What Is Killing People with Hepatitis C Virus
Infection?
Jason Grebely, B.Sc., Ph.D.,1 and Gregory J. Dore, M.B.B.S., Ph.D., F.R.A.C.P., M.P.H.1
ABSTRACT
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The burden of hepatitis C virus (HCV)-related morbidity and mortality continues
to rise. Progression to advanced liver disease among HCV-infected individuals generally
requires decades, but we are entering an era where those infected with HCV in the 1970s
and 1980s are at significant risk of mortality. Liver disease has overtaken drug-related harm
as the major cause of mortality in HCV-infected individuals in many settings. Directacting antiviral therapies have provided renewed optimism, but HCV treatment uptake will
need to increase markedly to reduce liver disease mortality. This review provides updated
information on the natural history of HCV, disease-specific causes of mortality among
people with HCV, estimates and projections of HCV-related disease burden and mortality
and individual and population-level strategies to reduce mortality. The considerable
variability in mortality rates within subpopulations of people with HCV will be outlined,
such as in people who inject drugs and those with HIV co-infection.
KEYWORDS: Hepatitis C virus, assessment, treatment, care, barriers
T
he next decade will be a crucial period in the
public health response to hepatitis C virus (HCV)
infection. The rapid development of direct-acting antiviral (DAA) therapy for chronic HCV infection has
brought considerable optimism to the HCV sector,1
with the realistic hope that therapeutic intervention
will soon be more effective and offer shorter treatment
duration. The initial phase of combination pegylated
interferon (PEG-IFN), ribavirin, and one or more DAA
agents will be associated with increased toxicity and
complexity of therapeutic management,1 but over the
course of this decade, strategies including interferon-free
regimens with enhanced tolerability, dosing schedules,
and simplified monitoring protocols should emerge.
These therapeutic advances are urgently required,
as a high HCV incidence 20 to 30 years ago is now
reflected in a growing burden of advanced HCV-related
liver disease.2–8 Without effective therapeutic intervention, the projected liver disease burden will continue to
rise in many countries,9–14 for at least the next one to two
decades, and beyond in those settings that have experienced ongoing high-level HCV transmission.
Despite the prospect of greatly improved therapies, the challenges ahead for HCV infection are considerable. HCV treatment uptake is very low in many
countries12,15,16 and within marginalized subpopulations
in countries with higher treatment uptake.16–20 The
explanations for low uptake are multifactorial21 and
not the focus of this review, but interferon-related
toxicity, lack of HCV treatment infrastructure, suboptimal government subsidization programs and medical
insurance coverage, as well as competing patient health
1
HCV in 2011: Ebb Tide, or the Gathering Storm?; Guest Editor,
Andrea D. Branch, Ph.D.
Semin Liver Dis 2011;31:331–339. Copyright # 2011 by Thieme
Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001,
USA. Tel: +1(212) 584-4662.
DOI: http://dx.doi.org/10.1055/s-0031-1297922.
ISSN 0272-8087.
Viral Hepatitis Clinical Research Program, The Kirby Institute for
Infection and Immunity in Society, The University of New South
Wales, Sydney, Australia.
Address for correspondence and reprint requests: Professor
Gregory J. Dore, The Kirby Institute for Infection and Immunity in
Society, University of New South Wales, CFI Building, Corner of
Boundary and West Streets, Sydney NSW 2010, Australia (e-mail:
[email protected]).
331
SEMINARS IN LIVER DISEASE/VOLUME 31, NUMBER 4
2011
and social priorities are likely to remain as contributing
factors in the near future.
An improved understanding of morbidity and
mortality among people with HCV infection will
guide clinical management and therapy decision-making, both at the individual patient and population
strategic levels. This review will provide updated information on the natural history of HCV infection,
disease-specific causes of mortality among people with
HCV infection, estimates and projections of HCVrelated disease burden and mortality, the potential
impact of HCV treatment on disease burden, and
individual and population-level strategies to reduce
mortality. The considerable variability in mortality
rates within subpopulations of people with HCV will
be outlined, and a particular focus given to the issue of
competing mortality risk among people who inject
drugs and those with human immunodeficiency virus
(HIV) co-infection.
