Seminar

Hepatitis C
Marianne Martinello, Sunil S Solomon, Norah A Terrault, Gregory J Dore

Hepatitis C virus (HCV) is a hepatotropic RNA virus that can cause acute and chronic hepatitis, with progressive liver Lancet 2023; 402: 1085–96
damage resulting in cirrhosis, decompensated liver disease, and hepatocellular carcinoma. In 2016, WHO called for Viral Hepatitis Clinical Research
the elimination of HCV infection as a public health threat by 2030. Despite some progress, an estimated Program, Kirby Institute,
UNSW Sydney, Sydney, NSW,
57 million people were living with HCV infection in 2020, and 300 000 HCV-related deaths occur per year. The
Australia (M Martinello PhD,
development of direct-acting antiviral therapy has revolutionised clinical care and generated impetus for elimination, Prof G J Dore PhD); Department
but simplified and broadened HCV screening, enhanced linkage to care, and higher coverage of treatment and of Infectious Diseases, Prince of
primary prevention strategies are urgently required. Wales Hospital, Sydney, NSW,
Australia (M Martinello);
Division of Infectious Diseases,
Introduction drugs in many high-income countries,4 sustained high or Johns Hopkins University
Hepatitis C virus (HCV) is a hepatotropic positive sense increasing incidence has been reported in the USA and School of Medicine,
single-stranded RNA virus belonging to the family some low-income and middle-income countries.5–7 Baltimore, MD, USA
(Prof S S Solomon MBBS);
Flaviviridae, which causes acute and chronic hepatitis. Eight HCV genotypes have been identified.3,8 HCV Division of Gastrointestinal
Chronic HCV infection with progressive liver injury genotype 1 is prevalent in North and South America, and Liver Diseases, University
can result in cirrhosis and associated complications, Europe, Australia, and central and east Asia. HCV of Southern California,
including decompensated liver disease and hepato­ genotype 3 accounts for most infections in India and Los Angeles, CA, USA
(Prof N A Terrault MD);
cellular carcinoma. Following identification of HCV Pakistan, and genotype 4 is predominant in Egypt and Department of Infectious
in 1989, there has been enormous progress in basic, central and sub-Saharan Africa.3 The clinical relevance of Diseases, St Vincent’s Hospital,
translational, clinical, and public health research, genotype and subtype determination has waned with pan- Sydney, NSW, Australia
culminating in the development of direct-acting genotypic DAA therapy; however, HCV genotype could (Prof G J Dore)

antiviral (DAA) therapy, which is a curative oral
treatment for HCV infection.
Given the global burden of disease, WHO adopted the
first global hepatitis strategy in 2016, proposing to
eliminate viral hepatitis as a public health threat by 2030,
with targets focused on reducing incidence and
mortality, and increasing diagnosis and treatment
(appendix p 2).1 The availability of DAA therapy has
revolutionised HCV clinical care and provided impetus
for elimination. However, despite major advances in
therapeutics, only 21% of people with chronic HCV
infection have been diagnosed and 13% have started
HCV treatment.1
Epidemiology
Global occurrence
In 2020, 57 million people were estimated to be living
with chronic HCV infection (HCV RNA viraemic
prevalence 0·7%), with over 70% residing in low-income
and middle-income countries.2 The decline in estimated
chronic HCV infections over the preceding 5 years
(from 64 million in 2015) occurred more as a result of
revised prevalence data than elimination progress,
although substantial country-specific treatment-related
reductions have also contributed (eg, in Egypt).2,3
Countries with the highest burden of HCV include
China, India, Pakistan, Russia, and the USA, with
30 countries accounting for 80% of the burden of those
living with HCV infection.2
An estimated 1·5 million new HCV infections occur
each year,3 with transmission related largely to injecting
drug use and unsafe health-care injections. Although
annual HCV incidence peaked in most countries
between 1970 and 2005 and is falling in people who inject
affect natural history, liver disease progression, and Correspondence to:
Dr Marianne Martinello, Viral
treatment response.9 Hepatitis Clinical Research
Program, Kirby Institute, UNSW
Transmission and key populations Sydney, Sydney, NSW 2052,
HCV is a bloodborne virus, with common routes of Australia
mmartinello@kirby.unsw.edu.
transmission including unsafe skin-penetrating health- au
care practices, transfusion of unscreened blood and
blood products, and injection drug use. Less common See Online for appendix
routes of transmission include vertical and sexual
transmission. Approximately 5% of infants born to
women with HCV (ie, detectable HCV RNA) will acquire
HCV infection, with increased risk associated with
maternal HIV co-infection (10%), higher maternal
HCV RNA (≥6·0 log10 IU/mL), amniocentesis, prolonged
rupture of membranes, and invasive fetal monitoring.10–14
Sexual permucosal transmission can occur in men who
have sex with men, with increased risk in men with HIV
infection.15 Sexual behaviours associated with HCV
acquisition in this population include condomless anal
intercourse, high number of sexual partners, group
sex, and ulcerative sexually transmitted infections.16,17
Sexual transmission between men and women is rare
Search strategy and selection criteria
We searched PubMed, Embase, and Google Scholar with the
search terms “hepatitis C” or “HCV”, with no language or date
restrictions, from database inception to Nov 3, 2022.
We predominantly selected publications in the past 10 years,
given developments in the field. We also searched the
reference lists of articles identified by this search strategy and
selected those we judged relevant. Additional references were
included following peer review.

