Table Of ContentHEALTHCARE UTILIZATION AMONG PERSONS LIVING WITH HIV
WITH ATTENTION TO THE INFLUENCES OF HEPATITIS
CO-INFECTION AND ELITE CONTROL
by
Trevor Adam Crowell, M.D.
A dissertation submitted to Johns Hopkins University in conformity with the
requirements for the degree of Doctor of Philosophy
Baltimore, Maryland
January, 2015
© 2015 Trevor A. Crowell
All Rights Reserved
ABSTRACT
HIV infection has evolved from a consistently fatal diagnosis into a chronic
condition that requires lifelong medication and care. These do not come cheaply. In 2015,
the United States government is expected to spend $17.5 billion on health care services
and treatment for persons living with HIV (PLWH). PLWH are living longer than they
were earlier in the epidemic and beginning to experience age-related complications of
comorbidities, such as viral hepatitis. Chronic co-infection with hepatitis B virus and/or
hepatitis C virus is common among PLWH and plays an increasingly important role in
the morbidity and mortality observed in this population. Understanding its impact on
healthcare utilization can help to inform the allocation of limited healthcare resources,
improve the cost-effectiveness of HIV care, and guide clinical decision-making.
Understanding factors associated with healthcare utilization and costs has become
especially important as the Patient Protection and Affordable Care Act (ACA) is poised
to dramatically alter the way healthcare is delivered in the United States. Optimism about
improved access to care as a result of the ACA is mirrored by newfound optimism about
the possibility of someday developing interventions to achieve a functional cure of HIV,
or HIV remission. Elite controllers are a unique and rare subset of PLWH that
demonstrate spontaneous virologic control without a need for antiretroviral therapy
(ART). In these patients, investigation of healthcare utilization provides insight into the
clinical outcomes of elite control that may then inform not only our understanding of
costs of care associated with elite control, but also the wisdom of trying to induce a state
similar to elite control as a means of achieving HIV remission.
ii
The research presented here explores healthcare utilization among PLWH with
particular emphasis on the influences of hepatitis co-infection and elite control. This
research uses data collected by the HIV Research Network (HIVRN), a consortium of
specialty HIV care clinics in 11 cities across the United States.
The first study investigates the potential role of hepatitis co-infection as a risk
factor for hospitalization among adult patients receiving longitudinal HIV care at nine
clinical care sites. In 2010, a total of 2,793 hospitalizations were observed among 12,819
patients. In this study, PLWH who were co-infected with hepatitis B and/or hepatitis C
had hospitalization rates that were about 50% higher than those seen among persons with
HIV mono-infection, after adjusting for factors such as age, CD4 count and HIV viral
load. Hospitalization rates for non-AIDS-defining infections were almost twice as high
among PLWH with any hepatitis co-infection as compared to those with HIV mono-
infection. Hepatitis B co-infection was associated with more hospitalizations for
gastrointestinal/liver disease and hepatitis C co-infection was associated with more
hospitalizations for psychiatric illnesses. Since hospitalization is a particularly costly
form of healthcare utilization, it is important to identify interventions that may attenuate
the risk of hospitalization among PLWH with hepatitis co-infection. Policy-makers and
third-party payors should be aware of the higher hospitalization rates associated with
hepatitis co-infection when allocating healthcare resources and considering models of
healthcare delivery.
The second study investigates the associations between hepatitis co-infection and
utilization of primary HIV care, mental health, and hospital services at four sites from
2006-2011. Outpatient HIV visits did not differ by hepatitis serostatus and decreased over
iii
time, likely reflecting evolving professional society guidelines that recommend less
frequent monitoring for patients with well-controlled HIV. Mental health visits were
more common among HIV/HCV co-infected persons than among HIV mono-infected
persons, emphasizing the important role of psychiatric disease in this population. As
observed in the first study, hospitalization rates were higher among all hepatitis-infected
groups than in the HIV mono-infected group. Importantly, this observation has not
changed over time. With safer, more effective therapies for hepatitis C becoming
available, it will be important to determine whether use of these therapies decreases
hospitalization risk. If so, this may provide an important counterbalance to the high cost
of these medications. Again, these observations can critically inform the decisions of
policy-makers and third-party payors in the setting of an evolving United States
healthcare system.
The third study investigates hospitalization rates among elite controllers as
compared to persons with medically controlled HIV at 11 sites from 2005-2011. With
149 elite controllers, the data from this study represent one of the largest published
cohorts. After adjustment for demographic and clinical factors, elite control was
associated with higher rates of all-cause (adjusted incidence rate ratio 1.77 [95% CI 1.21-
2.60]), cardiovascular (3.19 [1.50-6.79]) and psychiatric (3.98 [1.54-10.28])
hospitalization than was medical control. Hospitalizations for cardiovascular disease were
disproportionately common among elite controllers. These findings represent some of the
first data on clinical outcomes in this population and are consistent with prior studies
demonstrating high rates of inflammation and a high burden of apparent cardiovascular
disease on radiographic screening. Care providers may consider these findings when
iv
deciding whether or not to initiate ART in patients with elite control. These data also
suggest that elite control may not be an ideal model for the functional cure of HIV, since
patients treated with ART appear to have better outcomes in terms of hospitalization
These studies have each been published in medical journals and are reprinted here
with permission. They provide insights that can guide the clinical care of PLWH who are
co-infected with hepatitis or who demonstrate elite control. They also improve our
understanding of factors related to healthcare utilization and, therefore, costs of HIV care.
