,
1990 – 2002 19
Table 2: Comparisons of characteristics
of HIV/AIDS related death and
non-HIV/AID related death among
adults/adolescents with AIDS in
Los Angeles County, 1990-2002 22
Table 3: Univariate analysis -- Significant
risk factors associated with dying
from major cardiovascular diseases
(CVDs) among non-HIV/AIDS related
death in Los Angeles County,
1990-2002 30
Table 4: Multivariate analysis –- Significant
risk factors associated with dying
from major cardiovascular diseases
(CVDs) among non-HIV/AIDS related
death in Los Angeles County,
1990-2002 32
v
LIST OF FIGURES
Figure 1: Annual death rates (per 10,000
population) of AIDS cases in Los
Angeles County population, during
the pre-HARRT era 19
Figure 2: Annual death rates (per 10,000
population) of AIDS cases in Los
Angeles County population, during
the post-HARRT era 20
Figure 3: Deaths among adults/adolescents
with AIDS in Los Angeles County,
1990-2002 24
Figure 4: Deaths among adults/adolescents with
AIDS by gender in Los Angeles
County, 1990-2002 24
Figure 5: Deaths among adults/adolescents
with AIDS by race in Los Angeles
County, 1990-2002 25
Figure 6: The top five leading causes of
death among adults/adolescents with
HIV/AIDS in Los Angeles County,
1990-2002 26
Figure 7: Comparison for the top five
underlying causes of death
unrelated to HIV/AIDS among
adults/adolescents with AIDS in Los
Angeles County, Pre-HAART era vs.
Post-HAART era 27
Figure 8: Trends for the top five underlying
causes of death unrelated to
HIV/AIDS among adults/adolescents
with AIDS in Los Angeles County,
1990-2002 27
Figure 9: Estimated annual HIV incidence,
AIDS deaths, and expected AIDS
deaths, USA, 1978-2002 34
vi
ABSTRACT
To investigate the impact of highly active
antiretroviral therapy (HAART) on the causes of
death among AIDS patients, a population-based Los
Angeles County AIDS surveillance registry data in
1990-2002 were analyzed (18,149 deaths). Results
showed that total AIDS deaths were significantly
reduced in post-HAART, with the reduction
predominantly in the HIV/AIDS-related death, not the
non-HIV/AIDS-related death. Deaths due to
cardiovascular diseases (CVDs) were significantly
increased in post-HAART among non-HIV/AIDS-related
death (P<0.001). Logistic regression identified that
being in post-HAART was significantly associated
with CVD death (ORadjusted=1.6, 95%CI: 1.2-2.0,
compared to pre-HAART). In addition, African
American AIDS patients had a higher risk of dying
from CVDs compared to Whites (ORadjusted=1.9,
95%CI=1.5-2.5). Thus, treatments and prevention
programs among AIDS patients could be targeted on
CVDs in the post-HAART era, especially in the
disadvantaged population.
1
CHARTER 1: INTRODUCTION
The advent of active antiretroviral therapy (HAART)
has dramatically reduced mortality rates for Human
Immunodeficiency Virus (HIV)-infected and Acquired
Immune Deficiency Syndrome (AIDS) patients in
developed countries since 1996. This led to a change
in the underlying causes of death among HIV/AIDS
patients. Along with the decrease in HIV/AIDS related
deaths, the increase in the proportion of non-HIV/AIDS
related deaths among HIV/AIDS patients has recently
gained many scholars’ attentions.
Although the subsequent increase in the proportion of
non-HIV/AIDS related deaths may be partially explained
by the decrease in HIV/AIDS related deaths, the long
term adverse effect of HAART might play an important
role for this increase. Several studies have reported
that the antiviral drug toxicity may contribute to the
increase in deaths due to non-HIV/AIDS related
conditions, such as non-AIDS-defining malignancies,
cardiovascular disease, liver disease, and kidney
2
disease (Louie, Hsu, Osmond, Katz & Schwarcz, 2002;
Currier, Taylor, Boyd, Dezii, Kawabata & Burtcell,
2003; Friis-Moller, Weber, Reiss, Thiebaut, Kirk,
Monforte & et al., 2003). For example, some scholars
observed a significantly increased percentage of non-
AIDS-related malignancies in the post-HARRT era (13%)
compared to the pre-HARRT era (less than 1%) (Bonnet,
Lewden, May, Heripret, Jougla, Bevilacqua & et al.,
2004). Krentz, Kliewer, and Gill also reported
similar findings in their study (2004).
While many studies continue to focus on non-AIDS-
defining malignancies, more and more scholars are
concerned about HARRT’s impacts on the cardiovascular
system because of the dramatically disproportionate
increased number of cardiovascular diseases (CVDs)
cases among people living with AIDS in the post-HAART
era.
HIV/AIDS, HAART, and cardiovascular diseases
It has been suggested that HIV infection is associated
with CVDs. According to the Kaiser Permanente
3
Registry study, HIV-positive men were at significantly
higher risk for CVDs than men without HIV (Klein,
Hurley, Quesenberry & Sidney, 2002). Similarly, Klein
et al. reported that the incidence of hospitalization
rates due to CVDs among HIV-infected patients was
significantly higher than among HIV-negative controls
(2004). Furthermore, a study conducted by Tabib and
his colleagues before the advent of HAART showed
consistent pathological evidences to support the above
conclusion (1992). In this study, scholars found that
striking coronary lesions existed in HIV-positive
patients.
Besides the potential pathological damages caused by
HIV infection, the side effect of HAART on the
cardiovascular system has attracted great interest
because of the emergence of case reports on CVDs in
patients receiving HAART (Gallet, Pulik, Genet, Chedin
& Hiltgen, 1998; Henry, Melroe, Huebsch, Hermundson,
Levine, Swensen & Daley, 1998). HAART was first
introduced in 1996 in the United States. It is the
combination of three or four drugs from any of the
4
four board classes [protease inhibitors (PIs),
nucleoside analogue reverse transcriptase inhibitors
(NRTIs), non-nucleoside reverse transcriptase
inhibitors (NNRTIs), and cell membrane fusion
inhibitors] that can inhibit the replication of HIV.
Among these medications, protease inhibitors
constitute the largest class of drugs in

