PRIMER

Hepatitis C virus infection

Michael P. Manns1–3, Maria Buti4, Ed Gane5, Jean-Michel Pawlotsky6,7, Homie Razavi8,
Norah Terrault9 and Zobair Younossi10
Abstract | Hepatitis C virus (HCV) is a hepatotropic RNA virus that causes progressive liver damage,
which might result in liver cirrhosis and hepatocellular carcinoma. Globally, between 64 and
103 million people are chronically infected. Major risk factors for this blood-borne virus infection are
unsafe injection drug use and unsterile medical procedures (iatrogenic infections) in countries with
high HCV prevalence. Diagnostic procedures include serum HCV antibody testing, HCV RNA
measurement, viral genotype and subtype determination and, lately, assessment of resistance-
associated substitutions. Various direct-acting antiviral agents (DAAs) have become available,
which target three proteins involved in crucial steps of the HCV life cycle: the NS3/4A protease,
the NS5A protein and the RNA-dependent RNA polymerase NS5B protein. Combination of two or
three of these DAAs can cure (defined as a sustained virological response 12 weeks after treatment)
HCV infection in >90% of patients, including populations that have been difficult to treat in the past.
As long as a prophylactic vaccine is not available, the HCV pandemic has to be controlled by
treatment‑as‑prevention strategies, effective screening programmes and global access to treatment.

Correspondence to M.P.M.
Department of
Gastroenterology,
Hepatology and
Endocrinology, Hannover
Medical School,
Carl-Neuberg-Str. 1,
30625 Hannover, Germany.
manns.michael@
mh‑hannover.de
Article number: 17006
doi:10.1038/nrdp.2017.6
Published online 2 Mar 2017
Hepatitis C is an infectious disease caused by the hep­
atitis C virus (HCV), which is an RNA virus of the family
Flaviviridae. HCV infection can cause acute hepatitis C;
following acute infection, 50–80% of patients develop
chronic hepatitis C. Chronic HCV infection triggers
a chronic inflammatory disease process, which might
lead to liver fibrosis, cirrhosis, hepatocellular ­carcinoma
and death1. Hepatitis C is the leading indication for liver
transplantation in many parts of the world2,3.
Since the discovery of the virus in 1989, an intense
interplay between basic, translational and clinical
research has led to continuous progress in diagnostic
tools and management strategies4–9 (FIG. 1). Following
an era dominated by interferon (IFN)-based therapies,
targeted drugs — known as direct-acting antiviral agent
(DAA)-based regimens — have been developed that
cure chronic HCV infection in the majority of patients,
even in patient populations who were difficult to treat
in the past (for example, patients with HCV and HIV
co-infection, patients with decompensated liver disease
and patients with renal impairment)10. Cure is defined
as undetectable HCV RNA levels in the blood (that is,
a sustained virological response (SVR)) at 24 weeks
or, more recently, 12  weeks after the end of ther­
apy 11,12. In contrast to previous IFN-based regimens,
the quality of life (QOL) of patients improves during
DAA therapy 13. Diagnostic tools include anti-HCV
antibody testing, measurement of HCV RNA in the
serum as well as genotyping, subtyping and analysis
of resistance-associated substitutions (RASs). RASs are
amino acid substitutions in the viral RNA that form
the molecular basis for t­ reatment failures with new
DAA-based regimens14.
This Primer describes the latest developments and
aspects of the global combat against the worldwide hep­
atitis C epidemic in the era of highly effective therapies
without a prophylactic vaccine at the horizon.
Epidemiology
HCV prevalence
Global prevalence of individuals infected with HCV
based on positivity for anti-HCV antibodies has been
estimated at 1.6% (range: 1.3–2.1%), which corresponds
to 115 million (range: 92–149 million) individuals2.
However, not all of these people are currently infected
with HCV; some have cleared the virus either spon­
taneously or as a result of treatment. Thus, the global
­viraemic prevalence (that is, positive for HCV RNA) is
lower and estimated at 1% (range: 0.8–1.14%) or 71 mil­
lion (range: 62–79 million) individuals with HCV infec­
tion15. These estimates are based on extrapolations from
100 countries where generalizable studies have been
conducted. Availability of robust global data is a limita­
tion, with only 29% of low-income countries and 60%
of high-income countries reporting HCV prevalence.
The quality of the reported prevalence data also varies
across countries15.
Prevalence of HCV infection shows considerable
variation across the globe, with the highest infection
rate found in countries with a past or present history of

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PRIMER

Author addresses also occur, but are less common, except in the case of
HIV-infected men having unprotected sex with men26,27.
1
Department of Gastroenterology, Hepatology and Causes of iatrogenic infections include blood transfusion
Endocrinology, Hannover Medical School, or administration of clotting factors (with contaminated
Carl-Neuberg-Str. 1, 30625 Hannover, Germany. blood before the start of blood screening in the 1990s),
2
German Center for Infection Research (DZIF), Partner Site
long-term haemodialysis, injection of multiple individ­
Hannover-Braunschweig, Germany.
3
Helmholtz Centre for Infection Research (HZI), uals with the same syringe and reuse of glass syringes for
Braunschweig, Germany. medical injections. The importance of these risk factors
4
Liver Unit, Hospital Universitari Vall d’Hebron and differs between countries. The reuse of glass syringes for
CIBEREHD del Instituto Carlos III, Barcelona, Spain. medical injections continues to this day in some regions
5
New Zealand Liver Transplant Unit, Auckland City and remains, for example, the key risk factor in Pakistan.
Hospital, Auckland, New Zealand. In Europe and the United States, the greatest risk for HCV
6
National Reference Center for Viral Hepatitis B, C and D, infection is unsafe injection drug use, which accounts
Department of Virology, Hôpital Henri Mondor, Université for 50–60% of acute HCV infections24,28–31. In the past,
Paris-Est, Créteil, France. health care exposure was an important source of transmis­
7
INSERM U955, Créteil, France.
sion. Currently, needle-stick injuries among health care
8
Center for Disease Analysis, Lafayette, Colorado, USA.
9
Viral Hepatitis Center, Division of Gastroenterology, workers and patient-to‑patient transmission are still risk
University of California at San Francisco, San Francisco, factors for HCV transmission, as is receiving a tattoo in
California, USA. an unregulated setting32,33. However, no risk factors can be
10
Beatty Center for Integrated Research, Falls Church, identified in a considerable proportion (up to 40% in the
Virginia, USA. western world) of patients with HCV infection.

Comorbidities and mortality

iatrogenic infections (that is, infections due to the activ­
ity of a physician or medical therapy) (FIG. 2). Cameroon,
Egypt, Gabon, Georgia, Mongolia, Nigeria and
Uzbekistan2,16–21 all have an anti-HCV antibody preva­
lence of >5% in the adult population; iatrogenic infection
is a key risk factor in these countries. The source of HCV
infection in Egypt is well documented and attributed to
intravenous treatment for schistosomiasis (flat worm)
in the 1960–1970s22,23. Western countries account only
for a small percentage of global HCV infections, with
China, Pakistan, India, Egypt and Russia accounting for
approximately half of the total viraemic HCV infections2.
The age distribution of the HCV-infected population
correlates to the primary source of infection in specific
countries. Countries where injection drug use is an ongo­
ing important risk factor (for example, Australia, Czech
Republic, Finland, Luxembourg, Portugal, Russia and
the United Kingdom), the HCV-infected population
has a peak age of mid‑30s years, whereas the peak age
is usually older (50–60 years) in countries where iatro­
genic infections dominate as the cause24,25. This difference
is explained by the fact that active injection drug users
are typically young, whereas most iatrogenic infections
occurred before the 1990s when diagnostics for HCV
became available. In some countries, the age profile is
mixed owing to the presence of several risk factors.
HCV genotype distribution varies by region (FIG. 3).
This genotypic distribution has implications on clinical
course and the requirements for treatment and drug devel­
opment. Pan-genotypic drugs are, in particular, needed in
lower-middle-income and low-income ­countries where
genotype 1 accounts for less than half of all infections2.
Chronic HCV infection can result in hepatic fibrosis,
cirrhosis and hepatocellular carcinoma. The progres­
sion through these stages is a function of time since
infection and age of initial infection. Japan, which has
the oldest HCV-infected population, is already seeing
a drop in hepatocellular carcinoma cases34, as infected
individuals are dying of other causes before progress­
ing to hepato­cellular carcinoma. However, in nearly
every other country, the projected number of hepato­
cellular carcinoma and decompensated cirrhosis cases
as a result of HCV infection has been increasing and
will continue to increase in the absence of treatment and
universal screening programmes and interventions35–37.
A recent study showed that, worldwide, the number of
hepatitis C-related deaths as a result of hepatocellular
carcinoma and cirrhosis increased from 895,000 deaths
in 1990 to 1,454,000 deaths in 2013; the proportion of
deaths that were attributed to hepatitis C without hepato­
cellular carcinoma also increased in the same period
from 33.8% in 1990 to 48.4% in 2015 (REF. 1).
In addition to liver-related complications, HCV infec­
tion is associated with numerous extrahepatic manifes­
tations38. Individuals with chronic HCV infection are
more likely to develop cryoglobulinaemia and non-­
Hodgkin lymphoma38. In addition, these individ­uals are
at increased risk of developing insulin resistance and dia­
betes mellitus, which may lead to the increase in cardio­
vascular mortality as a result of stroke and myo­cardial
perfusion defects39. Finally, fatigue is more common
among those with chronic HCV infection and in patients
with lower health-related QOL (HRQOL); fatigue and
HRQOL scores improve after achieving a SVR.