At a time when access to care is expanding, it is essential to understand and manage costs
of care. At a time when functional cure of HIV has become a realistic goal, it is essential
to understand precisely the goal we wish to achieve.
v
THESIS COMMITTEE
Research Mentor
Kelly A. Gebo, M.D., M.P.H.
Academic Advisor
David Newman-Toker, M.D., Ph.D.
Readers
Stephen J. Gange, Ph.D. (Thesis Committee Chair)
Marie Diener-West, Ph.D.
vi
PREFACE
This dissertation is the culmination of my work as both a graduate student and a
fellow in infectious diseases at Johns Hopkins University. I am tremendously grateful to
the people who made this exceptional combination of educational experiences possible.
As my research mentor, Kelly Gebo provided me with outstanding opportunities to apply
my analytic skills to projects that complemented my coursework. She provided feedback
and guidance that has doubtlessly made me a better investigator. Stephen Berry provided
me with my first glimpses at the code used to conduct statistical analyses and followed
that with detailed and insightful guidance as I developed my own analyses. His editorial
comments on my manuscripts have made me a much better scientific writer. Throughout
my training and research, I have benefitted from the wisdom of colleagues and teachers
including Stuart Ray, Khalil Ghanem, Yuka Manabe, Joel Blankson, Joel Gallant,
Stephen Gange, David Newman-Toker, Jonathan Zenilman and countless others.
My participation in the Graduate Training Program in Clinical Investigation was
made possible through funding mechanisms that remain mysterious to me. I know that I
am forever grateful to Charlie Flexner and Franklin Adkinson for giving me this
opportunity. Through this program, I have developed a skill set that enables me to
conduct exciting and rewarding work. The program connected me to a wonderful
network of classmates who have provided essential intellectual and emotional support.
For such support, I am particularly indebted to Emily McGowan and Allison Lambert.
I dedicate this work to Thea, who nurtured my intellectual curiosity and always
believed I could do great things.
vii
TABLE OF CONTENTS
Abstract ................................................................................................................................. ii
Thesis Committee .................................................................................................................. vi
Preface................................................................................................................................. vii
Table of Contents ................................................................................................................ viii
List of Tables .........................................................................................................................x
List of Figures ....................................................................................................................... xi
Chapter 1: Introduction ..........................................................................................................1
HIV: Early Reports and Outcomes of a New Infectious Disease .............................................2
Antiretroviral Therapy and the Hope for Survival..................................................................3
The Growing Importance of Hepatitis Co-Infection among Persons Living with HIV ..............6
Failures of Healthcare in the United States for Persons Living with HIV ................................8
Changes in Healthcare in the United States for Persons Living with HIV .............................. 11
Costs of Healthcare among Persons Living with HIV .......................................................... 13
Elite Control and the Promise of HIV Remission ................................................................ 16
Specific Aims ................................................................................................................... 18
References........................................................................................................................ 22
Chapter 2: Impact of Hepatitis Co-Infection on Hospitalization Rates and Causes in a Multi-
Center Cohort of Persons Living with HIV ............................................................................. 35
Abstract ........................................................................................................................... 36
Background ...................................................................................................................... 38
Methods ........................................................................................................................... 39
Results ............................................................................................................................. 43
Discussion ........................................................................................................................ 46
Acknowledgments ............................................................................................................ 50
References........................................................................................................................ 52
Chapter 3: Impact of Hepatitis Co-Infection on Healthcare Utilization among Persons Living
with HIV.............................................................................................................................. 63
Abstract ........................................................................................................................... 64
Introduction...................................................................................................................... 65
Methods ........................................................................................................................... 65
Results ............................................................................................................................. 68
viii
Discussion ........................................................................................................................ 71
Acknowledgments ............................................................................................................ 74
References........................................................................................................................ 76
Chapter 4: Hospitalization Rates and Reasons among HIV Elite Controllers and Persons With
Medically Controlled HIV Infection....................................................................................... 87
Abstract ........................................................................................................................... 88
Background ...................................................................................................................... 89
Methods ........................................................................................................................... 89
Results ............................................................................................................................. 94
Discussion ........................................................................................................................ 97
Acknowledgments .......................................................................................................... 103
References...................................................................................................................... 105
Chapter 5: Conclusion........................................................................................................ 118
References...................................................................................................................... 127
Curriculum Vitae ................................................................................................................ 131
ix
LIST OF TABLES
Table 2-1: Study Population Characteristics Stratified by Hepatitis Serostatus ............... 55
Table 2-2: Univariate and Multivariate Analyses of Risk Factors for All-Cause
Hospitalization .................................................................................................................. 57
Table 2-3: Most Common Individual Diagnoses Within Diagnostic Categories ............. 59
Table 3-1: Population Demographic and Clinical Characteristics at Study Entry............ 79
Table 3-2: Multivariable Analysis of Risk Factors for Healthcare Utilization................. 81
Table 3-3: Healthcare Utilization Rates by Hepatitis Serostatus. ..................................... 83
Table 4-1: Demographic and Clinical Characteristics at Study Entry by HIV Control
Status ............................................................................................................................... 109
Table 4-2: Univariable and Multivariable Analyses of Factors Associated with All-Cause
Hospitalization ................................................................................................................ 112
Table 4-3: Hospitalizations by Diagnostic Category at Nine Sites with ICD-9 Data..... 114
Table 4-4: Multivariable Analyses of Factors Associated with Cause-Specific
Hospitalization at Nine Sites with ICD-9 Data ............................................................... 115
x