the current
fight against HIV, which can stop the cell’s

ability to
cleave the proteins onto active viral particles (Wynn,
Zapor, Smith, Wortmann, Oesterheld, Armstrong & et
al., 2004).
Although HAART has significantly reduced the HIV/AIDS
related death rate and improved survival of HIV/AIDS
patients, it seems that HAART is associated with an
increased risk of CVDs. It was reported that HAART
would induce and/or enhance some important risk
factors for CVDs. These include higher serum total
cholesterol and triglycerides, diabetes mellitus,
increased insulin resistance, and arterial
hypertension (Carr, Samaras, Burton, Law, Freund,
Chisholm & et al., 1998; Dube & Sattler, 1998). In
5
SoRelle’s study, he stated that 60% of patients
receiving HAART had developed risk factors of CVDs
such as hyperlipidemia, hyperglycemia, and central
obesity (1998). Also, Barbaro et al. showed that the
incidence of CVDs among HIV-infected patients was
related to lipodystrophy (OR = 26.9, 95% CI = 8.3 -
43.5), dyslipidemia (OR = 14.2, 95%CI = 3.06 - 26.7),
and if they were currently smoking (OR = 9.7, 95% CI =
3.5 - 16.7) (2002).
The relationship between CVDs and the use of HAART
among HIV-infected patients is still under debate due
to the inconsistent outcomes from various studies.
While some studies found no difference in CVDs between
HIV-infected patients with and without PI treatment
(Bozzette, Ake, Tam, Chang & Louis, 2003), many
studies found increased risk of CVDs with PI treatment
patients. In a retrospective study, Rickerts et al.
reported that HIV-infected patients who received PI
treatment were 2.6 times more likely to develop
myocardial infarction compared to those without PI
treatment (2000). Mary-Krause et al. also found
6
similar results (2001). They reported the relative
hazard rate of myocardial infection among HIV-infected
patients with PI exposure was 2.56 compared to those
without PI exposure. In addition, they found the
relative risk of myocardial infarction increased along
with the duration of the PI treatment. Compared to
HIV-negative individuals, they reported that the
relative risk of myocardial infarction for HIV-
infected patients treated with PI for 18-30 months and
more than 30 months was 1.5 (95% CI = 0.8 ~ 2.5) and
2.9 (95% CI=1.5 ~ 5.0), respectively. Similarly,
Friis-Moller et al. reported that the adjusted risk
rate per year of exposure ranged from 0.32 for no
HAART use to 2.93 for more than six years of HAART
use (2003).
Besides the use of HAART, some other common risks of
CVDs among HIV-infected patients have been reported.
These include male gender, increased age, longer
duration of HIV infection, a high prevalence of
tobacco use, lower CD4 lymphocyte counts, and a
disproportionately increased number of African-
7
American and Hispanic ethnicity (David, Hornung &
Fichtenbaum, 2002; Friis-Moller, Weber, Reiss,
Thiebaut, Kirk, Monforte & et al., 2003). In the Data
collection of Adverse Event Study, scholars found that
a history of CVDs (OR=5.8, P<0.001), current or former
smoking (OR=2.17, P<0.007), older age (OR=1.38,
P<0.001), and male sex (OR=1.99, P<0.04) were all
significant predictors of myocardial infarction among
HIV-infected patients(Friis-Moller, Sabin, Weber,
d'Arminio Monforte, El-Sadr, Reiss & et al., 2003).
Since the life-expectancy of people with HIV/AIDS has
increased because of HAART, the goal of HIV infection
therapy has been changed from simply keeping the
patient alive to enhancing the patient’s life quality.
As a potential adverse event of HAART, better
understanding of the CVDs will be necessary to
implement appropriate prevention, screening, and
treatment recommendations in the post-HAART era. To
date, however, no large-scale study of the
distribution of cardiovascular diseases among AIDS
patients has been performed in Los Angeles County, and
8
thus the extent to which the management of AIDS
patients in this area could be suitably modified
remains unknown.
This study was conducted to evaluate the impact of
HAART on the distribution of HIV/AIDS related deaths
and non-HIV/AIDS related deaths in Los Angeles County.
It helped to gain further insight of the changes in
the underling causes of non-HIV/AIDS related deaths
among AIDS patients in the post-HARRT era. The study
was also conducted to identify the risk factors for
dying from major cardiovascular diseases among AIDS
patients. In addition, as the most ethnically diverse
county in the United States, we were particularly
interested in knowing whether or not there were any
differences among the major racial/ethnic AIDS patient
groups for dying from major cardiovascular diseases in
Los Angeles County. The California population-based
AIDS surveillance registry provided a sample size
necessary to address these research questions.
9
CHARTER 2: MATERIALS AND METHODS
Study Population
All the subjects from this study were retrieved from
the HIV/AIDS Reporting System (HARS) registry in Los
Angeles County (LAC). HARS is a national surveillance
system for AIDS cases maintained by the Centers for
Disease Control and Prevention. The Los Angeles
Department of Health Service (LADH) maintains a
registry with demographic and clinical data on
incident and prevalent AIDS reported by local health
services in LAC. For each case, multiple variables
are documented, including patient’s demographic
information, date of AIDS diagnosis, mode of exposure
to HIV, specific AIDS-defining condition(s), and some
follow-up measurements such as CD4 lymphocyte counts.
The study population consisted of people who were
initially diagnosed with AIDS-defining conditions in
LAC and died between 1990 and 2002. AIDS cases were
classified based on the definition established by the
10
Centers for Disease Control and Prevention. The
period was chosen because it spanned the treatment
transition to HAART.
Since the pediatric AIDS infection and progress models
are different from adult cases, subjects under 13
years old with AIDS were excluded from the analysis.
Subjects with an unknown race were also excluded from
the analysis, as ethnicity is an important variable to
address the research questions. The final study
population consisted of 18,149 subjects. To further
investigate the impact of HAART on CVDs and the risk
factors for CVDs deaths, a subgroup population that
included HIV/AIDS non-related deaths was analyzed.
Variables
All information entered into the HARS system is based
on manual or electronic case reports completed by
providers or public nurses/public health investigators
in the LADH HIV Epidemiology Program. For each case,
over 150 variables are recorded into HARS. The
11
following variables were used for analysis in this
study:
Gender
Gender was categorized into two groups: male and