NATURAL HISTORY OF CHRONIC HCV
INFECTION
An estimated 75% of people who acquire HCV infection
progress to development of persistent of chronic HCV
infection,22 with associated risk of progressive liver
disease, cirrhosis, liver failure, or hepatocellular carcinoma.23 The remaining 25% of people achieve spontaneous HCV clearance22; however, these individuals may
be reinfected in the setting of ongoing HCV exposure.
Although many of those with reinfection undergo subsequent spontaneous viral clearance, others develop persistent infection.24–30
As reviewed elsewhere,31 the risk of HCV-related
liver disease morbidity and mortality depends on several
factors: (1) the duration of HCV infection32–34; (2) the
presence of cofactors for development of liver fibrosis
(such as male gender,35–37 ethnicity,38,39 older age at
infection,37,40–42 heavy alcohol intake,43–45 HIV46–49 or
chronic hepatitis B virus (HBV) co-infection,50,51 diabetes,52,53 obesity,54,55 and hepatic steatosis56,57); (3)
access to HCV therapy and a favorable treatment response58; and (4) competing mortality risk (such as
HIV7,49 and illicit drug-related overdose2,6–8,49). The
generally slowly progressive nature of chronic HCV,
with limited advanced liver disease in the initial 10 to
15 years of infection (even in those individuals with
cofactors for fibrosis development), means that duration
of HCV infection and its surrogate, age, are key determinants of mortality risk.31 Thus, a 50-year-old individual with 30 years chronic HCV is likely to have a
higher HCV-related mortality risk, even in the absence
of liver disease cofactors, than a 30-year-old individual
with 5 to 10 years infection and several cofactors.
However, the 50-year-old individual with 30 years infection, with heavy alcohol intake, obesity, and regular
Figure 1 Risk of hepatitis C virus- (HCV-) related cirrhosis
based on duration of infection as estimated through large
systematic reviews of disease progression studies in HCV
mono-infected and human immunodeficiency virus (HIV)/
HCV co-infected populations.33,34
cannabis smoking (recently shown to be a liver fibrosis
cofactor59) will be at particularly high risk.
The risk of HCV-related cirrhosis based on
duration of infection has recently been estimated
through large systematic reviews of disease progression
studies in HCV mono-infected and HIV/HCV coinfected populations (Fig. 1).33,34 The exponential relationship between duration of infection and cirrhosis
relates to the generally protracted disease course (few
very fast progressors), the cumulative nature of cirrhosis
prevalence (even linear rates of progression lead to a
nonlinear/upward curve for cirrhosis), and the potential
for more rapid fibrosis progression at older age.
Without therapeutic intervention, an estimated
7 to 18% of HCV mono-infected individuals will develop
cirrhosis over a 20-year infection period,31,34 and be at
considerable risk of HCC (1–6% per annum) or liver
failure (2–3% per annum).31 Thus, a significant minority
of people with chronic HCV (possibly 10–20%) are likely
to have shortened life expectancy through HCV-related
mortality. A further large proportion will have HCVrelated morbidity with reduced quality of life.60
CAUSES OF MORTALITY AMONG PEOPLE
WITH HCV INFECTION
The distribution of causes of death within a population
with a chronic disease will depend on several factors: (1)
disease-specific natural history and mortality risk, (2)
distribution of duration of chronic disease within the
population, (3) access to effective therapeutic intervention that alters natural history, and (4) age distribution
and competing mortality risk within the population.
The three major disease-specific groupings for
mortality among people with HCV infection are drugrelated, liver disease-related, and HIV-related. Drugrelated mortality includes drug overdose and suicide.
