Matthew R. Gingo1, G. K. Balasubramani2, Lawrence Kingsley2,3, Charles R. Rinaldo Jr.3,4,
Christine B. Alden5, Roger Detels6, Ruth M. Greenblatt7,8,9, Nancy A. Hessol7,8, Susan Holman10,
Laurence Huang8, Eric C. Kleerup11, John Phair12, Sarah H. Sutton12, Eric C. Seaberg13,
Joseph B. Margolick14, Stephen R. Wisniewski2, Alison Morris1,15*
1Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 2Department of Epidemiology, School of
Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 3Department of Infectious Diseases and Microbiology, School of Public Health,
University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 4Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh,
Pennsylvania, United States of America, 5WIHS Data Management and Analysis Center, Department of Epidemiology, The Johns Hopkins University Bloomberg School of
Public Health, Baltimore, Maryland, United States of America, 6Department of Epidemiology, School of Public Health, University of California Los Angeles, Los Angeles,
California, United States of America, 7Department of Clinical Pharmacy, School of Pharmacy, University of California San Francisco, San Francisco, California, United States
of America, 8Department of Medicine, School of Medicine, University of California San Francisco, San Francisco, California, United States of America, 9Department of
Epidemiology and Biostatistics, School of Medicine, University of California San Francisco, San Francisco, California, United States of America, 10Department of Medicine,
SUNY Downstate Medical Center, Brooklyn, New York, United States of America, 11Department of Medicine, David Geffen School of Medicine, University of California San
Francisco, San Francisco, California, United States of America, 12Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United
States of America, 13Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America,
14Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America,
15Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
Objective: To review the incidence of respiratory conditions and their effect on mortality in HIV-infected and uninfected
individuals prior to and during the era of highly active antiretroviral therapy (HAART).
Design: Two large observational cohorts of HIV-infected and HIV-uninfected men (Multicenter AIDS Cohort Study [MACS])
and women (Women’s Interagency HIV Study [WIHS]), followed since 1984 and 1994, respectively.
Methods: Adjusted odds or hazards ratios for incident respiratory infections or non-infectious respiratory diagnoses,
respectively, in HIV-infected compared to HIV-uninfected individuals in both the pre-HAART (MACS only) and HAART eras;
and adjusted Cox proportional hazard ratios for mortality in HIV-infected persons with lung disease during the HAART era.
Results: Compared to HIV-uninfected participants, HIV-infected individuals had more incident respiratory infections both pre-HAART
(MACS, odds ratio [adjusted-OR], 2.4; 95% confidence interval [CI], 2.2–2.7; p,0.001) and after HAART availability (MACS, adjusted-OR,
1.5; 95%CI 1.3–1.7; p,0.001; WIHS adjusted-OR, 2.2; 95%CI 1.8–2.7; p,0.001). Chronic obstructive pulmonary disease was more
common in MACS HIV-infected vs. HIV-uninfected participants pre-HAART (hazard ratio [adjusted-HR] 2.9; 95%CI, 1.02–8.4; p=0.046).
After HAART availability, non-infectiouslung diseases were notsignificantly more common in HIV-infected participantsin either MACS
those without infections (MACS adjusted-HR, 1.5; 95%CI, 1.3–1.7; p,0.001; WIHS adjusted-HR, 1.9; 95%CI, 1.5–2.4; p,0.001).
Conclusion: HIV infection remained a significant risk for infectious respiratory diseases after the introduction of HAART, and
infectious respiratory diseases were associated with an increased risk of mortality.
