Making it happen: managed care considerations in vanquishing hepatitis C.

Abstract

Chronic hepatitis C virus (HCV) infection is an area of medical and economic concern. Studies show a substantial and increasing use of healthcare resources by patients with this disease. However, analysis of available data regarding virologic efficacy, impact on outcomes, and cost-effectiveness in chronic HCV infection appear to justify the initial costs for antiviral treatment, considering the future cost savings generated by prevention of liver disease. To further demonstrate cost-effectiveness, enhanced methods for identifying and treating patients are needed. Greater clinician awareness of available guidelines, patient education, close monitoring of antiviral therapy, emphasis on adherence to therapy, and management of adverse effects are recommended to ensure the best possible care for patients and to maximize outcomes.

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VOL. 13, NO. 12
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Making It Happen: Managed Care Considerations
in Vanquishing Hepatitis C
John G. McHutchison, MD; Bruce R. Bacon, MD;
and Glenda S. Owens, RPh, MHA, CDM
Address correspondence to: John G. McHutchison, MD, Associate Director, Duke Clinical
Research Institute, Duke University Medical Center, P .O. Box 17969, Durham, NC 27715. E-mail:
mchut001@mc.duke.edu.
Abstract
Chronic hepatitis C virus (HCV) infection
is an area of medical and economic con-
cern. Studies show a substantial and
increasing use of healthcare resources
by patients with this disease. However,
analysis of available data regarding
virologic efficacy, impact on outcomes,
and cost-effectiveness in chronic HCV
infection appear to justify the initial costs
for antiviral treatment, considering the
future cost savings generated by preven-
tion of liver disease. To further demonstrate
cost-effectiveness, enhanced methods
for identifying and treating patients are
needed. Greater clinician awareness of
available guidelines, patient education,
close monitoring of antiviral therapy,
emphasis on adherence to therapy,
and management of adverse effects
are recommended to ensure the best
possible care for patients and to maximize
outcomes.
(Am J Manag Care. 2007;13:S327-S336)
I REPORTS I
A
tality.1-4Most cases of HCV were acquired during the 1960s to the
1980s, and infection is usually asymptomatic during both the acute and
chronic phases.1,5Symptoms usually only develop after the establish-
ment of advanced stages of liver disease.6The majority of currently
infected individuals have not yet been diagnosed.1,3As these baby
boomers with asymptomatic infection advance in age, a proportion will
likely develop clinical liver disease.1
The economic burden of this will largely fall on managed care
organizations (MCOs) and private insurers.1,5HCV infection has not
escaped the need to use newer and more expensive injectable antiviral
agents. Optimizing the use of these agents, and the overall manage-
ment of HCV infection, will be essential to assure that the best possi-
ble patient outcomes are achieved while long-term healthcare costs are
minimized.
The objective of this review is to discuss the present medical and
economic burden of HCV infection and projections for the future.
Emphasis is placed on the medical and economic implications of these
burdens for managed care. Methods to increase treatment efficacy and
potentially lessen HCV-related costs are also discussed.