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 Seminar
(<0·1% per year in monogamous heterosexual couples).18
In high-income countries, populations at high risk are
people who inject drugs, gay or bisexual men, and men
who have sex with men with HIV.15,19 In low-income and
middle-income countries, unsafe health-care practices
account for a large proportion of new infections, with an
increasing burden related to injection drug use.6 Globally,
the greatest burden of infection is in countries where
transmission was primarily related to past or current
unsafe health-care practices.3
Clinical presentation and natural history of HCV
infection
Acute HCV infection
Most people (>70%) have no symptoms attributable to
acute HCV infection, making early diagnosis challenging.
Symptoms associated with acute infection include
jaundice, fever, headache, malaise, anorexia, nausea,
vomiting, diarrhoea, and abdominal pain. Transaminases
can be elevated (eg, alanine aminotransferase >5–10 times
the upper limit of normal), and HCV RNA has a broad
range from high (10⁷ IU/mL) to low (<10⁴ IU/mL), with
fluctuating levels (>1 log10 IU/mL) on serial assessment.20
Although most people have viral persistence and
develop chronic HCV infection, many undergo sponta­
neous clearance (15–35%), usually within 6 months.21–23
Host factors associated with spontaneous clearance
include female sex, younger age, white race, symptomatic
acute hepatitis with jaundice, absence of HIV infection,
interferon-λ3/4 genotype, HLA class II alleles, and HCV-
specific T-cell responses.17,24,25 People who are immuno­
compromised have a reduced chance of spontaneous
clearance (<20%).22,23 Monitoring HCV RNA kinetics
might assist in predicting natural history, with
spontaneous clearance associated with more than
2 log10 IU/mL HCV RNA decline in the 4 weeks following
diagnosis.26
Chronic HCV infection
Chronic HCV infection is associated with liver
inflammation and fibrosis in most individuals. Initial
estimates of cirrhosis were biased by cohorts enrolled
from liver clinics, but evaluation of community and
population-based cohorts indicates a 5–10% prevalence
after 20 years of infection.27,28 Key factors associated with
increased fibrosis progression include older age at
infection, male sex, post-menopausal status in women,
HIV or hepatitis B virus (HBV) co-infection, HCV
genotype 3, high alanine aminotransferase concen­tration,
alcohol use, diabetes, and obesity.29 Once cirrhosis is
established, the risk of hepatic decompensation is around
3% per year and the risk of hepatocellular carcinoma is
around 2% per year.30 Factors associated with increased
hepatocellular carcinoma risk include older age, male sex,
and markers of advanced cirrhosis and portal
hypertension, including low albumin, elevated bilirubin,
prolonged prothrombin time, and thrombocytopenia.31
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Chronic HCV infection is also associated with several
extrahepatic manifestations and diseases, including
mixed cryoglobulinaemic vasculitis (purpura, arthralgia,
membranoproliferative glomerulonephritis, and peri­
pheral neuropathy), porphyria cutanea tarda, lichen
planus, B-cell non-Hodgkin lymphoma, and diabetes.32
Diagnosis, screening, and linkage to care
Diagnosis
The standard HCV testing algorithm is a two-step process
involving serology, with detection of anti-HCV antibodies
indicating past or current infection, followed by
quantitative or qualitative nucleic acid testing, with
detection of HCV RNA indicating current infection. After
exposure, anti-HCV antibodies are usually detectable
within 6–12 weeks;33 although uncommonly, detectable
antibodies can be delayed or absent in people who are
severely immunocompromised.34 Once a person has been
infected, anti-HCV antibodies will be detectable
indefinitely. Detection of HCV RNA is required to
diagnose current (ie, active or viraemic) infection,
including reinfection and acute infection before
seroconversion, with HCV RNA detectable approximately
2 weeks after exposure.
Routine HCV testing (by both serology and nucleic
acid testing) requires blood sample collection by
venepuncture, with processing and analysis in a
centralised laboratory. The complexity and price of HCV
diagnostics are barriers to large-scale testing. Assays that
use samples that are more easily attained and require
little or no processing could improve HCV testing uptake
and allow decentralisation of care. Different modalities
that have been shown to improve testing uptake and
diagnosis include dried blood spot testing, point-of-care
antibody and RNA testing, reflex RNA testing, and opt-
out screening.35 Diagnostic simplification is required for
broad implementation, particularly in low-income
settings and among key populations.
Point-of-care tests for HCV have simplified testing
algorithms, increased diagnosis, and facilitated linkage
to care and treatment.35 Point-of-care anti-HCV antibody
testing can be done with fingerstick blood, whole blood,
or oral fluid samples, with results available in less than
20 min.36 Point-of-care HCV RNA testing can be done
with fingerstick37,38 or whole blood37 samples, with results
available within 1 h. Point-of-care HCV antibody and
HCV RNA assays have been shown to have excellent
diagnostic performance in different populations and
settings, including community health centres, drug
treatment clinics, prisons, homelessness settings,
supervised drug consumption rooms, and residential
rehabilitation facilities.39
In addition, immunoassays to detect the HCV core
protein have been developed, referred to as HCV core
antigen tests. HCV core antigen assays have shown high
sensitivity, high specificity, and good correlation with
HCV RNA greater than 500–3000 IU/mL, depending on
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 Seminar

genotype.40–42 In settings where nucleic acid testing is not

available, HCV core antigen testing can be considered as
a stable, more affordable alternative and is recommended
by WHO.
Interventions to enhance testing, diagnosis, and
linkage to care
Several interventions are effective in increasing HCV
testing and diagnosis, including simplified testing
strategies, patient and provider education and reminders,
and care coordination.35,43,44 In primary care and hospital-
based settings, automated medical chart reminders and
risk-based or birth cohort screening have increased HCV
testing, diagnosis, and linkage to care in experimental
and real-world settings.35 Among people who inject
Adults with HCV infection without cirrhosis or with compensated cirrhosis
who have not previously had unsuccessful direct-acting antiviral treatment
Pre-treatment assessment
• Non-invasive liver fibrosis assessment (eg, transient elastography and validated
algorithm [fibrosis-4, APRI])
• Review medications and comorbidities, consider drug–drug interactions*
• Education (eg, transmission, adherence, and reinfection)
• Laboratory testing: full blood count, liver function tests, renal function, and
HIV and HBV serology
Recommended direct-acting antiviral regimens
• 300 mg glecaprevir and 120 mg pibrentasvir (three tablets) daily for 8 weeks
• 400 mg sofosbuvir and 100 mg velpatasvir (one tablet) daily for 12 weeks
• Sofosbuvir 400 mg (one tablet) plus daclatasvir 60 mg (one tablet) daily for
12 weeks†

