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Management of chronic hepatitis C virus infection: Initial antiviral

therapy in adults
AUTHORS: Andrew J Muir, MD, MHS, Camilla S Graham, MD
SECTION EDITOR: Adrian M Di Bisceglie, MD
DEPUTY EDITOR: Allyson Bloom, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Mar 2024.

This topic last updated: Jan 24, 2024.

INTRODUCTION

Hepatitis C virus (HCV) can cause both acute and chronic hepatitis. The acute process is self-limited, rarely
causes hepatic failure, and usually leads to chronic infection. Chronic HCV infection often follows a progressive
course over many years and can ultimately result in cirrhosis, hepatocellular carcinoma, and the need for liver
transplantation. (See "Clinical manifestations and natural history of chronic hepatitis C virus infection".)

Successful antiviral treatment of chronic HCV infection halts the progression of liver disease and is associated
with improvement in liver-related morbidity and mortality. This topic will review the antiviral selection and
administration for initial therapy of chronic HCV infection.

Our recommendations are generally consistent with joint guidelines on HCV management from the American
Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA), which
can be accessed at www.hcvguidelines.org [1,2].

Management issues other than initial antiviral selection for chronic HCV infection are discussed elsewhere:

● (See "Overview of the management of chronic hepatitis C virus infection".)

● (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection".)
● (See "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults".)
● (See "Clinical manifestations, diagnosis, and treatment of acute hepatitis C virus infection in adults".)

GENERAL PRINCIPLES

Treatment objective — We recommend antiviral treatment for all patients with chronic HCV infection. The
clinical objective of HCV treatment is cure of the infection. In the clinical setting and in HCV treatment trials, the
marker for treatment success is a sustained virologic response (SVR), which is defined as an undetectable HCV
viral level 12 weeks after the completion of therapy. An SVR at this time period has been associated with a >99
percent chance of sustained clearance of HCV, an effective cure of HCV infection [3]. SVR has also been
associated with patient-important outcomes such as decreased mortality, decreased liver-related complications,
and improved quality of life. These issues are discussed elsewhere. (See "Patient evaluation and selection for
antiviral therapy for chronic hepatitis C virus infection", section on 'Benefits of treatment'.)
Prioritizing access to therapy — A major barrier to achieving SVR and HCV cure is access to therapy. This may
be related to limited access to pretreatment testing or monitoring in resource-constrained or nontraditional
care settings, nonspecialty provider unfamiliarity with treatment options, concern that patients may not return
for follow up visits, or payor restrictions. Given the high efficacy rates of contemporary antiviral regimens for
initial therapy of HCV infection, regardless of genotype and the presence of compensated cirrhosis, we favor a
simplified approach that may circumvent some of these limitations. This includes:

● A streamlined approach to regimen selection with limited pretreatment evaluation (see 'Limited
pretreatment evaluation' below)

● A minimalist approach to monitoring (see 'Potential for minimal monitoring during treatment' below)

● A low threshold to offer therapy despite unstable housing or active injection drug use (see "Patient
evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Active drug
use')

Data suggest that a simplified approach to care does not compromise the success of initial treatment [4]. High
SVR rates can be achieved among patients treated by nonspecialists (including primary care physicians, nurse
practitioners, and pharmacists) [5,6], without on-treatment monitoring [4,7], and despite injection drug use [8].

Limited pretreatment evaluation — Prior to regimen selection for initial HCV therapy, limited pretreatment
evaluation includes:

● Assessment for cirrhosis – This entails assessment through history, examination, and basic laboratory
testing. If readily available, noninvasive testing for cirrhosis can also identify advanced fibrosis or cirrhosis.
However, since the initial treatment regimens are largely the same for those with and without
compensated cirrhosis, non-invasive tests for fibrosis are not essential to making treatment decisions, as
long as there is no clinical suspicion for decompensated cirrhosis (eg, ascites, history of varices, hepatic
encephalopathy). Although not necessary for determining treatment regimens, identifying advance
fibrosis or cirrhosis remains important for clinical care, as these patients require ongoing surveillance for
hepatocellular carcinoma. The clinical evaluation for cirrhosis is discussed in detail elsewhere. (See "Patient
evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Assessment
of fibrosis stage'.)

● Evaluating for other conditions that might impact management – These include testing for HIV,
hepatitis B virus (HBV) infection, and pregnancy. Additionally, reviewing all the medications the patient is
taking (prescription, over-the-counter, and herbal medications) is important to inform the potential for
drug interactions. These are discussed in detail elsewhere. (See "Patient evaluation and selection for
antiviral therapy for chronic hepatitis C virus infection", section on 'Evaluation for comorbidities or
conditions that might affect therapy'.)

● Optional genotype testing – For initial therapy, knowledge of the HCV genotype is not necessary for
regimen selection, and we do not routinely check it. Lack of genotype testing results should not be a
barrier to HCV treatment. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C
virus infection", section on 'HCV genotype in selected cases'.)

Having to check a genotype may not be easily accessible in non-traditional care sites or lead to delays in care.
On the other hand, if genotype testing is readily available and will not impede access to or delay treatment, it is
reasonable to check it. In some cases (specifically, for patients who have cirrhosis and genotype 3 infection),
knowledge of the genotype may allow for more specific regimen selection that could result in slightly higher SVR
rates. Documentation of the baseline genotype can also help distinguish relapse versus reinfection if patients
are found to have HCV viremia after treatment, although making this distinction is not always necessary. (See
"Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults", section on
'Distinguishing relapse from reinfection'.)

PATIENTS WITHOUT KNOWN CIRRHOSIS

Initial HCV therapy for patients without cirrhosis can generally be selected without knowledge of the genotype.