Citation: Gingo MR, Balasubramani GK, Kingsley L, Rinaldo CR Jr, Alden CB, et al. (2013) The Impact of HAART on the Respiratory Complications of HIV Infection:
Longitudinal Trends in the MACS and WIHS Cohorts. PLoS ONE 8(3): e58812. doi:10.1371/journal.pone.0058812
Editor: Jason F. Okulicz, Infectious Disease Service, United States of America
Received October 15, 2012; Accepted February 7, 2013; Published March 12, 2013
Copyright: ? 2013 Gingo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Sources of support: National Institutes of Health (NIH) T32 HL007563 and K23 HL108697 (MG); R01 HL090339 and HL083461 (AM); Data in this
manuscript were collected by the Multicenter AIDS Cohort Study (MACS) with centers (Principal Investigators) at the Johns Hopkins Bloomberg School of Public
Health (Joseph B. Margolick, Lisa P. Jacobson), Howard Brown Health Center, Feinberg School of Medicine, Northwestern University, and Cook County Bureau of
Health Services (John P. Phair, Steven M. Wolinsky), University of California, Los Angeles (Roger Detels), and University of Pittsburgh (Charles R. Rinaldo, Lawrence
Kingsley). The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer
Institute. UO1-AI-35042, UL1-RR025005 (GCRC), UO1-AI-35043, UO1-AI-35039, UO1-AI-35040, UO1-AI-35041. Website located at http://www.statepi.jhsph.edu/
macs/macs.html. Data in this manuscript were collected by the Women’s Interagency HIV Study (WIHS) Collaborative Study Group with centers (Principal
Investigators) at New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, NY (Howard Minkoff); Washington, DC, Metropolitan Consortium (Mary Young);
The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago
Consortium (Mardge Cohen); Data Coordinating Center (Stephen Gange). The WIHS is funded by the National Institute of Allergy and Infectious Diseases (UO1-AI-
35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590) and by the Eunice Kennedy Shriver National Institute of Child Health and
Human Development (UO1-HD-32632). The study is co-funded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute
on Deafness and Other Communication Disorders. Funding is also provided by the National Center for Research Resources (UCSF-CTSI Grant Number UL1
RR024131). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes
of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PLOS ONE | www.plosone.org1March 2013 | Volume 8 | Issue 3 | e58812
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: firstname.lastname@example.org
The incidence of respiratory diseases and their effect on survival
in the era of highly active antiretroviral therapy (HAART) are
largely unknown. Few studies have examined changes in
respiratory diseases incidence spanning different treatment eras
of the Human Immunodeficiency Virus (HIV) epidemic. Infec-
tious respiratory complications of HIV infection have historically
been a major cause of morbidity and mortality in the HIV-infected
population[1–4]. Although infectious lung diseases have decreased
after HAART, they still occur, and the impact of HAART on non-
infectious lung diseases, such as obstructive pulmonary disease[5–
7], bronchogenic carcinoma[8–10], pulmonary hypertension
[11,12], and pulmonary fibrosis  is less clear.
The Pulmonary Complications of HIV Study (PCHIS),
spanning 1988–1994, demonstrated that HIV-infected individuals
had higher rates of upper and lower respiratory infections than
HIV-uninfected participants . The PCHIS generated much of
the information known about HIV-associated pulmonary diseases
and significantly impacted patient care. The study reflected the
HIV/AIDS population early in the HIV epidemic, with most
participants being men who had sex with men, and stopped prior
to the availability of HAART. Since the PCHIS study, epidemi-
ology and treatment of HIV have drastically changed. More
women, minorities, and intravenous drug users are now HIV-
infected; and receipt of HAART is the leading predictor of survival
in HIV infection[1,13–17]. Epidemiologic
changes with respect to HIV infection in the United States
severely limit our ability to generalize the findings of the PCHIS
and similar studies to the current environment.
To address this question, we have reviewed the incidence of
respiratory conditions and their effect on mortality in the era of
HAART in two large cohorts comparing HIV-infected and
The Multicenter AIDS Cohort Study (MACS) is an ongoing
multicenter prospective cohort study started in 1984 at four
centers across the United States, enrolling 6,972 HIV-infected or
at-risk men who have sex with men : 4,954 in 1984; 668
between 1987 and 1991; and 1,350 between 2001 and 2003. The
Women’s Interagency HIV Study (WIHS) is an ongoing
multicenter prospective cohort study from six centers across the
United States which began in 1994 enrolling 3,766 women with or
at risk for HIV : 2,625 in 1994–1995 and 1,143 in 2001–2002.
The institutional review boards of participating institutions
(University of Pittsburgh; Women’s Interagency HIV Study Data
Management and Analysis Center; Johns Hopkins University;
University of California, Los Angeles; University of California,
San Francisco; State University of New York Downstate Medical
Center; Northwestern University; and the Center for Analysis and
Management of Multicenter AIDS Cohort Study) approved the
study protocol, and written informed consent was obtained from
Baseline and 6-month follow-up visits consisted of interviewer-
administered, structured assessments and specimen collection.
Infectious diagnoses confirmed by medical record review with
standardized criteria in each cohort included Pneumocystis pneu-
monia (PCP), bacterial pneumonia, non-tuberculosis mycobacte-
rial infection (NTM), and pulmonary tuberculosis (TB) per cohort
protocols [18,19]. Infectious diagnoses obtained from participant
self-report were acute sinusitis and acute bronchitis in both MACS
and WIHS by asking at each six-month visit if they had had an
episode of acute sinusitis or bronchitis. Self-reported lung cancer
cases were confirmed for both cohorts by either searches of
statewide cancer registries or medical record confirmation.