substantial increase in the prevalence of chronic hepatitis
C virus (HCV) infection is projected in decades to come,
suggesting a future increase in the burden of HCV-related
chronic liver disease with its attendant morbidity and mor-
Health Burden: Liver-related
The Present. Cirrhosis, end-stage liver disease, and hepatocellular
carcinoma (HCC) are the most significant clinical sequelae of chronic
HCV infection. Based on present data, about 20% of patients with
chronic HCV infection will progress to cirrhosis after 20 to 30 years.1,7
Factors that have been shown to be associated with cirrhosis develop-
ment are older age at time of infection, coinfection with human
immunodeficiency virus (HIV) or hepatitis B virus, high levels of alco-
hol use, and male sex.3,8Neither viral load nor HCV genotype has sig-
nificantly affected the risk for progression of liver disease.3
Each year, hepatic decompensation is seen in 3% to 6% of patients
with HCV-related cirrhosis; these patients are potentially candidates for

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liver transplantation.1,3,4,8In addition, HCC devel-
ops in up to 4% of patients with HCV cirrhosis.1,3,8
Overall, HCV infection is the most common indica-
tion for liver transplantation in the United States. It
accounts for about one third of cases of HCC.3Liver
transplantation was performed in 1517 patients with
HCV infection in 1998, with an increase in trans-
plantation rates in subsequent years; however, the
availability of cadaver livers has remained constant
at only 4000 to 5000 per year.4,8
Studies show a substantial and increasing use of
healthcare resources by patients with chronic HCV
infection.9Outpatient visits and hospitalizations
are now more frequent. From 1994 through 2001 in
one study, HCV-related hospitalizations, deaths,
and the costs incurred increased at average annual
rates of greater than 20%, which were 3-fold high-
er than rates for all-cause hospitalizations.9In
1998, there were 317 000 outpatient visits related
to chronic HCV infection and an estimated
140 000 hospital discharges listing an HCV diagno-
sis.4,8Each year, 10 000 to 12 000 deaths are attrib-
uted to HCV infection, although this is likely an
underestimate.3,8Deaths in association with HCV
are more often related to decompensated cirrhosis
as opposed to HCC.3
In general, life expectancy is reduced in those
chronically infected with HCV. In the average
middle-aged adult receiving no treatment, life ex-
pectancy is estimated to decrease by 3 years and
9 years in those with mild and moderate hepatitis,
respectively; for those with compensated cirrhosis,
life expectancy falls by 16 years.6Decompensated
cirrhosis offers a much poorer prognosis, with a 28-
year decrease in life expectancy, although liver
transplantation in these patients can limit the
decrement to about 22 years.6
The Future. Trends toward steady increases in
morbidity and mortality due to chronic HCV infec-
tion have already been shown during the period
from 1980 to 2000, perhaps providing a hint of what
can be expected in years to come. This included
increases in HCV-related hospitalization, liver
transplantation, and mortality.1,4,8,9Hospitalization
for HCV liver-related reasons also increased during
this period in patients coinfected with HIV; in this
group, 7.5 times as many patients were hospitalized
in 2001 compared with 1994.9
These trends may continue on an even greater
scale in the future, presenting a major challenge to
MCOs. Morbidity and mortality related to HCV
liver sequelae are expected to double or even triple
over the next 2 decades, because of the expected
increase in the number of patients with mature
HCV infection (ie, those acquired in the 1960s to
1980s).1,6,8,10,11The need for liver transplantation
will increase dramatically over this period, poten-
tially overwhelming the capacity of transplant cen-
ters. An urgent need will be forthcoming to increase
availability of transplant services through increased
organ donation or alternative techniques,10unless
more effective treatments become available to erad-
icate HCV and prevent cirrhosis from developing.
With the use of Markov modeling, Davis and
colleagues10projected the HCV-related burden in
the United States over the next 40 years (Table 1).
In a more recent analysis, Deuffic-Burban et al12
projected the future disease burden associated with
HCV infection in the United States by the use of
the back-calculation model. Deaths from HCV-
related liver disease and HCC were estimated to be
3700 in 1998 and were projected to rise over the
subsequent 25 years, peaking at 13 000 in 2030. It
was estimated that future mortality from HCV will
likely exceed that related to HIV.
A caveat arising from studies that have project-
ed disease burden is that methodology and tech-
niques for estimating this burden have varied.
Similarly,the studies varied with respect to inclusion
or noninclusion of the beneficial effect of antiviral
therapy in potentially reducing future disease com-
plications and their costs. The confounding effects
of therapy, such as accounting for those who are
nonresponders or noncompliant, are also problemat-
ic in assessing costs and economic benefits.
Thus, the actual disease burden in the present
or the future remains largely unknown. What is
known with certainty, however, is that the burden
will increase substantially over the next 20 years.
Extrahepatic Complications. Patients with chronic
HCV infection can present with numerous extra-
hepatic complications, many of which are clinically
significant.3,8Some of these include glomeru-
lonephritis, lichen planus, keratoconjunctivitis
sicca, porphyria cutanea tarda, and various neu-
ropathies.3,8Although cryoglobulins are found in

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the serum of up to 50% of HCV patients, the clini-
cal disease associated with mixed cryoglobulinemia
is infrequently observed.