Risk factors Mechanisms/pathophysiology

HCV is primarily transmitted through percutaneous HCV is a member of the Flaviviridae family and the
exposure to blood, owing to medical procedures or genus Hepacivirus, which also includes GB virus B and
sharing contaminated devices for injection drug use. the recently identified non-primate, rodent and bat
Mother-to‑infant transmission and sexual transmission hepaci­viruses40–44. HCV virions are 45–65 nm in diameter

2 | ARTICLE NUMBER 17006 | VOLUME 3 www.nature.com/nrdp

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 PRIMER

and are enveloped in a lipid bilayer in which two envel­
ope  glyco­proteins (E1 and E2) are anchored. The
­envelope surrounds the non-­icosahedral nucleo­capsid,
which is composed of multiple copies of the small basic
HCV core protein and contains the positive-strand RNA
genome of approximately 9.6 kb, with an open reading
frame encoding a single polyprotein of approximately
3,000 amino acids. The structural proteins (core, E1
and E2) are encoded by the amino‑­terminal part of the
open reading frame, whereas the remaining portion
codes for the non-structural proteins (p7, NS2, NS3,
NS4A, NS4B, NS5A and NS5B)45. HCV virions are
associ­ated with host low-density lipoproteins (LDLs) and
very-low-­density lipoproteins (VLDLs), forming what are
known as lipoviroparticles. The lipoviroparticles also
contain apolipoprotein B (APOB) and other exchange­
able apolipo­proteins, such as APOC and APOE46. Poorly
infectious non-enveloped viral capsids may also be
­present in the blood of infected patients.
HCV is a very heterogeneous virus. Phylogenetic
analyses of HCV strains isolated in various regions of
the world have led to the identification of seven main
HCV genotypes, designated 1–7. The HCV genotypes
comprise a large number of subtypes, identified by
lower-­case letters (1a, 1b, and so on)44. The genotype
influences the­disease course and the response to ­antiviral
therapy (FIG. 3).
HCV life cycle
Viral attachment involves the two envelope glyco­proteins,
E1 and E2, apolipoproteins present at the surface of
the lipoviroparticles and several cell surface mol­ecules
(FIG. 4). Glycosaminoglycans and the LDL receptor seem
to be involved in low-affinity initial cell binding. Then,
E1–E2 interacts with CD81 and scavenger receptor class B
member 1, whereas claudin 1, occludin and possibly
other molecules, such as claudin 6 or claudin 9, epider­
mal growth factor receptor or ephrin receptor type A2,
are required for cell entry 47. This multi-receptor complex
mediates uptake and defines organ and species specifi­
city. The E2 envelope glycoprotein contains hypervariable
regions that play the part of immunodominant neutral­
ization epitopes. Antibodies against these hypervariable
regions in patient sera are protective. However, the high
variability of HCV with different viral quasi-­species in
the same patient has so far prevented the develop­ment a
successful prophylactic vaccine based on these viral pro­
teins. HCV–receptor complexes are seemingly associated
with tight junctions, which enable direct cell–cell trans­
mission48. After attachment, HCV entry into cells results
in clathrin-mediated endocytosis, followed by fusion
between viral and endosomal membranes, which leads
to the release of the nucleocapsid into the cytoplasm. The
E1 envelope glycoprotein is believed to be the fusogen
(the glycoprotein that facilitates cell fusion).

IFN used for the Nucleic acid test for HCV Evidence that early treatment Proof of In vitro October
treatment of of acute HCV infection with IFN concept system Approval of sofosbuvir/ledipasvir
non-A, non-B IFN plus prevents chronic infection for the for HCV
hepatitis ribavirin first HCV infection December
PEG-IFN plus ribavirin as standard protease Approval of ombitasvir/paritaprevir/r
of care for the next decade inhibitor plus dasabuvir

1986 1989 1993 1996 1998 1999 2001 2003 2005 2013 2014 2015 2016

Identification of HCV Crystal structure Replicon November July January

of NS3/4A system Approval of simeprevir Approval of Approval of elbasvir/grazoprevir
daclatasvir in the United States
December
Approval of sofosbuvir June
Approval of sofosbuvir/velpatasvir

Advances in HCV biology July

IFN treatment era Approval of elbasvir/grazoprevir
All oral, IFN-free treatment era in Europe

Figure 1 | Milestones in HCV research and management. Recombinant
interferon‑α (IFN) injected three times a week was given to patients with
non‑A, non‑B hepatitis — a term used for hepatitis C before the hepatitis C
virus (HCV) was discovered in 1989 (REF. 179). Subsequently, the dose of IFN
and duration of treatment were increased; then, IFN was empirically
combined with ribavirin, which is a non-specific antiviral agent180,181.
Between 2001 and 2011 (REF. 182) , the combination of long-acting
pegylated (PEG)-IFNs, PEG‑IFNα2a or PEG‑IFNα2b, in combination with
ribavirin became the standard of care183,184. Treatment of chronic hepatitis C
between 12 and 72 weeks resulted in sustained virological response (SVR)
rates (that is, undetectable HCV RNA levels in the blood 12 or 24 weeks after
the end of treatment) of 40% for patients with HCV genotype 1 infection
and 80% for patients with HCV genotype 2 infection, but considerable
adverse effects were the price to pay. Unravelling of the HCV life cycle,
crystallography of HCV viral enzymes and the development of the HCV
replicon system4 paved the way towards direct-acting antiviral agents
(DAAs), which specifically interfere withNature
the HCVReviews | Disease
life cycle 55 Primers
. BILN 2061,
a NS3/4A protease inhibitor, became the first DAA to show significant
inhibition of viral replication in humans, but further clinical development
was terminated owing to safety concerns. Subsequently, DAAs against
three different targets of the HCV life cycle were approved55. In 2011, two
HCV protease inhibitors, boceprevir and telaprevir, were approved, but
treatment had to be combined with PEG-IFN and ribavirin at the cost of
adverse effects. Several NS3/4A and NS5A inhibitors and one nucleotide as
well as one non-nucleotide NS5B polymerase inhibitor were approved
between 2013 and 2016. When two or three DAAs are combined, cure
rates between 90% and 100% are achieved. These new all-oral, IFN-free
DAA regimens are administered for durations of 8–24 weeks and are
associated with excellent tolerability and safety. Paritaprevir/r, paritaprevir
ritonavir-boosted.

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PRIMER

Viraemic prevalence (%)

<0.6
0.6–0.74
0.75–1.29
1.3–2.8
>2.9
Infected individuals
>5 million
1 million–5 million
<1 million

Figure 2 | HCV prevalence. Schematic representation of the actual viraemic hepatitis C virus
Nature Reviews
(HCV) | Disease
prevalence andPrimers
the
extrapolated total HCV infections per country. Figure based on data obtained from REF. 15.

Uncoating of the viral nucleocapsid liberates the
positive-strand genomic RNA into the cytosol, where it
serves as mRNA for synthesis of the HCV polyprotein.
The HCV 5ʹ untranslated region contains an internal
ribosome entry site, which controls HCV open reading
frame translation49. The large precursor polyprotein
gener­ated is translated at the endoplasmic reticulum
membrane where the processing events take place, result­
ing in the generation of the three structural proteins and
the seven non-structural proteins50. At least two host
cellular peptidases (signalase and signal peptide pepti­
dase) are required for the processing of the HCV struc­
tural proteins, whereas two viral peptidases (NS2 and
NS3/4A) are involved in the processing of the HCV non-­
structural proteins. The viral proteins remain a­ ssociated
with i­ ntracellular membranes after processing 51.
Replication is catalysed by the NS5B protein. The
NS5A protein and the helicase-NTPase domain of NS3
play an important regulatory part in virus replication52,53.
NS5A acts as a dimer with a basic channel involved in
RNA binding. Domain I and domain II of the NS5A pro­
tein are required for HCV replication in the replication
complex. The phosphorylation state of NS5A modu­
lates the balance between replication and later stages of
the HCV life cycle. The NS3 helicase has an important
role in separating nascent and template RNA strands,
unwinding RNA secondary structures and displacing
RNA-binding proteins53. NS4B is an integral membrane
protein with a role in membrane rearrangements that
are induced by HCV proteins, leading to the formation
of the ‘membranous web’ or replication complex that
supports and compartmentalizes HCV replication. The
positive-strand genome RNA serves as a template for the
synthesis of a negative-strand intermediate of replication.
Then, negative-­strand RNAs serve as templates to prod­
uce numerous strands of positive polarity that are subse­
quently used for polyprotein translation, the synthesis of
new intermediates of replication or packaging into new
virus particles52. Various host factors have also been shown
to have important functional roles in the HCV life cycle.
Cyclophilin A (also known as peptidylprolyl isomerase A)
binds to both NS5A and NS5B, thereby inducing the con­
formational changes that are required for efficient HCV
replication. MicroRNA‑122 (miR‑122), an abundant
liver-­specific miRNA, binds to two conserved sites in the
internal ribosome entry site, which is required for effi­
cient HCV replication and RNA stabilization. Other host
factors and pathways are involved in HCV replication,
such as phosphatidylinositol 4‑kinase IIIα or the choles­
terol and fatty acid biosynthesis pathways. Viral particle
formation is initiated by the interaction of the core and
NS5A proteins with genomic RNA in cytoplasmic lipid
droplets. HCV uses the VLDL production pathway at the
later stages of assembly and for release54.
DAAs
Targets. The multiple steps in the HCV life cycle prov­ide
the targets for DAAs14,53,55 (FIG. 4). The NS3/4A protease
was identified as a major target for antiviral intervention,
as its blockade shuts down the intra­cellular life cycle by
inhibiting maturation of the viral poly­protein. Replication
has been identified as a major target for antiviral drugs.
Replication can be directly inhibited by NS5B inhibitors.
These include nucleotide analogues, which function