drugs, patient education and navigation, provider care

coordination, point-of-care antibody and dried blood spot Post-treatment follow-up
testing, and integrated care have enhanced testing and • Qualitative or quantitative HCV RNA (or HCV core antigen) 12 weeks following
linkage to care in experimental and real-world settings, treatment completion‡

highlighting the value of multiple interventions at the

levels of patients, providers, and health systems.45
Simplified models of care can increase linkage to care No cirrhosis Cirrhosis Virological failure Reinfection
and treatment uptake, including decentralisation
(ie, testing and treatment provided at the same site) and
integration of HCV care with other services (ie, harm No follow-up required Screening for: Retreatment Retreatment as above
unless at risk of hepatocellular 400 mg sofosbuvir, Education and harm
reduction in prison health).35,46 Among people in prison, a reinfection§ carcinoma (6-monthly 100 mg velpatasvir, reduction
so-called one stop shop intervention involving point-of- ultrasound with or and 100 mg
without alpha- voxilaprevir for
care testing and nurse-led care has been shown to fetoprotein) and 12 weeks
increase DAA treatment uptake and reduce time to oesophageal varices¶
treatment initiation.47 Task-shifting is supported by high
HCV treatment effectiveness, regardless of care location Figure: Management of HCV infection among adults with and without compensated cirrhosis
(ie, tertiary or primary health care) or provider type Simplified models of care are suitable for most people with HCV infection who do not have cirrhosis or who have
compensated cirrhosis and have not had virological failure following previous DAA therapy. Characteristics or
(ie, specialist or non-specialist).
comorbidities that would make a person unsuitable for such a model include HBV infection (HBsAg positive),
hepatocellular carcinoma, liver transplantation, and current pregnancy. A history of treatment with interferon
Screening strategies and a first-generation protease inhibitor is not a contraindication to this model, as cure with DAA regimens in this
The optimal regional or national screening strategy should group is high and similar to those who are treatment naive. APRI=aspartate alanine aminotransferase-to-platelet
ratio index. DAA=direct-acting antiviral. HBV=hepatitis B virus. HCV=hepatitis C virus. SVR=sustained virological
be determined by local epidemiology, health infrastructure,
response. *Consider use of an online resource to review clinically relevant drug–drug interactions. †If available,
and financing. Examples of screening strategies that have glecaprevir–pibrentasvir or sofosbuvir–velpatasvir are recommended; in settings where these regimens are not
been recommended or implemented include testing of available or are unaffordable, sofosbuvir plus daclatasvir is recommended—the duration can be extended to
key populations, birth cohorts, and general populations 24 weeks, depending on genotype, HCV treatment history, and presence of cirrhosis. ‡Qualitative or quantitative
HCV RNA (or HCV core antigen) testing at or beyond post-treatment week 12 is the established timepoint to assess
with intermediate or high prevalence (>2%) and efficacy; however, opportunistic HCV RNA testing at any time after post-treatment week 4 should be considered
integration with testing for other infectious diseases.48 In given the high correlation between SVR4 and SVR12, particularly if loss to follow-up is likely. §People without
the USA, birth cohort and risk-based screening with anti- cirrhosis and with normal liver enzymes (ie, male alanine aminotransferase ≤35 U/L; female alanine
HCV antibody was previously recommended. However, aminotransferase ≤25 U/L) do not require ongoing liver-specific follow-up, unless at risk of reinfection (in which
case, annual HCV RNA or core antigen testing should be performed). ¶Screening for oesophageal varices should be
this recommen­ dation was updated after changing strongly considered in people with cirrhosis and portal hypertension, particularly those with thrombocytopenia.
epidemiology and cost-effectiveness analyses to support
one-time screening of all adults (aged ≥18 years) in
addition to periodic risk-based screening.49 The feasibility should be screened at least once.52 Men who have sex For an example of an online
and success of large-scale general population screening with men, especially men with HIV, who report risk resource to review clinically
relevant drug–drug
was shown in Egypt—almost 50 million people were factors for acquisition should be screened every interactions see https://www.
screened in 6 months with a decentralised model and 6–12 months.52,53 hep-druginteractions.org/
point-of-care testing.50,51
Key populations with high prevalence and incidence Management of HCV infection
require targeted screening. People who have ever injected All people with HCV infection should be considered for
For more on recommendations
drugs should be screened at least once, and people who treatment. The goal of treatment is cure of infection,
for testing, managing, and
report ongoing injected drug use should continue to be referred to as sustained virological response (SVR) and treating hepatitis C see http://
tested every 6–12 months.52 People with HIV infection defined as undetectable HCV RNA in whole blood or www.hcvguidelines.org

