Hepatitis C Disease Burden in the United States in the Era of Oral Direct‐Acting Antivirals

51 Pages·2016·1.64 MB·English

Hepatitis C Disease Burden in the United States in the Era of Oral Direct-Acting Antivirals

Jagpreet Chhatwal, PhD,1,,2,3 Xiaojie Wang, MS,4,5 Turgay Ayer, PhD,4 Mina Kabiri, MS,6
Raymond T. Chung, MD,2,3 Chin Hur, MD, MPH,1,2,3 Julie M. Donohue, PhD,6 Mark S. Roberts,
MD, MPP,*6 Fasiha Kanwal, MD, MSHS,*7,8

1 Massachusetts General Hospital Institute for Technology Assessment, Boston, MA
2 Harvard Medical School, Boston, MA
3 Liver Center and Gastrointestinal Division, Massachusetts General Hospital, Boston, MA
4 H. Milton Stewart School of Industrial and Systems Engineering, Georgia Institute of
Technology, Atlanta, GA
5 Department of Industrial and Systems Engineering, University of Florida, Gainesville, FL
6Department of Health Policy and Management, University of Pittsburgh, Pittsburgh, PA
7 Houston Veterans Affairs Health Services Research and Development Center of Excellence,
Michael E. DeBakey Veterans Affairs Medical Center
8 Department of Medicine, Gastroenterology and Hepatology, Baylor College of Medicine,
Houston, TX USA

* Equal contribution

Key words: HCV treatment, HCV screening, Affordable Care Act, liver deaths, simulation
model.

Correspondence: Jagpreet Chhatwal, PhD
MGH ITA
101 Merrimac Street, Floor 10th
Boston, MA 02114
Email: [email protected]
Phone: [phone]

List of abbreviations: HCV, hepatitis C virus; DAA: direct-acting antiviral; AASLD, American
Association for the Study of Liver Diseases; HEP-SIM, Hepatitis C Disease Burden Simulation
model; NHANES, National Health and Nutrition Examination Survey; CDC, Centers for Disease
Control and Prevention.

Financial support: This project was in parts funded by the National Institutes of Health under
award number KL2TR000146, and Gilead Sciences, Inc.

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as
doi: 10.1002/hep.28571

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Abstract
Oral direct-acting antivirals (DAAs) represent a major advance in hepatitis C virus (HCV)
treatment. Along with recent updates in HCV screening policy and expansions in insurance
coverage, the treatment demand in the United States is changing rapidly. Our objective was to
project the characteristics and number of people needing antiviral treatment, and HCV-
associated disease burden in the era of oral DAAs. We used a previously developed and
validated Hepatitis C Disease Burden Simulation model (HEP-SIM). HEP-SIM simulated the
actual clinical management of HCV from 2001 onwards, which included antiviral treatment with
peginterferon-based therapies as well as the recent oral DAAs, risk-based and birth-cohort HCV
screening, and the impact of the Affordable Care Act. We also simulated two hypothetical
scenarios—no treatment and treatment with peginterferon-based therapies only. We estimated
that in 2010, 2.5 (95% CI: 1.9–3.1) million non-institutionalized people were viremic, which
dropped to 1.9 (95% CI: 1.4–2.6) million in 2015, and projected to drop below 1 million by 2020.
A total of 1.8 million HCV patients will receive HCV treatment from the launch of oral DAAs in
2014 until 2030. Based on current HCV management practices, it will take 4–6 years to treat the
majority of patients aware of their disease. However, 560,000 patients would still remain
unaware by 2020. Even in the oral DAA era, 320,000 patients will die, 157,000 will develop
hepatocellular carcinoma, and 203,000 will develop decompensated cirrhosis in the next 35
years. Conclusions: HCV-associated disease burden will still remain substantial in the era of
oral DAAs. Increasing HCV screening and treatment capacity is essential to further decreasing
HCV burden in the United States.
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INTRODUCTION
Chronic infection with hepatitis C virus (HCV) is a major public health problem in the United
States. Chronic hepatitis C is the leading cause of cirrhosis, hepatocellular carcinoma, and
death from liver diseases; it is also the leading indication for liver transplantation in the United
States (1). Between 2 and 4 million people are chronically infected with HCV, with the majority
unaware of their infection (2, 3).