Liver disease-related mortality includes decompensated
cirrhosis and HCC. The mortality distribution based on
these major groupings in population-based HCV noti-
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332
Figure 2 Contribution of human immunodeficiency virus(HIV-) related, liver-related, drug-related, and other causerelated mortality (percentage of total number of deaths) in
large population-based studies of people diagnosed with
HCV infection in Australia (New South Wales),8 Sweden,6
Scotland,7 and Denmark2 (Lars Omland, personal communication, August 11, 2011).
fication—death registry linkage studies in Australia
(New South Wales),8 Sweden,6 Scotland7 and Denmark2 (Lars Omland, personal communication, August
11, 2011) is shown in Fig. 2. In these four countries, the
proportion of liver disease-related deaths varied from 19
to 24%, and for drug-related from 18 to 27%. A high
proportion of drug-related mortality is consistent with
injection drug use (IDU) being the major mode of HCV
acquisition in all four settings. The proportion of HIVrelated deaths was highest in Scotland (7.9%)7 where 4%
of the HCV-notified population was HIV co-infected,
and lowest in Australia (0.4%)8 where only 0.5% was
HIV co-infected. Settings in which the HIV co-infection rate is even higher than Scotland, such as in
developed countries in North America and Europe,
would be expected to have larger proportions of deaths
related to HIV disease.
Temporal trends in mortality rates and distribution among people with HCV infection are clearly
important to monitor. From 1992 to 2006 in New South
Wales, Australia, there has been a steady increase in the
number of people with HCV dying from liver-related
Figure 3 Total number of deaths due to liver-related, drugrelated, and other causes in a large population-based study of
people diagnosed with hepatitis C virus (HCV) infection in
New South Wales, Australia, from 1992 to 2006 (Scott
Walter, personal communication, August 11, 2011).
causes (Scott Walter, personal communication, August
11, 2011) (Fig. 3). In contrast, the number of deaths
from drug-related causes increased rapidly during the
1990s, but has declined since 1999 due to the welldocumented heroin ‘‘drought’’ starting in late 1999 and
its likely subsequent reductions in IDU. The number of
liver disease-related deaths reflects the expanding pool of
chronic HCV including larger numbers with prolonged
duration of infection (aging cohort effect). From 1997 to
2006 the age-adjusted liver disease mortality rate was
stable (around 15 deaths per 10,000 person years),
indicating no impact of improved HCV therapy.8 The
lack of an effect of HCV treatment on individual risk of
liver-disease mortality probably relates to the generally
low-treatment uptake rate, suboptimal efficacy (particularly among those with advanced liver disease), and the
relatively short period of follow-up since improvements.
Consistent with increasing numbers of people
with HCV dying from liver-related causes, the proportion of all liver disease deaths with underlying HCV is
increasing in many settings, as demonstrated in a population-based study in Scotland.4 The burden of HCVrelated advanced liver disease is also seen in increasing
numbers of HCV-related liver transplants in many
countries.16
Mortality among Injection Drug Users with HCV
infection
The prevalence of HCV among regular IDUs and people
receiving opioid substitution therapy (OST) is 60 to
80%61; thus, mortality studies in these populations are
likely to reflect mortality among IDUs with HCV infection. Overall, mortality rates in these two populations
are 1 to 2 per 100 person years,62,63 although there is
evidence that OST reduces drug-related mortality.64,65 A
study among the OST population in Australia demonstrated a considerably higher drug-related mortality rate
compared with liver-disease mortality, with the ratio
varying from threefold when receiving OST to 18-fold
when not receiving OST.65 However, this study covered a
period during the 1990s with very high rates of drugrelated mortality. A more recent mortality linkage study in
New South Wales that included people on OST in 1980
to 1984 has demonstrated increasing rates of liver disease
mortality, which in recent years is the leading cause of
death overtaking drug-related mortality.66 This study is of
great importance as it demonstrates the impact of liver
disease on mortality within an aging cohort, particularly
when rates of IDU decline.