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 Seminar

sexual behaviour, and managing factors associated with

Formulation Usual dose Duration
(weeks) disease progression, including alcohol use, obesity, and
diabetes.
Glecaprevir–pibrentasvir
Laboratory testing should be done for HIV, HBV, and
Adults and adolescents Tablet 300 mg glecaprevir and 120 mg 8
(≥12 years) ≥45 kg pibrentasvir (three tablets) once daily pregnancy. HCV genotype testing is not mandatory
Children (3–11 years) Granules 250 mg glecaprevir and 100 mg 8 before commencement of pan-genotypic DAA therapy
≥30 to <45 kg pibrentasvir (five sachets) once daily but should be done before initiating genotype-specific
Children (3–11 years) Granules 200 mg glecaprevir and 80 mg pibrentasvir 8 therapy. Presence of cirrhosis should be evaluated with
≥20 to <30 kg (four sachets) once daily non-invasive liver disease assessment, including validated
Children (3–11 years) <20 kg Granules 150 mg glecaprevir and 60 mg pibrentasvir 8 algorithms based on routine laboratory tests and age,
(three sachets) once daily commercial serum assays, or imaging (ie, transient
Sofosbuvir–velpatasvir elastography). The algorithms most used are the aspartate
Adults and adolescents Tablet 400 mg sofosbuvir and 100 mg velpatasvir 12 aminotransferase-to-platelet ratio index and fibrosis-4
(≥12 years) ≥30 kg (one tablet) once daily
score, both of which have high specificity and negative
Children (3–11 years) Tablet; 200mg sofosbuvir and 50 mg velpatasvir 12
≥17 to <30 kg granules (one tablet or four sachets) once daily predictive values for advanced fibrosis or cirrhosis and
Children (3–11 years) <17 kg Granules 150 mg sofosbuvir and 37·5 mg velpatasvir 12
require only routine, readily available information.
(three sachets) once daily Additional evaluation in people with cirrhosis includes
Sofosbuvir–daclatasvir determination of the Child-Pugh-Turcotte score and
Adults and adolescents Tablet 400 mg sofosbuvir (one tablet) and 60 mg 12* screening for hepatocellular carcinoma (ultrasound with
(≥12 years) ≥26 kg daclatasvir (one tablet) once daily or without serum alpha-fetoprotein) and oesophageal
Children (3–11 years) 14–25 kg Tablet 200 mg sofosbuvir (one tablet) and 30 mg 12* varices (with upper gastro­intestinal endoscopy, particu­
daclatasvir (one tablet) once daily larly if thrombocytopenia is present).
Sofosbuvir–velpatasvir–voxilaprevir
Adults and adolescents Tablet 400 mg sofosbuvir and 100 mg velpatasvir 12 Direct-acting antiviral therapy
(≥12 years) ≥30 kg and 100 mg voxilaprevir (one tablet) once
daily
The development and availability of simple oral
treatment for HCV infection has revolutionised clinical
Sofosbuvir plus daclatasvir is not approved for use in children and adolescents but is recommended by WHO based on
real-world data and pharmacokinetic modelling for use in this population in low-income and middle-income
management in the past decade (appendix p 3). DAAs
countries. *For people who have been previously treated or who have cirrhosis, consider extending duration to inhibit specific non-structural (NS) viral proteins
24 weeks. necessary for HCV replication and are divided into
Table: Pan-genotypic direct-acting antiviral regimens approved and recommended for use in adults and
classes defined by their mechanism of action and target:
children with hepatitis C virus infection, with or without compensated cirrhosis (1) NS3/4A protease inhibitors (medications ending in
-previr), (2) non-nucleoside and nucleotide analogue
NS5B RNA-dependent RNA-polymerase inhibitors
plasma at least 12 weeks after treatment completion. (medications ending in -buvir), and (3) NS5A inhibitors
HCV treatment and attainment of SVR have been (medications ending in -asvir).
associated with reductions in all-cause mortality, liver- The first interferon-free and ribavirin-free regimens,
related mortality, liver-related and non-liver related sofosbuvir–ledipasvir and sofosbuvir plus simeprevir, were
morbidity (eg, cirrhosis, hepatocellular carcinoma, approved for genotype 1 HCV infection in 2014, and the
decompensated liver disease, liver transplantation, and first pan-genotypic fixed-dose combination regimen,
extrahepatic manifestations), improvements in liver sofosbuvir–velpatasvir, was approved in 2016. Three pan-
fibrosis stage and quality of life, and prevention of genotypic fixed-dose combination regimens are available:
transmission.32,54–56 sofosbuvir–velpatasvir,57–59 glecaprevir–pibrentasvir,60–62 and
sofosbuvir–velpatasvir–voxilaprevir (table).63 Sofosbuvir–
Pre-treatment assessment velpatasvir–voxilaprevir was developed as a second-line
Evaluation of people with HCV infection should include regimen for people with virological failure after DAA
an assessment of liver disease stage (ie, presence or therapy. Although fixed-dose combination regimens for
absence of cirrhosis), history of previous treatment, co- HCV are recommended if available, the most used and
morbidities, and concurrent medications (figure). lowest cost pan-genotypic regimen in low-income and
Relevant comorbidities include HIV infection, HBV middle-income countries is sofosbuvir plus daclatasvir
infection, and other causes of liver disease (eg, alcoholic (table),64 with sofosbuvir plus ravidasvir as another low-cost
liver disease and metabolic-associated fatty liver disease). regimen.65
Education and counselling about factors associated Important features of pan-genotypic DAA regimens
with HCV transmission and liver disease progression include high efficacy across genotypes (ie, SVR ≥95%,
should be provided in a non-stigmatising manner and including compensated cirrhosis), excellent tolerability,
should not influence whether to initiate HCV treatment. short treatment duration (ie, 8–12 weeks, including
This approach might include information on measures compensated cirrhosis), oral once-daily dosing, and low
to reduce transmission risk, including drug use and resistance-related failure. DAA therapy is safe and effective

