| Hi M., it's Andrea from Lloyd Wright's office.
I'm sorry I had to hang up on Friday - I usually wouldn't
but I had to chase down the FedEx guy to give him a package
we forgot to give him when he was here... Anyway, I have attached
some of the information we talked about:
1. The fibrotest attachment described an
alternative to a biopsy for finding out the condition of your
liver. It is a simple blood test and provides almost the same
info, I understand. Maybe you could ask your GI doctor if
he/she would be satisfied with this test. I'm not sure if
all labs have it and I'm not sure if your insurance will cover
it.
2. The California Naturopath Doctors is a
list of doctors who belong to the International College of
Integrative Medicine. I didn't see Modesto but maybe Sacramento
or another city is close enough? We don't know anything about
these doctors except that they are MDs (most of them) who
belong to this College which implies that they are atleast
open to alternative medicines.
3. The JAMA article is one that we think
admits that the combo therapy (PegIntron + Ribavirin) is not
as viable of an option than once thought, especially when
you consider its cost, side effects, and the fact that the
prognosis for people with Hepatitis C is not as bad as we
once thought. I like this article cause it is very credible
- written by atleast one MD and printed in the Journal of
American Medical Association.
4. Finally, the article I promised you on
PegIntron is too big to attach. Remember I was telling you
it is Schering Plough's (the manufacturer of PegIntron) own
study on the drug, submitted to the CBER (part of FDA) for
its approval? When you read this it's pretty scary that the
CBER approved it. Anyway, to read it go
here. (this is Lloyd's comments on the study) the link
at the bottom that says "PegIntron Biologic License Application"
(this is the actual study). It is really long but Lloyd has
indicated in his comments what pages are of particular interest.
Whew! Please call our office for anything we can help you
with (866)437-2373
Hope to talk to you soon! Andrea
Hi Andrea, thanks for the list of doctors, I've e-mailed
one so far, there is acouple more, not in my area, but not
to far that I can't travel it easily enough. Also thanks for
the info on the alternative, ( Fibrotest), for biopsy, when
I find out where it is practiced I'll let you know.
Got word today from my friend in Virginia, his wife e-mailed
me, said his latest tests revealed not only lower viral loads,
but the lowest alt and ast ever, they are thrilled. She said,
now she gets to send the results to their Hepatologist, who
told them, about your program," watch out there are alot
of scams," Vicki said, she is going to reply with,"
yeah!, and interferon is the biggest of them all. She should
write him a prescription for your book, haha.
Andrea, can you please recommend which one of Lloyds diets/programs
would be best fitted for my needs? I see the doctor next on
2/22, and would like to excelerate to more items, thanks.
M.
Cost-effectiveness of Treatment
for Chronic Hepatitis C Infection
in an Evolving Patient Population
ABSTRACT
Context Approximately 2.7 million US individuals are chronically
infected with the hepatitis C virus (HCV). As public health
campaigns are pursued, a growing number of treatment candidates
are likely to have minimal evidence of liver damage.
Objective To examine the clinical benefits and cost-effectiveness
of newer treatments for chronic hepatitis C infection in a
population of asymptomatic, HCV sero-positive but otherwise
healthy individuals.
Design and Setting Cost-effectiveness analysis using a Markov
model of the natural history of HCV infection and impact of
treatment. We used an epidemiologic model to derive a range
of natural history parameters that were empirically calibrated
to provide a good fit to observed data on both prevalence
of HCV seropositivity and time trends in outcomes related
to HCV infection.
Patients Cohorts of 40-year-old men and women with elevated
levels of alanine aminotransferase, positive results on quantitative
HCV RNA assays and serologic tests for antibody to HCV, and
no histological evidence of fibrosis on liver biopsy.
Interventions Monotherapy with standard or pegylated interferon
alfa-2b; combination therapy with standard or pegylated interferon
plus ribavirin.
Main Outcome Measures Lifetime costs, life expectancy, quality-adjusted
life-years (QALYs), and incremental cost-effectiveness ratios.