Pulmonary Kaposi sarcoma was not included in lung cancer
diagnoses. Participant self-report of chronic obstructive pulmonary
disease (COPD) in MACS and asthma in WIHS were also
recorded. Participant characteristics and clinical data were
prospectively collected and were extracted for current analysis
either at baseline or at the appropriate study visit and included:
age, race, ethnicity, smoking history, alcohol use, illicit drug use,
antiretroviral drug use, opportunistic infection prophylaxis, CD4
lymphocyte counts, HIV serostatus, and plasma HIV RNA
quantification. Self-reports of smoking at each visit were used to
determine smoking status (current, former, or never smokers) and
pack-year history of smoking. Alcohol use was determined for each
visit and classified into none, light drinking (,3 drinks/week),
moderate drinking (3–13 drinks/week), and heavy drinking ($14
drinks/week). Classification of illicit drug use was based on
participant self-report data at each visit for use of marijuana,
crack, cocaine, heroin, methamphetamines, poppers (inhaled alkyl
nitrites), and other drugs. Participants were classified as having
used illicit or intravenous drugs during the six months prior to
their visit by self-report. HAART was classified as use of
combination antiretroviral therapy as previously described .
Data were analyzed with SAS v9.2 (SAS Institute, Inc., Cary,
NC). We analyzed respiratory diseases data collected in the pre-
HAART (from 1984 until October 31, 1994) and HAART
(January 1, 1996 until data were frozen for analysis on December
31, 2008) eras. Outcomes included infectious and non-infectious
respiratory diseases and all-cause mortality. Incidence rates were
computed as number of observed incident events divided by
number of person-years of follow-up, where follow-up time
available for each person was the number of years from baseline
visit until the earliest of the disease diagnosis date (for non-
infectious diagnoses), death, loss to follow-up, or the date of the last
study visit on or prior to December 31, 2008. An infectious
outcome was defined as the presence of any of the following: PCP,
bacterial pneumonia, TB, NTM, acute sinusitis, or acute
bronchitis. A non-infectious outcome was defined as the presence
of lung cancer or COPD for MACS and lung cancer or asthma for
WIHS. For infectious diagnoses, repeated events in a single
participant were considered in the analysis. Once a participant
had a non-infectious respiratory diagnosis, data from further visits
were excluded from analyses of that diagnosis, but were included
in analyses of other non-infectious or infectious diagnoses.
Incidence data were determined separately for participants in
HIV Lung Disease
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MACS pre-HAART and HAART periods, and in WIHS for the
HAART period only. The cohorts were analyzed separately
because of differences in the populations sampled such as gender,
proportions of minorities, socioeconomic status, access to health
care, and substance use as well as variations in data collection
procedures. Only the MACS had sufficient duration of data
collection during the pre-HAART era for analysis.
Summary statistics of demographics, social, and clinical
characteristics were calculated for the MACS (pre-HAART and
HAART) and WIHS (HAART) for those with HIV and without
HIV. To evaluate the association between infectious respiratory
diseases and HIV status for the pre-HAART and HAART eras,
we fit separate multivariate models and analyzed longitudinally
with Generalized Estimating Equations (GEE) [21,22]. The
outcome variable is the odds of a respiratory illness and the unit
of analyses are six month person visit. GEE method was used to
account for multiple observations within a patient.
To evaluate the association between non-infectious respiratory
diseases and HIV status for the pre-HAART and HAART eras,
the Cox’s proportional hazard model was used.Cox-proportional
regression methods were used to assess all-cause mortality related
to having any infectious or non-infectious respiratory disease,
adjusting for age, race, pack-years smoking, intravenous drug use,
and alcohol use. Data were censored at date of death or, if alive,
date of last follow-up visit. Models considered covariates time-
variant (age, pack-years smoking, intravenous drug use, and
alcohol use) and included both any infectious outcome and any
non-infectious outcome, excluding events that occurred within one
year prior to death. Cox models considering the covariates at the
time of origin of the survival period were also performed and had
similar results as the models considering covariates as time-variant.
Only the results of the models with time-variant covariates are
reported. The main predictor, respiratory illnesses, in the mortality
models were accounted as the occurrence of the first ever event.
The time of origin for all Cox models are from the beginning of
the post HAART era (i.e. From January 1, 1996). Cox models
performed with and without including acute sinusitis and
bronchitis (infections not likely associated with mortality) did not
differ in interpretation, and only models including sinusitis and
bronchitis are reported.