The recent availability of oral direct-acting antivirals (DAAs) has changed the HCV treatment
paradigm. With updates in HCV testing to include one-time screening of persons born between
1945–1965 (4), the number of patients who can be treated successfully with new therapies is
expected to increase; this may substantially reduce the burden of HCV in the United States (5).
Furthermore, changes in insurance coverage as a result of the Affordable Care Act (ACA) can
further extend HCV testing and treatment to several thousand more HCV patients (6).

The American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases
Society of America (IDSA) recently updated their recommendations to emphasize timely
treatment for all HCV infected patients (7) and not just those with advanced fibrosis and
cirrhosis. However, the cost of DAAs has sparked controversy regarding the value and
affordability of HCV treatment in the United States. Several modeling studies have
demonstrated that HCV treatment provides favorable value for cost (8-10); however the funds
needed to treat all eligible persons could be prohibitive because of limited funding and high
prevalence of HCV (8). Therefore, some payers remain cautious about treating all HCV patients
who are aware of their disease (11).

With HCV screening and treatment policies in flux, our understanding of the number of patients
currently needing treatment is also limited. Besides the treatment demand, the number of HCV
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patients who remain undiagnosed in the era of oral DAAs is not precisely known. Recent
evidence also indicates that HCV incidence in increasing in the US (12). Furthermore, we have
a limited understanding of the long-term effects of any antiviral treatment restrictions, such as
prior authorization policies that limit coverage to a particular fibrosis score (11). Therefore, our
objective was to project the number of HCV patients eligible for treatment in the United States in
2015 and beyond, and determine HCV-associated disease burden under various treatment
rates in the era of DAAs.

METHODS
Traditional epidemiological studies may not be suitable to characterize the current dynamic HCV
landscape. Therefore, we used a mathematical disease model to simulate the changing HCV
environment and predict future trends.

Model Overview
We used our previously developed Hepatitis C Disease Burden Simulation model (HEP-SIM),
which has been used to project the changing prevalence of HCV in the United States (5). The
HEP-SIM model simulated the progression of HCV disease from 2001 onwards and closely
replicated the results of the National Health and Nutrition Examination Survey (NHANES) 1999-
2002 and 2003–2009 studies (2, 13). The model’s results have also been validated with reports
from the Centers for Disease Control and Prevention (CDC) (14) and with a large multicenter
follow-up study of patients with advanced fibrosis (15). Below we describe the key components
of HEP-SIM; comprehensive details have been published elsewhere (5).

Patient Demographics
The base-case population in HEP-SIM represented HCV-infected patients in the United States.
We defined the age distributions and sex based on the NHANES data, and defined HCV
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genotype, chronic stage of HCV, and prior antiviral treatment history based on published studies
(Supplementary Tables S1–S3).

Natural History of HCV
The natural history of HCV was defined using METAVIR fibrosis scores (no fibrosis [F0], portal
fibrosis without septa [F1], portal fibrosis with few septa [F2], numerous septa without fibrosis
[F3], or cirrhosis [F4]), decompensated cirrhosis, hepatocellular carcinoma, liver transplantation,
and liver-related death. We used a published meta-analysis to estimate fibrosis progression
from F0 to F4 (Supplementary Table S4) (16). We estimated disease progression in cirrhosis
and decompensated cirrhosis from published observational studies (17, 18). Patients
developing decompensated cirrhosis or hepatocellular carcinoma were eligible to receive a liver
transplant (19-21), and had higher mortality rate (22).

HCV Awareness and Screening
Patients who were unaware of their HCV status could potentially get diagnosed either by
screening or usual care. In 2008, 57.0% for those with insurance and 23.7% without insurance
were aware of their HCV status (23). In addition, awareness status was dependent on person’s
insurance status as well as age (Supplementary Table S5).

Our model simulated the actual clinical practice of HCV management from 2001 onwards. We
implemented risk-based screening until 2013 and added one-time birth-cohort screening of
people born between 1945 and 1965 starting in 2013, reflecting changes in CDC’s guidelines on
HCV screening. In the model, 90% of the patients covered by healthcare insurance and 10% of
those who were uninsured were offered HCV testing (24) (Supplementary Table S6). Based on
the assumptions made by the CDC’s study to evaluate birth-cohort HCV screening, we
assumed that among those who were offered testing, 91% would accept it, and 90% of those
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who tested positive would receive those results (25). We assigned the uptake of screening such
that the majority of these patients would receive screening gradually during the 7 years
beginning in 2013. In addition to birth-cohort screening, we implemented HCV diagnosis through
usual care, which also included risk-based screening. We estimated the probability of getting
diagnosed with HCV by patient’s age and insurance status (Supplementary Table S7).