female. For transgender special cases, biological
genders were considered.
Race/Ethnicity
Being considered the principal ethnical groups in the
Southern California, race/ethnicity was categorized
into four groups in this study: White, African
American, Hispanic, and Others. Subjects with unknown
race/ethnicity were excluded from the analysis.
Age of Diagnosis
The subject’s age at the time of initial diagnosis of
AIDS was recorded as the age of diagnosis in this
study. This was divided into five groups with 10 year
gap intervals: less than 31 years old, 31 ~ 40 years
old, 41 ~ 50 years old, and over 50 years old.
12
Age at Death
Age at death was divided into 10 year gap intervals
based on the categories used in the U.S. population
census: less than 35 years old, 35 ~ 44 years old, 45
~ 54 years old, 55 ~ 64 years old, and over 64 years
old.
Mode of Exposure
Mode of exposure referred to the mode of HIV
transmission in this study. This was categorized into
groups such as Male-to-Male sex (MSM), Injection Drug
Use (IDU), combined group of Male-to-Male sexual
contact and Injection Drug Use (MSM/IDU), Heterosexual
Contact (HC), and Others. The Others group included
hemophilia/coagulation disorder, transfusion
recipient, and undetermined risks. The mode of
exposure of a subject was assigned exclusively in
HARS. Among these categories, MSM had the highest
priority unless a case was MSM/IDU. For example, if
a male experienced bisexual behavior, his mode of
exposure would be assigned as MSM only, not HC or
both.
13
Country of Origin
Country of origin referred to the subject’s birth
country. In this study, a subject’s country of origin
was either U.S. born or Others.
Categories of AIDS Diagnosis
Subjects diagnosed with AIDS were classified as having
been diagnosed on the basis of an AIDS-defining
opportunistic infection (O.I.) (CD4 >= 200 cells/µL)
or immunologic status (CD4 < 200 cells/µL or <14%).
Pre-HAART era & Post-HAART era
The years of study were divided into pre-HAART era
(1990-1995) and post-HAART era (1996-2002).
Duration of AIDS
Duration of AIDS was defined as the survival time
after the date of initial diagnosis of AIDS. It was
classified into two groups: less than six years and
equal to or more than six years.
14
Vital Status and Cause of Death
The vital status and underlying cause of death of
subjects reported to the HARS were updated through
record linkage with the Los Angeles County and State
of California Vital Statistics Master Files. In
addition, matches with the National Death Index were
done to ascertain vital status and the underlying
cause of death of persons diagnosed in LAC who may
have subsequently moved and/or died elsewhere in the
United States. Deaths were classified as being due to
HIV/AIDS or other causes using the International
Classification of Diseases, 9
th
Revision (for deaths in
1990-1998) and 10
th
Revision (for deaths in 1999-2002).
Important terms used in the study include death due to
HIV/AIDS, which was defined as death attributable to a
category C disease listed by the Centers for Disease
Control and Prevention, or an immunodeficiency-related
disease (e.g., bacterial pneumonia cased by
Streptococcus pneumonia, chronic diarrhea). A cause
of death not attributable to an AIDS-defining or HIV-
related illness was characterized as “non-HIV/AIDS
related death” (e.g., suicide, liver disease, injury).
15
A death due to CVDs was defined as death attributable
to major cardiovascular disease, listed in the
International Classification of Diseases, 9
th
Revision
(code 390-434, 436-448) and 10
th
Revision (code I00-
I78).
Statistical Analyses
The impact of HAART on distribution of HIV/AIS related
deaths and non-HIV/AIDS related deaths
For this, the primary statistical analysis approach
used as descriptive statistics. Temporal trends among
AIDS deaths were analyzed and plotted in three ways.
First, the AIDS crude death rate was expressed as
deaths per 10,000 in Los Angeles County’s population
(retrieved from 1990 U.S. census) adjusted by age, and
was calculated per year over the period 1990-2002.
Second, temporal trend of total and proportions of
HIV/AIDS related deaths and HIV/AIDS non-related
deaths in the pre-HAART and post-HAART eras were
plotted. Linear regression was used to calculate the
16
slope of the trends over time. Third, total and
proportion of major leading causes of deaths among
subjects dying from HIV/AIDS non-related conditions in
the pre-HAART and post-HAART eras were analyzed. The
single underlying cause of non-HIV/AIDS related death
was used for the numerator, and the denominator
included the total number of subjects dying from non-
HIV/AIDS related conditions. Proportions were compared
using chi-square statistics.
Risk factors for dying from major cardiovascular
diseases among non-HIV/AIDS related death patients
The characteristics of the AIDS patients who died from
CVDs were compared with those who died from other
HIV/AIDS non-related conditions using the logistic
regression model. Data analyses were pursued from
univariated followed by multivariate logistic
regression to identify independent risk factors. Odds
ratios were used as estimates of relative risks for
presentation with CVDs as a leading cause of death.
The variables considered in comparing the CVDs death
17
group and the non-CVDs death group were: gender, age
at diagnosis, age at death, AIDS duration time,
race/ethnicity, mode of exposure, country of origin,
CD4 lymphocyte counts, and era of death (Pre-HAART era
& Post-HAART era).
18
CHARTER 3: RESULTS
The impact of HAART on distribution of HIV/AIDS
related deaths and non-HIV/AIDS related deaths
A total of 18,149 deaths occurred among persons living
with AIDS in Los Angeles County from January 1990
through December 2002. Of these, 14,262 deaths (73%)
occurred in the pre-HAART era, and 3,887 deaths (27%)
occurred in the post-HAART era. The annual death rate
consistently increased during the pre-HAART era, and
peaked in 1994 and 1995 (4.23 per 10,000 populations
vs. 4.11 per 10,000 populations) (Table 1 & Figure 1).
Then, it steadily declined in the post-HAART era to
the current rate (1.04 per 10,000 populations) in 2002
(Figure 2). Overall, there was a 71% decrease in
deaths from 1990 to 2002. The mean time of survival
after the diagnosis of AIDS was 19 months during the
pre-HAART era, compared to 37 months during the post-
HAART era (P<0.001).
19
Table 1. Annual death rates (per 10,000 population*) of AIDS cases in Los Angeles
County population, 1990-2002
Year Number of Deaths Annual Death Rate
* Based on the population of Los Angeles County, 1990 U.S. census
Figure 1. Annual death rates (per 10,000 population*) of AIDS cases in Los Angeles
County population, during the pre-HARRT era