Adjusted odds ratios (adjusted-OR) or hazards ratios (adjusted-
HR) and 95% confidence intervals (CI) are reported unless
otherwise noted. An alpha level of 0.05 was used to indicate
There were 2,799 HIV-infected men and 2,821 HIV-uninfected
men from the MACS cohort who were enrolled and followed
during the pre-HAART era. For the HAART era, there were
1,706 HIV-infected and 1,774 HIV-uninfected men from the
Table 1. MACS participant characteristics.
MACS Pre-HAARTMACS HAART era
N 28212799 17741706
Follow-up, years; median (Q1–Q3)9.5 (6.3–9.9)6.4 (3.0–9.6) 6.5 (4.5–12.0) 8.5 (5.2–12.3)
Age at baseline visit, years, mean (SD)33.8 (8.3)32.2 (6.9)
, ,0.001 34.8 (8.6)34.1 (8.3) 0.01
Race, n (%)White 2556 (90.6) 2387 (85.3)
, ,0.001 1293 (72.9) 1097 (64.3)
Black 223 (7.9) 376 (13.4)403 (22.7) 480 (28.1)
Other 39 (1.4)34 (1.2)78 (4.4) 129 (7.6)
Ethnicity, Hispanic, n (%)110 (3.9) 189 (6.8)
, ,0.001 136 (7.7) 240 (14.1)
Smoking statusa, n (%)Never1227 (44.8) 1063 (39.4)
, ,0.001394 (29.7)326 (27.1)0.17
Former 431 (15.7)367 (13.6)421(31.8)421 (35.0)
Current 1082 (39.5) 1265 (47.0)511(38.5)456 (37.9)
Pack-years smoking (ever smokers), median (Q1–Q3) 17.7 (5.2–31.5)15.6 (5.1–29.1) 0.018.2 (0.9–27) 12.8 (2–30.6)0.006
Alcohol usea, n (%)None297 (11.5)250 (9.6)
, ,0.001376 (28.4)431 (35.9)
Light755 (29.3)647 (24.9) 360 (27.1)349 (29.1)
Moderate1070 (41.5)1161 (44.7)439 (33.1)328 (27.3)
Heavy456 (17.7)538 (20.7)151 (11.4)92 (7.7)
Intravenous drug use, evera, n (%)109 (3.9)372 (13.4)
, ,0.001160 (9)307 (18)
Illicit drug use, evera, n (%)2310 (86.0)2567 (94.7)
, ,0.0011427 (81)1432 (84.3)0.01
Pneumocystis prophylaxis use, evera, n (%)– 1026 (46.9)–– 686 (40.2)–
HAART use, ever, n (%)–––1407 (82.5)–
CD4 lymphocyte count, cells/mL, median (Q1–Q3)893 (692–1160) 595 (423–826)
, ,0.001912 (720–1144)357 (193–536)
Log10HIV RNA level, copies/ml, mean (SD)–3.6 (1.4)––4.1 (1.1)–
HIV RNA level ,400 copies/ml, n (%)––––1220 (76)–
Visits with HIV RNA,400 copies/ml, median % (Q1–Q3)––––70 (41–95)
aSome variables do not sum to the total n due to missing data at baseline.
HAART=highly active antiretroviral therapy, SD=standard deviation, Q1=quartile 1, Q3=quartile 3.
HIV Lung Disease
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MACS cohort, and for the WIHS cohort, there were 2,507 HIV-
infected and 879 HIV-uninfected females. Person-years of follow-
up are reported in Tables 1 and 2. Median years of follow-up
ranged from 5.5 to 9.5. In MACS, the baseline characteristics age,
race, ethnicity, smoking status and pack-years of smoking, alcohol
use, and intravenous and illicit drug use differed between HIV-
infected and -uninfected participants in both the pre-HAART and
HAART eras (Table 1). The WIHS participants in the HAART
era were more evenly matched, but HIV-infected participants
differed from HIV-uninfected participants in age, pack-years of
smoking, alcohol use, and illicit drug use (Table 2).
Infectious Respiratory Diseases
HIV-infected individuals in MACS had greater risk of incident
respiratory infections than HIV-uninfected participants in the pre-
HAART era (Table 3). There were 30.59 cases of PCP, 0.22 cases
of NTM, and 0.50 cases of TB per 1,000 person-years of follow-up
in HIV-infected participants compared to no cases of these
diseases in HIV-uninfected participants (Table 4). HIV-infected
participants also had increased risk of bacterial pneumonia, acute
sinusitis, acute bronchitis, and any infectious respiratory disease
(i.e. PCP, NTM, TB, bacterial pneumonia, sinusitis, or bronchitis).
