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.
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.
Table of Contents
Abstract 2
Thesis Committee 6
Preface 7
Table of Contents 8
List of Tables 9
List of Figures 10
Chapter 1:
Introduction 11
HIV: Early Reports and Outcomes of a New Infectious Disease 12
Antiretroviral Therapy and the Hope for Survival 13
The Growing Importance of Hepatitis Co-Infection among Persons Living with HIV 16
Failures of Healthcare in the United States for Persons Living with HIV 18
Changes in Healthcare in the United States for Persons Living with HIV 21
Costs of Healthcare among Persons Living with HIV 23
Elite Control and the Promise of HIV Remission 26
Specific Aims 28
References 32
Chapter 2:
Impact of Hepatitis Co-Infection on Hospitalization Rates and Causes in a Multi-Center Cohort of Persons Living with HIV 45
Abstract 46
Background 48
Methods 49
Results 53
Discussion 56
Acknowledgments 60
References 62
Chapter 3:
Impact of Hepatitis Co-Infection on Healthcare Utilization among Persons Living with HIV 74
Abstract 75
Introduction 76
Methods 76
Results 79
Discussion 82
Acknowledgments 85
References 87
Chapter 4:
Hospitalization Rates and Reasons among HIV Elite Controllers and Persons With Medically Controlled HIV Infection 101
Abstract 103
Background 104
Methods 104
Results 109
Discussion 112
Acknowledgments 118
References 120
Chapter 5:
Conclusion 134
References 143
Curriculum Vitae 147
List of Figures
Chapter 1:
Introduction
HIV: Early Reports and Outcomes of a New Infectious Disease
On June 4, 1981, a report of five unusual cases of Pneumocystic pneumonia in previously healthy homosexual men in Los Angeles became the first description of what would later be called acquired immune deficiency syndrome (AIDS).1 Soon thereafter, similar cases were described among homosexual men in New York and other cities, injection drug users, Haitian immigrants and hemophiliacs.2-7 By 1983, scientists identified the causative agent of AIDS, a retrovirus that would eventually be named the human immunodeficiency virus (HIV).8 From these first few clusters of cases, the disease spread quickly. By the beginning of 1985, studies demonstrated HIV seroprevalence rates of 35%-65% among homosexual men in the United States,9-11 87% among injection drug users presenting for rehabilitation in New York City,12 and 56% among persons with hemophilia A presenting for antihemophilic factor concentrates.13 HIV/AIDS quickly emerged as one of the most significant infectious diseases in the United States and worldwide.
In addition to being notable for its rapid spread, particularly within specific populations, HIV/AIDS was also immediately remarkable for its morbidity and mortality. In addition to Pneumocystic pneumonia, clinical manifestations recognized among those first cases of HIV/AIDS included Kaposi sarcoma, non-Hodgkin lymphoma, oral and esophageal Candidiasis, central nervous system Toxoplasmosis, progressive herpes simplex virus, chronic enteric coccidiosis, and other opportunistic infections.5-7,14 The disease was almost uniformly fatal, with five-year mortality rates of 85% or more in various early reports.15-17 The disease had no specific treatment and no cure.