HCV Treatment
We modeled antiviral treatment in different phases reflecting clinical practice starting with
peginterferon-ribavirin until 2011, followed by the launch of first-generation protease inhibitors in
May 2011, sofosbuvir and simeprevir in 2014, and finally all-oral DAA combinations in 2015. We
differentiated treatment regimens by treatment-naïve and -experienced, interferon tolerance
status, and presence of cirrhosis, as described in our previous study (5). Though most clinical
trials of oral DAAs reported sustained virologic response rates as high as 95%, we used a
conservative estimate of 90% to account for any potential differences in real world setting (26).
We gave treatment priority to patients in F3 and F4 stages, if the number of patients needing
treatment exceeded the annual treatment penetration rate. We further assumed that patients
who failed to achieve sustained virologic response could get retreated up to 3 more times.

Health Insurance and Affordable Care Act
We updated our HEP-SIM model to assign insurance status to each individual based on
NHANES data (23, 27). We assumed that all patients age 65 and above were covered by
Medicare, and 90% of them had drug coverage through Medicare Part D or some other sources
(28). Among non-Medicare patients, we estimated the percentage of patients who have private,
Medicaid and other public insurance, and uninsured as 49.8%, 9.2%, 14.3%, and 26.7%,
respectively (Supplementary Table S8).

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We also incorporated changes in the insurance pool because of the implementation of the
Affordable Care Act using a report by the Congressional Budget Office and the staff of the Joint
Committee on Taxation (29). We estimated that compared to 2013, 22.2% uninsured patients
obtained access to insurance in 2014, and this rate would further increase to 35.2% in 2015,
46.3% in 2016 and 48.1% in 2015 because of the implementation two sources of coverage: new
insurance marketplaces with subsidized coverage and the Medicaid expansion (30)
(Supplementary Table S9). Because of the lack of data on particular effect of the Affordable
Care Act on HCV-infected population, we assumed that insurance status of HCV patients was
affected proportional to the overall changes for the US population.

Treatment Prioritization and Uptake Rate
In the base case, we assigned priority to F3 and F4 patients for HCV treatment as observed in
2014, after oral DAAs became available. However, we assumed that F0–F2 patients would get
treatment if the total number of candidates needing treatment was below the annual treatment
capacity. Because it is difficult to quantify the absolute treatment capacity, we estimated the
annual number of patients treated using historic data until 2013 and drug sales afterwards as a
surrogate for the maximum number of patients that could be treated in a given year. In 2014,
approximately 150,000 patients initiated DAA treatment (31). In 2015, we anticipate that
approximately 280,000 initiated treatment based on reported drug sales (32). We assumed that
from 2015 onwards, the maximum annual treatment penetration would stay at 280,000
(Supplementary Table S10). However, we performed additional analysis using differing annual
treatment rates.

Model Outcomes and Sensitivity Analysis
We projected the changing HCV disease burden in the US over time in the era of DAAs
(Supplementary Table S11). Model accounted for key steps in the HCV care cascade.
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Outcomes included the number of viremic patients, number of people aware of their infection,
number of people with access to antiviral treatment, number of people who receive antiviral
treatment, those who achieved SVR, and HCV-associated disease burden in the era of DAAs.
In order to estimate confidence in model outcomes, we conducted a probabilistic sensitivity
analysis by simultaneously considering uncertainty in all key model inputs. We defined
uncertainty in input parameters using the recommended statistical distributions (Supplementary
Appendix 1).

Model Validation
We validated our model’s outcomes with published studies including the predicted average
prevalence with NHANES 2003-2010 (2), liver-related deaths, and HCC incidence with
published studies (21, 33) (Supplementary Table S12). We also cross-validated the natural
history of HEP-SIM model by comparing the 10-year cumulative incidence of decompensated
cirrhosis, HCC, and liver-related deaths for cirrhosis patients who achieved/failed SVR with a
long-term follow-up study (15) (Supplementary Table S13).