Our preferred regimens

Selecting among preferred regimens — For initial therapy of chronic HCV infection, we recommend one of
the following direct-acting antiviral (DAA) regimens ( algorithm 1):

● Sofosbuvir-velpatasvir for 12 weeks (see 'Sofosbuvir-velpatasvir' below)

● Glecaprevir-pibrentasvir for 8 weeks (see 'Glecaprevir-pibrentasvir' below)

These two regimens have very high efficacy regardless of genotype and good safety profiles. Although they
have not been compared directly, they have each resulted in sustained virologic response (SVR) rates in excess
of 95 percent among individuals undergoing initial HCV antiviral therapy and are reasonably expected to have
similar effectiveness.

The choice between them is primarily limited by availability; in the United States, some payers will only provide
coverage for a single preferred regimen. If both are options, the choice depends on potential for drug
interactions and patient preference:

● Drug interactions with each are generally manageable but should be evaluated prior to initiation. For other
specific drug interactions, refer to the drug interactions program included with UpToDate. Specific drug
interactions are discussed below and in the drug interactions program included with UpToDate. (See
'Sofosbuvir-velpatasvir' below and 'Glecaprevir-pibrentasvir' below.)

Rare drugs (eg, carbamazepine and rifampin) are not recommended for co-administration with either
option. Patients taking such drugs should be managed in consultation with a specialist; a potential
approach is switching the medication that interacts with the DAAs to a different option. Data on co-
administration with such drugs are extremely limited [9,10].

● Administration differences may impact patient choice. Sofosbuvir-velpatasvir is given as a single

combination tablet once daily with or without food for 12 weeks, whereas glecaprevir-pibrentasvir is given
as three combination tablets once daily with food for 8 weeks. Some patients prioritize the shorter
regimen duration, whereas others prefer the simplicity of a single pill. Some patients do not have a regular
meal schedule and thus prefer a regimen that can be taken without regard to food.

In the United States, each daily dose of glecaprevir-pibrentasvir is packaged in a separate box, so the
monthly supply is bulky. Sofosbuvir-velpatasvir is available in a bottle containing the monthly supply of 28
tablets. Patients, particularly those with unstable housing and limited storage options, may have a
practical preference between the packaging.

Although the joint American Association for the Study of Liver Diseases (AASLD)/Infectious Diseases Society of
America (IDSA) guidelines label other regimens (ledipasvir-sofosbuvir for genotypes 1, 4, 5, and 6; elbasvir-
grazoprevir for genotypes 1b and 4) as preferred, we almost never use them since they offer no clear advantage
over the preferred pangenotypic regimens and using them optimally may require additional testing that could
be a barrier to care. Occasionally, payers may suggest one of these alternative regimens. These regimens are
discussed elsewhere. (See 'Alternative regimens' below.)

Sofosbuvir-velpatasvir — For the vast majority of patients with chronic HCV infection, the pangenotypic
regimen of sofosbuvir-velpatasvir is one of our preferred antiviral regimens for initial treatment.

● Dosing and administration – It is available as a fixed-dose combination tablet of the NS5B inhibitor
sofosbuvir (400 mg) and the NS5A inhibitor velpatasvir (100 mg) and is administered once daily with or
without food for 12 weeks. It can be used in patients with any degree of renal or hepatic impairment.

● Efficacy – Support for sofosbuvir-velpatasvir comes from several trials that have demonstrated very high
efficacy for initial therapy of all genotypes (SVR rates 95 to 100 percent) [11-17] and from real world
observational data that match trial findings [18]. Although some studies suggest a numerically lower SVR
rate for patients with genotype 3, the response rate remains very high for that genotype.

As an example, in a randomized, placebo-controlled trial that included 624 patients with genotype 1, 2, 4,
5, or 6 who received sofosbuvir-velpatasvir for 12 weeks, the overall SVR rate was 99 percent compared
with 0 percent among the 116 patients who received placebo [11]. In two other randomized trials,
sofosbuvir-velpatasvir resulted in superior SVR rates among 266 patients with genotype 2 infection (99
versus 94 percent, absolute difference 5.2 percent, 95% CI 0.2-10.3) and 552 patients with genotype 3
infection (95 versus 80 percent, absolute difference 14.8 percent, 95% CI 9.6-20) compared with sofosbuvir
plus ribavirin for 12 weeks, which had been the previously recommended regimens for those genotypes
[14]. Among the 197 patients with genotype 3 infection who did not have cirrhosis, the SVR rate with
sofosbuvir-velpatasvir was 97 percent [14]. In all three trials, virologic failure (either failure to suppress on
therapy or relapse after therapy) was only identified in 2 of 328 patients with genotype 1 infection (<1
percent) and in 11 of 277 patients with genotype 3 infection (4 percent); other reasons for failure to achieve
SVR included loss to follow up, treatment discontinuation, and consent withdrawal. These trials included
patients with and without compensated cirrhosis as well as patients undergoing antiviral therapy for the
first time and those who had failed prior interferon-based therapy.

Certain genotype 3 subtypes are associated with lower SVR rates with sofosbuvir-velpatasvir. In a
multinational trial in Asia, the SVR rate was only 89 percent among the 28 patients with genotype 3b, a
subtype identified in that area but rare elsewhere [16].

Similarly high SVR rates overall were reported in an analysis of 12 cohorts from different clinical settings
North America and Europe [18]. Among 5196 patients who received sofosbuvir-velpatasvir for 12 weeks,
SVR rates were 99.1 percent for genotype 1, 99.3 percent for genotype 2, 98.3 percent for genotype 3, 99.6
percent for genotype 4, and 98.5 percent for genotypes 5 and 6.