Results The probability of patients with chronic HCV developing
cirrhosis over a 30-year period ranged from 13% to 46% for
men and from 1% to 29% for women. The incremental cost-effectiveness
of combination therapy with pegylated interferon for men ranged
from $26 000 to $64 000 per QALY for genotype 1 and from $10
000 to $28 000 per QALY for other genotypes; and for women
ranged from $32 000 to $90 000 for genotype 1 and from $12
000 to $42 000 for other genotypes. Because the benefits of
treatment were realized largely in the form of improvements
in health-related quality of life, rather than prolonged survivorship,
cost-effectiveness ratios expressed as dollars per year of
life were substantially higher. Results were most sensitive
to assumptions about the gains and decrements in health-related
quality of life associated with treatment.
Conclusions While newer treatment options for hepatitis C
appear to be reasonably cost-effective on average, these results
vary widely across different patient subgroups and depend
critically on quality-of-life assumptions. As the pool of
persons eligible for treatment for HCV infection expands to
the more general population, it will be imperative for patients
and their physicians to consider these assumptions in making
individual-level treatment decisions.
In the United States, an estimated 2.7 million individuals
are chronically infected with the hepatitis C virus (HCV)1
and are at risk for long-term sequelae, such as cirrhosis,
decompensated liver disease, and hepatocellular carcinoma
(HCC).2 Recently, rising interest in HCV infection from patient
advocacy groups, public health advisory groups, the lay press,
and affected individuals has been accompanied by a range of
policy initiatives, such as a government lookback campaign
launched in 1998 to notify people who had received blood from
potentially infected donors and an open letter from the surgeon
general in July 2000 warning the public about the "silent
epidemic" and encouraging at-risk individuals to get
tested.3-5
Individual clinical decisions about treatment for HCV infection
are complicated by inconsistent progression,6-7 the lack of
reliable prognostic information at the patient level,8 and
the costs and adverse effects of therapy for HCV infection.9-11
Consensus guidelines for the management of hepatitis C remain
ambivalent regarding the treatment of patients with persistent
elevated levels of alanine aminotransferase but with no histological
evidence of fibrosis.12 Asymptomatic patients who are HCV
seropositive, but who are otherwise healthy, are likely to
represent a growing segment of treatment candidates. Because
this population also may be least likely to develop severe
sequelae from HCV infection, it is worthwhile to consider
the costs, benefits, and cost-effectiveness of HCV therapy
in this expanded pool of patients.
In a prior study, we developed a simulation model of the
natural history of HCV infection that was used to estimate
the rates of fibrosis progression in the population seropositive
for HCV consistent with both clinical studies reported in
the literature and observed epidemiologic data on the prevalence
of HCV infection seroprevalence and mortality from primary
liver cancer.13 A key finding from that study was that progression
rates in this general population not only were lower and more
uncertain than previously assumed, but also were heterogeneous
in ways that were not explained by factors such as age and
sex. Incorporating this heterogeneity in decision analytic
models may have important implications for treatment decisions
in an evolving patient population. A model that accounts for
between-patient variability and uncertainty offers the opportunity
to build on the findings of previous decision analytic studies14-30
as the decision context changes. Our objective in this study
was to use this empirically calibrated natural history model
to examine the cost-effectiveness of the latest available
treatments for HCV infection in patients with the mildest
histological form of chronic hepatitis C.
Analytic Overview
We developed a Markov model to simulate disease progression
in treated and untreated cohorts of individuals who were seropositive
for HCV to estimate the life expectancy, quality-adjusted
life expectancy, and total lifetime costs associated with
different treatment strategies for patients with chronic hepatitis
C infection. Natural history parameter values in the model
were derived from our previous empirical calibration study.13
The target population in the analysis was a cohort of 40-year-old
patients (stratified by sex) with elevated levels of alanine
aminotransferase, positive results on quantitative HCV RNA
assays and serologic tests for antibody to HCV, and no histological
evidence of fibrosis on liver biopsy. The analyses were stratified
by genotype to allow for substantial variation in response
rates to treatment. Strategies for HCV infection included
(1) no treatment; (2) monotherapy with interferon alfa-2b;
(3) monotherapy with pegylated interferon alfa-2b; (4) combination
therapy with interferon and ribavirin; and (5) combination
therapy with pegylated interferon and ribavirin. To be consistent
with current guidelines,12 we assumed that (1) monotherapy
was administered for 48 weeks; (2) combination therapy was
administered for 48 weeks in patients with HCV genotype 1
and 24 weeks in patients with all other HCV genotypes; and
(3) treatment was discontinued in patients with detectable
HCV RNA levels after either 12 weeks of receiving monotherapy
or 24 weeks of receiving combination therapy.