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as RNA chain terminators after being activated intra­
cellularly by two rounds of phosphoryl­ation, and non-­
nucleoside inhibitors of NS5B that target allosteric
sites of the enzyme and make it non-­functional. NS5A
inhibitors alter the regulatory role of NS5A and seem to
disorganize the replication complex, thereby inhibiting
HCV replication in a potent manner, enhanced by their
ability to also inhibit viral assembly and release. Besides
well-known DAA targets, host-­targeted replication inhib­
itory approaches are attractive, because of their potential
for high barrier to resistance. Cyclophilin inhibition by
non-­immunosuppressive analo­gues of cyclosporine A is
credible, but no drugs have reached the market thus far,
owing to adverse effects that are ­unrelated to cyclophilin
inhibition. miR‑122 antagonists have reached clinical
development in an injectable form56, but safety issues
caused clinical hold.
Resistance to DAAs. HCV has a viral quasi-species
distrib­ution57. The viral populations that constitute the
quasi-­species differ by amino acid polymorphisms that
were generated during replication and subsequently
selected based on their effect on the corresponding virus
replication capacity. Natural polymorphisms that are
present in a region targeted by a DAA may confer reduced
susceptibility to the DAA class or the speci­fic DAA. Upon
DAA administration, selection of viral vari­ants with
reduced susceptibility to the drug (or drugs) defines ‘viral
resistance’. The term ‘resistance-­associated variant’, which
has been often used to indiffer­ently character­ize substitu­
tions that confer reduced susceptibil­ity to a drug or drug
class and the viral variants that carry these substitutions,
is incorrect. Substitutions (that is, amino acid changes)
that confer resistance are now called RASs, whereas
the viral variants that carry these RASs and thus have
reduced susceptibility to the DAA are called ‘­resistant
variants’ (REF. 14).
100
Genotype
90 1a
Distribution of HCV genotypes (%)
In DAA-based antiviral treatments, each viral popu­
lation that is present in the quasi-species at baseline
evolves following individual kinetics that depend on
its amount at treatment initiation, its susceptibility to
the antiviral action of the DAAs and its fitness in the
presence of the DAA combination. Sensitive viral popu­
lations are rapidly eliminated, whereas resistant variants
are selected. Failure during treatment is called break­
through. However, most often treatment failure with
current regimens is due to relapse (that is, the recurrence
of the virus in the blood after treatment). The major­
ity of viral populations are resistant to one or several of
the drugs administered. They are characterized by the
presence of class-specific or drug-specific RASs on their
genomes. After treatment failure, variants that are resist­
ant to NS3/4A protease inhibitors disappear within a few
weeks to months after termination of therapy, whereas
variants that are resistant to NS5A inhibitors persist for
years, probably for ever in most cases14.
Immune response
Both innate and adaptive immune responses are impor­
tant for HCV viral clearance. For the innate immune
response, natural killer (NK) cells seem to be involved
in resolving HCV infection; it has been shown that
certain NK cell receptor genes (those encoding killer
cell immunoglobulin-like receptor 2DL3 (KIR2DL3)
and HLA‑C1) are associated with viral clearance58. For
adaptive immune responses, humoral antibody and
T cell responses are usually involved in controlling viral
infections. For HCV infection, most antibodies seem to
have no relevant activity against HCV owing to the high
variability of the virus and the quasi-species populations
in a single patient. Nevertheless, neutralizing antibodies
against certain epitopes may be protective59, and rapid
induction of neutralizing antibodies has been associated
with the control of infection60. Most data are available
on T cell responses. Broad and multi-specific CD4+ and
CD8+ T cell responses are associated with spontaneous
viral clearance, and the persistence of infection is attrib­

uted to an insufficient or early loss of T cell responsive­

80 1b
ness61. Several studies have shown a reduction in the
70 1 (other)
2
frequency and proportion of subpopulations of T cells
60
3 in the circulation when acute HCV infection develops
50 4 into chronicity 62,63. Studies in chimpanzees have prov­
40 5 ided evidence that loss of T helper cell activity results in
6 immune evasion of CD8+ T cells and viral persistence64.
30
Experimental depletion of CD8+ T cells in chimpan­
20
zees resulted in viral persistence until the CD8+ T cell
10 response recovered64.
0 HCV has evolved several immune escape or evasion
High Upper middle Lower middle Low strategies that are linked to the persistence of infection65.
Income countries For example, the HCV NS3/4A protein can efficiently
Figure 3 | HCV genotype distribution. Hepatitis C virus Nature
(HCV)Reviews Disease Primers
is a very |heterogeneous cleave and inactivate two host signalling pathways that
virus; seven genotypes have been detected thus far, but this figure focuses on six. react to HCV pathogen-associated molecular patterns to
Genotype distribution differs between countries according to the World Bank income
induce the IFN pathway. Nevertheless, IFN-stimulated
categories. Genotype 1 is more prevalent in the Americas, Europe, Australia,
New Zealand, Central Asia and East Asia. Genotype 3 is most common in India185 genes are induced during acute HCV infection, but this
and Pakistan186, whereas genotype 4 dominates in Egypt187–189 and Central sub-Saharan response is not very effective at clearing the virus. IFN-
Africa15. Genotype 5 accounts for more than one-third of HCV infections in responsive gene expression remains high in chronic
South Africa190,191, whereas genotype 6 is found in South East Asia192–197. Figure based infection66, which was associated with poor response to
on data obtained from REF. 15. IFN-based treatment.

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PRIMER

Sinusoidal lumen
Viral
particle
Viral
attachment

Hepatocyte LDLR
SRB1

CD81

Clathrin-mediated
Claudin 1 endocytosis Viral
release

Golgi
Occludin

RNA
uncoating
Nucleocapsid Viral miR-122?
assembly
RNA +
accumulation
Membranous
HCV RNA
web (replication – +
Structural and
+
Cytosol Processing complex) RNA
non-structural
miR-122? viral proteins RNA
Polyprotein Polyprotein NS4B replication
translation
and processing
NS4A NS5B
NS3 NS5A
ER lumen
Nucleus ER

Figure 4 | HCV life cycle. Schematic representation of the hepatitis C virus (HCV) life cycle involving
Nature viral| attachment,
Reviews Disease Primers
clathrin-mediated endocytosis, polyprotein translation and processing, RNA replication and, finally, viral assembly and
release. ER, endoplasmic reticulum; LDLR, low-density lipoprotein receptor; miR‑122, microRNA‑122; SRB1, scavenger
receptor class B member 1.

In addition, the evolution to chronic HCV infection
is associated with a rapid exhaustion or alteration of
immune responses. Mucosal-associated invariant T cell
(innate-like effector T cells) levels are severely reduced in
chronic HCV infection67. NK cells exhibit alterations
in phenotype and function during chronic HCV infec­
tion68. In addition, liver-infiltrating intrahepatic T cells
are phenotypically exhausted and dysfunctional69–71;
programmed cell death protein 1 and other markers of
functional exhaustion and apoptosis are upregulated68,72.
Despite intensive studies of the innate and adaptive
immune responses in acute and chronic HCV infection,
the precise interplay between the innate and adaptive
immune responses that determines resolution versus
viral persistence remains incompletely understood.
Pathogenesis of HCV-associated liver disorders
Fibrogenesis — characterized by the activation of hepatic
stellate cells into myofibroblasts, which produce fibrous
extracellular matrix in excess — is the main complica­
tion of chronic HCV infection73. It leads to progressive
liver fibrosis and, ultimately, the development of cirrho­
sis and its complications. Local inflammation seems to
be an important driver of fibrogenesis. Chronic HCV
infection is associated with chronic hepatic inflam­
mation, as a result of oxidative stress and immune
response directed to infected hepatocytes that express
viral epitopes74. The T helper 2 cell response observed
during chronic HCV infection seems to have an
important role in chronic inflammation. In addition,
numerous growth factors, chemokines and cytokines
are produced in the infected hepatocytes; these ­factors
partici­pate in the recruitment of immune cells, the
perpetu­ation of the local inflammatory response and
the activation of hepatic stellate cells into myofibro­
blasts 75. CD8 + T cell-induced apoptosis of hepato­
cytes might also have an important role in sustaining
inflammation and activating hepatic stellate cells76,77.
In addition, the virus itself could participate in the
fibrogenic process; indeed, HCV has been suggested to
directly interact with hepatic stellate cells and this inter­
action could accelerate the fibrogenic process73. Finally,
changes in hepatocyte proliferation during HCV
infection also seem to be involved in the progression
of liver fibrosis. These changes could be due to direct
intra­cellular interactions between HCV proteins and