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in key populations, including people who inject drugs, are
incarcerated, have HIV infection, or have chronic kidney
disease. Although DAA therapy was approved for use in
chronic HCV infection, it is also safe and effective in
acute infection.17,66 Assessment for DAA treatment is
recommended for all people with HCV infection,
regardless of comorbidities or infection duration.
Simplified treatment algorithms are suitable for most
adults with HCV infection (figure). For people without
cirrhosis or with compensated cirrhosis, evidence from
clinical trials and real-world cohort studies supports
treatment with glecaprevir–pibrentasvir for 8 weeks and
sofosbuvir–velpatasvir for 12 weeks; if either combination
is unavailable (eg, in low-income settings), sofosbuvir
plus daclatasvir for 12 weeks is recommended.52 Given
exceptional safety, the entire DAA course could be
provided at initiation without on-treatment monitoring,
unless adverse events are reported.67,68 Not all people with
HCV infection are suitable for this model, with additional
management considerations in specific populations,
including people with HBV infection, decompensated
liver disease, previous liver transplantation, hepatocellular
carcinoma, and previous DAA treatment failure.
Management of virological failure after pan-genotypic
DAA therapy
Despite high efficacy of first-line regimens, some people
will have virological failure and require retreatment. In
general, retreatment with a DAA regimen that includes
drugs from multiple classes is well tolerated and
successful (SVR >90%). However, lower retreatment
efficacy (SVR 80–90%) has been seen among particular
subgroups, including people with cirrhosis, genotype 3
infection, and treatment failure after contemporary pan-
genotypic regimens (eg, glecaprevir–pibrentasvir and
sofosbuvir–velpatasvir).69,70
In people who did not respond to a sofosbuvir-based
regimen, retreatment with 12 weeks of sofosbuvir–
velpatasvir–voxilaprevir has shown high efficacy and
safety;63 the addition of ribavirin or treatment extension to
24 weeks should be considered for people with genotype 3,
cirrhosis, or previous treatment with sofosbuvir–
velpatasvir.69,70 An alternative regimen is glecaprevir–
pibrentasvir for 16 weeks.71 In people with virological
failure after glecaprevir–pibrentasvir, retreatment with
either sofosbuvir–velpatasvir–voxilaprevir for 12 weeks,
or sofosbuvir plus glecaprevir–pibrentasvir plus ribavirin
for 12 or 16 weeks can be considered.72,73 For the
small proportion who do not respond to retreatment
with sofosbuvir–velpatasvir–voxilaprevir, limited clinical
experience and expert opinion support a second course of
retreatment with sofosbuvir plus glecaprevir–pibrentasvir
or sofosbuvir–velpatasvir–voxilaprevir with ribavirin for
16 or 24 weeks.52,74
The role of resistance-associated substitution testing
to guide individualised retreatment regimens is
uncertain. Clinical trials63 have not shown an impact of
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Seminar
NS5A resistance-associated substitution on cure in people
receiving retreatment with triple class DAA regimens
(ie, sofosbuvir–velpatasvir–voxilaprevir and sofosbuvir
plus glecaprevir–pibrentasvir). Complex resistance-
associated substitution patterns involving NS3 and NS5A
can be seen in people with multiple episodes of virological
failure after DAA therapy, but there are little data available
for this unique and infrequent group.74
Management of HCV in people who inject drugs
DAA therapy has transformed HCV clinical management
in marginalised populations, including people who inject
drugs, facilitated by population-specific clinical trials
showing high safety and efficacy.75 Pivotal studies in
people reporting use of injecting drugs (with or without
opioid agonist therapy) within the previous 6 months
showed similar outcomes to broader study populations,
with SVR attained in 92% of those who received elbasvir–
grazoprevir for 12 weeks and 94% of those who received
sofosbuvir–velpatasvir for 12 weeks.76,77 Further evaluation
of clinical trial data detailed high treatment adherence
and relative tolerance for non-adherence, with cure
generally attained in those who completed most of the
prescribed course, including those who missed at least
7 consecutive days.78
Specific issues to consider among people who inject
drugs are drug dependency management, choice of DAA
regimen, model of care for treatment delivery, and socio-
structural determinants, including housing stability,
employment, and incarceration. Pre-treatment review
of drug use patterns, needle-syringe access, and
consideration of opioid agonist therapy for those with
opioid use disorder should be done. DAA regimen choice
should be individualised and discussed in the context of
potential adherence issues—shorter duration with higher
daily pill burden (glecaprevir–pibrentasvir) or longer
duration with low pill burden (sofosbuvir–velpatasvir).
Concerns around adherence could be allayed through
supervised dosing; however, randomised evaluation
showed similarly high HCV cure in people on opioid
agonist therapy receiving directly observed therapy, group
treatment, or self-administered therapy,79 and in people
who inject drugs receiving directly observed therapy or
patient navigation.80 Increasingly, DAA therapy for people
who inject drugs is embedded within harm reduction and
community health programmes, facilitating treatment
delivery and follow-up for HCV reinfection. The addition
of peer-based support might play an important role in
improving engagement, building trust, and assisting with
treatment.81
Management of HCV in people with advanced liver
disease and liver transplantation
People with HCV infection and cirrhosis should be
prioritised for treatment, but for those with a history of
liver decompensation (eg, oesophageal varices, ascites,
and hepatic encephalopathy) or abnormal liver