Following the recommendations of the US Panel on Cost-Effectiveness
in Health and Medicine,31 we adopted a societal perspective
(although we excluded patient-time costs) and discounted all
costs and clinical consequences at a rate of 3% per year.
The comparative efficiencies of alternative treatment strategies
were measured by the incremental cost-effectiveness ratio,
defined as the additional cost of a specific treatment strategy,
divided by its additional health benefit, expressed as quality-adjusted
life-years (QALYs) gained. The incremental ratio for a strategy
was computed in reference to the next most effective option
after eliminating strategies that were dominated (ie, more
costly and less effective than other options) and strategies
ruled out by extended (weak) dominance (ie, strategies having
higher incremental cost-effectiveness ratios than more effective
options). We accounted for uncertainty around progression
rates by using an array of natural history parameters that
provided a good fit to observed epidemiologic data,13 and
we performed sensitivity analyses on costs, treatment efficacy,
and health-related quality of life.
Data on Progression of HCV Infection
Assessing the natural history of chronic infection with HCV
has been difficult because acute infection is often asymptomatic,
and the duration between infection and development of advanced
stages of liver disease is typically long. Data from retrospective
studies performed at tertiary referral centers2, 32-37 have
described relatively high rates of disease progression to
cirrhosis, but these are subject to referral bias, since these
centers attract individuals with already established chronic
liver disease. Data from prospective studies38-48 have generally
described much lower probabilities of severe liver disease.
Both age and sex have been found to be powerful determinants
of the rate of progression from chronic HCV infection to cirrhosis,
with the lowest rates observed in women infected as young
adults.2, 43, 47, 49-50 Other factors aside from age and sex
may produce unexplained heterogeneity in fibrosis progression.
Alter and Seeff,8 in a synthesis of the available data on
natural history, concluded that 30% to 70% of infected individuals
may never progress to cirrhosis before dying from other causes.
To define the natural history of HCV infection, we first
developed an epidemiologic model of HCV infection in the US
population, which included acquisition of infection, probability
of persistence, and risks of progression to end-stage liver
disease. The entire US population, stratified by age and sex,
was represented in a set of mutually exclusive categories
in the model defined in terms of status of serologic infection
and of clinical liver disease. Early stages of liver disease
were classified using the METAVIR scoring system, which characterizes
the extent of fibrosis that results as damaged liver cells
are repaired, including no fibrosis, portal fibrosis without
septa, portal fibrosis with few septa, and numerous septa
without cirrhosis.51 Advanced stages of liver disease were
defined clinically as compensated cirrhosis, decompensated
cirrhosis, and primary HCC.
We specified plausible ranges for all model parameter values
based on a systematic literature review. Because disease progression
usually occurs over several decades, the most critical parameters
governing the natural history of HCV after acute infection
are the age- and sex-specific rates of fibrosis progression
and, to account for heterogeneity in this progression, an
additional parameter distinguishing a proportion of individuals
as nonprogressors (ie, exempt from risks of developing severe
liver disease). Ranges of rates for fibrosis progression were
extrapolated from intervention trials that included serial
liver biopsy specimen results52-53 and cross-sectional studies
that included the stage of fibrosis as it related to the duration
of infection.49, 54
Numerical simulations of the model were undertaken based
on sampling jointly from all parameter ranges to examine the
different outcomes implied by different sets of parameter
values. For thousands of different sets of sampled parameter
values, examined through a multistage fit procedure, modeled
outcomes were compared with available epidemiologic data on
prevalence of seropositivity of HCV and mortality due to HCC,
and statistical measures of goodness-of-fit were computed.
This procedure led to the identification of a subset of 50
parameter combinations that provided good fits to observed
population trends (Table 1).13 Variation in the parameter
values across this range of empirically calibrated sets reflects
uncertainty with respect to progression from chronic HCV infection,
within the constraints of providing a close match to empirical,
population-based data.