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proteins involved in the regulation of the cell cycle, and
to disorganization of cell cycle checkpoints by DNA
damage that is induced by the oxidative stress generated
during infection.
Patients with hepatitis C-related cirrhosis have a 4–5%
cumulative annual incidence of hepatocellular carci­
noma78. Cirrhosis is the main determinant of hepato­
cellular carcinoma, given that this carcinoma is rare in
patients infected with HCV who do not have cirrhosis78.
HCV infection seems to have a role in the carcinogenic
process. Indeed, HCV can hijack molecular pathways
involved in the control of the cell cycle. Together, DNA
damage and abnormalities of cell cycle and apoptosis
control could lead to hepatocyte transformation. In addi­
tion, increased proliferation due to the loss of infected
cells may participate, together with local inflammation
and oxidative stress, in triggering hepatocyte trans­
formation79. The role of the local immune response in
­subsequent tumour progression remains unclear.
Diagnosis, screening and prevention
Clinical course
In the majority of cases, acute infection occurs with­
out symptoms and without clinically overt disease.
A minority of patients develop acute hepatitis C with
jaundice, fatigue, right upper abdominal pain or dis­
comfort, or arthralgia (joint pain). If acute HCV infec­
tion is associated with acute symptomatic hepatitis C,
the chronicity rate is lower than with asymptomatic
infection. Acute HCV infection leads to a chronic
infection in around 75–85% of people; over the course
of 20–30 years, a proportion of patients will progress
to liver cirrhosis and other consequences of cirrhosis,
such as hepatic decompensation (which is characterized
by ascites, upper gastro­intestinal bleeding, hepatorenal
syndrome and hepatic encephalopathy) and hepato­
cellular carci­noma. Before developing symptoms of
decompen­sation, patients may experience symptoms
such as fatigue, weight loss, muscle and joint pain,
or right upper abdominal discomfort, pain or itching.
Progression is not necessarily a linear process and can be
accelerated by numerous factors, including the age of the
patient, male sex, alcohol consumption and co‑­infection
with other viruses, such as hepatitis B virus (HBV) and
HIV, or other infectious agents, such as schisto­somiasis.
Many patients with chronic HCV infection remain
asymptomatic over years and only become aware of
this life-threatening ­disease once they have already
­developed cirrhosis80.
The natural course, and therefore the clinical out­
come of acute and chronic HCV infection, is like in every
infectious disease: the result of the interplay between
the infectious agent and the host, in particular, the genet­
ically determined immune system of the patient. The
level of viral replication (measured as HCV levels in the
blood) does not predict natural course and outcome of
disease, but has been and still is a predictor of treatment
response, in particular, in the pegylated (PEG)-IFN plus
ribavirin era; it is of less importance for DAA treatment.
However, viral genotypes differ in clinical course and
treatment response. HCV genotype 3 infection seems
to run a more aggressive course, including increased
risk for the development of hepatocellular carcinoma,
than do the other genotypes. Patients infected with HCV
genotype 1 were the most difficult to treat in the PEG-
IFN plus ribavirin era; patients with HCV genotype 3
infection are the most difficult to treat with DAAs.
HCV subtypes also matter. For HCV genotype 1a, the
response rates are lower with the so‑called 3D regimen
(comprising ombitasvir/paritaprevir ritonavir-boosted
(paritaprevir/r) plus dasabuvir) and with the recently
approved elbasvir/grazoprevir (a one tablet combination
therapy) regimen.
Diagnostic and monitoring tools
Several virological tools can be used to diagnose and
monitor HCV infection. Third-generation enzyme-
linked immunosorbent assays are currently used for the
detection of anti-HCV antibodies in serum or plasma.
These tests are sensitive and specific, can be fully auto­
mated and are relatively inexpensive. The serological
window between infection and seroconversion when
anti-HCV antibodies become detectable is variable and
ranges on average between 2 and 8 weeks; thus, testing
only for anti-HCV antibodies might miss early infec­
tion. Anti-HCV antibodies then persist in patients who
develop chronic infection81. In patients clearing the
virus, anti-HCV antibodies persist for years or even
decades82. Rapid diagnostic tests for the detection of
anti-HCV antibodies are being increasingly used for the
screening of infected individuals in middle-to-low-risk
populations. An additional advantage is that they can be
used not only with serum or plasma but also with whole
blood from a finger prick blood sample or crevicular
oral fluid83,84. Only rapid diagnostic tests with validated
analytical performance (high sensitivity and specificity)
must be used.
Detection and quantification of HCV RNA are useful
to diagnose active infection (characterized by virus rep­
lication), identify patients with an indication for therapy
and evaluate the response to antiviral therapy, and detect
treatment resistance in patients receiving DAAs85. HCV
RNA detection and quantification are based on real-time
PCR or transcription-mediated amplification methods,
which are both sensitive and specific. The results are
expressed in IU per ml.
HCV genotype and, in the case of genotype 1, subtype
determination is needed to guide treatment indications
(the treatment regimen, the duration of therapy and the
addition of ribavirin). The reference method is phylo­
genetic analysis of the nucleotide sequence of a portion
of the viral genome, which is generated by population
(direct) sequencing. In clinical practice, standardized
methods based on direct sequence analysis or reverse
hybridization (line probe assay) are used81,86.
The HCV core antigen — epitopes that are expressed
on the HCV nucleocapsid protein — is a surrogate
marker of HCV replication and can be detected and
quantified in the blood of the patient. Thus, it can be
used as an alternative to HCV RNA assays in the diag­
nosis of infection and antiviral treatment monitoring 87,88.
HCV core antigen detection and quantification are

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based on an automated enzyme immunoassay. Its lower
limit of detection is equivalent to 500–3,000 HCV RNA
IU per ml according to the HCV genotype. HCV core
antigen represents an interesting and cost-effective alter­
native to HCV RNA assays to diagnose infection and
assess the SVR to antiviral therapy. However, this test is
not widely used in clinical practice.
Resistance testing is currently based on population
sequencing of the drug target region in patients who fail
during or, most often, after an IFN-free antiviral regi­
men. Population sequencing detects variants that rep­
resent at least 15% of the viruses in a patient. There is
only one commercial assay available in the United States
thus far. As a result, most resistance testing is based on
in‑house methods, the performance and reproducibil­
ity of which have not always been properly validated.
Resistance tests detect RASs that are present in large pro­
portions (approximately >15%) of HCVs in the blood of
patients. Deep sequencing technology is more sensitive
(the detection of RASs present in 1% of the viruses).
However, population sequencing with a sensitivity of
15% is more appropriate to detect clinically relevant RAS
populations that confer DAA resistance.
Diagnostic algorithm
Diagnostic tests for HCV infection should be applied
for all patients with increased levels of liver enzymes
in the blood, such as the transaminases alanine amino­
transferase and aspartate aminotransferase; increases
in the levels of these enzymes indicate increased rates
of liver cell death and, therefore, damage. Otherwise,
all blood donors are screened for anti-HCV antibodies
and, in some countries, also for HCV RNA because a
considerable proportion of anti-HCV antibody-positive
patients do not have increased levels of liver enzymes,
Suspected HCV infection
Measurement of anti-HCV antibodies
+ –
Detection of HCV RNA – No HCV infection
+
Patients diagnosed with replicative HCV
or chronic hepatitis C if HCV RNA test
remains positive for 6 months
If HCV infection is still suspected,
perform determination of HCV RNA.
If therapy is planned: If positive‡, patients are diagnosed
• Quantitative assessment of HCV RNA with acute HCV infection or chronic
• Liver tests* infection in immunocompromised
• No routine RAS testing pretreatment patients
Figure 5 | Diagnostic algorithm for HCV infection. Minus Nature Reviews
arrow | Disease
indicates Primers
negative
results, plus arrow indicates positive results and dashed arrow indicates inconclusive
cases. RAS; resistance-associated substitution. *Currently, non-invasive methods
(such as elastography) are widely used for staging of liver disease. Liver biopsy is not used
for the diagnosis of hepatitis C virus (HCV) infection; its value is to determine grading
and, in particular, staging of liver disease (that is, the degree of liver fibrosis) and to
exclude other liver pathologies. ‡Negative result for anti-HCV antibodies, but positive
result for HCV RNA in blood samples.
meaning that these patients carry HCV, have no liver
damage, but can transmit the virus. The targets of HCV
screening programmes vary between different countries
and regions (see below).
HCV screening and diagnosis are based on the detec­
tion of anti-HCV antibodies by means of an enzyme-
linked immunosorbent assay or a rapid diagnostic test
(FIG. 5). In the absence of recent exposure or profound
immune suppression, a negative result indicates the
absence of infection. In case of positive detection of
anti-HCV antibodies, the detection of HCV RNA or
HCV core antigen should be performed to confirm
active infection. If acute hepatitis of unknown origin is
suspected, the presence of both anti-HCV anti­bodies
and HCV RNA (or HCV core antigen) should be deter­
mined. The sole presence of HCV RNA, but not antibod­
ies, indicates acute HCV infection; a second test should
be performed a few weeks later to show seroconversion,
which proves acute HCV infection. If only anti-HCV
antibodies are present, the patient may have cured
HCV infection spontaneously following antiviral treat­
ment in the past or the result may be a false positive. The
simultaneous presence of both markers proves infection
but does not differentiate acute from chronic infec­
tion. Chronic hepatitis C is defined by the persistence
of HCV RNA over 6 months after acute infection and
is characterized by the simultaneous presence of anti-
HCV antibodies and HCV RNA. Genotype or subtype
determination should be performed in patients with an
indication for treatment, to tailor the treatment regimen
(the choice of DAAs, the duration of treatment and the
addition of ribavirin).
Virological tools are particularly useful in the con­
text of chronic hepatitis C treatment monitoring 85. The
goal of therapy is SVR, defined as an undetectable HCV
RNA (or HCV core antigen) in the serum 12 weeks after
the end of treatment, which corresponds to a definitive
cure of infection11,12. In theory, all patients with detect­
able HCV RNA are candidates for antiviral therapy.
Monitoring of treatment efficacy is based on repeated
measurements of HCV RNA levels (or HCV core anti­
gen) during and after therapy. With IFN-free regimens,
it is recommended to assess HCV RNA levels at baseline,
week 2 or week 4 (to assess treatment adherence), at the
end of treatment and 12, 24 or 48 weeks after the end
of treatment 85.
The indications of RAS testing are still unclear.
In ­general, resistance testing should not be performed
before first-line therapy, because most treating physi­
cians do not have access to these tests and it is unlikely
that the result will influence treatment decision.
However, when available, pre-treatment resistance test­
ing can help to intensify therapy in patients with detect­
able NS5A RASs at baseline. At the moment, pre-existing
NS5A RASs seem to be of utmost importance for failures
following treatment with NS5A inhibitor-­containing
regimens. In Asian countries, such as Japan and Korea,
where the daclatasvir plus asunaprevir regimen is
approved and used for patients with HCV genotype 1b
infection, pre-treatment NS5A RAS testing is everyday
practice. For the elbasvir/grazoprevir regimen, which has