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 Seminar
synthetic function (eg, albumin, total bilirubin, and
prothrombin time), there are additional considerations
before commencing treatment. First, for any person
with cirrhosis, the Child-Pugh-Turcotte score should
be calculated. DAA regimens that include an
NS3/4a protease inhibitor are contraindicated in people
with decompensated cirrhosis (Child-Pugh-Turcotte
score ≥7). For people with decompensated cirrhosis,
sofosbuvir–velpatasvir or sofosbuvir plus daclatasvir are
recommended; both regimens are safe and effective. The
recommended duration of therapy is also different in
people with decompensated cirrhosis—12 weeks with
ribavirin or 24 weeks without ribavirin. Second, there
should be concurrent consideration of the need for liver
transplantation referral. For people with decompensated
cirrhosis who are potential transplantation candidates,
deferral of HCV treatment until after the transplantation
evaluation is appropriate and allows coordination
of treatment with transplantation plans.82 In some
transplantation centres, people with HCV infection
might have earlier access to a transplant because they
can receive a liver from a donor with HCV. Finally, setting
expectations related to the clinical outcomes after DAA
therapy in people with decompensated cirrhosis is
important. Reversal of decompensation is possible, but
dependent upon the severity of portal hypertension and
liver synthetic dysfunction.83,84
Current DAA regimens are safe and highly effective
(SVR >90%) in transplant recipients, with similar
outcomes after 12 weeks of treatment in those with and
without a liver transplant. Of note, glecaprevir–
pibrentasvir for 8 weeks has not been robustly studied in
this population.85 Although early studies of DAA therapy
post-transplantation included ribavirin, subsequent
investigation has established that ribavirin is not
necessary. Some drug–drug interactions with immuno­
suppressive medications require attention but are not a
barrier to treatment. Given the excellent safety profile of
DAA therapy, earlier treatment is preferred, typically
initiated within weeks to months of transplantation.
There are uncommon reports of transplant rejection
occurring during or shortly after DAA therapy,86 possibly
related to an altered intrahepatic milieu or the amount of
immunosuppression with improved liver function and,
as such, monitoring of immunosuppression and liver
enzymes is recom­mended during DAA therapy.
Management of HCV in people with hepatocellular
carcinoma
In people with HCV and hepatocellular carcinoma, there
is a need for a coordinated approach. In general,
establishing the treatment plan for hepatocellular
carcinoma takes priority. Although initial studies
suggested that treatment of HCV in people with
untreated hepatocellular carcinoma promoted cancer
progression,87 those concerns have largely been
resolved.88,89 However, many experts recommend that
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hepatocellular carcinoma treatment be done before HCV
treatment. The proportion reaching SVR in people with
hepatocellular carcinoma is lower than in people
without,90 but whether SVR is influenced by the presence
of untreated hepatocellular carcinoma is controversial.
For people with decompensated cirrhosis (ie,
Child-Pugh-Turcotte scores ≥7 or clinical evidence of
decompensation), concurrent treatment of HCV and
hepatocellular carcinoma might be warranted, with the
goal of improving or stabilising liver function to improve
tolerability of hepatocellular carcinoma therapy.91 DAA
interactions with immunotherapies for hepatocellular
carcinoma are not a concern. As nuanced decision
making is required, case review and discussion by a
multidisciplinary tumour board is the best option.
Management of HCV in children and adolescents
In 2018, an estimated 3·3 million children and adolescents
(<18 years of age) were living with HCV infection.92 As
with adults, children and adolescents usually do not have
symptoms attributable to chronic HCV infection, and
HCV-related cirrhosis and hepatocellular carcinoma
are rare.93 Mother-to-child and health-care-associated
transmission contribute to the burden of infection in
childhood, whereas injecting drug use is the predominant
mode of transmission in adolescence.93
DAA therapy has been approved for use in children and
adolescents, with recommendations for use of pan-
genotypic regimens, including sofosbuvir–velpatasvir,
glecaprevir–pibrentasvir, and sofosbuvir plus daclatasvir
(appendix p 3).94–97 High efficacy and safety of glecaprevir–
pibrentasvir and sofosbuvir–velpatasvir have been shown
in adolescents (aged 12–17 years) and children (3–11),
similar to registration studies in adults (per-protocol
SVR >95%).94–96 In addition to the standard fixed-dose
combination tablet recommended for adults and
adolescents, glecaprevir–pibrentasvir is available as a
granule formulation (containing 50 mg of glecaprevir and
20 mg of pibrentasvir) and sofosbuvir–velpatasvir is
available as a granule formulation (containing 50 mg of
sofosbuvir and 12·5 mg of velpatasvir) and a lower-dose
combination tablet (200 mg sofosbuvir and 50 mg
velpatasvir) to permit individualised dosing. Dose
adjustments are recom­mended based on weight and age
(table).
Management of HCV in low-income settings
Clinical trials have confirmed the efficacy of sofosbuvir–
velpatasvir and glecaprevir–pibrentasvir in people in low-
income settings, including those with HCV genotypes
and subtypes that are uncommon in high-income
countries (ie, genotype 4k and 4r in Rwanda).68,98,99
However, access to fixed-dose combination regimens is
limited due to cost. The price of DAA therapy has fallen in
many low-income and middle-income countries through
price negotiation with pharmaceutical companies,
availability of generic formulations, competition between
www.thelancet.com Vol 402 September 23, 2023