HIV-infected individuals in MACS continued to have a greater
risk for incident respiratory infections compared to HIV-uninfect-
ed participants in the HAART era (Table 3), but much less than
in the pre-HAART era. There were 2.51 cases of PCP per 1,000
person-years in HIV-infected participants (Table 4), and there
were no cases of NTM or TB in either group. HIV-infected
participants remained more likely to have bacterial pneumonia,
acute sinusitis, acute bronchitis, or any infectious respiratory
HIV-infected individuals in WIHS had more incident respira-
tory infections comparedto
(Table 3). There were 3.50 cases of PCP, 1.53 cases of NTM,
and 0.82 cases of TB per 1,000 person-years in HIV-infected
participants compared to no cases of these diseases for HIV-
uninfected participants (Table 4). HIV-infected participants had
increased rates of bacterial pneumonia, acute sinusitis, or any
infectious respiratory disease.
Non-infectious Pulmonary Diseases
Incident non-infectious lung diseases were more common in the
HIV-infected MACS participants prior to HAART availability
(Table 3). There was no significant difference in the risk for lung
cancer, but in HIV-infected participants there was an increased
risk for COPD compared to HIV-uninfected participants.
During the HAART era, HIV-infected individuals in MACS
had no significant increased risk of COPD or lung cancer
compared to HIV-uninfected participants (Table 3). There was
one incident lung cancer recorded in the HIV-uninfected group,
while in the HIV-infected group there were five cases.
Table 2. WIHS participant characteristics.
WIHS HAART era
HIV- HIV+ +
N 879 2507
Follow-up, years; median (Q1–Q3)5.5 (4.9–11.0)5.7 (4.6–11.1)
Age at baseline visit, years, mean (SD)31.9 (8.8)35.3 (7.8)
Race, n (%)White211 (24.0) 578 (23.1) 0.83
Black505 (57.5)1464 (58.4)
Other159 (18.1) 459 (18.3)
Ethnicity, Hispanic, n (%) 243 (27.7) 653 (26.0)0.34
Smoking statusa, n (%)Never 268 (30.6)791 (31.8) 0.32
Former136 (15.6) 427 (17.2)
Current 471 (53.8)1270 (51.0)
Pack-years smoking (ever smokers), median (Q1–Q3) 13 (6.5–21)17 (10–23)
Alcohol usea, n (%)None 398 (46.0) 1387 (56.4)
Light248 (28.7)611 (24.8)
Moderate143 (16.5)304 (12.4)
Heavy 76 (8.8) 157 (6.4)
Intravenous drug use, evera, n (%) 105 (11.9)1326 (13.0) 0.42
Illicit drug use, evera, n (%)576 (72.5)1332 (62.2)
Pneumocystis prophylaxis use, ever, n (%) – 1698 (67.7)–
HAART use, ever, n (%)– 1963 (78.3)–
CD4 lymphocyte count, cells/mL, median (Q1–Q3) 1008 (794–1257)382 (211–581)
Log HIV RNA level, copies/ml, mean (SD)– 3.8 (1.1)–
HIV RNA level ,400 copies/ml, n (%)– 1822 (73.3)–
Visits with HIV RNA,400 copies/ml, median % (Q1–Q3)–47.3 (23.8–75)–
aSome variables do not sum to the total n due to missing data at baseline.
HAART=highly active antiretroviral therapy, SD=standard deviation, Q1=quartile 1, Q3=quartile 3.
HIV Lung Disease
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In the WIHS cohort during the HAART era, there was not a
significant effect of HIV status on incident non-infectious
respiratory diagnoses (Table 3). HIV-infected participants had a
greater lung cancer rate, but this difference was not statistically
During the HAART era, having respiratory disease was
associated with an increased risk of all-cause mortality. Having
any infectious respiratory disease was associated with increased
mortality in MACS HIV-infected participants (adjusted-HR, 1.5;
p,0.001) (Figure 1a) and HIV-uninfected participants (adjusted-
HR, 1.8; p=0.002) and WIHS HIV-infected participants
(adjusted-HR, 1.9; p,0.001) (Figure 1b) and HIV-uninfected
participants (adjusted-HR, 6.3; p,0.001). Having any non-
infectious respiratory disease was associated with mortality in
MACS HIV-infected participants (adjusted-HR, 3.4; p=0.04)
(Figure 1c) and HIV-uninfected participants (adjusted-HR, 7.6;
p=0.04) and WIHS HIV-uninfected participants (adjusted-HR,
1.9; p=0.04), but not in WIHS HIV-infected participants
This study is the first to report the associations of HIV infection
and respiratory diseases both before and after HAART availability
and to assess the impact of respiratory disease on mortality during
the HAART era. We tracked incidence of multiple infectious and
non-infectious respiratory conditions in two large cohorts of HIV-
infected and HIV-uninfected participants over a 20-year period.