1990 1,965 3.61
1991 1,987 3.65
1992 2,115 3.88
1993 2,177 4.00
1994 2,306 4.23
1995 2,238 4.11
1996 1,474 2.71
1997 815 1.50
1998 673 1.24
1999 658 1.21
2000 579 1.06
2001 595 1.09
2002 567 1.04
20
Figure 2. Annual death rates (per 10,000 population*) of AIDS cases in Los Angeles
County population, during the post-HARRT era
The underlying cause of death was an AIDS-defining
disease in 15,706 patients (87%) and non-HIV/AIDS
related disease in 2,443 (13%) patients. The
demographic and risk characteristics (Table 2) of the
non-HIV/AIDS related deaths were similar to those of
patients that died from HIV/AIDS related deaths in the
same time period, occurring mostly among men (91%),
Whites (49%), men who have sex with men (63%), U.S.
born (73%), and were diagnosed at a private facility
(65%). However, compared to subjects dying from
HIV/AIDS related condition, subjects dying from a non-
21
HIV/AIDS related condition had more proportion of
female, were diagnosed with AIDS at an older age (mean
= 42 years old), less proportion of Hispanic ethnicity
and MSM, and slightly longer survival time.
The total number of HIV/AIDS death were decreased
since the introduction of HARRT, however, this
decrease was predominantly due to HIV/AID related
death, not non-HIV/AIDS related death (Figure 3).
Total numbers of non-HIV/AIDS related death were
relatively stable between pre and post HARRT era.
Relatively, among total death in AIDS patients, the
proportion of non-HIV/AIDS-related deaths increased
significantly from 10% in pre-HAART era to 21% in the
post-HAART era (P<0.007; Figure 3). Similar trends
were observed among male AIDS patients. The number of
death due to HIV/AIDS related conditions among male
AIDS patients declined significantly in the post-HAART
era, which was much striking than the decline observed
among female patients (Figure 4). Relatively, the
proportion of non-HIV/AIDS-related deaths among male
AIDS patients increased significantly from 10% in the
22
pre-HAART era to 25% in the post-HAART era. Yet the
change was much less steep among female AIDS patients.
The change was also varied by different ethnicities.
Compared to African Americans and Hispanics, Whites
had a greater decrease in the number of total cases
dying from HIV/AIDS related conditions in the post-
HAART era (Figure 5).
Table 2. Comparisons of characteristics of HIV/AIDS related death and non-HIV/AIDS
related death among adults/adolescents with AIDS
in Los Angeles County, 1990-2002
HIV/AIDS
Related Death
Non-HIV/AIDS
Related Death
P-value
N
(15,706)
%
(87%)
N
(2,443)
%
(13%)
Gender
Male
Female
14,662
1,044
93.50
6.65
2,233
210
91.40
8.60
<0.0001
3,122
6,677
3,913
1,994
19.88
42.51
24.91
12.70
331
943
683
486
13.55
38.60
27.96
19.89
P=0.004 Age at Diagnosis
13~30 yrs
31~40 yrs
41~50 yrs
> = 51 yrs
Mean 38.88 41.67 <0.0001
Race/Ethnicity
White
Black
Hispanic
Other/Unknown
7,689
3,210
4,392
415
48.96
20.44
27.96
2.64
1,243
558
570
72
50.88
22.84
23.33
2.95
<0.0001
Country of Origin
U.S. born**
Foreign born
Unknown
11,347
3,464
895
72.25
22.06
5.70
1,788
412
243
73.19
16.86
9.95
<0.0001
23
Table 2. Comparisons of characteristics of HIV/AIDS related death and non-HIV/AIDS
related death among adults/adolescents with AIDS
in Los Angeles County, 1990-2002 (continue)
HIV/AIDS
Related Death
Non-HIV/AIDS
Related Death
P-value
N
(15,706)
%
(87%)
N
(2,443)
%
(13%)
Mode of Exposure
MSM
IDU
MSM/IDU
Heterosexual
Other*
Unknown
11,452
1,144
976
656
250
1,228
72.91
7.28
6.21
4.18
1.59
7.82
1,541
296
174
119
74
239
63.08
12.12
7.12
4.87
3.03
9.78
<0.0001
Age at Death
25~34 yrs
35~44 yrs
45~54 yrs
55~64 yrs
>= 65 yrs
4,457
6,431
3,256
1,216
346
28.38
40.95
20.73
7.74
2.20
495
916
626
275
131
20.26
37.49
25.62
11.26
5.36
<0.0001
Mean 40.86 43.93 <0.0001
AIDS Duration Time
Mean (months) 23.73 27.10
<0.0001
Facility at Diagnosis
Public
Private
Unknown
5,608
10,040
58
35.71
63.92
0.37
834
1,597
12
34.14
65.37
0.49
P=0.23
*Includes transfusion recipient, hemophilia or coagulation disorder and mother with/at
risk for HIV.
**Includes U.S. territories.
24
Figure 3. Deaths among adults/adolescents with AIDS
in Los Angeles County, 1990-2002
Figure 4. Deaths among adults/adolescents with AIDS by gender
in Los Angeles County, 1990-2002
0
500
1000
1500
2000
2500
90 91 92 93 94 95 96 97 98 99 00 01 02
Year of Death
Number of Deaths
0
10
20
30
40
50
60
70
80
90
100
Percent of Deaths
HIV/AIDS-Related Death Non-HIV/AIDS Related Death
%HIV/AIDS-Related Death %Non-HIV/AIDS Related Death
0
500
1000
1500
2000
2500
90 91 92 93 94 95 96 97 98 99 00 01 02
Year of Death
Number of HIV/AIDS Related Deaths
0
5
10
15
20
25
30
Percent of non-HIV/AIDS related Death
HIV/AIDS Related Death (Male) HIV/AIDS Related Cases (Female)
% Non-HIV/AIDS-Related Death (Male) % Non-HIV/AIDS-Related Cases (Female)
25
Figure 5. Deaths among adults/adolescents with AIDS by race
in Los Angeles County, 1990-2002
The top five leading causes of deaths associated with
non-HIV/AIDS related conditions between 1990 and 2002
were malignant neoplasm (22%), major cardiovascular
diseases (15%), other infectious or parasitic diseases
(14%), unintentional injuries (6%), and suicide (5%)
(Figure 6). Remaining as the most common leading
cause of deaths other than HIV/AIDS related diseases,
malignant neoplasm was not significantly different
when comparing the pre-HAART and post-HAART eras (18%
to 26%, P=0.12). Though the proportion of deaths due
0
200
400
600
800
1000
1200
1400
1600
90 91 92 93 94 95 96 97 98 99 00 01 02
Year of Death
Number of HIV/AIDS Related Death
0
5
10
15
20
25
30
35
40
45
50
Percentage of Non-HIV/AIDS Death
HIV/AIDS-Related Cases (Non-Hispanic White)
HIV/AIDS-Related Cases (Non-Hispanic Black)
HIV/AIDS-Related Cases (Hispanic)
%Non-HIV/AIDS-Related Cases (Non-Hispanic Black)
%Non-HIV/AIDS-Related Cases (Hispanic)
%Non-HIV/AIDS-Related Cases (Non-Hispanic White)
26
to other infections or parasitic diseases and suicide
both declined from the pre-HAART era to the post-HAART
era (19% to 8%, P<0.0001; 6% to 4%, P=0.08;
respectively), deaths occurring in the post-HAART era
were significantly more likely than in the pre-HAART
era to be related to an unintentional injury (4% to
8%, P<0.0001; Linear trend <0.01), specifically
related to cardiovascular diseases (11% to 19%,
P<0.0001; Linear trend <0.01) (Figure 7 & Figure 8).
Total Cases
Figure 6. The top five leading causes of death among adults/adolescents with HIV/AIDS
in Los Angeles County, 1990-2002
0 100 200 300 400 500 600
Malignant Neoplasm
Cardiovascular Diseases
Infectious Disease (Other than Influena & Pneumonia)
Unintentional Injuries
Suicide
27
Total cases
Figure 7. Comparison for the top five underlying causes of death unrelated to HIV/AIDS
among adults/adolescents with AIDS in Los Angeles County,