In Canada, the Vancouver community-based
CHASE cohort (81% and 42% have used illicit and
injection drugs in the past 6 months; HCV prevalence is
64%) has also examined all-cause and liver-related mortality through data linkage to a death registry.49 Between
2003 and 2007, the rate of mortality was 1.9 per 100
333
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2011
person-years, with causes of death being 7% liver-related, 20% drug-related, 21% HIV-related, and 52%
other cause-related. All-cause mortality was associated
with age > 50 years and HIV infection. Further, those
> 50 years of age were at significant risk of liver-related
mortality. Given that many communities of IDUs were
infected with HCV in the 1970s and 1980s, there will
inevitably be greater incidence of liver disease over the
next decade.
The potential future burden of advanced liver
disease within aging cohorts is also reflected in an
autopsy study among individuals dying from opioid
toxicity in New South Wales, Australia.67 Among 841
deaths over a 5-year period (1998–2002), the HCV
prevalence was 71% and cirrhosis was present in 7%.67
However, in those aged > 44 years at death (n ¼ 75),
cirrhosis prevalence was 25%.
Mortality in Other Populations with HCV
Infection
Injection drug use has been the major mode of HCV
acquisition in North America, Europe, and Australia.
However, in other settings, HCV transmission has
largely been through non-IDU modes and the contribution of drug-related mortality is therefore considerably reduced. Thus, the impact of HCV-related
disease on mortality rates and distribution is more
evident.
In one study from the United Kingdom, 924
individuals who had acquired HCV infection via blood
transfusion were traced during a look-back program.68
By the end of 2004, 28% had died (255 of 924), with
26% dying of liver-related causes. The risk of liverrelated mortality in those with HCV infection was three
times higher than the control group of anti-HCV
negative transfusion recipients. In Taiwan, 23,785 persons (aged 30 to 65 years, HCV prevalence 4.5%) were
recruited from seven townships between 1991 and 1992
and followed through 2004.69,70 Among participants
with HCV mono-infection (n ¼ 1,040), 171 died by
2004; 28% of deaths were liver-related. After adjusting
for gender, age, cigarette smoking, and alcohol consumption, those with HCV mono-infection were two
times more likely to die of any cause and five times more
likely to die of chronic liver disease and cirrhosis compared with those without HCV. These data suggest that
HCV still leads to excess mortality when drug-related
and HIV effects are removed.
Mortality in People with HIV/HCV
Co-Infection
As reviewed elsewhere,71 co-infection with HIV decreases spontaneous clearance of HCV infection,72
increases HCV RNA levels,73 increases HCV-related
liver disease progression,46,74 and reduces response to
IFN-based therapy.75,76 Since the introduction of
triple-combination antiretroviral therapy in the mid1990s, overall mortality rates among HIV-infected
populations have declined dramatically.77 Further,
the distribution of causes of death have altered considerably, with a declining proportion of acquired
immunodeficiency syndrome- (AIDS-) related mortality and increasing proportions of cardiovascular and
liver disease mortality.78,79 The contribution of liver
disease to mortality is particularly high in settings with
a high HIV/HCV co-infection prevalence78; however,
even in Australia where only 10 to 15% of people
with HIV are HCV co-infected, liver disease contributes to 11% of deaths (Kathy Petoumenos, personal
communication, August 12, 2011).
Within the HIV/HCV co-infected population,
factors that influence rates and distribution of mortality
are access to antiretroviral therapy, access to and effectiveness of HCV therapy, drug use, and age distribution.71 In Australia, within the HIV/HCV co-infected
population there is universal access to antiretroviral
therapy and high levels of uptake, relatively limited
regular ICU (the vast majority are men who have sex
with men), and an aging population. Among HIV/HCV
co-infected patients enrolled in the Australian HIV
Observational Database (AHOD; n ¼ 3,531), liver disease has been the underlying cause in 26% of deaths
(14 of 55 deaths) as compared with only 9% of deaths
(16 of 181) in those with HIV alone (Kathy Petoumenos, personal communication, August 12, 2011).