Quality of Life. Health-related quality of life
(HRQOL) is of major importance to patients with
any chronic disease or disorder and is impaired in
those with chronic HCV infection, as measured by
generic and hepatitis-specific scales.1,3,4,6,8,13Fatigue,
depression, impaired social function, reduced vitali-
ty, and cognitive and other neuropsychiatric disor-
ders are relatively common. Fatigue, which can be
severe, occurs in about two thirds of infected
patients.6HRQOL impaired as a result of HCV
infection does return to normal after successful viral
eradication. It should be noted, however, that a his-
tory of intravenous drug use and alcohol abuse may
contribute substantially to impaired HRQOL.
Similar to HIV infection, the cognitive and neu-
ropsychiatric impairment in HCV infection has
correlated with an increased choline/creatinine
ratio in the basal ganglia and white matter on cere-
bral proton magnetic resonance spectroscopy.6
Economic Burden
Studies indicate that most privately insured indi-
viduals receiving employer healthcare coverage are
enrolled in managed care, and MCOs will bear the
burden of most costs related to treating HCV-relat-
ed liver complications.5For the year 1997, costs
related to HCV infection in the United States were
estimated at $5.5 billion; about one third of this was
attributable to direct medical costs and two thirds
to indirect costs.14The total direct healthcare cost
for HCV infection in 1998 was estimated at more
than $1 billion.4A US survey by the American
Gastroenterological Association (AGA) indicated
that the cost for outpatient physician services relat-
ed to the more than 300 000 outpatient visits for
hepatitis C in 1998 amounted to $24 million; this
survey also found that about $530 million was spent
on antiviral treatment during this year.4
The economic burden imposed by HCV is simi-
lar to that reported in recent years for rheumatoid
arthritis ($7 billion in 1994) and asthma ($5.8 bil-
lion in 1994); although less than that for HIV ($30
billion in 1992), HCV alone is projected to have an
increasing disease burden relative to these other
conditions.15
When considering the expected rise in morbidi-
ty and mortality, one economic model projects
direct medical costs of $10.7 billion over the period
of 2010 to 2019.1Societal costs are expected to
reach $21 billion during this period, attributed to
the projected 720 000 years lost because of decom-
pensated cirrhosis and HCC, whereas indirect costs
related to mortality are estimated to exceed $50
billion.1These data do not consider the economic
burden of HRQOL issues, including pain and suffer-
ing, or caregiver time. When considering these
latter expenses, some investigators project a total
economic burden of HCV infection of more than
$180 billion between 2010 and 2019.15
Per-patient Costs. Actual per-patient costs more
effectively arm MCOs with the information needed
to determine cost-effectiveness of available HCV
treatments. In a retrospective review of a medical
and pharmacy claims database of HCV-diagnosed
patients in an MCO, the median annual total
healthcare cost in those receiving interferon alfa
was $4634, and the median annual total HCV-relat-
I Table 1. Future Projections: Numbers of Patients With Chronic HCV Infection, Cirrhosis, and Complications
Over Four 1-decade Intervals
2000 20102020 20302040
HCV infection2 940 678 2 870 391 2 681 5562 433 709 2 177 089
Cirrhosis472 103 720 807858 788 879 747828 134
Decompensated cirrhosis 65 294 103 117 134 743 146 408142 732
Hepatocellular carcinoma 727111 185 13 18313 39012 528
Liver-related death 13 00027 73236 483 39 875 39 064
HCV indicates hepatitis C virus.
Used with permission from Reference 10.

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ed cost was $2472. Costs in patients receiving inter-
feron alfa plus ribavirin were higher, with a median
annual total healthcare cost of $6649 and median
annual HCV-related total cost of $4303. This
review found that total healthcare costs were sub-
stantially higher in HCV-infected patients with
comorbid HIV infection.16These costs would be
even higher if the current standard of treatment,
pegylated interferon (peginterferon) and ribavirin,
were analyzed. Drug costs for a year of therapy are
about $20 000.