Pre-HAART era vs. Post-HAART era
Figure 8. Trends for the top five underlying causes of death unrelated to HIV/AIDS
among adults/adolescents with AIDS in Los Angeles County, 1990-2002
0
10
20
30
40
90 91 92 93 94 95 96 97 98 99 00 01 02
Year of Death
Percent
Malignant Neoplasm Major Cardiovascular Diseases**
Unintentional Injuries** Suicide*
Other Infectious/Parasitic Disease**
0
100
200
300
400
500
Pre-HAART Post-HAART
Malignant Neoplasm
Cardiovascular Diseases
Infectious Disease (Other then Influena & Pneumonia)
Unintentional Injuries
Suicide
28
Risk factors for dying from major cardiovascular
diseases among non-HIV/AIDS related death patients
As deaths from cardiovascular diseases among persons
with AIDS experienced a much steeper increased trend
in the post-HAART era in Los Angeles County, analysis
was conducted to estimate the relative risk for
presentation with CVDs as a primary leading cause of
death among patients dying from non-HIV/AIDS related
conditions.
Table 3 presents the results of the univarite analysis
for risk factors of dying from CVDs among non-HIV/AIDS
related deaths during the study period. Though fewer
women than men presented CVDs as their primary leading
cause of death, this difference was not significant
(OR=0.97, 95% C.I. = 0.65-1.45). In comparison to
Whites, African Americans had a significantly higher
risk of dying from CVDs (OR=1.78, 95% C.I. = 1.37-
2.32). Hispanics had a risk similar to Whites
(OR=1.06, 95% C.I. = 0.79-1.42). With regard to age,
there appeared to be a trend of increasing risk with
increasing age (Linear trend P<0.01). Individuals who
29
were older than 65 years old were significantly more
likely to present CVDs as a leading cause of death
(OR=4.08, 95% C.I. = 2.44-6.83). Laboratory data
showed that patients dying from CVDs were more likely
to have a lower CD4 count (< 200 cells/µL) compared
with those dying from non-HIV/AIDS related conditions
other than CVDs (OR=1.45, 95% C.I.=1.15-1.83). Longer
AIDS duration time significantly predicted the
possibility of dying from CVDs (OR=1.59, 95% C.I. =
1.13-2.25). In addition, those dying in the post-
HAART era were almost two times more likely to die
from CVDs compared with those dying in the pre-HAART
era (OR=1.9, 95% C.I.=1.52-2.40).
30
Table 3. Univariate analysis -- Significant risk factors* associated with dying from
major cardiovascular diseases (CVDs) among non-HIV/AIDS related death
in Los Angeles County, 1990-2002
Deaths not
Due to
Cardiovascular
Deaths
Due to
Cardiovascular
N
(2,079)
%N
(358)
%
Unadjusted OR
(95% C.I.)
Gender
Male
Female
1,900
179
85.28
14.72
328
30
91.62
8.38
1.00
0.97(0.65~1.45)
Age at Diagnosis
13 ~ 30 yrs
35 ~ 44 yrs
45 ~ 54 yrs
> = 55 yrs
304
835
564
376
14.62
40.16
27.13
18.09
26
107
116
109
7.26
29.89
32.40
30.45
1.00
1.66(1.20~2.29)
2.77(1.98~3.90)
2.84(1.96~4.12)
Age at Death
25 ~ 34 yrs
35 ~ 44 yrs
45 ~ 54 yrs
55 ~ 64 yrs
>= 65 yrs
456
806
507
213
97
21.93
38.77
24.39
10.25
4.67
38
107
118
62
33
10.61
29.89
32.96
17.32
9.22
1.00
1.59(1.08~2.35)
2.79(1.90~4.11)
3.49(2.26~5.40)
4.08(2.44~6.83)
AIDS Duration
Time
< 6 yrs
>=6 yrs
1,899
180
91.34
8.66
311
47
86.87
13.13
1.00
1.59(1.13~2.25)
Race/Ethnicity
White
Black
Hispanic
Others
1,085
443
494
57
52.19
21.31
23.76
2.74
158
115
76
9
44.13
32.12
21.23
2.51
1.00
1.78(1.37~2.32)
1.06(0.79~1.42)
1.08(0.53~2.23)
Categories of
AIDS Diagnosis
O.I.¹
CD4<200µl or <14%
1,426
653
68.59
31.41
215
143
60.06
39.94
1.00
1.45(1.15~1.83)
HAART
Pre- (<=1995)
Post- (>=1996)
1,188
891
57.14
42.86
147
211
41.06
58.94
1.00
1.91(1.52~2.40)
* Except for gender
1. O.I. = Opportunistic Infections
31
Table 4 shows the results of the multivariate logistic
regression model that was constructed using the
variables gender, age at diagnosis, race/ethnicity,
age at death, category of AIDS diagnosis, and
diagnosis era (pre-HAART or post-HAART). Odds ratios
adjusted for all other variables in the model
indicated that subjects were at a significantly higher
risk of dying from CVDs in the post-HAART era
(OR=1.58, 95% C.I. = 1.23-2.04). African Americans
are almost two times more likely to die from CVDs than
Whites (OR=1.90, 95% C.I. = 1.45-2.50). Similar to
the univariate analysis, older age groups experienced
a significantly higher risk. AIDS patients who were
older than 65 were three times more likely to die from
CVDs as compared to the reference group of 25-34 year
olds. However, age at diagnosis, AIDS duration time,
and category of AIDS diagnosis were no longer
significant risk factors of dying from CVDs after
adjusting all other variables in the model.
32
Table 4. Multivariate analysis -- Significant risk factors associated with dying from
major cardiovascular diseases (CVDs) among non-HIV/AIDS related death
in Los Angeles County, 1990-2002
Adjusted OR* 95% C.I.
Age at Death
25 ~ 34 yrs
35 ~ 44 yrs
45 ~ 54 yrs
55 ~ 64 yrs
>= 65 yrs
1.00
1.32
1.99
2.43
2.78
0.78~2.24
1.01~3.92
1.02~5.80
1.08~7.14
Race/Ethnicity
White
Black
Hispanic
Others
1.00
1.90
1.20
1.24
1.45~2.50
0.88~1.62
0.59~2.60
HAART
Pre- (<=1995)
Post- (>=1996)
1.00
1.58 1.23~2.04
* Adjusted by gender, age at time of diagnosis, age at time of death, AIDS duration
time, race/ethnicity, category of AIDS diagnosis, and pre and post HAART era.
33
CHARTER 4: DISCUSSIONS
Deaths from HIV/AIDS have dramatically declined since
1996 (Crum, Robert, Wegner, Agan, Tasker, Spooner & et
al., 2006; Selik, Byers & Dworkin, 2002). Yet there
were considerable disparities of the range of
reduction in HIV/AIDS mortality among regions across
the world. Casseb and his colleagues reported a 20.7%
mortality reduction in Brazil (1999), while patients
in Australia showed a 79% reduction (1998). Other
than the treatment itself, the wide range of reduction
might be explained by variation in study design,
recruitment criteria, and difference in the years
analyzed (Chan, Cheng, Chan & Wong, 2005).
In our study, there was a total reduction of 73% in
deaths of HIV/AIDS in the post-HAART era compared to
pre-HAART era, with a more rapid reduction in 1996 (a
66% reduction from 4.11 per 10,000 persons in 1995 to
2.71 per 10,000 persons in 1996). This was consistent
with the decreasing pattern found for the country
(Figure 8). Many studies have concluded this
34
declining trend as the result of the advent of HAART
introduced in 1995 (Louie, Hsu, Osmond, Katz,
Schwarcz, 2002; Crum, Riffenburgh, Wegner, Agan,
Tasker, Spooner & et al, 2006). The dramatic drop in
AIDS deaths right after 1995 in our study likely
reflected the beneficial effects of HAART in this
population.
Annual HIV incidence Estimated annual AIDS deaths
Figure 9. Estimated annual HIV incidence, AIDS deaths, and expected AIDS deaths,
USA, 1978-2002 (Adopted from Holtgrave, 2005)
35