● Potential drug interactions – Coadministration is not recommended with amiodarone, certain

anticonvulsants (eg, phenytoin, carbamazepine, phenobarbital, oxcarbazepine), rifamycins, certain HIV
antiretrovirals (eg, efavirenz), and St. John’s wort.

Additionally, increased gastric pH levels decrease absorption of velpatasvir; thus, coadministration with
proton pump inhibitors is ideally avoided. However, if necessary, omeprazole 20 mg can be
coadministered, with sofosbuvir-velpatasvir taken with food and four hours prior to the omeprazole dose
[19]; the use with other proton pump inhibitors in this way has not been studied, and we avoid it. We also
counsel patients to avoid over-the-counter products that may contain stomach acid neutralizers until they
discuss it with a clinician. If they cannot stop taking antacids or H2-receptor antagonists during the course
 of HCV treatment, they can cautiously take them at least four hours following the sofosbuvir-velpatasvir
dose. We carefully counsel any patient continuing to take an acid-reducing medication in this way to
ensure they understand the importance of the timing of administration.

For other specific drug interactions, refer to the drug interactions program included with UpToDate.

● Adverse effects – Sofosbuvir-velpatasvir is well tolerated, with <1 percent of trial participants
discontinuing a 12-week regimen for adverse events. The most common adverse events are fatigue,
headache, nausea, nasopharyngitis, and insomnia [11,14,20].

Additional details on the dosing, adverse effects, and drug interactions of sofosbuvir-velpatasvir are
discussed elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection", section
on 'Sofosbuvir-velpatasvir'.)

Glecaprevir-pibrentasvir — For the vast majority of patients with chronic HCV infection, the pangenotypic
regimen of glecaprevir-pibrentasvir is one of our preferred antiviral regimens for initial treatment.

● Dosing and administration – It is available as a fixed-dose combination of the NS3/4A protease inhibitor
glecaprevir (300 mg) and the NS5A inhibitor pibrentasvir (120 mg) and is administered as three tablets
once daily with food for eight weeks. It can be used in patients with any degree of renal impairment but
should not be used in patients with decompensated cirrhosis (Child Pugh Class B or C) because of
increased drug levels and risk of worsening liver function or failure.

● Efficacy – Support for sofosbuvir-velpatasvir comes from several trials that have demonstrated very high
efficacy for initial therapy of all genotypes (SVR rates 95 to 99 percent) [21-27] and from real world
observational data that match trial findings [28-30]. Although some studies suggest a numerically lower
SVR rate for patients with genotype 3, the response rate remains very high for that genotype.

As an example, in a pooled analysis of nine randomized trials comparing glecaprevir-pibrentasvir for 8

versus 12 weeks in 2041 patients without cirrhosis, the 8-week regimen resulted in SVR in 99 percent for
genotype 1, 98 percent for genotype 2, 95 percent for genotype 3, 95 percent for genotype 4, 100 percent
for genotype 5, and 92 percent for genotype 6 [31]. These SVR rates were similar to those with the 12-week
regimen. Among the 965 patients who received the 8-week regimen, virologic failure (either failure to
suppress on therapy or relapse after therapy) occurred in only nine (one genotype 1, two genotype 2, and
six genotype 3). Other reasons for failure to achieve SVR included loss to follow-up or missing data and
treatment discontinuation. Certain genotype 3 subtypes are associated with lower SVR rates with
glecaprevir-pibrentasvir; in particular, SVR rates are low for genotype 3b, a subtype identified in Asia but
rare elsewhere [32].

Similarly high SVR rates were reported in an analysis of 15 unique cohorts from the United States, Europe,
and Japan [28]. Among 8583 patients who received glecaprevir-pibrentasvir for eight weeks, SVR rates
were 95.7 percent for genotype 1, 97.6 percent for genotype 2, 95 percent for genotype 3, and 99 percent
for genotype 4.

● Potential drug interactions – Because of expected and observed drug interactions, coadministration is
contraindicated with rifampin and atazanavir and not recommended with carbamazepine, oral
contraceptive agents, St. John's wort, cyclosporine, and certain other HIV antiretrovirals.

For other specific drug interactions, refer to the drug interactions program included with UpToDate.
 ● Adverse effects – Glecaprevir-pibrentasvir is well tolerated. In an analysis of pooled data from multiple
clinical trials, including over 2000 patients with chronic HCV infection, most adverse effects were mild, with
headache and fatigue the most common complaints [33]. Fewer than 0.5 percent of patients discontinued
therapy because of adverse effects. Elevations in aminotransferase or bilirubin levels were rare and not
clearly related to the drug.

Additional details on the dosing, adverse effects, and drug interactions of glecaprevir-pibrentasvir are
discussed elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection", section
on 'Glecaprevir-pibrentasvir'.)

Alternative regimens — The preferred regimens discussed above are widely available in the United States and
many other countries. Alternative regimens may be needed for individuals who cannot access preferred
options, mainly in countries that have preferred pricing or generic forms for other HCV regimens.

Internationally, the most widely used alternative regimen is:

● Sofosbuvir plus daclatasvir – In open-label trials of patients with genotypes 1, 2, 3, and 4 infection, a
once-daily regimen of sofosbuvir plus daclatasvir for 12 weeks resulted in SVR rates of 95 percent or higher
[34-36]. Observational data have also supported the efficacy of this regimen [37,38].

Sofosbuvir plus daclatasvir are given as two separate tablets. The regimen is not available in the United
States. Details on dosing, adverse effects, and drug interactions with sofosbuvir and daclatasvir are
discussed in detail elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection",
section on 'Daclatasvir' and "Direct-acting antivirals for the treatment of hepatitis C virus infection", section
on 'Sofosbuvir'.)