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Box 1 | Scoring systems to assess severity and prognosis of liver disease
Child–Pugh scoring system
The Child–Pugh scoring system172,173 assesses the prognosis of chronic liver disease,
based on five clinical measures: total bilirubin level, serum albumin level, prothrombin
time, ascites severity and hepatic encephalopathy grade. Patients are classified in one
of three groups of predicted survival rates.
• Child–Pugh score A: well-preserved liver function with a median 2‑year survival
of 85%
• Child–Pugh score B: moderate liver dysfunction with a median 2‑year survival of 57%
• Child–Pugh score C: severe, decompensated liver dysfunction with a median 2‑year
survival of 35%
Model for End-Stage Liver Disease
Model for End-Stage Liver Disease is a scoring system used to assess the severity and
prognosis of chronic liver disease based on the serum bilirubin level, serum creatinine
level and prothrombin time. The higher the value, the higher the mortality risk.
been recently approved in the United States, Canada,
and Europe, pre-treatment NS5A RAS testing is recom­
mended for patients with HCV genotype 1a infection89.
Resistance testing (including NS3 protease, and NS5A
and NS5B polymerase regions) is useful in patients who
failed on a DAA-containing regimen at re-treatment,
to guide the choice of drugs for r­ e-treatment and the
­duration of treatment.
HCV infection can lead to liver complications,
including fibrosis, cirrhosis and hepatocellular carci­
noma. Monitoring of liver parameters is required in
patients with chronic hepatitis C. Apart from liver
biopsy, non-invasive methods, such as serum fibrosis
markers (including FibroTest (known as FibroSure in
the United States), Enhanced Liver Fibrosis score and
Fibrosis‑4 index) or liver stiffness measurement by tran­
sient elastography (such as Fibroscan and Shear Wave),
are well established to diagnose or exclude cirrhosis. Liver
biopsies are less often used these days to determine the
level of fibrosis (staging of liver disease). Non-invasive
tests, as ­mentioned above, are preferred. Effectiveness
of achieving a SVR following DAA treatment does not
differ between patients without and with compensated
Child–Pugh score A cirrhosis (BOX 1). However, SVR rates
seem to drop when liver disease moves to Child–Pugh
score B or score C. In particular, portal hypertension
seems to be a predictive parameter for non-response to
DAA treatment. Reliable methods to determine hepatic
vein pressure, for example, hepatic vein pressure gradi­
ent, are invasive and not widely used in clinical practice.
Thrombocyte counts in peripheral blood may be an easy
and cost-effective surrogate marker for portal hyperten­
sion. Non-invasive measures for portal hypertension
would be most welcome to determine the stage of liver
disease and to m ­ onitor treatment outcome.
Screening
Screening for HCV infection through anti-HCV anti­
body detection is crucial for diagnosis, improving the
health of those with active infection and preventing
transmission. It is estimated that 45–85% of infected
­p eople are ­u naware of their condition because
HCV infection usually does not produce symptoms
until late stages of the disease. A recent study from
Germany, which screened >20,000 patients, reported
that 65% of the identified individuals who were pos­
itive for anti‑HCV antibodies were unaware of their
HCV infection90.
HCV testing is recommended in specific populations
(BOX 2), based on the HCV prevalence, proven benefits
of care (that is, signs of disease progression and/or
impaired liver function) and treatment in reducing the
risk of hepatocellular carcinoma and all-cause mortality,
and the potential public health benefit of reducing trans­
mission32,33. In 2012 in the United States, the US Centers
for Disease Control and Prevention expanded its guide­
lines for risk-based HCV testing, recommending a one-
time HCV test for everyone born between 1945 and
1965, regardless of HCV risk factors. This birth cohort
recommendation was supported by evidence that risk-
based strategies alone fail to identify >50% of HCV
infections33. Furthermore, the 1945–1965 birth cohort
accounts for nearly three-fourths of all HCV infections,
with a fivefold higher prevalence (3.25%) than in other
cohorts in the United States. A retrospective review
showed that 68% of people with HCV infection would
have been identified through a birth cohort testing
strategy versus only 27% by risk factor screening 91. This
strategy can be applied to other countries with a similar
epidemiological pattern (a generation with a prevalence
of HCV infection, owing to, for example, a preva­
lence of intravenous drug use in the United States), but
not to others, such as, for example, Germany (reviewed
in REF. 92).
In May 2016, the World Health Assembly adopted the
first ‘Global Health Sector Strategy on Viral Hepatitis,
2016–2021’. The strategy has a vision of eliminating viral
hepatitis as a public health problem, and the global tar­
gets are reducing new viral hepatitis infections by 90%
and reducing deaths due to viral hepatitis by 65% by
2030 (REF. 93).
Prevention
No vaccines are available to prevent HCV infection,
because IgGs are not effective for post-exposure prophy­
laxis. Studies assessing the use of antiviral agents as
post-exposure prophylaxis are lacking 94,95. Hence, to
reduce the burden of HCV infection and related dis­
ease, primary prevention activities that lower the risk of
acquiring this infection are required. Primary prevention
is aimed at reducing or eliminating HCV transmission
due to: blood, blood components and plasma derivatives;
high-risk activities, such as unsafe injection drug use and
unprotected sex with multiple partners; and exposure
to blood in health care settings and others (for example,
tattooing and body piercing)96. Identification of people
who are at risk of acquiring HCV infection provides
the opportunity for counselling on how to reduce their
risk (BOX 3).
Secondary prevention activities can reduce the risk
of chronic disease by identifying people infected with
HCV through screening and providing appropriate med­
ical management and antiviral therapy 97–99. One of the
main problems in the prevention of HCV infections is

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that the disease does not immediately produce symp­
toms, therefore many individuals do not know they are
infected. Identification of the large number of people
who unknowingly have chronic HCV infection should
be a major focus of current prevention programmes.
An important aspect after testing is linkage to care,
including referral for medical evaluation and manage­
ment. Counselling can prevent disease transmis­
sion (for example, injection drug use) and progression
(for example, excessive alcohol intake) by encour­aging
patients to reduce high-risk practices. Currently, avail­
able measures to prevent HCV transmission are treat­
ment of individuals with chronic infection as well
as patients with acute infection100. HCV therapy has
changed and improved dramatically since the introduc­
tion of DAAs, which effectively result in a SVR, thereby
lowering the risk of transmission97,98. In several countries,
the combined efforts of various stakeholders to design
effective treatment-­as‑prevention strategies include,
for example, treating HCV-positive prison inmates.
Recommendations on how and who to test and then con­
sequently who to treat in low-income and h ­ igh-income
countries were recently published by the WHO92.
Management
Acute hepatitis C
Recommendations for treating acute hepatitis C have
been published, are still under debate and will be
influenced by ongoing and future studies with DAAs
(the latest European Association for the Study of
the Liver (EASL) and American Association for the
Study of the Liver (AASLD) guidelines)101,102. Only
patients with proven HCV infection, meaning detect­
able HCV RNA in the serum, should receive antiviral
therapy. There is no indication to treat for hepatitis C
Box 2 | Recommendations for HCV screening
In most countries, hepatitis C virus (HCV) testing is
recommended in the following populations at
increased risk:
• Current or past injection drug users
• Those who received clotting factor concentrates
before 1990
• Transfusion recipients who received blood from a donor
who later tested HCV-positive, and recipients of blood,
blood components or organ transplants before the 1990s
• Those currently or formerly on long-term
haemodialysis and with persistently abnormal levels
of alanine aminotransferase (a marker of liver function)
• Individuals with invasive medical procedures in the
past, such as surgery and endoscopic interventions
• Individuals with HIV infection
• Health care and public safety workers after needle
sticks, sharp injury or mucosal exposure to
HCV-positive blood
• Children born to HCV-positive women
• Individuals with multiple sexual partners
• Birth cohort screening, for example, in the United States
(individuals born between 1945 and 1965)
prophylactically (for example, in health care workers
after needle-stick injury). Individuals with acute HCV
infection with increased levels of liver enzymes and
bilirubin (that is, with jaundice, so-called symptomatic
acute hepatitis C) more often clear the virus spontane­
ously. However, response rates to treatment are similar.
Acute hep­atitis C has been successfully treated with a
short dur­ation of IFN monotherapy since over a decade
ago with SVR rates of >90%103. Initially, patients were
treated with conventional recombinant IFN, but simi­
lar results were obtained with PEG-IFN104. Immediate
treatment with PEG-IFN monotherapy was shown to be
­superior to delayed therapy with PEG-IFN plus ribavi­
rin in patients without spontaneous HCV clearance after
12 weeks105. Overall, high SVR rates were achieved with
IFN-based therapies.
In 2016, the first results with DAA therapies were
reported for patients with HCV genotype 1 infection106.
After 6 weeks of treatment with sofosbuvir/­ledipasvir,
100% of patients achieved a SVR, which means cure.
Lower SVR rates were reported after 12  weeks for
patients who are positive for HIV with acute hep­
atitis C107. Studies with the latest treatment regimen,
sofosbuvir/­velpatasvir, are under way to explore the
shortest possible treatment regimen and to develop a
pan-genotypic regimen. Although HCV DAA treatment
is not yet approved for acute HCV infection, results are
encouraging at least in HCV mono-infected patients, but
enrolment in prospective clinical trials is preferred for
now to confirm efficacy.
Chronic hepatitis C
The development of DAAs has led to a revolution in the
treatment of chronic HCV infection. In recent years,
research achieved the elucidation of the HCV life cycle,
which led to the development of DAAs that target three
proteins involved in crucial steps in the HCV life cycle:
the NS3/4A protease, the NS5B polymerase and the
NS5A protein (BOX 4; FIG. 4). A combination of one to
three of these different DAAs with or without ribavi­
rin leads to cure rates of 90–100%. Owing to the rap­
idly growing field, with new drug approvals every few
months, HCV treatment recommendations have been
updated regularly over the past 5 years. Thus, national
and international scientific societies, in particular, the
EASL (www.easl.eu) and the AASLD (www.aasld.org)
together with the Infectious Diseases Society of America
(IDSA; www.idsociety.org), regularly update their HCV
practice recommendations online.
All patients with chronic hepatitis C and detect­
able HCV RNA in the serum should be considered for
antiviral treatment (TABLE 1). Before starting treatment,
other causes of liver disease need to be excluded and
bio­chemical disease activity and stage of liver disease
need to be assessed. As of today, an individualized
approach to HCV therapy is still necessary. Which
regi­men is preferred, with or without ribavirin, for 8,
12, 16 or 24 weeks depends on the viral genotype, sub­
type, whether the patient has cirrhosis or not, on pre­
vious treatment experience and, in some settings, drug
costs. In the West (Europe and North America) and