However, some scholars stated the application of
prevention strategy was indeed the main reason
contributing to this declining trend (Holtgrave,
2005). As Figure 8 shows, the AIDS death curve mode
occurred about one decade after the HIV incidence mode
in the United States. Accompanied with the 75%
reduction in the HIV incidence from 1985 to 1990 and a
flattening curve since then, there was a 66% reduction
in deaths from AIDS from 1995 to 2000, followed by a
flattening curve. This indicated that previous
prevention successes were responsible in large part to
the AIDS death drop in the United States since 1995.
Yet the more widespread availability of HARRT might
have caused the AIDS deaths drop to occur more rapidly
than would have otherwise been the case. While more
and more studies focus on studying the benefits of
HAART on AIDS mortality, policy makers should not
ignore the importance of the application of successful
prevention strategies, as these are the primary ways
to drop AIDS mortality in the first place.
36
Although there has been a decline in the number of
deaths from AIDS since 1990, we found proportionally
more deaths associated with non–AIDS-defining
malignancies and other chronic diseases. This is
mainly because HAART could significantly reduce the
chance of opportunistic infections (OIs), which was an
important cause of HIV/AIDS related deaths in the pre-
HAART era (Kaplan, Hanson, Dworkin, Frederick,
Bertolli, Lindegren & et al., 2000; Schmidt-
Westhausen, Priepke, Bergmann, Reichaart, 2000).
Thus, a higher proportion of patients were dying from
non-HIV/AIDS related conditions as a consequence of
the decrease of HIV/AIDS related deaths. This can
also explain our finding that Whites had a greater
increase in proportion of non-HIV/AIDS-related deaths
in the post-HAART era when compared to African
Americans and Hispanics (Figure 3). Studies have
found that Whites had better health care access than
minority groups (Cargill & Stone, 2005; Heslin,
Andersen, Ettner & Cunningham, 2005), and thus more
benefited from the advent of HAART. This led to a
significant decrease of deaths from AIDS-defining
37
illnesses among Whites, which increased the proportion
of non-AIDS-defining condition deaths as well. This
explanation might be also applied to the significant
reduction of AIDS related deaths among male patients
when compared to female patients. Female AIDS patients
were usually less active than male AIDS patients to
look for treatments, thus less benefit from the HAART.
However, whether there are any genetic factors among
these populations lead to the differences merits
further investigation.
In addition, our data showed that non-HIV/AIDS related
condition patients lived longer than AIDS-defining
illness patients. With a better survival, AIDS
patients are now living long enough to experience
growing morbidity and mortality from coexisting
conditions that are not intrinsically related to AIDS.
As AIDS becomes more of a manageable chronic disease,
some common advanced diseases that occur in patients
with AIDS could pose more risk than HIV (Friis-Moller,
Sabin, Weber, d'Arminio Monforte, El-Sadr, Reiss & et
38
al., 2003). Many studies have stated the need to
emphasize controlling certain co-conditions of AIDS.
The significant contribution of deaths from CVDs in
our study population consistently corroborates these
suggestions. Others also reported similar results for
an increased proportion of deaths attributed to
cardiac disease (Savès, Chêne, Ducimetière, Leport, Le
Moal, Amouyel & et al., 2003; Mary-Krause, Cotte,
Partisani, Simon & Costagliola, 2003; Crum,
Riffenburgh, Wegner, Agan, Tasker, Spooner, & et al.,
2006).
The causes for the increased rate of CVDs in persons
with AIDS are still unclear. A variety of potential
etiologies have been postulated in HIV-related heart
disease. Some studies have suggested lifestyle
factors such as tobacco, alcohol use, or non-injection
drug use may play a role in the increasingly higher
proportion of developing CVDs in this population
(Stein, 2005). Niaura and Shadel (2000) reported that
smoking prevalence is high among HIV-infected persons.
The importance of tobacco exposure as a mediator is
39
supported by our finding that lung cancer was the most
common cause of death for non-AIDS-defining
malignancies. Our finding also suggested that
increased age was a common risk factor of CVDs (Friis-
Moller, Weber, Reiss, Thiebaut, Kirk, Monforte & et
al., 2003). The trend of increasing risk with
increasing age in this study confirmed the general
finding that acquisition of CVDs was age-related with
increasing atherosclerotic burden (Egger, Junghans,
Friis-Moller & Lundgren, 2001).
It is also reported that HIV infection might be
associated with CVDs. Danesh, Collins, and Peto found
that chronic inflammation from HIV infection could
promote atherosclerosis (1997). In addition, the
virus could induce endothelia injury by enhancing
cytokines secretion and cell adhesion molecules
(Schecter, Berman, Yi, Mosoian, McManus, Berman & et
al., 2001). The atherosclerosis and coronary lesions
then might contribute to higher rates of CVDs at
baseline (Tabib, Greenland, Mercier, Loire & Mornex,
1992; Klein & Hurley, 2002). The increased risk of
40
CVDs with a longer duration of HIV infection found in
our study might be evidence to support these previous
findings, as longer infection time was responsible for
more serious coronary damage.
However, recent studies have brought more attention to
the potential for HAART to increase cardiovascular
morbidity among HIV-infected persons. Several
potential mechanisms of developing CVDs under HAART
have been proposed. A well known mechanism is that
the usage of HAART can induce insulin resistance,
which decreases sensitivity to insulin in the
peripheral tissues (Yarasheski, Tebas, Sigmund & et
al. 1999). Consequently, classical risk factors of
CVDs, dyslipidaemia, hypertriglyceridaemia, and
diabetes, develop later as the result of this
metabolic abnormality (Murata, Hruz & Mueckler, 2000).
Observational studies showed that up to 60% of
patients receiving HAART had developed lipodystrophy,
hyperlipidemia, lyperglycemia, and insulin resistance
(Koppel, Bratt, Eriksson & Sandstrom, 2000; Hadigan,
Meigs, Corcoran, Rietschel, Piecuch, Basgoz & et al.,
41
2001). The vitro and animal models have elaborated
this mechanism for the higher risk of CVDs observed in
HIV-infected patients receiving HAART (Stein, 2003).
The finding of an increased proportion of deaths
attributable to CVDs in the post-HAART era in our
study continuously represents evidence addressing this
mechanism.
Likewise, consistent with results of previous studies,
lower baseline CD4 T-cell counts in our study