Other alternatives have very limited role in therapy and are used only if the preferred regimens are not
available:

● Ledipasvir-sofosbuvir – This is a once-daily regimen that is given for 12 weeks and is a highly effective
option for initial therapy of genotypes 1, 4, 5, and 6 infection (SVR rates greater than 95 percent) [39-45].
For patients who have documented genotype 1 infection and meet certain clinical criteria (noninvasive
testing that rules out cirrhosis, viral load <6 million international units/mL, no HIV infection, and fewer
than two traditional negative predictors of response [eg, being male, obese]), comparably high SVR rates
can be achieved with an eight-week regimen, which may be attractive to some patients [40,46]. However,
the genotype testing and complex clinical assessment needed to ensure optimal use outweigh this
potential advantage of a more streamlined approach to treatment. Details on the dosing, adverse effects,
and drug interactions of ledipasvir and sofosbuvir are discussed elsewhere. (See "Direct-acting antivirals
for the treatment of hepatitis C virus infection", section on 'Ledipasvir-sofosbuvir'.)

● Elbasvir-grazoprevir – This is a once-daily regimen that is given for 12 weeks and is highly effective for
genotypes 1 and 4 infection [47-55]. However, it is not widely available. Additionally, optimal use in patents
with genotype 1a infection includes testing for pre-existing NS5A resistance-associated substitutions
(RASs), which complicates the treatment approach. Details on the dosing, adverse effects, and drug
interactions of elbasvir-grazoprevir are discussed in detail elsewhere. (See "Direct-acting antivirals for the
treatment of hepatitis C virus infection", section on 'Elbasvir-grazoprevir'.)

Potential for minimal monitoring during treatment — Given the availability of antiviral regimens that are
highly effective for all genotypes and have good safety profiles, administration of antiviral therapy with minimal
on-treatment monitoring is an appropriate approach for certain patients undergoing initial therapy for HCV.
These include patients who meet the following criteria:

● No known cirrhosis or hepatocellular carcinoma

● No active HBV coinfection (ie, the HBsAg is negative)
● No concerning symptoms during treatment
● No potential drug interactions that may impact therapy of other conditions (eg, glucose control or
anticoagulation)
● Taking one of the preferred regimens (see 'Our preferred regimens' above)

Minimal monitoring involves prescription or delivery of the full antiviral regimen without planned visits or
laboratory testing during the antiviral course. Such patients should return following completion of the course to
assess for treatment response. (See "Overview of the management of chronic hepatitis C virus infection",
section on 'Follow-up after antiviral therapy'.)

For patients who do not meet criteria for minimal monitoring, on-treatment monitoring includes evaluation for
rare adverse effects and is discussed in detail elsewhere. (See "Overview of the management of chronic hepatitis
C virus infection", section on 'Monitoring during antiviral therapy'.)

A minimal monitoring approach is particularly attractive for HCV treatment in nontraditional settings, such as
opioid treatment centers, syringe exchange sites, and remote or resource-limited settings. Non-clinical staff in
such settings can also provide counseling and other psychosocial support to enhance adherence.

The feasibility of such an approach was evaluated in a single-arm trial of 399 treatment-naïve patients who were
treated with sofosbuvir-velpatasvir without pre-treatment genotyping, with the entire treatment regimen
dispensed at the first visit, without scheduled visits or lab tests, and with remote assessment of adherence at
week 4 [4]. The overall SVR rate was 95 percent. Only 4 percent reported a serious adverse event, but none were
deemed related to treatment.

Some data suggest that SVR rates with minimal monitoring may be slightly lower than with traditional
monitoring, although this is mainly related to loss to follow-up. In a randomized trial of 380 patients who
received glecaprevir-pibrentasvir, the SVR rates among those who had limited clinic follow-up (at baseline and
post-treatment, with nursing calls at weeks 4 and 8) was 92 percent, compared with 95 percent among those
who also had clinic follow-up at weeks 4 and 8 with on-treatment testing (SVR difference -3.2 percent, 95% CI
-8.2-1.8) [7]. After excluding participants who were lost to follow up or had missing data, SVR rates were 97 and
98 percent.

PATIENTS WITH KNOWN CIRRHOSIS

Compensated cirrhosis (Child-Pugh class A)

Antiviral regimen selection — For patients with compensated cirrhosis (ie, Child-Pugh class A ( table 1)),
knowledge of the genotype is not essential to antiviral regimen selection, as the pangenotypic regimens are
highly effective in such patients regardless of genotype ( algorithm 1). However, if the genotype is already
known, or if checking the genotype does not pose a potential barrier to treatment, knowing that an individual
has genotype 3 infection can allow more specific tailoring of the regimen for a subset of those patients, which
may increase the likelihood of sustained virologic response (SVR) by a few percentage points.
 Known genotype 3 infection — For initial treatment of patients with known genotype 3 infection and
compensated cirrhosis, the main options are glecaprevir-pibrentasvir and sofosbuvir-velpatasvir
( algorithm 1). In general, we suggest glecaprevir-pibrentasvir because the same eight-week regimen used for
other genotypes can be used without additional testing. However, if glecaprevir-pibrentasivr cannot be used (eg,
because of unmitigable drug interactions) or if the patient prefers not to use it, a sofosbuvir-velpatasvir-based
regimen can be used with resistance testing to inform the optimal administration:

● Glecaprevir-pibrentasvir – This regimen is given for eight weeks. In a single-arm trial of patients with
compensated cirrhosis who received this regimen, the SVR rate among the 63 patients with genotype 3
infection was 95 percent [56]. There was only one virologic failure (relapsed infection).

● Sofosbuvir-velpatasvir-based regimen – If a sofosbuvir-velpatasvir-based regimen is planned for initial

therapy of genotype 3 infection in a patient with compensated cirrhosis, testing for NS5A resistance-
associated substitutions (RASs) should be performed to determine the presence of the Y93H variant, which
is associated with treatment failure.