pharmaceutical companies and generic suppliers, volume-
based procurement, and acquisition of voluntary licenses;
as such, a 12-week course of generic sofosbuvir plus
daclatasvir costs less than US$50 in many settings.64
Although DAA prices have decreased, access to and
cost of diagnostics, particularly HCV RNA testing, is a
major barrier. In many low-income and middle-income
countries, out-of-pocket payment for diagnostics and
treatment poses an additional challenge in the absence of
national programmes. Many HCV programmes in low-
income settings have transitioned to decentralised models
of care with point-of-care HCV RNA testing when available
and no or minimal on-treatment monitoring.100,101
Prevention
Harm reduction for people who inject drugs
Implementation of evidence-based harm reduction
programmes and drug policy reform is crucial.102 Opioid
agonist therapy with high-coverage needle and syringe
programmes has been associated with a 74% reduction in
risk of HCV infection, and opioid agonist therapy has been
associated with a reduction of 50% without needle and
syringe programmes.103 However, access to harm reduction
is grossly inadequate globally, with less than 1% of people
who inject drugs residing in countries with high coverage
of both needle and syringe programmes (>200 needle-
syringes per year per person who injects drugs) and opioid
agonist therapy (>40 opioid agonist therapy recipients
per 100 people who inject drugs),104 in part due to political
resistance, stigma, discrimination, and criminalisation of
drug use. Access to harm reduction is particularly
inadequate in prisons and should be addressed.
Post-treatment surveillance and management of
reinfection
Reinfection presents a challenge to elimination. HCV
reinfection risk is higher in people who report ongoing
injecting drug use or sexual behaviour associated with
transmission, emphasising the need for education,
harm reduction, post-treatment surveillance, expedient
diagnosis of reinfection, and access to retreatment.103,105–107
People at risk of reinfection should have at least
annual HCV RNA and liver enzyme testing (ie, alanine
aminotransferase testing).108 However, adherence to this
recommendation is suboptimal.109 Additional strategies to
reduce reinfection include testing and treating sexual and
injecting partners and networks,110 and management of
medical and psychiatric comorbidity.111 Most importantly,
treatment for HCV infection should be offered as often as
required, without stigma or discrimination, with DAA
regimens as recommended for people who are treatment
naive (figure).
Prevention of health-care-associated HCV infection
Unsafe health-care practices (eg, unsafe health-care
injection, blood transfusion, and other invasive medical
procedures) continue to contribute to a sizeable
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proportion of HCV infections in low-income and middle-
income countries (15–20%).1,112 In 2010, an estimated
5% of all health-care injections were given with
unsterilised or reused equipment (resulting in
315 000 new HCV infections);112 some improvement has
been seen, with 3·5% of health-care injections in 2020
estimated to have been unsafe.1 Success in prevention of
HCV transmission in people receiving haemodialysis in
high-income countries highlights the value of universal
infection control procedures, screening, and blood and
injection safety, including safety-engineered single-use
needles and syringes.113,114
HCV elimination: what is required to achieve the
WHO 2030 targets?
Achieving the WHO HCV elimination targets by 2030
would be an enormous global health success, although
few countries are considered on-track. In Egypt,
since 2015, screening of 50 million people, predominantly
with point-of-care antibody testing, and treatment of
more than 4 million people have been followed by marked
estimated declines in HCV RNA prevalence (6% to 0·5%)
and incidence (2·4 to 0·37 per 1000),115 showing what can
be achieved in a low-income to middle-income country
with national leadership, low drug pricing, and effective
treatment delivery infrastructure. In Australia, since 2016,
95 000 of an estimated 180 000 people with HCV have
been treated through the government-funded DAA
programme, with high uptake in key populations. This
HCV therapeutic success, together with a strong harm
reduction foundation, has produced substantial declines
in estimated HCV RNA prevalence (44% to 17%)116 and
incidence (from 13 to 5 per 100 person-years) in people
who inject drugs, along with general population-level
reductions in liver-related morbidity and mortality.117
In contrast to these elimination exemplars, despite
large numbers treated in the USA since 2015, inequity in
DAA access, fragmented and inadequate harm reduction,
and rising injecting drug use have driven increasing
numbers of new HCV infections. Addressing inequities
in access and key social determinants of health, including
housing stability, mental health, and legal difficulties, is
crucial for HCV elimination, particularly within
marginalised communities. Striving for HCV elimination
requires a broader focus on health equity, health systems
strengthening, universal health coverage, and multi-
sectoral collaboration.
Globally, there are enormous gaps to fill in 7 years to
reach the WHO elimination targets (appendix p 2). In
many countries, declining DAA treatment numbers
followed an initial warehouse effect (ie, treatment of
those in clinics awaiting approval of new therapies), and
the COVID-19 pandemic impacted HCV testing and
linkage to care. However, major strides have been made
in the international response. Reductions in DAA
pricing, generic production, and voluntary licences in
low-income and middle-income countries should ensure
1091
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that drug cost is not a major impediment to HCV
elimination. DAA restrictions, including those related to
liver disease stage, drug and alcohol use, and prescriber
type, continue to be removed.118 Successful micro-
elimination efforts (ie, tailored treatment and prevention
interventions in specific populations or geographical
areas) in key populations in different countries,119
including people who inject drugs, are incarcerated, have
HIV, or receive haemodialysis, provide a template for
broader elimination strategies, highlighting what can be
achieved with a thorough understanding of the target
population, including the enablers and barriers to
accessing care and treatment.
Initiatives to improve linkage to care and treatment are
required, but there is an even greater need for strategies
to massively increase screening and diagnosis
(appendix p 4). The highly successful HCV screening
programmes in Egypt, Mongolia, and Georgia show what
can be achieved in diverse settings with sustained societal
and political engagement, along with adequate funding,
infrastructure, and personnel. Despite evidence of utility,
the potential of point-of-care testing for enhancing
diagnosis has yet to be realised in most countries with
inadequate uptake, particularly in high-income settings.
A national programme to scale up decentralised HCV
point-of-care antibody and RNA testing commenced in
Australia in 2022, but few such initiatives exist.120
Important WHO guidance for HCV elimination
validation in 2022 included new outcome targets.1 The
proposed targets are population-based absolute incidence
measures, rather than relative declines from 2015, for
HCV-related mortality (<2 per 100 000 total population
per annum) and HCV incidence (<5 per 100 000 total
population per annum and <2 per 100 person-years in
people who inject drugs). In keeping with elimination of
HCV as a public health threat, these measures are
focused on current population-level disease burden and
are more readily measured in settings with limited
pre-DAA era surveillance and monitoring.
Future directions in treatment and prevention
Clinical care following HCV treatment
SVR at or beyond post-treatment week 12 (SVR12) is the
established efficacy endpoint following DAA therapy.
People without cirrhosis and normal liver enzymes after
SVR do not require liver-specific follow-up, although
people who engage in behaviours associated with
transmission should have at least annual HCV RNA
testing (figure). People with abnormal liver tests despite
SVR should be assessed for other causes of liver disease.
Although assessment at post-treatment week 12 is
recommended, this might be difficult in some settings
and populations. With high correlation between
undetectable HCV RNA at post-treatment week 4 and
SVR12,121 opportunistic HCV RNA testing at any time
after post-treatment week 4 should be considered, if loss
to follow-up is likely.
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People with cirrhosis should continue to receive
care, with appropriate surveillance for hepatocellular
carcinoma and clinically significant portal hypertension.
Indefinite hepatocellular carcinoma surveillance with
monthly ultrasound examinations is recommended,
despite SVR and potential normalisation of non-invasive
liver fibrosis assessment tools.52 By contrast, surveillance
for clinically significant portal hypertension could be
discontinued if improvement is seen following SVR
(liver stiffness measurement <12 kPa and platelet
count >150 × 10⁹/L).122
Expanding transplant eligibility: organ donation in
people with HCV
The number of people awaiting organ transplantation far
exceeds available donors. Expanding the donor pool
through use of organs from people with HCV infection
has gained acceptance in the DAA era. Organs from
HCV viraemic donors have been used successfully for
heart,123 lung,124 kidney, and liver transplantation,125 but
with variable approaches to timing and duration of DAA
therapy. Experts recommend a pre-emptive or early
treatment strategy to minimise any HCV-related risk
post-transplantation (eg, hepatitis and glomerulone­
phritis) and to reduce the risk of rejection or other
immunological events related to clearance of HCV
infection. For non-liver solid organ transplant recipients
from HCV viraemic donors, DAA therapy initiated at the
time of transplantation and continued for 2–4 weeks is
effective (SVR 100%). Deferral of DAA therapy until after
discharge (days to weeks post-transplant) requires
prescription of the usual 12-week duration. For liver
transplantation recipients from HCV viraemic donors,
the standard 12-week DAA course is required, because
the donor graft has established HCV infection.126
Vertical transmission: screening and management of
pregnant women
Screening women for HCV during pregnancy provides a
unique opportunity for diagnosis and linking women
with care. In addition to vertical transmission, HCV
infection is associated with other adverse pregnancy
outcomes, including intrahepatic cholestasis of
pregnancy and preterm delivery.13 Universal HCV
antenatal screening has been recommended in several
jurisdictions and endorsed by policy makers, reflecting
changing epidemiology and a rise in incident infections
among women of childbearing age, particularly in
the USA, but testing and linkage to care is inadequate.127–129
Treating women with HCV infection in the third
trimester of pregnancy has been considered, but data on
the use of DAA therapy in pregnancy are scarce.
Evidence suggests sofosbuvir-based DAA regimens
initiated after the first trimester are well tolerated and
safe;130–132 in ten women who received sofosbuvir–
ledipasvir for 12 weeks, all achieved SVR with no
adverse maternal or infant outcomes.131 Prospective
www.thelancet.com Vol 402 September 23, 2023