After identifying the array of different plausible parameter
sets using the steps described above, we incorporated these
parameter sets in a separate Markov model that simulated disease
progression in a cohort of individuals with chronic HCV infection,
under a variety of different treatment scenarios. Health states
included histological stages defined in terms of METAVIR scores
and long-term complications defined as compensated cirrhosis,
decompensated cirrhosis (ascites, variceal hemorrhage, and
hepatic encephalopathy), and primary HCC (Figure 1). Transition
probabilities determined the movements of patients through
different health states until all members of the cohort had
died. Each year, patients faced probabilities of fibrosis
progression, complications from cirrhosis, and competing mortality
risks from decompensated cirrhosis, HCC, and other causes
unrelated to HCV infection. Patients with decompensated cirrhosis
could receive an orthotopic liver transplantation.
The structure of the Markov model used in this decision analysis
included a more detailed specification of the complications
of cirrhosis than did the model used for empirical calibration
to build on an existing body of cost-effectiveness work,15,
17, 21-24,26-28 including published data pertaining to the
annual costs of care for specific states of ascites, variceal
hemorrhage, and hepatic encephalopathy.15 Values for the additional
parameters demanded by the more detailed structure were derived
from the empirically calibrated parameters listed in Table
1, combined with other estimates from the literature. Specifically,
rates of progression from compensated cirrhosis to states
of ascites, variceal hemorrhage, and hepatic encephalopathy
were computed by multiplying the overall rate of progression
to decompensated cirrhosis in each empirically calibrated
parameter set by the proportionate frequencies of each complication
reported by other investigators (62% for ascites, 28% for
variceal hemorrhage, and 10% for hepatic encephalopathy).15,
55 Mortality rates for the different decompensated states
were computed for each empirically calibrated parameter set
by multiplying the aggregate mortality rate for decompensated
cirrhosis in each set, relative to the mean value across all
sets, by estimates of state-specific annual mortality rates
from the literature: 11% for ascites15, 56; 40% and 13% for
variceal hemorrhage in the first and subsequent years15, 57;
and 68% and 40% for hepatic encephalopathy in the first and
subsequent years.15, 58
Other Clinical Data
Estimates for treatment efficacy were based on pooled results
of randomized controlled trials (Table 2).9, 59-62 Based on
accumulated evidence of a strong link between virological
and histological end points,52-53,63-68 the principal end
point of interest in most studies has been clearance of HCV
RNA, referred to as a virological response, measured both
at the completion of treatment (end-of-treatment response)
and at 6 months after treatment completion (sustained response).
The following assumptions were made in the base case: (1)
chronic HCV infection may resolve spontaneously or through
successful treatment, in either case implying clearance of
HCV RNA; (2) spontaneous resolution occurs only in individuals
without evidence of fibrosis; (3) patients with sustained
response to treatment do not experience subsequent histological
progression of fibrosis; and (4) patients who do not have
sustained treatment response receive no further treatment.
Our analysis has several challenges relating to the inclusion
of health-related quality of life. First, health-related quality
weights specific to each histological stage of liver disease
are not available. Second, the impact of treatment on health-related
quality of life, especially for patients with mild chronic
HCV infection, is uncertain. Third, the magnitude of short-
and long-term decrements in quality of life associated with
adverse and toxic effects of treatment has not been empirically
quantified. For the base case analysis, we applied previously
published quality weights to each health state (Table 2)17
and made the following assumptions: (1) a sustained virological
response to treatment eliminates all decrements in health-related
quality of life associated with living in the mild chronic
HCV infection state; (2) mild and moderate adverse effects
of treatment reduce quality of life by 2% during the duration
of therapy, as specified in a previous study17; and (3) the
consequences of severe adverse effects of treatment are captured
as a small mortality risk. We evaluated alternative assumptions
in sensitivity analyses.
Cost Data
Annual costs for patients in each of the clinical states
in the model were derived from a published study that included
detailed estimates of resource utilization, including hospitalizations,
outpatient visits, laboratory tests and medications, and interventions
(Table 2).15 Treatment costs were based on mean wholesale
drug costs,69 combined with previously published cost estimates
for clinic visits, laboratory tests, and the treatment of
adverse events.21
The costs of therapy accounted for the discontinuation of
treatment in patients who did not experience a virological
response after receiving 12 weeks of monotherapy or receiving
24 weeks of combination therapy, and also in patients who
experienced moderate-to-severe adverse events.21 The costs
of time spent receiving medical care have not been included
in the model, although they were assumed to be small relative
to the costs of medications and treatment interventions. The
ranges used for cost estimates are consistent with the costs
reported in other studies of treatment for HCV infection16,
18 as well as studies of interventions for more severe states
of liver disease, such as variceal hemorrhage.70-72 In a sensitivity
analysis, we examined ranges spanning from 50% to 150% of
the base case costs.