• If the Y93H variant is absent, sofosbuvir-velpatasvir is given for 12 weeks. This regimen is estimated to
result in SVR rates of 97 percent [14].

• If the Y93H variant is present, we use sofosbuvir-velpatasvir-voxilaprevir instead of sofosbuvir-

velpatasvir. It is highly effective for patients with cirrhosis [15]; although the optimal duration is
uncertain in this setting, 12 weeks is generally recommended [57,58]. An alternative is to add weight-
based ribavirin to sofosbuvir-velpatasvir for 12 weeks when the Y93H variant is present to try to
improve the suboptimal SVR rate [59].

In the setting of Y93H, SVR rates with sofosbuvir-velpatasvir for 12 weeks are lower than in those
without the variant (in one trial, 84 versus 97 percent) [14].

Daclatasvir plus sofosbuvir is an alternative regimen that is not available in the United States but may be used
elsewhere when access to other options is limited. However, the optimal duration for patients with cirrhosis is
uncertain. We give it for 24 weeks. In a large French cohort, daclatasvir plus sofosbuvir for 24 weeks resulted in
SVR rates of approximately 86 percent among patients with genotype 3 infection and cirrhosis [60].

Unknown or non-genotype 3 infecton — For initial treatment of patients with compensated cirrhosis
who have genotypes 1, 2, 4, 5, or 6 infection or who have not had genotype assessment, regimen selection and
administration are the same as for patients without cirrhosis, as outlined elsewhere. (See 'Our preferred
regimens' above.)

Specifically, our preferred regimens include the following. In trials, response rates among patients with
compensated cirrhosis were similarly high as in those without cirrhosis:

● Sofosbuvir-velpatasvir for 12 weeks – In a trial of patients with genotype 1, 2, 4, 5, and 6 infection, the SVR
rate among the 121 patients with compensated cirrhosis was 99 percent [11]. Other trials have reported
similar findings [12-14].

● Glecaprevir-pibrentasvir for 8 weeks – In a single-arm trial of 343 patients with genotype 1 to 6 infection
and compensated cirrhosis, this regimen resulted in an overall SVR rate of 98 percent [56]. Only one
patient had virologic failure (relapse of genotype 3 infection).

In locations where access to these options is limited, daclatasvir plus sofosbuvir for 24 weeks is a potential
alternative; it is not available in the United States. Other alternatives with limited role include ledipasvir-
sofosbuvir for 12 weeks for genotypes 1, 4, 5, and 6 infection [39], or elbasvir-grazoprevir for 12 weeks [47,48].
(See 'Alternative regimens' above.)

Overall, data on regimen efficacy for patients who have genotypes 4, 5, or 6 and cirrhosis are limited given the
small samples sizes of such patients in clinical trials.

Safety — Preferred antiviral regimens have good safety profiles in patients with compensated cirrhosis.

In trials of sofosbuvir-velpatasvir and glecaprevir-pibrentasvir, adverse effects among those with compensated
cirrhosis were similar to those without cirrhosis, and mainly included fatigue, headache, nausea, and diarrhea
[11,56,61]. Although reports of hepatic failure with use of other HCV protease inhibitors (eg, boceprevir,
simeprevir, paritaprevir-ritonavir) had raised concern for potential toxicity with glecaprevir-pibrentasvir, there
does not appear to be an increased risk of drug-induced liver injury or hepatic decompensation with
glecaprevir-pibrentasvir among patients with compensated cirrhosis [61].

Monitoring — Monitoring during treatment is discussed in detail elsewhere. (See "Overview of the
management of chronic hepatitis C virus infection", section on 'Monitoring during antiviral therapy'.)

Decompensated cirrhosis (Child-Pugh class B or C) — Antiviral treatment should only be undertaken by or in

close consultation with an expert in the management of patients with decompensated cirrhosis (eg, Child-Pugh
class B or C ( table 1), with ascites, with hepatic encephalopathy, or with gastroesophageal variceal
hemorrhage), preferably at a transplant center. The possibility of liver transplantation should be assessed for
patients with decompensated cirrhosis or a MELD score greater than 10 prior to initiation of antiviral therapy.

For individuals who are transplant candidates, the timing of antiviral therapy depends on various factors,
including the severity of disease and the expected wait time to transplant. These issues are discussed in detail
elsewhere. (See "Hepatitis C virus infection in liver transplant candidates and recipients", section on 'Deciding to
treat before or after transplant'.)

The outcomes and benefits of antiviral treatment among patients with decompensated cirrhosis are also
discussed elsewhere. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus
infection", section on 'Decompensated cirrhosis'.)

● Antiviral selection – If antiviral treatment is planned prior to transplant (or for patients who are not
transplant candidates), options are limited since certain antiviral agents are contraindicated in the setting
of severe hepatic impairment.

For initial treatment of any genotype, we suggest:

• Sofosbuvir-velpatasvir plus weight-based ribavirin for 12 weeks. In a randomized trial of 267 patients
with Child-Pugh class B cirrhosis, SVR rates were 94 percent with sofosbuvir-velpatasvir plus ribavirin
for 12 weeks compared with 83 to 86 percent with sofosbuvir-velpatasvir for 12 to 24 weeks; the
differences were not statistically significant [62]. SVR rates with sofosbuvir-velpatasvir plus ribavirin
were 100 percent for all genotypes except 1a (94 percent) and 3 (85 percent). Results from
observational studies are similar [63].