Both prior to and during the HAART era, infectious respiratory
diseases such as PCP, bacterial pneumonia, and acute bronchitis
were more frequent in HIV-infected compared to HIV-uninfected
men and women. Prior to HAART, HIV-infected men were more
likely to have COPD than uninfected men. In contrast, HIV was
not an independent risk factor for non-infectious diagnoses in men
or women after the introduction of HAART. Infectious respiratory
conditions in HIV-infected individuals were associated with an
increased risk of death whether sinusitis was included or not, while
for non-infectious conditions this was true only in men. Although
respiratory infections were also associated with increased mortality
in the HIV-uninfected population, the higher incidence of
respiratory infections in HIV-infected people suggests that
improved prevention of infectious respiratory complications could
be particularly important in the HIV-infected population.
Our findings mirror findings in the PCHIS and in the HAART
era in the Veterans Aging Cohort study (VACS) [3,6,23].
Respiratory diseases with the highest incidence in HIV-infected
individuals in PCHIS and MACS during the pre-HAART era
were acute sinusitis, acute bronchitis, PCP, and bacterial
pneumonia; and HIV was an independent risk factor for these
infections in both cohorts. Similar to the VACS, during the
HAART era HIV infection was still an independent risk factor for
bacterial pneumonia, PCP, and TB . It should be noted that TB
incidence was quite low in these cohorts and may not relate to
areas where TB is more common such as Africa and Asia.
COPD was increased in MACS HIV-infected compared to
HIV-uninfected participants before HAART, but HIV infection
was not an independent risk factor for non-infectious respiratory
diseases in MACS or WIHS during the HAART era. The VACS
found HIV infection to be a risk factor for non-infectious
respiratory disorders such as COPD, lung cancer, pulmonary
hypertension, and pulmonary fibrosis . We did not find that
HIV infection was significantly associated with lung cancer, similar
to prior publications in the MACS/WIHS cohorts. [10,24] This
conflict may be due to non-infectious diagnoses of COPD and
asthma in the present study were based on self-report, and use of
self-report could potentially bias the findings or underestimate the
true prevalence of diseases such as COPD and asthma as we have
previously reported that HIV-infected individuals with chronic
Table 3. Unadjusted and adjusted estimates of infectious and
non-infectious complications in HIV-infected persons.
MACS Pre-HAARTOR (95% CI) p-value OR (95% CI)p–value
Bacterial pneumonia21.9 (11.9–40.5)
,0.001 21.8 (11.7–40.6) ,0.001
Acute sinusitis 1.39 (1.24–1.55)
,0.0011.64 (1.44–1.86) ,0.001
Acute bronchitis 1.70 (1.46–1.97)
,0.0011.78 (1.48–2.13) ,0.001
,0.0012.43 (2.20–2.68) ,0.001
HR (95% CI)p–valueHR (95% CI) p-value
Lung Cancer 1.39 (0.36–5.36) 0.631.84* (0.42–8.10) 0.42
COPD2.84 (1.06–7.59) 0.04 2.92 (1.02–8.38) 0.05
2.09 (0.94–4.64) 0.071.95 (0.80–4.74) 0.14
MACS HAART era OR (95% CI)p-valueOR (95% CI) p-value
Bacterial pneumonia 3.78 (2.35–6.10)
,0.0014.14 (2.43–7.08) ,0.001
Acute sinusitis1.59 (1.38–1.83)
,0.0011.46 (1.28–1.68) ,0.001
Acute bronchitis 1.60 (1.32–1.94)
,0.0011.51 (1.24–1.84) ,0.001
,0.001 1.50 (1.34–1.68) ,0.001
HR (95% CI) p-valueHR (95% CI)p-value
Lung Cancer3.48 (0.40–30.3) 0.262.65* (0.29–24.4) 0.39
COPD1.16 (0.29–4.68) 0.841.61@ (0.36–7.19)0.53
1.53 (0.48–4.93)0.471.68@ (0.49–5.72)0.41
WIHS HAART eraOR (95% CI) p-value OR (95% CI)p-value
Bacterial pneumonia13.5 (4.3–42.6)
,0.001 9.55 (2.93–31.1) ,0.001
Acute sinusitis2.27 (1.89–2.73)
,0.0012.17 (1.79–2.63) ,0.001
Acute bronchitis1.47 (0.83–2.63)0.191.46 (0.79–2.68) 0.22
,0.0012.22 (1.84–2.68) ,0.001
HR (95% CI)p-valueHR (95% CI) p-value
Lung Cancer 1.63 (0.47–5.64)0.44 2.45 (0.55–10.9) 0.24
Asthma0.90 (0.74–1.11)0.321.01 (0.87–1.20) 0.82
1.17 (0.85–1.61)0.331.28 (0.88–1.86) 0.19
Adjusted models include the variables age, race, cumulative pack-years
smoking, alcohol use, and intravenous drug use unless otherwise noted.