Base Case
Across the array of empirically calibrated natural history
parameter sets, the probability of patients infected with
HCV developing cirrhosis over a 30-year period ranged from
13% to 46% for men and from 1% to 29% for women, with mean
probabilities of 30% and 9%, respectively. To facilitate comparisons
with previous studies, which have used models that differed
in structure, starting points for the analyses and progression
rates, Figure 2 presents the corresponding 30-year cumulative
probabilities of developing cirrhosis implied by the models
in other decision analyses, derived under the same assumptions
of competing mortality risks as those used in the present
study. For the target population in our study (ie, seropositive
patients with no evidence of fibrosis), our model produces
an overall 30-year probability of cirrhosis that is, on average,
53% to 77% lower than in previous analyses that have targeted
patients with more advanced liver disease. If we considered
a target population starting with more advanced disease, the
30-year probability of cirrhosis projected with our model
would appear similar to those from previous studies, although
the rise over time would begin more slowly (Figure 2D).
The costs, benefits, and incremental cost-effectiveness of
treatment strategies are reported in Table 3 for all genotypes
and both sexes combined, averaged across the different sets
of progression parameters. The incremental costs for each
strategy ranged from $2000 to $4000, with incremental gains
in life expectancy ranging from 1 to 2 months. Interferon
therapy was weakly dominated by pegylated interferon therapy,
and the incremental cost-effectiveness ratios of the combination
strategies were between $24 000 and $35 000 per QALY gained.
The results stratified by sex and genotype showed substantial
differences (Figure 3). The mean quality-adjusted life expectancy
gains per person for the different therapeutic regimens compared
with that for no treatment were considerably higher for patients
with genotypes other than genotype 1 because of higher response
rates, and costs were lower because of shorter treatment durations.
In men, the mean quality-adjusted life expectancy gains per
person for treatment compared with no treatment ranged from
0.6 months (for monotherapy with interferon) to 6.0 months
(for combination therapy with pegylated interferon) for patients
with genotype 1, and from 2.8 months to 11.6 months for patients
with all other genotypes. The comparable quality-adjusted
life expectancy gains in women were smaller (0.3-4.0 months
for genotype 1 and 1.8-7.9 months for all other genotypes),
reflecting lower risks of progression to cirrhosis. The most
effective strategy was combination therapy with pegylated
interferon, which provided an additional 1.7 months of quality-adjusted
life expectancy and cost $36 000 per QALY gained for men with
genotype 1 and an additional 1.8 months of quality-adjusted
life expectancy at a cost of $15 000 per QALY gained for men
with all other genotypes, compared with combination therapy
with standard interferon. The rank order of treatment strategies
was the same in women, but the incremental cost-effectiveness
ratios were approximately 50% higher, irrespective of genotype.
For example, the cost-effectiveness ratios per QALY gained
for women receiving combination therapy with pegylated interferon
vs standard interferon were $55 000 for genotype 1 and $24
000 for all other genotypes.
The mean results for all parameter sets mask important differences
that appear across the array of empirically calibrated parameters.
Among men, combination therapy with pegylated interferon had
incremental cost-effectiveness ratios that ranged from $26
000 to $64 000 per QALY gained for genotype 1 and $10 000
to $28 000 per QALY for all other genotypes. Among women,
the incremental cost-effectiveness ratios for combination
therapy with pegylated interferon ranged from $32 000 to $90
000 per QALY gained for genotype 1 and from $12 000 to $42
000 per QALY gained for all other genotypes. In both men and
women, strategies based on monotherapy with either pegylated
or standard interferon were dominated in all sets of empirically
calibrated parameters for patients with genotypes other than
genotype 1, while only monotherapy with standard interferon
was dominated for patients with genotype 1.