For patients with genotypes 1, 4, 5, or 6, another option is:

• Ledipasvir-sofosbuvir plus weight-based ribavirin for 12 weeks [64,65]. In one trial that randomly
assigned patients with decompensated cirrhosis (Child-Pugh class B or C) and creatinine clearance >40
mL/min to receive ledipasvir-sofosbuvir plus ribavirin for 12 or 24 weeks, SVR rates were relatively high
 (87 to 89 percent) [64]. In another trial of patients with genotypes 1 and 4 infection, ledipasvir-
sofosbuvir plus ribavirin for 12 weeks and ledipasvir-sofosbuvir for 24 weeks results in similarly high
SVR rates (96 and 97 percent) [66].

For both regimens, the target dose of ribavirin is 1000 mg daily for individuals <75 kg and 1200 mg daily
for individuals ≥75 kg. However, because ribavirin may not be optimally tolerated in patients with
decompensated cirrhosis, we start ribavirin at a lower dose (eg, 600 mg daily) and increase as tolerated to
target dose. If ribavirin cannot be used at all, a 24-week duration of the ribavirin-free regimen is
recommended to maximize the likelihood of SVR [1]. However, for genotypes 1 and 2 infection, 12 weeks
without ribavirin may be reasonably effective [62,67].

● Safety – Serious adverse events are common in general among patients with decompensated cirrhosis. In
trials of sofosbuvir-velpatasvir and ledipasvir-sofosbuvir-based regimens, serious adverse events occurred
in 10 to 42 percent, depending on the level of decompensation and on the precise regimen administered,
but few were deemed related to the treatment [62,64,65].

In observational studies of patients with decompensated cirrhosis undergoing therapy with contemporary
direct-acting antiviral (DAA) regimens, serious adverse events occurred in approximately 20 percent
[63,68]. In one cohort, approximately 13 percent had a new decompensating event during or shortly after
therapy; hepatic encephalopathy, new ascites, and bacterial peritonitis were reported in 4, 1, and 1 percent
[68]. Anemia is also common among these patients, particularly in those receiving ribavirin [63].

● Monitoring – Patients with decompensated cirrhosis who are undergoing HCV antiviral therapy should
have frequent clinical and laboratory monitoring, including monitoring of liver synthetic function and
hemoglobin (particularly if receiving ribavirin). General management issues for patients with
decompensated cirrhosis are discussed elsewhere. (See "Cirrhosis in adults: Overview of complications,
general management, and prognosis", section on 'Major complications'.)

● Antiviral agents to avoid – Glecaprevir-pibrentasvir, elbasvir-grazoprevir, sofosbuvir-velpatasvir-

voxilaprevir, and simeprevir are contraindicated in patients with Child-Pugh classes B and C cirrhosis
because of increased drug levels in the setting of hepatic impairment. Although they are not available in
the United States and of uncertain availability or utility elsewhere, ombitasvir-paritaprevir-ritonavir-based
regimens are also contraindicated in patients with Child-Pugh classes B and C cirrhosis because of the risk
of worsened hepatic decompensation.

MANAGEMENT OF MISSED DOSES

Given the potency of contemporary antiviral regimens, patients who miss a few doses intermittently do not
jeopardize their likelihood of treatment success, and we counsel them to restart and continue the regimen for
the originally planned duration (making up for the missed doses).

The optimal approach to those who miss more than a few consecutive doses is uncertain. We agree with the
approach suggested by the joint American Association for the Study of Liver Diseases (AASLD) and the Infectious
Diseases Society of America (IDSA) ( algorithm 2) [2]:

● For those who miss more than 8 but less than 21 consecutive days of therapy:

• Restart the regimen immediately.

Check an HCV viral level as soon as possible (but do not delay therapy restart for this).
 • - If the HCV RNA is undetectable, complete the originally planned duration (making up for missed
doses). If the patient has compensated cirrhosis or known genotype 3 infection, the guidelines
recommend extending the treatment course for another four weeks.

- If the HCV RNA is detectable, next steps depend on how much of the regimen had been completed.
Patients who had completed <28 days of therapy prior to missing doses should extend the
originally planned duration by four weeks. Patients who had completed ≥28 days of therapy prior
to missing doses should stop the current regimen and be evaluated for retreatment.

● For those who missed more than 21 consecutive days of therapy, next steps depend on how much of the
regimen had been completed.

• Patients who had completed <28 days of therapy prior to missing doses should take the approach
outlined above.

• Patients who had completed ≥28 days of therapy prior to missing doses should stop the current
regimen and have an HCV viral level checked 12 weeks after the completion of therapy. If HCV RNA is
undetectable, they have achieved SVR and do not warrant additional therapy. If HCV RNA is detectable,
they should be evaluated for retreatment.

The approach to retreatment is discussed in detail elsewhere. (See "Management of chronic hepatitis C virus
infection: Antiviral retreatment following relapse in adults", section on 'Regimen selection for relapse after DAA
therapy'.)

Limited data suggest that minor adherence issues do not have a substantive negative impact on treatment
success. In a study of 190 patients who were taking a once- or twice-daily direct-acting antiviral (DAA) regimen,
which was dispensed in an electronic blister pack that recorded the time of pill removal, 90 percent missed at
least one day of treatment, 48 percent missed between one and eight days of treatment, and 13 percent missed
seven or more consecutive days [69]. Although there was a nonsignificant trend towards lower SVR rates among
those whose calculated adherence was <90 percent (89 versus 95 percent), there were no differences among
those who did nor did not miss at least seven consecutive doses (92 versus 93 percent). Most of the 14 patients
who did not achieve SVR had been lost to follow up; only three had virologic failure.

SPECIAL PATIENT POPULATIONS

Patients with renal impairment — The selection of HCV antiviral regimens for patients with renal disease is
largely the same as that among patients without renal disease. Antiviral treatment in such patients is discussed
in detail elsewhere. (See "Treatment of chronic hepatitis C infection in adults with kidney function impairment".)