In another analysis involving patients with con-
firmed HCV infection in a managed care population
(N = 191), total medical costs amounted to about
$75 million over a 3-year period, which translates
into a mean annual cost of approximately $13 000
per patient.17Of importance to health plans, the
total healthcare costs in these latter 2 studies were
larger than total costs related to HCV infection,
emphasizing the cost burden due to healthcare needs
above that due to HCV infection alone.16
Implications for Managed Care
Perhaps most important, hepatitis C is a disease
that spans a long, indolent course. In addition, the
aging of the large pool of individuals with asympto-
matic infection will lead to increased morbidity, mor-
tality, and attendant costs over the next 2 decades.
The cornerstone of therapy is the use of injectable
peginterferon preparations, which are expensive.
Central questions to be addressed by MCOs are: Will
the initial expense of such therapies be offset by cost
savings from the prevention of future disease burden?
If so, how can we be assured that we are providing the
best care to patients with the most efficient use of
healthcare resources? What methods can we use dur-
ing treatment to further reduce total HCV costs?
Finally, what can be done to ensure diagnosis and
appropriate treatment of infected patients, which
will reduce future health burden?
These questions require consideration of virolog-
ic efficacy, effects of this therapy on clinical out-
comes, cost-effectiveness of antiviral regimens, and
viable methods to enhance identification and treat-
ment of HCV-infected patients and optimize pre-
scribed antiviral therapy.
Virologic Efficacy. The current regimens of choice
for chronic HCV infection are (1) weight-based sub-
cutaneous (SC) peginterferon alfa-2b plus oral rib-
avirin or (2) fixed-dose SC peginterferon alfa-2a plus
oral ribavirin.18-20The dosages and cost of therapy of
these combinations are shown in Table 2. These
combination therapy regimens produce sustained
virologic response (SVR—undetectable HCV RNA
6 months after therapy stops) rates of 54% to 56%
overall, with rates of 42% to 52% in the less respon-
sive genotype 1 and 76% to 84% in genotypes 2 and
3. They are more effective than pegylated interferon
alfa alone or nonpegylated interferon alfa, either
alone or combined with ribavirin, in producing SVR.
However, compared with nonpegylated interferon
alfa plus ribavirin, the greater virologic efficacy of
peginterferon plus ribavirin comes at the expense of
more adverse events, such as neutropenia.21
Although the ultimate goal of therapy is to pre-
vent long-term complications of chronic HCV
infection, attaining SVR is the initial and primary
measurable goal.1As virtually all patients achieving
SVR after a course of therapy will remain so indefi-
nitely, this in essence constitutes a cure of chronic
infection, which is supported by histologic and viro-
logic data.1,11
Optimal Duration of Treatment. Patients with
genotype 1 should be treated with peginterferon alfa
plus ribavirin for 48 weeks, using higher doses of rib-
avirin, whereas those with the more treatment-
favorable genotypes 2 and 3 can receive a shorter
duration of therapy with a lower ribavirin dose.
The recommended duration for genotypes 2 and 3
is 24 weeks.3,18
Twelve-week Virologic Response: A Clinical Mile-
stone. The early virologic response (EVR—unde-
tectable HCV RNA or a 2-log drop) is a marker of
eventual treatment success or failure. Clinical stud-
ies have shown that patients not achieving EVR by
12 weeks of treatment, defined as at least a 2-log
reduction in HCV RNA levels, have only a small
chance (<3%) of achieving SVR at the end of a full
course of therapy.3,11,22-24This “12-week rule” is
most important for patients with genotype 1, who
typically require a 48-week course of therapy. In
genotype-1 patients failing to achieve the 12-week
EVR, discontinuation of therapy is indicated. This
not only spares the patient of subsequent adverse
events but also generates considerable cost savings.