Because a minority of our target population would progress
to severe liver disease even in the absence of therapy, the
benefits of treatment would be attributable largely to improvements
in quality of life. For example, averaging across the range
of empirical parameter sets, approximately 60% to 75% of the
total benefits of the most effective treatment strategy compared
with no treatment would be realized in terms of health-related
quality of life, rather than survivorship, gains. The predominance
of benefits from reductions in nonfatal health outcomes translates
into substantial differences between cost-effectiveness ratios
expressed as costs per life-year vs costs per QALY (Table
4). For example, for men with genotype 1, combination therapy
with pegylated interferon had a ratio of $91 000 per unadjusted
life-year as opposed to a ratio of $36 000 per QALY.
Sensitivity Analysis
The results were insensitive to variation in the annual costs
of managing chronic hepatitis C or its complications, and
relatively insensitive to assumptions about the efficacy of
different treatment regimens. If costs of a specific treatment
regimen for HCV infection were to vary within a range of ±
50%, the given strategy typically would dominate or be dominated
by adjacent strategies at the extreme values of the ranges.
Results were sensitive to the discount rate used; with no
discounting, the incremental cost-effectiveness of all treatment
strategies were lower than in the base case (discount rate
of 3%) by approximately 60% to 80%, and with a discount rate
of 5%, the ratios for all strategies were higher by approximately
70% to 150%.
Results were highly sensitive to plausible alternative assumptions
about the impact of chronic HCV infection and treatment on
quality of life. For example, in the base case we assumed
that patients with mild HCV infection who experienced viral
clearance returned to a quality of life comparable with that
of persons of similar age and sex without HCV infection. At
the opposite extreme, if we assumed that treatment offered
no immediate quality-of-life improvements in patients with
mild HCV infection, the incremental cost-effectiveness ratio
of combination therapy with pegylated interferon vs standard
interferon increased by approximately 45% for men and 85%
to 90% for women. Results of this sensitivity analysis were
magnified in women because with their lower rates of progression
to advanced liver disease, the benefits of treatment depend
more on any immediate quality-of-life gains associated with
resolution of HCV infection.
Results also were sensitive to alternative assumptions about
the decrements in quality of life (ie, disutility) associated
with treatment. If adverse effects reduced quality of life
during treatment by 50%, as found in a recent study using
rating scale responses from both patients and their physicians,73
the only nondominated treatment strategy in men with genotype
1 would be combination therapy with pegylated interferon ($652
000 per QALY gained), and all treatment strategies would be
dominated by the no-treatment strategy in women with genotype
1. With a treatment disutility of 25%, the incremental cost-effectiveness
of combination therapy with pegylated interferon compared
with no treatment for patients with genotype 1 (all other
treatment strategies would be dominated) would be approximately
$57 000 per QALY in men and $158 000 per QALY in women. When
we simultaneously considered alternative assumptions about
quality-of-life benefits associated with viral clearance and
disutility associated with treatment, even modest changes
in our base case assumptions substantially increased the cost-effectiveness
ratios associated with treatment. For example, if successful
treatment eliminated half of the quality-of-life decrement
for mild HCV infection, and treatment was associated with
a disutility of 25%, all treatments would be dominated except
combination therapy with pegylated interferon, with an incremental
cost-effectiveness of $82 000 per QALY for men and $742 000
per QALY for women with genotype 1, compared with no treatment.
In this study, we conducted a decision analysis of treatment
for chronic HCV infection that included natural history parameters
calibrated to be consistent with both available clinical data
on progression of HCV infection and epidemiologic data on
prevalence of HCV seropositivity and mortality from liver
cancer in the population. Focusing on patients with the mildest
histological form of chronic HCV infection, we found that
accounting for heterogeneity in disease progression can reveal
substantial differences in the benefits of treatment in different
population strata. Across the array of empirically calibrated
natural history parameter sets, the probability of developing
cirrhosis during a 30-year period was between 13% and 46%
for men and between 1% and 29% for women. Results on the costs,
benefits, and cost-effectiveness of treatment varied widely
across the range of different sets of empirical parameter
values.