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Box 3 | Primary prevention of HCV infection
The recommendations to prevent hepatitis C virus (HCV) transmission are the following:
• Avoid direct exposure to blood or blood products. This recommendation, targeting
medical workers and health care providers, encourages precautionary measures to
avoid all direct contact with blood. Any devices used to draw blood in the workplace
should be discarded safely or sterilized appropriately to prevent HCV infection.
Health care workers have to follow universal blood and body fluid precautions and
safely handle needles and other sharp objects.
• Do not share needles or personal care items. Intravenous drug users are at high risk of
becoming infected with HCV because many share the needles and other equipment
used with illicit drugs. Certain personal care items, such as toothbrushes, razors and
scissors, can also be contaminated with small amounts of blood that can potentially
transmit HCV infection.
• Only use licensed tattoo and piercing parlours with appropriate sanitary procedures.
All others should be avoided.
• Avoid risky sexual activities. People having sex with more than one partner should
always use latex condoms to prevent the spread of sexually transmitted diseases,
including HCV infection. HIV-infected men who have sex with men are at highest risk
of HCV infection through sexual transmission.
Japan, all-oral, IFN-free DAA regimens are preferred,
whereas in some parts of the world, such as several
Asian countries, IFN-based regimens are still the most
frequently used option. Between 2014 and 2016, 11 dif­
ferent DAAs against the three viral proteins have been
approved (BOX 4; TABLE 1). The latest approved regi­mens
were elbasvir/grazoprevir in the United States, Canada
and Europe, and sofosbuvir/­velpatasvir in the United
States and Europe. Elbasvir/­grazoprevir is given for
12 weeks, except for patients infected with HCV geno­
type 1a or genotype 4 and patients with pre-­existent
NS5A RASs. In these patients, 16 weeks of elbasvir/
grazoprevir plus ribavirin is recommended to prevent
treatment failure108. Sofosbuvir/­velpatasvir is given as
a once-daily fixed-dose combination, is pan-genotypic
and has a SVR at 12 weeks of >95%109–111. Sofosbuvir/
velpatasvir is given for 12 weeks without ribavirin,
except for patients with Child–Pugh score B (BOX 1) or
those infected with HCV genotype 3; these patients
should receive 12 weeks of fixed-dose ­combination
sofosbuvir/velpatasvir plus ­ribavirin109,111 (TABLE 1).
Apart from drug approval by the US FDA, the
European Medicines Agency and other national author­
ities, the preferred treatment regimen is influenced by
various national reimbursement strategies. In some
countries, such as France, Germany and Portugal, oral
DAA therapies are reimbursed for all patients infected
with HCV independent of stage of fibrosis, whereas in
other parts of the world, including various European
countries, reimbursement is limited to patients with
advanced fibrosis scores (F2–F4 according to the
Metavir scoring system). In China, HCV prevalence
seems to be high and varies considerably between differ­
ent regions. For economic reasons and because of good
response rates for the most prevalent HCV genotype 1b
infection, the combination of PEG-IFN plus ribavirin
is still widely used in several parts of the world, such
as in China and other Asian countries. An interesting
pilot study 112 showed that triple therapies with approved
DAAs can be shortened from 12 to 3 weeks if viral load
was reduced to <500 IU per ml 48 hours after treatment
initiation. Given that HCV RNA tests using PCR with a
limit of detection of 500 IU per ml are widely available
in China, this approach is highly cost-effective as two-
thirds of the patients qualified for tailoring therapy to
3 weeks only.
Special populations
Some patient populations have been difficult to treat in
the IFN era owing to poor efficacy and/or tolerability
of IFN and ribavirin, including patients with HIV co‑­
infection, those with renal failure and those with decom­
pensated liver disease. The development of DAAs has
also substantially improved treatment outcomes in these
special often difficult to treat populations. Other patient
groups, such as those who are on the waiting list or have
received a liver transplantation or those co‑infected with
HBV, also require special attention.
HIV co‑infection. More than 2.6 million people are
estimated to be co‑infected with HIV and HCV; end-
stage liver disease has become a leading cause of death
in this patient group113. Effective treatment with DAAs
with or without ribavirin has not only reduced overall
AIDS-related mortality in this patient population but has
also slowed the progression of liver disease114. However,
the rising incidence of liver-related complications will
only be halted by successful HCV eradication in this
patient population.
Several regimens are now available that can be
used to successfully treat HCV infection in patients
co-­infected with HIV and HCV. In fact, treatment out­
comes are comparable between patients infected with
HCV and patients co-infected with HIV and HCV, and
these patients are no longer regarded as a difficult to
treat HCV population. The phase II ERADICATE study
showed that treatment of patients infected with HIV and
HCV genotype 1 with sofosbuvir/ledipasvir for only
12 weeks achieved a SVR in 98% of patients115. Safety
and tolerability were excellent with only few drug inter­
actions with current HIV medications. The phase III
TURQUOISE‑1 study showed that treatment with
ombitasvir/paritaprevir/r plus dasabuvir with ribavirin
achieved SVR rates in 94% patients co‑infected with
HIV and HCV genotype 1 (REF. 116). Again, safety and
tolerability were excellent, although potential drug–drug
interactions necessitated a change in HIV medications
(that is, efavirenz and lopinavir plus ritonavir) in some
patients. Finally, in the phase III ASTRAL‑5 study,
treatment of patients co-infected with HIV and HCV
with sofosbuvir/velpatasvir for 12 weeks achieved SVR
rates of 95% across all HCV genotypes with excellent
safety and no significant drug–drug interactions, except
with efavirenz117.
Renal failure. The prevalence of HCV in patients with
end-stage renal disease is almost 10‑times greater than
in the general population because of increased risk of
parenteral transmission of HCV infection through trans­
fusions and nosocomial spread118–120. Because chronic
HCV infection is associated with reduced survival

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Box 4 | Three different classes of DAAs against HCV
NS3/4A protease inhibitors
All drug names in this class end with ‘previr’; also referred
to as protease inhibitors.
• Boceprevir: first-generation direct-acting antiviral
agent (DAA)
• Telaprevir: first-generation DAA
• Paritaprevir
• Simeprevir
• Asunaprevir
• Grazoprevir
NS5B polymerase inhibitors
All drug names in this class end with ‘buvir’; also referred
to as polymerase inhibitors.
• Sofosbuvir: a nucleotide inhibitor, acts at the active site
of enzymes, has a role in chain termination and is
non-genotype specific
• Dasabuvir: a non-nucleotide inhibitor, does not bind
to the active site of the enzyme but changes the three-
dimensional conformation of the enzyme and therefore
inhibits enzymatic function, and is genotype specific
NS5A replication complex inhibitors
All drug names in this class end with ‘asvir’; also referred
to as NS5A inhibitors.
• Daclatasvir
• Elbasvir
• Ledipasvir
• Ombitasvir
• Velpatasvir
HCV, hepatitis C virus.
among dialysis patients, treatment of HCV infection is
recommended in all patients with end-stage renal dis­
ease. The introduction of IFN-free and ribavirin-free
DAA regimens offers the opportunity to treat this unmet
medical need.
However, several of the DAAs are excreted through
the kidney and might require dose adjustment or should
be avoided when renal function is impaired. The recently
updated AASLD and IDSA recommendations state
that, for patients with a creatinine clearance (CrCl) of
>30 ml/min, no dosage adjustment is required when
using sofosbuvir, simeprevir, sofosbuvir/­ledipasvir,
sofosbuvir/velpatasvir, elbasvir/grazoprevir or the
combin­ation involving the three different drug classes
(3D regimen; ombitasvir/paritaprevir/r with or without
dasabuvir). For patients with a CrCl of <30 ml/min, the
combination of elbasvir/grazoprevir and ombitasvir/
paritaprevir/r with or without dasabuvir is preferred.
However, these regimens are only approved for HCV
genotype 1 and genotype 4 infections. Treatment with
any other DAAs or a combination of DAAs should only
be considered under expert supervision121 (BOX 5).
Compensated and decompensated liver cirrhosis. It is
estimated that, worldwide, almost 15 million individ­
uals infected with HCV have progressed to cirrhosis, of
which almost 1 million already have developed clinical
evidence of decompensation, with a median survival
of <5 years after developing evidence of decompensa­
tion without transplantation24. A recent study estim­
ated 8 million individuals with cirrhosis due to HCV
infection in 2016 (REF. 15). Of these individuals, 750,000
have progressed to decompensated cirrhosis. In addi­
tion, there are approximately 410,000 individuals with
hep­atocellular carcinoma globally due to HCV. These
­numbers may be lower owing to the high mortality in
these populations. Patients with cirrhosis have always
been prioritized for treatment because successful eradi­
cation might reduce the risks of future decompensa­
tion, hepatocellular carcinoma and transplantation.
In addition, viral eradication in patients with decom­
pensated cirrhosis may lead to clinical improvement
and improved survival122,123. As IFN-based treatments
have reduced efficacy and poor tolerability in patients
with advanced cirrhosis124, this patient population has
long been undertreated. This has finally changed since
the advent of the new DAA regimens. Several treat­
ment options are available (TABLE 1). Treatment choices
are influenced by the severity of liver and renal dis­
eases, anticipated time to liver transplantation and the
goal of therapy. In general, SVR rates in patients with
decompensated cirrhosis are reduced (typically ≥10%)
­compared with those with compensated cirrhosis122,123.
In two large phase III randomized controlled trials
(SOLAR‑1 and SOLAR‑2), >200 patients with Child–
Pugh score B or score C (BOX 1) who are infected with
HCV genotype 1 or genotype 4 were randomized to
receive either 12 or 24 weeks of sofosbuvir/ledipasvir
plus ribavirin122,123,125. In the SOLAR‑1 trial, 87% of
patients achieved a higher SVR at 12 weeks than pre­
viously reported at 24 weeks with just sofosbuvir plus
ribavirin123,126. SVR rates were similar in patients with
Child–Pugh score B and score C cirrhosis and with 12
or 24 weeks duration. Achievement of a SVR was associ­
ated with significant improvement in the levels of serum
bilirubin and albumin, and in the Model for End-stage
Liver Disease (MELD) and Child–Pugh scores (BOX 1)
at  4 and 24  weeks post-treatment. Although more
patients with HCV genotype 4 infection were included
in the SOLAR‑2 trial, results remain inconclusive owing
to a limited number of patients123. Overall, sofosbuvir/
ledipasvir plus ribavirin for 12 weeks is an option for
patients with Child–Pugh score B and score C (BOX 1)
who are infected with HCV genotype 1 and genotype 4.
Sofosbuvir plus daclatasvir for 12 weeks has success­
fully rescued liver transplant recipients with graft fail­
ure from recurrent hepatitis C and is an option for
patients with decompensated cirrhosis (Child–Pugh
score C), in particular, in those with genotype 3 infec­
tion127,128. Both daclatasvir and sofosbuvir are safe and
well tolerated and neither requires dose adjustment in
patients with decompensated cirrhosis. Most recently,
the combination of sofosbuvir/velpatasvir plus ribavirin
for 12 weeks has provided excellent results for patients
with Child–Pugh score B111. Sofosbuvir/velpatasvir is
approved in the United States and Europe for patients
with decompensated liver disease, Child–Pugh score B
but not score C.