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Effects on Other Outcomes. The impact of
peginterferon plus ribavirin on long-term outcomes
is still forthcoming. The main difficulty in outcome
assessment is the lengthy natural history of the dis-
ease—chronic HCV evolves slowly, extending to
decades in many patients, and long-term follow-up
in large studies of treated cases is needed. Most clin-
ical trials have been of short duration, using SVR as
the primary end point. The available data at present
do, however, suggest liver complications can be
reduced and survival prolonged after successful
antiviral therapy.22,25Reversal of liver fibrosis is also
associated with SVR.11
Data regarding a reduction in the risk and inci-
dence of HCC are somewhat equivocal, although
published and unpublished retrospective studies
suggest this benefit, particularly in patients with
sustained responses.20,22,25There is no clear evi-
dence at present to indicate a benefit of antiviral
therapy with respect to increasing the time to liver
transplantation or reducing the need for it.
Results of long-term trials, many of which are
under way, will offer more definitive data regarding
outcomes. However, most projections suggest that
successful antiviral therapy will ultimately be
shown to prevent cirrhosis, reduce mortality, reduce
or prevent HCC, and minimize the need for liver
transplantation.11
Cost-effectiveness. The efficacy of a given
treatment does not always correlate with cost-
effectiveness. However, based on projections of the
natural history of HCV disease and benefits of
antiviral therapy in available clinical trials, most
pharmacoeconomic analyses have concluded that
peginterferon-ribavirin regimens for chronic HCV
infection are indeed cost-effective, with cost-effec-
tiveness being comparable to or better than other
well-accepted clinical interventions.6,11,15,22,26-29
These cost-effective analyses agree that most costs
associated with chronic HCV infection are justified
considering the future cost savings generated by
prevention of liver disease. Cost-effectiveness
applies to patients in clinical trials as well as those
with milder disease or persistently normal alanine
aminotransferase levels.22,30,31Combined therapy of
peginterferon alfa plus ribavirin has also been
shown cost-effective in patients with coexistent
HCV and HIV infection.32
From his review of pharmacoeconomic studies,
Wong6suggests that, in general, incremental cost-
effectiveness ratios (ICERs) for antiviral treatment
of chronic HCV infection fall below the widely cited
$50 000 per quality-adjusted life-year (QALY)-
gained threshold. From a societal perspective, this
investigator indicates that the ICER of peginterfer-
on alfa plus ribavirin therapy would, at most, be
about $23 000 per QALY; this is almost identical to
the value for an effective, 3-drug antiretroviral reg-
imen employed in HIV infection.6Wong concludes
that most of the costs of antiviral therapy for HCV
infection should be offset by the prevention of
future liver disease.
Enhancing Patient Identification and Optimiz-
ing Therapy. The demonstrated cost-effectiveness
of peginterferon alfa combinations does not guaran-
tee a significant reduction in total treatment costs.
First, these agents have to be prescribed to have
benefit, and there is evidence of inadequacies in
testing for HCV, diagnosing HCV, and providing
treatment for those who are diagnosed. These inad-
equacies may have large implications for economic
burden in the near future.5In those given treat-
I Table 2. Peginterferons Combined With Ribavirin for
Chronic HCV Infection: Dose and Cost of Therapy
Adult
Dosage*
Cost of
Therapy ($)Regimen
Peginterferon alfa-2a
(Pegasys®) plus:
180 mcg once weekly SC
for 48 wk
21 913
Generic ribavirin800-1200 mg PO daily
for 48 wk
8534
Ribavirin as Copegus®
800-1200 mg PO daily
for 48 wk
12 889
Peginterferon alfa-2b
(PEG-Intron®) plus:
1.5 mcg/kg once weekly SC
for 48 wk
20 831
Generic ribavirin800-1200 mg PO daily
for 48 wk
800-1200 mg PO daily
for 48 wk
8534
Ribavirin as Rebetol®
13 964
*The 48-week regimen with full-dose ribavirin (1000-1200 mg) is indicated in
patients with HCV genotype 1.18,20A shorter course (24 weeks) and lower
dose of ribavirin (800 mg) may be given to patients with genotypes 2 and 3
(see text).
HCV indicates hepatitis C virus; SC, subcutaneously; PO, by mouth.
Adapted with permission from Reference 20.