Recently, results from a number of longer follow-up studies
have suggested that progression rates to cirrhosis and its
complications may vary considerably across different segments
of the HCV-infected population, and may be substantially lower
among those infected at relatively young ages than previously
assumed.46-48 As more aggressive efforts to identify infected
individuals proceed, we may expect a shift over time in the
composition of the patient population toward those with lower
probabilities of disease progression. To accommodate the new
information and evolving decision context, our analysis departs
from previous analyses in 4 ways: (1) we empirically calibrated
model parameters to reflect all available data regarding the
natural history of HCV infection in the general population
of infected persons; (2) we accounted for variability and
heterogeneity in disease progression by allowing rates to
depend on age and sex and also allowing for nonprogression
in a proportion of patients; (3) we used ranges of parameter
values that were wider than those explored previously in sensitivity
analyses; and (4) we focused on a population of asymptomatic
patients who are HCV seropositive but who are otherwise healthy.
Factors such as age and sex appear to be important sources
of variation in rates of disease progression, which may have
important implications for decisions regarding treatment for
chronic HCV infection. Based on our analyses, treatment for
women may offer substantially lower benefits than treatment
for men because women have a much lower probability of progressing
to cirrhosis and liver failure. With smaller likelihoods of
developing end-stage liver disease even in the absence of
treatment, the expected benefits of therapy would be realized
largely in the form of improvements in health-related quality
of life rather than survivorship outcomes. Information about
the smaller magnitude of the clinical benefits may be helpful
for individual women and their clinicians as they weigh the
risks and benefits of currently available treatment options.
Aside from age and sex, factors that have not yet been identified
may eventually help to narrow the focus of treatment on those
who are most likely to progress to chronic liver disease.
Recent assessments of the growing literature on the natural
history of HCV infection suggest that a sizeable proportion
of individuals infected with HCV may never progress from chronic
infection to cirrhosis before they succumb to other causes.8,
74 While age, sex, and other identifiable factors explain
some of this variation, other sources of heterogeneity remain
poorly understood.
The results of sensitivity analyses indicate that better
information is needed about the quality of life associated
with chronic liver disease, and in particular about the quality
weights associated with the mildest histological states and
the decrements in quality of life associated with treatment.
Results were sensitive to certain key assumptions relating
to the quality adjustment of years lived in the model. Developing
a better understanding of the spectrum of nonfatal health
outcomes for patients with chronic infection and how they
change with treatment remains a critical challenge in assessing
the cost-effectiveness of therapy.
Our study has several limitations. It does not address the
possibilities of retreating patients who relapse or pursuing
more aggressive treatment for nonresponders. Given the incomplete
rates of sustained response to available regimens, important
clinical decisions pertaining to nonresponders or relapsers
are beyond the scope of our analysis. Other important issues
regarding treatment of chronic HCV infection in injection
drug users,75 or in patients coinfected with human immunodeficiency
virus,76 are not considered in this article. Furthermore,
this study is not intended to inform clinical decisions about
management of patients with advanced liver disease. In anticipation
of an increasing number of patients with asymptomatic, histologically
mild disease, we chose to focus on patients with no fibrosis
rather than considering a mixture of patients with various
different stages of fibrosis.
Placing the results of this study within the context of previous
analyses is challenging because studies have differed as the
range of available treatment options has broadened, new evidence
on natural history has emerged, and the target population
has changed. Direct comparison is hampered somewhat by variation
in the methodologies and reporting in different studies, but
inferences regarding broad patterns of differences are possible
from a range of studies that have evaluated one or more common
interventions. Table 5 presents a comparison between the incremental
benefits and cost-effectiveness of interferon monotherapy
or combination therapy with interferon and ribavirin in selected
previous analyses and our study. The empirically calibrated
natural history parameters used in our study, applied to a
general population of seropositive patients without fibrosis,
produced lower benefits and higher cost-effectiveness ratios
than those found previously, with the differences ranging
up to a factor of more than 40 in some cases.
For large numbers of US individuals who are infected with
HCV but are not yet aware of these infections, the recent
emphasis on testing and treating individuals with chronic
HCV infection may lead to difficult decisions involving tradeoffs
between, on the one hand, uncertain benefits and, on the other
hand, considerable costs and risks associated with treatment.
Policy makers must be mindful of the implications that public
health campaigns targeted at HCV infection will have for the
individual clinical decisions that follow. While we found
that newer treatment options for HCV infection appear on average
to be reasonably cost-effective, these results depend critically
on assumptions about the quality of life associated with mild
HCV infection and treatment, and vary widely across different
patient subgroups.
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