Additional considerations for patients who are kidney transplant candidates or recipients are also discussed
elsewhere. (See "Hepatitis C infection in kidney transplant candidates and recipients".)

HIV-HCV coinfection — The selection of HCV antiviral regimens for patient with HIV and HCV coinfection is
largely the same as that for patients without HIV infection, although potential interactions between
antiretroviral agents and direct-acting antiviral (DAA) agents must be taken into consideration. Treatment of HCV
in patients with HIV is discussed in detail elsewhere. (See "Treatment of chronic hepatitis C virus infection in the
patient with HIV".)

HCV following liver transplantation — Management of HCV infection in liver transplant recipients is discussed
elsewhere. (See "Hepatitis C virus infection in liver transplant candidates and recipients", section on 'Treatment
approach for recipients of HCV-viremic donors' and "Hepatitis C virus infection in liver transplant candidates and
recipients", section on 'Post-transplant antiviral therapy'.)

Pregnant individuals — The safety and efficacy of all HCV antiviral agents during pregnancy are unknown;
thus, antiviral therapy of such patients should either be delayed until after delivery or be given through a clinical
trial. (See "Vertical transmission of hepatitis C virus".)

FOLLOW-UP AFTER TREATMENT

Follow-up after treatment includes checking the viral load 12 weeks after the cessation of therapy to evaluate for
a sustained virologic response (SVR). Patients with advanced fibrosis or cirrhosis also warrant ongoing screening
for hepatocellular carcinoma, regardless of antiviral treatment outcome. These issues are discussed in detail
elsewhere. (See "Overview of the management of chronic hepatitis C virus infection", section on 'Follow-up after
antiviral therapy'.)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around the world
are provided separately. (See "Society guideline links: Hepatitis C virus infection".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics
patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the
four or five key questions a patient might have about a given condition. These articles are best for patients who
want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade
reading level and are best for patients who want in-depth information and are comfortable with some medical
jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these
topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on
"patient info" and the keyword(s) of interest.)

● Basics topic (see "Patient education: Treatment for hepatitis C (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Benefits of HCV therapy – We recommend antiviral treatment for all patients with chronic HCV infection
(Grade 1A). A sustained virologic response (SVR), or an undetectable HCV viral level 12 weeks after the
completion of therapy, indicates effective cure of HCV infection. SVR has been associated with decreased
mortality, decreased liver-related complications, and improved quality of life, regardless of liver disease
stage. (See 'Treatment objective' above.)

● Prioritizing access to therapy – Extensive pretreatment testing or monitoring may unnecessarily limit
access to therapy in resource-constrained settings or by nonspecialty providers. Given the high efficacy
rates and safety of contemporary pangenotypic antiviral regimens for initial therapy of HCV infection, we
 instead favor a streamlined approach to regimen selection with limited pretreatment evaluation, a
minimalist approach to monitoring, and a low threshold to offer therapy despite unstable housing or drug
use. (See 'Prioritizing access to therapy' above.)

● Evaluation prior to initial therapy – Limited evaluation includes clinical assessment for cirrhosis, testing
for other conditions that may impact management, such as HIV, hepatitis B virus (HBV), and pregnancy,
and a review of the medication list for potential interactions. Since genotype is not essential for regimen
selection, we do not routinely check it; lack of genotype testing results should not be a barrier to HCV
treatment. (See 'Limited pretreatment evaluation' above.)

● Preferred regimens – For initial therapy, we suggest one of the pangenotypic regimens, sofosbuvir-
velpatasvir or glecaprevir-pibrentasvir, rather than other regimens ( algorithm 1) (Grade 2A). Sofosbuvir-
velpatasvir is given for 12 weeks and glecaprevir-pibrentasvir for 8 weeks; these regimens result in SVR
rates >95 percent with any genotype and have minor adverse effects. The choice between them depends
on availability, potential for drug interactions, and patient preference. (See 'Selecting among preferred
regimens' above.)

Non-pangenotypic regimens are also effective but offer no clear advantage over the pangenotypic
regimens, and using them optimally may require additional testing that could be a barrier to care. Their
main role is in locations where sofosbuvir-velpatasvir or glecaprevir-pibrentasvir is not available.
Internationally, the most widely used alternative regimen is sofosbuvir plus daclatasvir, which is given for
12 or 24 weeks for patients without or with cirrhosis, respectively. (See 'Alternative regimens' above.)

● Managing drug interactions – Drug interactions with sofosbuvir-velpatasvir or glecaprevir-pibrentasvir

are generally manageable but should be evaluated prior to initiation. Increased gastric pH levels decrease
absorption of velpatasvir; thus, we avoid coadministration of sofosbuvir-velpatasvir with proton pump
inhibitors and other acid-reducing medications (including over-the-counter medications) when possible.
For other specific drug interactions, refer to the drug interactions program included with UpToDate. (See
'Sofosbuvir-velpatasvir' above and 'Glecaprevir-pibrentasvir' above.)

● Monitoring – Typical monitoring includes evaluation for rare adverse effects and adherence assessment
throughout the treatment course. This is discussed in detail elsewhere. (See "Overview of the management
of chronic hepatitis C virus infection", section on 'Monitoring during antiviral therapy'.)

However, for patients who take one of the preferred regimens and have no cirrhosis, active HBV infection,
concerning symptoms, or potential drug interactions, we suggest minimal monitoring without planned
visits or laboratory testing during the antiviral course. (See 'Potential for minimal monitoring during
treatment' above.)