*Adjusted for alcohol use, smoke years and age.
@ Excluded IDU due to large missing values.
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respiratory symptoms often do not undergo formal pulmonary
function testing that would establish these diagnoses . Other
differences in the studies such as ethnicity, HIV risk factors,
socioeconomic status, or access to health care could also account
for the findings.
Few data exist about the interaction between HIV and asthma
risk. HIV infection was not found to be a risk factor for asthma in
Table 4. Incidence and person years for pulmonary disease.
PCP0– 554 30.59
Bacterial pneumonia9 0.41150 8.28
Acute sinusitis141465.041359 75.05
Acute bronchitis544 25.02650 35.89
Any infectious diagnosis*1753 80.642357 130.16
Lung Cancer4 0.185 0.28
COPD6 0.2811 0.61
Any non-infectious diagnosis10 0.4616 0.88
MACS HAART era
Bacterial pneumonia282.31 1086.29
Acute sinusitis 1495 123.3 2596 151.24
Acute bronchitis579 47.751047 61
Any infectious diagnosis* 1894 156.213312192.95
Lung Cancer1 0.085 0.29
COPD4 0.336 0.35
Any non-infectious diagnosis5 0.41 10 0.58
WIHS HAART era
Bacterial pneumonia5 0.8 120 6.56
Acute sinusitis 804135.2 4992273.1
Acute bronchitis 16 2.69703.83
Any infectious diagnosis** 807135.7 5216 285.2
Lung Cancer3 0.515 0.82
Asthma 12422.21 36721.31
Any non-infectious diagnosis 126 22.61379 22.01
IR is per 1,000 person-years.
PCP=Pneumocystis pneumonia, NTM=non-tuberculosis mycobacterial infection, TB=pulmonary tuberculosis, COPD=chronic obstructive pulmonary disease.
*includes PCP, bacterial pneumonia, NTM, TB, bronchitis, and sinusitis.
**Includes PCP, bacterial pneumonia, NTM, TB, and sinusitis (bronchitis not included in WIHS analyses).
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the HAART era either in WIHS in the current study or in the
VACS, and these data were not available in MACS. Contrary to
our findings, two studies in children that show an increase in
asthma diagnosis or asthma-related inhaler use in HIV-infected
children on HAART [25,26]. This discrepancy may reflect
differences in asthma between children and adults, other
differences between the populations, or the use of self-reported
diagnosis instead of pulmonary function testing as a recent study
found a high prevalence of reversible airway obstruction in an
HIV-infected population .
The association of HIV infection and lung cancer has not been
clearly determined, and results of different studies are conflict-
ing[6,8–10,28–36]. In the current study, we did not find a
significant association between HIV infection and lung cancer in
either cohort. Other studies from these cohorts have not found
HIV infection to be significantly associated with lung cancer,
though the absolute number of lung cancers is quite small, limiting
the power to detect a true association [10,24]. However, studies
from VACS show HIV infection to be independently associated
with lung cancer when controlling for confounders such as
smoking [6,36]. However, in both the MACS  and the VACS,
smoking was the greatest risk factor for lung cancer in both HIV-
infected and HIV-uninfected participants, highlighting the impor-
tance of smoking avoidance.
We found that infectious respiratory diseases were indepen-
dently associated with increased mortality during the HAART era.
These findings are consistent with other reports that show
increased mortality in HIV-infected persons related to lung
infections . Although increased risk of mortality in persons
with respiratory diseases was also seen in HIV-uninfected
participants, risk in HIV represents an important public health
issue given the greater incidence of these infections in HIV. We
found an association of non-infectious diagnoses with mortality in
HIV in the MACS participants, but not WIHS. Other studies
have found increased mortality from lung cancer in HIV-infected
persons[37–39]. Additionally, the increased incidence of COPD in
MACS pre-HAART may have contributed to increased mortality
post-HAART, while we do not know the incidence of COPD in
women. It is also possible that we did not see such an association
because numbers of lung cancer cases were low.