RESULTS
HCV Prevalence
The number of viremic patients in the United States is projected to decrease over time. We
estimated that in 2010, 2.5 (95% CI: 1.9–3.1) million non-institutionalized people were viremic,
which dropped to 1.9 (95% CI: 1.4–2.6) million in 2015 (Figure 1). We further projected that the
number of viremic patients will drop below 1.0 (95% CI: 0.8–1.3) million by 2020, and below 0.6
(95% CI: 0.5–0.8) million by 2030.

The insurance status of HCV population is changing over time. In 2015, 38% (95% CI: 33–44%)
of the viremic people were covered by private insurance, 24% (95% CI: 22–25%) by Medicare,
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13% (95% CI: 9–17%) by Medicaid, 6% (95% CI: 3–10%) by other public insurance, and 19%
(95% CI: 15–26%) did not have any insurance (Supplementary Figure S1). Because of aging of
HCV population, the proportion of patients enrolled in Medicare increased from 18% (95% CI:
17–19%) in 2010 to 24% (95% CI: 22–25%) in 2015. Because of the implementation of the
Affordable Care Act, the proportion of uninsured HCV patients decreased from 26% (95% CI:
20–34%) in 2010 to 19% (95% CI: 15–26%) in 2015. However, patients without insurance would
have low access to treatment, and as a consequence, the number of viremic patients would be
highest in uninsured population by 2019.

We also projected that in 2015, 932,000 (95% CI: 852,000–1,256,000) of the 1.9 million viremic
people were unaware of their disease status (Figure 2). The percentage of unaware patients in
2015 was 48% (95% CI: 46%–63%) of the total viremic patients in that year. By 2020, 597,000
(95% CI: 542,000–891,000) of the 834,000 viremic people would be unaware of their disease.
The percentage of unaware patients in 2020 would be 71% (95% CI: 63–77%) of the viremic
patients in that year, which would increase primarily because most patients aware of their
infection would have been successfully treated.

HCV Treatment Demand and Uptake
We estimated that a total of 1.85 million (95% CI: 1.30–2.32 million) HCV patients would receive
HCV treatment from the launch of oral DAAs in 2014 until 2030. In 2015, 923,000 HCV patients
were candidates for treatment (i.e., aware of their disease and had insurance), and among them
42% had either advanced fibrosis or cirrhosis. We projected that the number of such patients
would continue to decline as more people undergo successful treatment with oral DAAs (Figure
3A). At the current treatment rate of 280,000 per year, the demand for treatment (i.e., number of
patients aware of their infection and have health insurance) is projected to decrease below the
treatment capacity in 2019, suggesting that all diagnosed patients who have health insurance
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and seek care in a given year can be treated in that year irrespective of their fibrosis score.
However, until then, some form of treatment prioritization would be needed. By 2020, we
estimate that the number of HCV patients who are aware of their disease and have access to
insurance will decline below 55,000, i.e. a 70% drop from the previous year, and in 2030, it will
decrease below 30,000.

If the annual treatment uptake rate were to remain at 2014 levels (i.e., 150,000 per year), some
form of treatment prioritization would be needed until 2022 (Figure 3B). Under this scenario, it
would take 10 years to treat most of the HCV-infected patients. In contrast, if the treatment
uptake in 2015 and beyond was increased to 500,000 per year, treatment prioritization would be
needed only until 2016 (Figure 3C). Under this scenario, it would take 4 years to treat most of
the HCV-infected patients who are aware of their disease.

HCV Disease Burden
We projected the future HCV-associated disease burden in the era of oral DAAs and compared
it with that under two alternate scenarios—treatment with peginterferon-ribavirin, i.e. pre-DAA
era therapies, and no treatment. In the DAA era, the HCV-associated advanced outcomes are
expected to decrease from 2015 onwards (Figures 4A–D). In contrast, the disease burden
would have continued to increase under both pre-DAA and no-treatment scenarios before
starting to decline in 2020 and 2025, respectively.

We estimated that the cumulative number of HCV-associated deaths when treated with oral
DAAs, peginterferon-ribavirin, and no-treatment from 2015 to 2050 were 320,000 (95% CI:
126,000–549,000), 587,000 (95% CI: 229,000–828,000), and 776,000 (95% CI: 264,000–
1,122,000), respectively. The corresponding cumulative incidence of hepatocellular carcinoma
was 157,000 (95% CI: 57,000–302,000), 305,000 (95% CI: 90,000–645,000), and 415,000
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