studies evaluating pan-genotypic regimens in pregnant
women (ie, sofosbuvir–velpatasvir; NCT04382404 and
NCT05140941) are underway.
Treatment-as-prevention in settings with poor harm
reduction coverage
Mathematical modelling and, in the past 2 years,
empirical evidence have shown the potential of HCV
treatment-as-prevention in people who inject drugs and
people who are incarcerated.133–136 Highlighting the
benefits of broad DAA uptake, even in settings with
inadequate access to harm reduction, HCV treatment is
best coupled with optimal prevention strategies.
Evaluating short-duration DAA regimens or exploration
of technologies for delivery of long-acting DAA therapy,
which are potentially co-formulated with long-acting
opioid agonist therapy, is of particular interest in this
population. Additionally, further work to identify optimal
harm reduction strategies (eg, pharmacological
interventions) for people who inject stimulants is
necessary given the high reinfection incidence in this
population, including in the context of national
elimination programmes.137
Vaccine development
HCV elimination might not be feasible without
vaccination. There is renewed enthusiasm, with new
vaccine technologies that can generate high magnitude
T-cell and B-cell responses.138 A double-blind, randomised,
placebo-controlled phase 1–2 trial evaluated a
recombinant chimpanzee adenovirus 3 vector priming
vaccination, followed by a recombinant modified vaccinia
Ankara boost in people who inject drugs in the USA.139
Although this vaccine strategy was unsuccessful and did
not prevent chronic HCV infection, the strategy was safe,
elicited HCV-specific T-cell responses, and lowered peak
HCV RNA. One issue with vaccine development has
been the scarcity of an HCV animal model. With the
introduction of DAA therapy, a controlled human
infection model to assess vaccine candidates could be
considered and could substantially advance the field, as
has been seen for other infectious diseases.140
Contributors
All authors contributed to the conception, drafting, and revision of the
manuscript. All authors have seen and approved the final version.
Declaration of interests
SSS declares institutional grant support from the National Institutes of
Health, Elton John AIDS foundation, US President’s Emergency Plan
for AIDS relief and US Agency for International Development,
Gilead Sciences, and Abbott Laboratories, and honoraria from Gilead
Sciences and Abbott Laboratories. NAT declares institutional grant
support from the National Institutes of Health, GlaxoSmithKline,
Genetech-Roche, Helio Health, Durect Corp, Gilead Sciences, and Eiger
Pharmaceuticals, and consulting fees from Moderna. GJD declares
institutional grant support from Gilead Sciences, AbbVie, and Merck.
MM declares no competing interests.
Acknowledgments
The Kirby Institute is funded by the Australian Government
Department of Health and Ageing. The views expressed in this
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publication do not necessarily represent the position of the Australian
Government. The content is solely the responsibility of the authors.
MM and GJD are supported by the National Health and Medical
Research Council Fellowships.
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