● Missed doses – We counsel patients who miss a few doses intermittently (eg, fewer than seven) to restart
and continue the regimen for the originally planned duration (making up for the missed doses). For those
who have missed more, the approach depends on how many doses they missed and how far into the
treatment course they are ( algorithm 2). (See 'Management of missed doses' above.)

● Post-treatment follow-up – All patients should undergo HCV viral level testing at least 12 weeks after
completing therapy to assess for treatment success. Patients with advanced fibrosis or cirrhosis warrant
ongoing surveillance for hepatocellular carcinoma. These and other aspects of follow-up are discussed in
detail elsewhere. (See "Overview of the management of chronic hepatitis C virus infection", section on
'Follow-up after antiviral therapy'.)
ACKNOWLEDGMENT

The UpToDate editorial staff acknowledges Sanjiv Chopra, MD, MACP, who contributed to earlier versions of this
topic review.

Use of UpToDate is subject to the Terms of Use.

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Topic 16592 Version 93.0
GRAPHICS

Regimen selection for initial therapy of chronic HCV infection

This algorithm reflects our approach to initial therapy, for which we prioritize simplifying care to reduce barriers to access.
The measured outcome of therapy is SVR, which is defined as an undetectable HCV viral level 12 weeks after the
completion of therapy and reflects effective cure of infection. For additional details, including the evidence supporting this
approach, refer to other UpToDate content on treatment of chronic HCV infection.

SVR: sustained virologic response.

* For initial therapy, knowledge of the HCV genotype and stage of fibrosis is not essential to selecting an antiviral regimen,
as the preferred options are highly effective for all patients, regardless of genotype and cirrhosis. However, if these results
are already available or if obtaining them does not pose a potential barrier to treatment, the information can be used to
tailor regimen selection for a small subset of patients, which may increase their likelihood of SVR by a few percentage
points.

¶ In patients with genotype 3 and cirrhosis, testing for the Y93H NS5A resistance-associated substitution is used to guide
the optimal sofosbuvir-velpatasvir-based regimen. Because this testing is not always readily available, we generally favor
glecaprevir-pibrentasvir for such patients. Refer to other UpToDate content for more details.

Δ The selection between sofosbuvir-velpatasvir and glecaprevir-pribrentasvir is often dictated by access (eg, payers may
only reimburse one of the options). If both are accessible, the choice between them depends on the potential for drug
interaction and patient preference regarding practical administration issues.

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Child-Pugh classification of severity of cirrhosis

Points assigned
Parameter
1 2 3

Ascites Absent Slight Moderate

Bilirubin <2 mg/dL (<34.2 micromol/L) 2 to 3 mg/dL (34.2 to 51.3 >3 mg/dL (>51.3 micromol/L)
micromol/L)

Albumin >3.5 g/dL (35 g/L) 2.8 to 3.5 g/dL (28 to 35 g/L) <2.8 g/dL (<28 g/L)

Prothrombin time (seconds <4 4 to 6 >6

over control) or

INR <1.7 1.7 to 2.3 >2.3

Encephalopathy None Grade 1 to 2 Grade 3 to 4

Modified Child-Pugh classification of the severity of liver disease according to the degree of ascites, the serum
concentrations of bilirubin and albumin, the prothrombin time, and the degree of encephalopathy. A total Child-Pugh score
of 5 to 6 is considered Child-Pugh class A (well-compensated disease), 7 to 9 is class B (significant functional compromise),
and 10 to 15 is class C (decompensated disease). These classes correlate with one- and two-year patient survival: class A:
100 and 85%; class B: 80 and 60%; and class C: 45 and 35%.

INR: international normalized ratio.

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Approach to missed doses during initial therapy for chronic HCV infection [1]

Given the potency of contemporary antiviral regimens, patients who miss a few doses intermittently do not jeopardize their
likelihood of treatment success, and we counsel them to restart and continue the regimen for the originally planned
duration (making up for the missed doses).

Our approach in this algorithm is consistent with AASLD/IDSA recommendations for managing multiple missed
consecutive doses during initial therapy of chronic HCV infection with sofosbuvir-velpatasvir or glecaprevir-pibrentasvir in
patients without decompensated cirrhosis. This approach does not apply to patients treated with other regimens or to
those with decompensated cirrhosis.

AASLD: American Association for the Study of Liver Diseases; DAA: direct-acting antiviral; HCV: hepatitis C virus; IDSA:
Infectious Diseases Society of America; RNA: ribonucleic acid; SVR: sustained virologic response.

* The total duration should make up for the antiviral doses that the patient missed.

¶ The HCV RNA should be checked as soon as possible, ideally on the same day as restarting the regimen; however,
patients should not delay restarting the regimen in order to have the HCV RNA checked.

Δ Although the recommendation to extend the duration in these circumstances is consistent with the AASLD/IDSA
guidelines, it may not be feasible if payers do not provide coverage for the extension.

Reference:
1. Bhattacharya D, Aronsohn A, Price J, et al. Hepatitis C Guidance 2023 Update: AASLD-IDSA Recommendations for Testing, Managing, and Treating
Hepatitis C Virus Infection. Clin Inf Dis 2023.

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Contributor Disclosures
Andrew J Muir, MD, MHS Grant/Research/Clinical Trial Support: Gilead [HCV]. All of the relevant financial relationships listed
have been mitigated. Camilla S Graham, MD No relevant financial relationship(s) with ineligible companies to
disclose. Adrian M Di Bisceglie, MD Consultant/Advisory Boards: HighTide Therapeutics [Primary sclerosing cholangitis,
nonalcoholic steatohepatitis]; WCG ACI Clinical [Clinical trial conduct]. All of the relevant financial relationships listed have
been mitigated. Allyson Bloom, MD No relevant financial relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by
vetting through a multi-level review process, and through requirements for references to be provided to support the
content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

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