Antiretroviral Therapy and the Hope for Survival
On March 19, 1987, the U.S. Food and Drug Administration (FDA) approved the first antiretroviral drug, zidovudine (AZT).18 By inhibiting the viral reverse transcriptase, AZT halts viral replication and prevents infection of new cells.19,20 Studies showed that therapy with AZT caused a rapid decline in HIV viral load in the peripheral blood, as well as weight gain, improved cognition, immune reconstitution and substantial reductions in mortality.21-24 However, optimism about this new drug was tempered by the sometimes severe side effects that could include rash, nausea, headache, and, most importantly, dose-limiting bone marrow suppression.24-27 It also quickly became apparent that the benefits of AZT monotherapy were short-lived. Within 6-12 months of starting therapy, peripheral viral loads rebounded, CD4 counts returned to pre-treatment levels, and clinical evidence of immune reconstitution reversed.23,28-30 The rapid development of genotypic drug resistance severely limited the long-term efficacy of AZT and other early antiretroviral monotherapies.31-35 Once resistance developed, it was irreversible.36-40
The solution to the problem of drug resistance came with combination antiretroviral therapies. By combining drugs with different mechanisms of action, viral replication could be suppressed below the levels achieved with monotherapy alone.41-43 With less viral replication there was less viral evolution and, therefore, less development of drug-resistant variants.42 Multidrug regimens slowed disease progression and prolonged life.43-46 Three-drug therapy, generally consisting of drugs from at least two different classes and termed highly active antiretroviral therapy (HAART), reduced HIV-1 replication, increased CD4 cell counts, and decreased serum inflammatory markers more than prior one- and two-drug regimens.45,46 More importantly, these improvements appeared to persist indefinitely. When HAART became widely available in the United States in 1996, potent and lasting control of HIV became a realistic possibility for over 200,000 Americans living with HIV; this came too late for the 343,000 Americans who had already died of the disease.47
The impact of HAART on the HIV epidemic was swift and dramatic. In 1995, there were 49,985 deaths among persons with AIDS. In 1997, this number fell by over 56% to 21,909 deaths.48 In 1995, HIV was the leading cause of death among people 25 to 44 years old in the United States; In 1997, it was the fifth leading cause of death.49 Age-adjusted death rates directly attributable to HIV dropped 47.7% from 1996 to 1997 alone.49 In the HIV Outpatient Study (HOPS) cohort of clinics specializing in HIV care, mortality declined from 29.4 deaths per 100 person-years in the first quarter of 1995 to 8.8 deaths per 100 person-years in the second quarter of 1997.50 In 1994, the combined incidence of Pneumocystic pneumonia, Mycobacterium avium complex disease and cytomegalovirus retinitis in this cohort was 21.9 per 100 person-years, and by mid-1997 it was only 3.7 per 100 person-years.50
With effective therapy for HIV finally a reality, focus shifted to the development of antiretroviral drugs that were easier to use and had fewer side effects. In 1996, HAART regimens consisted of three drugs given 2-3 times per day.45,46 Side effects included moderate-to-severe fatigue, nausea, diarrhea, kidney stones, liver function abnormalities and bone marrow toxicities.45,46 With prolonged use, patients began to present with abnormal redistribution of body fat, elevated cholesterol, insulin resistance and elevated rates of cardiovascular disease.51-54 The drugs were so difficult to take and tolerate that after 8 months of use, only 60% of patients reported complete adherence to their regimen.55 Prolonged treatment interruptions, or “drug holidays,” were investigated in a number of studies that documented swift viral rebound upon HAART cessation.56-58 Shorter treatment interruptions, such as alternating weeks on and off therapy, also failed to continuously suppress viremia.59 Researchers also tried interruptions tied to CD4 counts, with therapy held at high CD4 counts and resumed when CD4 dropped below a certain threshold. This strategy demonstrated reasonable short-term safety with high CD4 thresholds for resumption of therapy and close monitoring, but increased risk of severe complications of HIV and death with lower CD4 thresholds and longer follow-up intervals.60-62 Ultimately, it became clear that continuous and lifelong therapy was the only realistic option for keeping the virus safely at bay.
Fortunately, in the nearly two decades since HAART became widely available in the United States, incredible advances have been made in antiretroviral drug development. In 1996, nine medications were FDA-approved for the treatment of HIV. In 2014, there are 33 FDA-approved medications for the treatment of HIV, including four multidrug one-pill-once-a-day regimens.63 Single tablet regimens in use today are more potent and have fewer side effects than regimens from earlier in the epidemic that contained nine or more pills. The term “highly active antiretroviral therapy” has even been replaced simply by antiretroviral therapy (ART), because essentially all therapies in use today are considered highly active. Concerns about limiting antiretroviral exposure in order to minimize toxicities have gradually been replaced by mandates to start therapy earlier and earlier in the course of infection.64,65
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