Further, although the lifespan of those with HIV
infection has been improved through the availability of
contemporary antiretroviral therapy, the lives of those
with HCV/HIV co-infection remain much shorter.71 In
Denmark, one study compared the mortality rates of
3,990 HIV-infected persons and the general population.80 The study demonstrated that although mortality
has dropped significantly in HIV-infected persons (from
a high of 124 per 1000 person years in the era preceding
HIV antiviral therapy to 25 per 1000 person years in
2000–2005), the impact was less pronounced among
those co-infected with HCV (57 per 1000 person-years
in those with HCV/HIV vs 19 per 1000 person-years
among those with HIV alone). In a large study of 23,441
HIV-infected persons (76,893 person-years of followup), the frequency of and risk factors associated with
liver-related deaths were assessed (66% with HCV coinfection, 17% active HBV co-infection).78 Among 1246
deaths (5.3%; 1.6 per 100 person-years), liver-related
death was the most frequent cause of non-AIDS related
death (14.5% were from liver-related causes). Predictors
of liver-related deaths were latest CD4 cell count, older
age, IDU, HCV infection, and active HBV infection.
Given the underreporting of liver-related disease, the
actual impact is probably even greater.71
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334
THE POTENTIAL IMPACT OF IMPROVING
HCV THERAPY ON MORTALITY RATES
The burden of HCV-related advanced liver disease is
projected to increase further in many countries.9–14 A
major public health issue is the potential impact of
improving HCV therapy on these projected increases
in mortality. In HIV, the availability of effective combination antiretroviral therapy from the mid-1990s dramatically reduced the overall mortality rate and altered
the distribution of causes of death (increasing proportion
of non-AIDS related deaths).78–80 The lower overall
disease-specific HCV mortality risk compared with HIV
and more protracted disease progression (life expectancy
for chronic HCV infection is on average reduced by
several years rather than decades for HIV) mean that a
more-effective and more broadly implemented therapeutic intervention will be unable to have the dramatic
impact that was seen for antiretroviral therapy. However,
there is considerable potential for improved HCV therapeutic intervention to alter expected HCV-related
mortality, particularly when the temporal ‘‘ageing cohort’’ effect is most pronounced.
The recent introduction of DAA therapy in
combination with PEG-IFN and ribavirin will enhance
treatment response rates for those with chronic HCV
genotype 1 infection and shorten duration of therapy for
many patients.1 However, low HCV treatment (PEGIFN/ribavirin) uptake rates for those with chronic HCV
genotype 2/3,12,15–20 despite treatment success of 70 to
80% and shorter duration therapy (generally 24 weeks),
suggest that initial DAA-based response rate improvements will have a modest impact at the population level.
Recent evidence suggests that IFN-free combination
DAA therapy with high rates of treatment response is
feasible.81 Improvements in DAA therapy tolerability
and dosing schedules are highly likely given agents in
phase II/III development.1 Large population-level impacts on HCV-related liver disease mortality will likely
require IFN-free combination therapy that is tolerable,
has a favorable dosing schedule, and is effective over a
relatively short duration. Such HCV therapeutic advances are within reach over the next decade.
HOW CAN WE CURRENTLY PREVENT
PEOPLE WITH HCV INFECTION FROM
DYING?
The availability of PEG-IFN/ribavirin-free regimens for
the treatment of HCV infection are still 5 to 10 years
away and other strategies will be required if we are to
stem the projected rise in liver-disease burden.9–14 Strategies that increase the proportion of individuals diagnosed, assessed, and treated for HCV infection with
currently available treatment regimens are required.