Smoking is an important risk factor for lung diseases such as
pneumonia, chronic obstructive pulmonary disease, and lung
cancer, [40,41] and smoking is important in the HIV-infected
population because of the prevalence of smoking. In these cohorts
in the HAART era, nearly 70–74% of the participants were
current or former smokers, and cumulative pack-years smoked
were greater in the HIV-infected participants. In light of these
issues, we took care to control for smoking in our models assessing
the association of HIV status and lung disease.
This study has several strengths compared to previous work
examining respiratory complications of HIV. First, it includes both
men and women and spans almost the entire course of the AIDS
epidemic. The cohorts analyzed allowed the study of the effects of
HIV infection on respiratory disease in a substantial number of
women, minorities, and illicit drug users, reflecting the current
HIV-infected population in the United States [17,42]. Second,
although there were differences between the HIV-infected and
HIV-uninfected groups, the uninfected groups included similar
populations of at-risk persons [18,19]. Finally, we investigated a
wide range of respiratory disorders and the impact of these
disorders on mortality.
This study has several limitations. The MACS cohort may not
reflect the current HIV epidemic in that it includes HIV-infected
participants who were followed prior to HAART and received
non-HAART antiretroviral regimens for a substantial period of
time. MACS may not represent the HIV population in other parts
of the world such as Africa where men who have sex with men is
not as common a mode of HIV transmission . The low
prevalence of a viral load response to treatment in the WIHS
cohort may not reflect the entire HIV-population as viral load
response in other cohorts is close to 80–90% . Diagnoses of
COPD, asthma, sinusitis, and bronchitis were self-reported and
not confirmed by specific criteria or testing in both groups which
may result in underreporting and the incidence rates reported may
Figure 1. Unadjusted cumulative HAART era mortality. Unad-
justed Kaplan-Meier mortality curves starting during the HAART era for
HIV-infected participants who had any infectious respiratory disease vs.
those who never had any infectious disease in the MACS (A) and WIHS
(B) cohorts and for HIV-infected participants who had any non-
infectious respiratory disease vs. those who never had any non-
infectious disease in the MACS (C) and WIHS (D) cohorts. Time zero
represents the start of the HAART era or seroconversion for participants
who seroconverted during the HAART era.
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not reflect the true incidence of these diseases in this population. It
is difficult to assess whether there might have been more
underdiagnosis in those with HIV infection or a greater chance
for diagnosis as a result of HIV-infected persons coming in contact
with medical care more often than HIV-uninfected persons. In
addition, influenza may be an important infection related to lung
disease in this cohort, but we did not have reliable data to
accurately determine the influence of influenza. We did not
evaluate other risk factors for infection like diabetes, renal disease,
or other comorbidities that may also influence the risk for
infections. Underdiagnosis of COPD is common in the general
population but may be more common in those with HIV given
decreased recognition of smoking behavior, lack of confidence in
smoking cessation counseling among primary care providers of
HIV-infected patients, and underutilization of pulmonary function
testing in HIV[6,16,45–51]. We were unable to evaluate incidence
of important conditions such as interstitial lung disease and
bronchiectasis, data not collected in either MACS or WIHS. We
chose not to determine the effect of duration or type of HAART
on specific respiratory disease, and we considered HAART in the
context of overall HIV care. We may have lacked the power to
detect differences in incidence of the less frequent conditions
including lung cancer and COPD. Also, in general, outcomes were
too few to stratify the analysis by time period or different levels of
treatment response to see how the effect of HIV-infection has
changed over time during the HAART era or in participants with
a good response to HAART. Given the relatively young age of the
cohorts during the HAART era, a longer follow-up period may be
needed to see any effect on these conditions. Therefore, we cannot
exclude the possibility that HIV infection is an independent risk
for COPD and lung cancer.
In conclusion, infectious and non-infectious respiratory diseases
remained frequent morbidities of HIV infection throughout the
course of the AIDS epidemic in both men and women. As in the
HIV-uninfected population, respiratory diseases increased the risk
of death in those with HIV. The specific contribution of HIV to
the pathogenesis of non-infectious respiratory diseases remains to
be determined, and interventions to treat or prevent both
infectious and non-infectious respiratory diseases in people living
with HIV could have an impact on health-related outcomes.
Statistical analysis: MG GB SW AM. Conceived and designed the
experiments: MG LK AM. Analyzed the data: MG GB LK CR CA RD
RG NH SH LH EK JP SS ES JM SW AM. Contributed reagents/
materials/analysis tools: GB LK CR RD RG NH SH LH JP SS JM SW.
Wrote the paper: MG AM.
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