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It is recommended that all these combinations should
be given with ribavirin in patients with ­decompensated
cirrhosis. However, the benefit of adding ribavirin is still
not proven. Although in the ASTRAL‑4 study 12 weeks
of sofosbuvir/velpatasvir plus ribavirin seemed to be
better than 24 weeks of the same combination without
ribavirin, sofosbuvir/ledipasvir without ribavirin was
never evaluated in rigorous randomized controlled
clinical trials in patients with decompensated cirrho­
sis111. As all sofosbuvir-­based therapies should not be
given to patients with a glomerular filtration rate of
<30 ml/min, patients who have decompensated liver
­cirrhosis and renal impairment remain difficult to treat.
Liver transplantation. For patients with complications of
cirrhosis including hepatocellular carcinoma, liver trans­
plantation is a life-saving procedure. In many countries,
hepatitis C remains the most common indication for liver
transplantation129. Reinfection of the new liver is essen­
tially universal in patients with pre-transplant viraemia,
and the rate of fibrosis progression is markedly acceler­
ated in post-transplant patients compared with immuno­
competent patients who are infected with HCV130.
On average, cirrhosis recurrence becomes evident by
8–10 years after liver transplantation; one-third of patients
are even progressing more rapidly, with cirrhosis present
within 5 years. Among patients infected with HCV who
are undergoing liver transplantation, the factors associated
with more-severe recurrent hepatitis C after transplanta­
tion are receipt of organs from older donors, treatment
of acute rejection, cytomegalovirus infection, HIV co-­
infection and IL28B (rs12979860) polymorphisms131.
Overall, the cumulative graft survival in patients with
hepatitis C has been 30% lower so far than in patients who
underwent transplantation for non-HCV liver disease129.
Achievement of SVRs after liver transplantation is
associated with improved outcomes, with graft survival
rates similar to those without HCV infection132. However,
treatment with PEG-IFN plus ribavirin was limited by
poor tolerability, risk of immune-mediated allograft dys­
function and SVR rates in only 30% of patients133. Thus,
liver transplant candidates and recipients have historically
been a group with a high unmet need for new therapies.
The availability of DAAs has been transformative
for liver transplant recipients, providing safe and well-­
tolerated DAA combinations that achieve SVR rates
simi­lar to non-transplant patients134. HCV treatment
can be considered pre-transplant and post-transplant,
depending on the goals of therapy and the clinical
­status of the patient. Patients with HCV infection and
concomi­tant hepatocellular carcinoma undergoing liver
transplantation usually have Child–Pugh score A (BOX 1).

Table 1 | Antiviral activity of various regimens

Regimen Genotype
1 2 3 4 5 6
Approved
Sofosbuvir plus ribavirin*,‡ X§ X|| X§ X§ X§ X§
Sofosbuvir plus PEG-IFN plus ribavirin X ||
X ||
X ||
X ||
X ||
X||
Sofosbuvir/ledipasvir*,‡,¶,# X§,||,# NA NA X|| X|| X||
Sofosbuvir/velpatasvir **
‡,
X ||
X ||
X ||,¶
X ||
X ||
X||
Sofosbuvir plus simeprevir*,¶ X|| NA NA X|| NA NA
Sofosbuvir plus daclatasvir* ,‡,¶
X §,||
X ||
X §,||
X ||,‡‡
X ||,‡‡
X||,‡‡
Ombitasvir/paritaprevir/r plus dasabuvir (with or without ribavirin§§)* X§,||,§§,|||| NA NA NA NA NA
Ombitasvir/paritaprevir/r plus ribavirin NA NA NA X|| NA NA
Elbasvir/grazoprevir X ||,¶¶
NA NA X ||,¶¶
NA NA
Daclatasvir plus asunaprevir X§,## NA NA NA NA NA
Advanced stage of clinical development
Sofosbuvir/velpatasvir/voxilaprevir X X X X X X
Ruzasvir/grazoprevir/MK‑3682 X X X X X X
Glecaprevir/pibrentasvir X X X X X X
‘/’ between treatments indicates a fixed-dose combination with one tablet therapy, whereas ‘plus’ indicates the combination of
two or more treatments formulated in different tablets. IFN, interferon-α; NA, not active against the specified hepatitis C virus
(HCV) genotype; paritaprevir/r, paritaprevir ritonavir-boosted; X, active against the specified HCV genotype. *Available for
post-liver transplantation treatment. ‡Treatment available for patients with Child–Pugh score A–C; sofosbuvir/velpatasvir is only
available for Child–Pugh score A or score B. §24 weeks of therapy. ||12 weeks of therapy. ¶Ribavirin can be added to the treatment
regimens depending on the characteristics of the patient (for example, cirrhosis, pre-treatment status and NS5A resistance-
associated substitution). #8 weeks of therapy for naive patients without cirrhosis with HCV RNA levels of <6 million IU per ml.
**Data collection underway and presumably positive for patients infected with any genotype who have Child–Pugh score A or
score B. ‡‡Data are limited. §§Ribavirin for patients with genotype 1a infection and 24 weeks of therapy for patients with genotype
1a infection and cirrhosis. ||||8 weeks of therapy for naive patients with genotype 1b infection without cirrhosis is possible.
¶¶
16 weeks of treatment combined with ribavirin for patients with genotype 1a and genotype 4 infections, with baseline HCV RNA
levels of >800,000 IU per ml and/or NS5A resistance-associated substitution. ##Approved for patients with genotype 1b infection
in some countries with a high genotype 1b prevalence (for example, Japan and Korea).

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These patients are usually treated before transplantation
as long as they have not already undergone hepatocellular
carcinoma therapies, whereas patients with decompen­
sated liver cirrhosis, in particular, with MELD scores of
>20, should receive treatment with the ­currently available
DAA regimens after transplantation135.
Guidelines for HCV treatment after liver transplan­
tation before the advent of DAAs recommended treat­
ment for moderate-to‑severe inflammatory activity or F2
Metavir fibrosis score or more-severe fibrosis136. In addi­
tion, those with fibrosing cholestatic hepatitis or evidence
of rapid fibrosis progression were additional targets for
treatment. In resource-limited areas, these guidelines
may continue to recommend prioritization for treatment.
However, given the high efficacy (SVR rates among regi­
mens including two or more DAAs are approximately
95%) and excellent safety profile of DAA combinations,
earlier treatment can also be considered, especially of
patients infected with HCV genotype 1, if resources
allow. Data in other HCV genotypes are more limited, but
as available data indicate that SVR rates in liver transplant
recipients approximate those of patients who have not
received a transplant, adoption of treatment algorithms
from the non-transplant setting is a reason­able strategy
for transplant recipients. Several DAA combinations
are available for liver transplant recipients with recur­
rent HCV infection post-transplantation127,128 (TABLE 1).
Head‑to‑head comparisons of different treatment regi­
mens are lacking and treatment will depend on the HCV
genotype, tolerability of ribavirin, severity of liver and
renal disease, risk of drug–drug interactions and prior
treatment history. Adverse effects are rarely limiting but
are more frequent in ribavirin-containing regimens.
DAAs for patients with severe hepatic ­impairment
and decompensated liver disease might reduce the
need of liver transplantation. Several regimens of
pre-­transplantation treatments are available (TABLE 1);
Box 5 | Selected DAAs and renal impairment
• Sofosbuvir: administered as a prodrug, its major metabolite GS‑331007, is eliminated
through the kidney. However, no considerable accumulation of GS‑331007 occurs
until the creatinine clearance is <30 ml/min (REF. 174). Whether either reduction in
sofosbuvir dose or increase in dosing interval to maintain GS‑331007 levels will alter
the antiviral efficacy of sofosbuvir is unclear. In a small phase II study of hepatitis C
virus (HCV)-positive patients with a creatinine clearance of <30 ml/min, reducing the
dose of sofosbuvir from the usual 400 mg to 200 mg resulted in suboptimal sustained
virological response rates in 4 out of 10 patients175.
• Daclatasvir and simeprevir: no drug adjustment required as daclatasvir is primarily
eliminated unchanged in faeces176 and simeprevir is not renally eliminated. However,
the need to combine these drugs with other direct-acting antiviral agents (DAAs),
in particular, sofosbuvir, limits their use in patients with renal impairment.
• Ombitasvir/paritaprevir ritonavir-boosted plus dasabuvir: none of the three DAAs of
the 3D combination undergo considerable renal clearance and therefore dose
reduction should not be required in patients with either mild, moderate or severe renal
insufficiency177. However, as ribavirin is still required in patients with HCV genotype 1a
infection, anaemia remains a problem in patients with severe renal impairment.
• Elbasvir/grazoprevir (without ribavirin): evaluation in a large number of patients
infected with HCV genotype 1 with a creatinine clearance of <30 ml/min and patients
who are on haemodialysis showed excellent sustained virological response rates, even
in patients with cirrhosis178. This combination is approved and recommended for
patients with end-stage renal disease with a glomerular filtration rate of <30 ml/min.
treatment choice depends on the goal of therapy. If the
primary goal is prevention of recurrent HCV infec­
tion after transplantation, achievement of a SVR pre-­
transplantation will assure that outcome. However,
treatment with a goal of achieving an on‑treatment
response at the time of liver transplantation is an alter­
native, although the timing to start treatment can be dif­
ficult as patients must be HCV RNA-negative for at least
30 days to avoid recurrent HCV infection137. In a study
of wait-listed patients with Child–Pugh score A (BOX 1)
and hepatocellular carcinoma treated with sofosbuvir
plus ribavirin, 95% of those who achieved undetect­
able HCV RNA levels for at least 4 weeks before trans­
plantation were HCV-free post-transplantation122,137.
Whether similar results can be obtained in patients with
more-advanced decompensation or improved by use of
two or more DAAs in combination, is unknown123,126,138.
Given these uncertainties, the risk–benefit of treating
pre‑transplantation versus post-transplantation needs
to be considered carefully. Another goal of treating
wait-listed patients is to prevent the need for transplan­
tation. Preliminary data show modest improvements in
liver function tests, and MELD and Child–Pugh scores
in patients with decompensated cirrhosis who have
achieved a SVR122,123,125,139, but whether this improvement
will be sufficient to avert a future transplantation is an
unanswered question. Thus, long-term follow-up stud­
ies beyond 24 weeks post-treatment are urgently needed.
Case reports show that some patients have been taken off
the transplantation waiting list following successful HCV
therapy. However, the point of no return until which anti-
HCV therapies are clinically beneficial for patients with
decompensated liver disease still needs to be defined;
this may be around MELD scores of 18–20 (REF. 135).
However, in various regions, patients usually only receive
donor organs when their MELD scores are >30, which
suggests that ­transplantation ­cannot be avoided when
cirrhosis is too advanced.
Co-infection with HBV. Treatment of HCV infection in
patients with HBV co-infection is not well established.
The era of DAA therapies differs from IFN-based thera­
pies used in the past, as, in contrast to DAAs, IFN has
activity against HBV. Efficacy of HCV DAA therapies
seems to be similar in patients co-infected with HBV and
HCV compared with patients with HCV infection only.
However, preliminary data indicate that there may be a
potential risk of HBV reactivation following clearance of
HCV infection with DAAs. Data are very limited and do
not allow a general recommendation of prophylaxis of
HBV reactivation by use of HBV nucleotide (or nucleo­
side) inhibitors. Currently, close monitoring of patients
co-infected with HBV and HCV after HCV clearance
seems appropriate.
Quality of life
QOL and HRQOL are measured using patient-­
reported outcomes140. Patient-reported outcome instru­
ments to measure HRQOL generally cover important
domains of mental health, physical health and social
health141. Instruments used in hepatitis C research