Increasing the number diagnosed with HCV
infection will be important as we move forward. In the
United States, the true number of people infected with
HCV is likely underestimated (5.2 million as compared
with previous estimates of 3.3 million from household
surveys), given that homeless people, prisoners, IDUs,
and other marginalized populations at high-risk of HCV
are often not included in national household surveys.82
Strategies to enhance diagnosis of HCV may include the
promotion of national HCV testing guidelines,83 and
enhanced education and training of general practitioners
about HCV testing and diagnostic criteria to enhance
diagnosis and referral. Further strategies include the
provision of mentoring diagnosis programs among general practitioners with higher case loads of HCV-infected patients,84 an improved awareness of programs
offering comprehensive multidisciplinary HCV care
(particularly for IDUs), and improved pathways for
referral. Incorporation of HCV assessment and treatment services into drug and alcohol treatment settings is
also required.
Enhancing the proportion assessed for HCV is
crucial. Non-invasive tests of fibrosis (e.g., FibroScan
and FibroTest) offer considerable opportunities for
enhanced screening and assessment of liver disease.
In a study at one hospital in France, a cohort of 1457
consecutive patients with chronic HCV were assessed
for liver fibrosis by liver biopsy, FibroScan, FibroTest,
aspartate aminotransferase to platelet ratio index
(APRI), and FIB-4 score to evaluate all-cause and
liver-related mortality during a 5-year follow-up period.85 Survival was significantly decreased among
patients diagnosed with severe fibrosis (regardless of
the noninvasive method employed) and all noninvasive
methods were able to predict shorter survival times,
although FibroScan and FibroTest had higher predictive values. These tools will help physicians determine
prognosis at earlier stages and therefore allow enhanced targeting of therapy to those with significant
liver disease.
Strategies are needed to enhance HCV assessment and treatment in the community to reduce mortality among people with HCV. Barriers to expanding
HCV treatment in the community are multifactorial
and include issues of access to therapy and barriers at
the level of the patient, practitioner, and system.86
HCV-infected patients often have complex social,
medical, and psychiatric comorbidities, complicating
decisions around care. Currently, there is limited infrastructure for the provision of HCV assessment and
treatment delivery beyond well-established, hospitalbased liver clinics. However, successful strategies to
improve engagement with HCV services and enhance
HCV assessment have been explored.21 One model to
enhance access to HCV care for underserved populations
focused on the integration of community-based health
centers in New Mexico using state-of-the-art telehealth
technology to provide training and support for primary
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WHAT IS KILLING PEOPLE WITH HEPATITIS C VIRUS INFECTION?/GREBELY, DORE
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2011
care providers to deliver best-practice HCV care.87 This
model was effective, with similar responses to HCV
treatment observed among community-based clinics as
compared with a university-based hospital.87 This approach represents a needed change from the conventional
approaches in which specialized care and expertise are
concentrated in academic medical centers in urban areas.
Lastly, given that 70 to 80% of current HCV
infections occur among IDUs,88 it is clear that strategies
to reduce mortality among those living with HCV will
require specific strategies for this marginalized group.
There is now overwhelming evidence that the treatment
of HCV infection in this population is safe and effective
across multiple models of care.89 As such, older IDUs in
particular will be an important group to follow clinically
(perhaps with noninvasive liver fibrosis screening) and
perhaps offer intensified HCV assessment and treatment
in an effort to reduce liver-related mortality.
CONCLUSION
Our understanding of morbidity and mortality among
people with HCV infection has greatly improved over
the past several decades. In large population-based
studies, liver-related and drug-related causes of
death account for approximately one-half of all
deaths (one-quarter each) among people with HCV
infection. Liver disease burden continues to rise in
many countries,9–14 particularly given the low HCV
treatment uptake in many countries12,15,16 and subpopulations.16–20 Although novel HCV treatments (particularly PEG-IFN/ribavirin-free regimens) offer great
hope for reducing the future mortality associated with
HCV, combinations with improved tolerability and
shorter duration are still 5 to 10 years away. Current
efforts will need to focus on enhancing the diagnosis,
assessment, and treatment of HCV-infected patients
at greatest risk of liver disease progression to reduce
mortality among those living with HCV infection.
ABBREVIATIONS
AIDS
acquired immunodeficiency syndrome
DAA
direct-acting antiviral
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IDU
injection drug use
PEG-IFN pegylated interferon
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