independently predicted a worse outcome of CVDs in the
univariate model. This might be due to the more
serious ongoing loss of the immune repertoire with
lower baseline CD4 T-cell counts, which impair the
surveillance system to detect the pathogenesis of
developing a CVDs (Stein, 2003). Our results help
clarify that CD4 counts might play a determinant role
in predicting the risk of dying from CVDs.
Finally, we found increasing proportionate deaths of
CVDs associated with African Americans. This is
consistent with the trend observed in the general
42
population. According to the data from the National
Center for Health Statistics in 2002, African
Americans have the highest rates of CVDs, and Native
Americans, Asians, and Hispanics have the lowest
rates. Ongoing efforts to explain the excess CVDs
burden in African Americans have targeted mechanisms
that lead to more CVDs risk factors and lower
responsiveness to medical therapy among this
population.
It is reported that African Americans are about three
to seven times more likely to have hypertension than
White Americans (Saunders, 1995; Flack, Ferdinand &
Nasser, 2003). African Americans also appear to
experience greater cardiovascular and renal damage at
any level of blood pressure than Whites (Cooper, Liao
& Rotimi, 1996). Other risk factors, such as smoking
and diabetes, are also more prevalent among African
Americans (Brancati, Kao, Folsom, Watson & Szklo,
2000; Bonds, Zaccaro, Karter, Selby, Saad & Goff,
2003). Nevertheless, African Americans experienced
much fewer benefits from the β-blocker therapy for
43
CVDs than Whites. While the aggregate benefit of β-
blockers for White Americans was a 31% reduction in
mortality, the apparent benefit of β-blockers in
African Americans was only 3%. (Packer, Bristow, Cohn,
Colucci, Fowler,Gilbert & et al., 1996; The Beta-
Blocker Evaluation of Survival Trial Investigators,
2001).
Some scholars also stated that low socioeconomic
status was associated with the high prevalence of CVDs
among African Americans. Salt sensitivity is twice as
prevalent in African Americans compared with Whites,
as they consume more high fatty and salty foods for a
low price (Nesbitt & Victor, 2004). Likewise, poor
access to medial care is another important contributor
to the high mortality of CVDs among African Americans.
In an analysis of 81 studies addressing racial/ethnic
differences in cardiac care, researchers stated that
African Americans were less likely to receive
appropriate and necessary treatments for cardiac
disease than Whites (The Henry J. Kaiser Family
Foundation and American College of Cardiology
44
Foundation, 2002). Thus, practitioners should apply
comprehensive strategies to decrease the deaths from
CVDs in this disadvantaged group, including educating
patients accordingly and improving access to
preventive, diagnostic, and interventional
cardiovascular therapies.
45
CHARTER 5: LIMITATIONS
Clearly, there are several limitations that exist in
our study. These limitations are mainly related to
the observational design of the study. The largest
limitation with our analysis is that we examined only
deaths during the study period and did not use data
among living patients. Thus, an external validity
issue may concern the generalizability of the
findings.
Another major limitation is the incompleteness in
reporting of information on the actual treatment. Our
study defines 1996-2002 as the post-HAART period
because HAART became widely available in the United
States in 1996, yet we do not know whether or not any
of the persons diagnosed in the post-HAART period
actually received HAART. Therefore, there might be
bias in the association between CVDs and HAART. Case-
control studies or randomized clinical trials should
be conducted in the future to explore this
relationship and further investigate whether or not
46
the risk of CVDs increases with longer duration of
usage of HAART.
Other limitations include the failure to capture
important traditional risk factors such as family
history of CVDs, cigarette smoking, and/or blood
pressure. Thus, residual confounding has not been
entirely eliminated and may account for our
observation of higher risk among African Americans if
these risk factors are linked to race/ethnicity.
In addition, the quality of our data depends on the
accuracy of underling causes of death on death
certificates. Furthermore, the surveillance data
might include possible measurement error due to
misclassification. For example, race/ethnicity might
represent a bias in our study if grossly
misclassified. However, studies on national AIDS
surveillance data have demonstrated that race
classification was in excellent agreement with death
certificates and with self-reports (Kelly, Chu, Diaz,
Leary & Buehler, 1996).
47
Finally, the analyses were based on a small number of
CVDs events and might be imprecise. However, we use
information collected over more than a decade from a
population-based surveillance system; therefore, they
do represent the real issues in some aspects. Yet the
results presented are only an association from which
no conclusions regarding causality can or should be
drawn due to the observational study methodology.
48
CHARTER 6: CONCLUSIONS
Despite the noteworthy limitations, the study does
indicate some important statements. The advent of
HAART definitely decreased the number of deaths among
HIV-infected persons in Los Angeles County, yet the
prevention strategies still play an important role in
this decline. While deaths from HIV/AIDS related
illnesses continuously drop, our findings suggest that
CVDs will be an increasing source of deaths among
patients with AIDS in the post-HAART era. Whether
HAART alters the biologic and immunologic milieu to
promote CVDs pathogenesis merits further
investigations.
In addition, African Americans of the AIDS population
in Los Angeles are at a higher risk than Whites and
Hispanics for CVDs death, even after accounting for
other covariates. Thus, future researches or
programmatic strategies must especially target this
disadvantaged population, with enhanced efforts to
49
remove differences in risk behaviors, preventive care,
and morbidity and mortality between the racial/ethnic
groups.
In conclusion, our study corroborated with others that
have demonstrated an association of HAART and
increased CVDs deaths among HIV-infected persons. This
analysis can contribute to the planning of new
strategies for AIDS care and to public health policies
to increase the early CVDs diagnosis among HIV-
infected persons. The increase of CVDs deaths remains
a challenge to be faced, and it may be accomplished
with some of the actions pointed out in this paper.
50
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Abstract (if available)