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are generic HRQOL instruments (such as the 36‑Item
Short Form Health Survey (SF‑36)), as well as disease-­
specific instruments (such as Chronic Liver Disease
Questionnaire-Hepatitis C Version (CLDQ-HCV)) and
fatigue questionnaires (such as Functional Assessment
of Chronic Illness Therapy-Fatigue (FACIT‑F))141,142.
Patient-reported outcomes are important from a health
policy perspective, are important predictors of progno­
sis and assist in quantifying the patient’s perspective and
their experience with the disease or its treatment89,143.
Over the past two decades, several studies have docu­
mented significant HRQOL impairment in patients with
chronic hepatitis C144,145. The HRQOL areas that are most
affected in patients with chronic hepatitis C are those
related to activity, energy, vitality and fatigue146,147. These
impairments in patients with chronic hep­atitis C worsen
with more-advanced liver disease148. Fatigue associ­
ated with chronic hepatitis C is not only an important pre­
dictor of HRQOL but is also an independent predictor of
work productivity (that is, the amount of work ­completed
while at work), presenteeism and absenteeism149–151.
With regard to the effect of hepatitis C treatment
on HRQOL, IFN-containing and ribavirin-containing
regi­mens can induce a profound negative effect on QOL
and HRQOL152–154. By removing IFN from the regimen,
a significant improvement of QOL and HRQOL can be
achieved. Nevertheless, IFN-free ribavirin-­containing
regimens can still produce a modest but reversible
negative effect on QOL and HRQOL13,153–156. Finally,
patients achieving a SVR after 12 weeks of treatment
led to significant improvement in some aspects of QOL
and HRQOL157.
Development of DAAs has led to unprecedented
advances in the field of HCV infection as these regimens
are simpler to use and have a shorter treatment duration,
with a significantly better adverse-effect profile than
IFN-containing regimens13,152–156,158–165. Furthermore,
DAAs have been shown to be associated with improve­
ment of QOL and HRQOL during treatment. These
improvements were noted within 2 weeks of administra­
tion of these regimens, which coincided with viral sup­
pression. More importantly, patient-reported outcome
scores that measure QOL and HRQOL were significantly
improved when patients achieved a SVR at 12 weeks
after treatment. The improvement in QOL and HRQOL
upon reaching a SVR was similar between patients with
early liver disease and those with advanced disease13,156.
Finally, patients with decompensated cirrhosis related
to HCV infection show the most prominent QOL and
HRQOL gains after achieving a SVR with DAAs166.
The data on QOL and HRQOL in chronic hepatitis C
have several important implications. The improvement
of QOL and HRQOL with the new DAA regimens will
probably reduce the gap between efficacy rates and
real-world effectiveness rates. The improvement after
achieving a SVR not only shows an improvement in the
well-being of patients but also in other important extra­
hepatic manifestations (such as HCV-related fatigue)
and work productivity, thereby reducing economic
losses. The comprehensive approach to assessing treat­
ment of chronic hepatitis C, which includes efficacy and
safety end points as well as patient-reported outcomes,
suggests that the new HCV treatment regimens improve
not only clinically relevant outcomes but also the QOL of
the patients, their families and the society 167.
Outlook
Prevention
Effective screening programmes, accessibility to drugs
and effective treatment‑as‑prevention strategies are
crucial to considerably reduce the HCV health burden
in times without a prophylactic vaccine. The majority
of patients are still unaware of their HCV infection32;
thus, only patients diagnosed with HCV infection will
be treated. Another issue is prevention of re‑infection in
high-risk groups, such as injectable drug users and men
who have sex with men. Finally, a vaccine against HCV
is still a major unmet need, and is particularly needed
for high-risk populations. Hopefully, efforts and invest­
ments into HCV vaccine research will grow again in the
years ahead. Unfortunately, all efforts have failed so far
to develop a prophylactic HCV vaccine that can prevent
infection, presumably as a result of the high variability
of the virus.
Management
Chronic hepatitis C might become an eradicable dis­
ease. Recent therapeutic developments allow cure rates
of >90% for all genotypes and almost all patient popu­
lations, including those with renal insufficiency and
decompensated liver disease. Remaining challenges
for HCV research are effective and safe HCV drug
regimens for decompensated liver disease with renal
impairment, as the regimens that are effective and safe
in renal insuffi­ciency are not allowed in decompen­
sated cirrhosis. In addition, the point of no return after
which HCV thera­pies are no longer beneficial to the
patient with decompensated liver disease needs to be
defined72. Separate analysis should be performed for
patients l­iving in areas where liver transplantation is an
option and in those where this procedure is not avail­
able. With regard to DAA therapy, the shortest possible
duration for chronic hepatitis C therapy still needs to be
defined, as well as the duration and optimum regimen
for the manage­ment of acute hepatitis C. A regimen also
still needs to be developed for those few patients who
failed previous DAA-based therapies. However, patients
in whom previous DAA therapies failed can now be
success­fully treated with another different DAA regimen,
independent of whether their previous regimen con­
tained an HCV NS5A inhib­itor or not. In these patients
in whom DAA therapy failed, resistance analy­sis may
be helpful. One such successful strategy is re-­treating
patients who failed to a dual DAA regimen with a ­triple
DAA regimen, for example, containing sofosbuvir/­
velpatasvir/voxilaprevir 168,169. Another area of debate is
whether extrahepatic manifestations of HCV infection
such as fatigue without considerable liver disease should
be treated38. Once HCV therapies become more afford­
able and unlimited access is a reality, extrahepatic symp­
toms and manifestations will attract more attention in
HCV research and clinical management.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17006 | 15

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Accessibility of DAA regimens as the risk of hepatocellular carcinoma development in

The most important remaining issue is probably the
accessibility of DAA regimens. Treatment uptake is still
low even in leading western countries, such as France
and Germany, with treatment rates still below 10%,
meaning that <10% of patients with known HCV infec­
tion received treatment. Reliable up‑to‑date data on
treatment uptake are missing for most countries. HCV
DAAs are unaffordable or unavailable in most countries.
In several areas of the world, more specifically several
eastern European and Asian countries, IFN-based
thera­pies are still in use. Since 2016, several DAAs have
become available in low-income countries through the
production of generic drugs, with excellent efficacy 170,
at <1% the cost in western countries.
HCV infection and hepatocellular carcinoma
Another aspect that requires further investigation is
the effect of HCV management on hepatocellular car­
cinoma risk. The potential of fibrosis regression as well
patients with cirrhosis after achieving a SVR need to be
defined. Although the risk of de novo hepato­cellular car­
cinoma development is considerably reduced in patients
with cirrhosis following successful IFN-based therapies,
the situation is less clear in the DAA era. Recent pub­
lications initiated a lively debate in the scientific com­
munity. Although de novo hepatocellular carcinoma
development seems to be reduced following DAA ther­
apy resulting in a SVR, the risk for early hepato­cellular
carcinoma recurrence might be increased 171. This
phenom­enon might be explained by the termin­ation
of the HCV–immune system interaction. Several other
open questions remain for the management of HCV
infection in patients with hepatocellular carcinoma;
in particular, the value of HCV therapies in patients
undergoing palliative HCV manage­ment is controver­
sial, acknowledging the limited life expectancy of these
patients and the unproven benefit of HCV therapy in
such patients.

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Acknowledgements
The authors thank S. Hardtke and P. Solbach, Hannover
Medical School, Hannover, Germany, for editorial assistance
and M. Cornberg, Hannover Medical School for helpful
discussions.
Author contributions
Introduction (M.P.M.); Epidemiology (H.R.); Mechanisms/
pathophysiology (J.-M.P.); Diagnosis, screening and
prevention (J.-M.P. and M.B.); Management (M.P.M., E.G.
and N.T.); Quality of life (Z.Y.); Outlook (M.P.M.); Overview of
Primer (M.P.M.).
Competing interests
M.P.M. has received research grants and or served as an
adviser for Roche, Bristol-Myers Squibb (BMS), Gilead,
Boehringer Ingelheim, Novartis, Merck, Janssen,
GlaxoSmithKline (GSK), Biotest and AbbVie. M.B. has served
as a speaker and/or adviser of AbbVie, Gilead, Janssen,
Merck and BMS. E.G. has served as an adviser for Roche,
Gilead, Janssen, Novira, AbbVie, Novartis, Achillion, Merck
and Alios. J.-M.P. has received research grants from Gilead
Sciences and AbbVie. He has served as an adviser for AbbVie,
BMS, Gilead, Janssen and Merck. H.R. has received research
funds from Gilead and AbbVie. N.T. has received research
grants and/or served as an adviser for Gilead, Cocrystal
Pharma, BMS, AbbVie, Merck and Echosens North America
Inc. She received royalty from UpToDate and is involved in
continuing medical education and the development of
educational material for CCO Hepatitis, Practice Point
Communications and Focus Medical Communications. Z.Y.
has received research funds from Gilead, BMS and AbbVie
and is a consultant or an adviser to BMS, Gilead, GSK,
Intercept and Tobira.
How to cite this article
Manns, M. P. et al. Hepatitis C virus infection. Nat. Rev. Dis.
Primers 3, 17006 (2017).

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