Abstract To investigate the impact of highly active antiretroviral therapy (HAART) on the causes of death among AIDS patients, a population-based Los Angeles County AIDS surveillance registry data in 1990-2002 were analyzed (18,149 deaths). Results showed that total AIDS deaths were significantly reduced in post-HAART, with the reduction predominantly in the HIV/AIDS-related death, not the non-HIV/AIDS-related death. Deaths due to cardiovascular diseases (CVDs) were significantly increased in post-HAART among non-HIV/AIDS-related death (P<0.001). Logistic regression identified that being in post-HAART was significantly associated with CVD death (ORadjusted=1.6, 95%CI: 1.2-2.0, compared to pre-HAART). In addition, African American AIDS patients had a higher risk of dying from CVDs compared to Whites (ORadjusted=1.9, 95%CI=1.5-2.5). Thus, treatments and prevention programs among AIDS patients could be targeted on CVDs in the post-HAART era, especially in the disadvantaged population.

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Asset Metadata

Creator Liu, Yihang (author)

Core Title Trends and charateristics of causes of death among persons with AIDS in Los Angeles County, 1990-2002

School Keck School of Medicine

Degree Master of Science

Degree Program Biostatistics

Publication Date 10/12/2008

Defense Date 10/11/2006

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag AIDS/HIV HAART CVDs,OAI-PMH Harvest

Language English

Advisor Xiang, Anny (committee chair), Azen, Stanley Paul (committee member), Cody, Michael J. (committee member)

Creator Email liuyihang@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-m90

Unique identifier UC1269122

Identifier etd-Liu-20061011 (filename),usctheses-m40 (legacy collection record id),usctheses-c127-17599 (legacy record id),usctheses-m90 (legacy record id)

Legacy Identifier etd-Liu-20061011.pdf

Dmrecord 17599

Document Type Thesis

Rights Liu, Yihang

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Repository Name Libraries, University of Southern California

Repository Location Los Angeles, California

Repository Email cisadmin@lib.usc.edu