Direct-acting antivirals for the treatment of hepatitis C virus infection

INTRODUCTION — A greater understanding of the hepatitis C virus (HCV) genome and proteins has enabled efforts to improve efficacy and tolerability of HCV treatment. Notably, this has led to the development of multiple direct-acting antivirals (DAAs), which are medications targeted at specific steps within the HCV life cycle (figure 1). DAAs are molecules that target specific nonstructural proteins of the virus and results in disruption of viral replication and infection. There are four classes of DAAs, which are defined by their mechanism of action and therapeutic target. The four classes are nonstructural proteins 3/4A (NS3/4A) protease inhibitors (PIs), NS5B nucleoside polymerase inhibitors (NPIs), NS5B non-nucleoside polymerase inhibitors (NNPIs), and NS5A inhibitors [1].

This topic reviews the mechanism of action, pharmacology, and spectrum of use of these various DAAs. It focuses on the most common agents used globally for antiviral treatment of HCV infection. However, availability of DAAs varies by location, and in some countries, DAAs not discussed in this topic may be in use.

Other important issues related to the treatment of chronic HCV infection, including patient evaluation, selection of treatment regimen, and other management issues are discussed in detail elsewhere. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection" and "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults" and "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults" and "Overview of the management of chronic hepatitis C virus infection".)

CLASSES OF DIRECT-ACTING ANTIVIRALS

Viral life cycle and replication overview — The main targets of the direct-acting antiviral (DAA) agents are the HCV-encoded proteins that are vital to the replication of the virus (figure 1).

●Viral structure – The infectious viral structure is comprised of envelope glycoproteins in a lipid bilayer that contain the viral core protein and RNA [2].

●RNA translation and protein processing – After cell entry, the viral RNA is translated through host machinery into a polyprotein, which is cleaved during and after translation by both host and viral-encoded proteases into 10 mature viral proteins, including a number of nonstructural (NS) proteins.

One of the viral proteases involved in this post-translational processing is a heterodimeric complex of the NS3 and NS4A proteins (NS3/NS4A). NS3 possesses the proteolytic activity and NS4 is a membrane protein that acts as a cofactor. (See 'NS3/4A protease inhibitors' below.)

●Synthesis and assembly of viral RNA – Synthesis of new viral RNA occurs in a highly structured replication complex that consists of NS3, NS4A, NS4B, NS5A, and NS5B.

NS5B is an RNA-dependent RNA polymerase that is essential for viral replication. (See 'NS5B RNA-dependent RNA polymerase inhibitors' below.)

NS5A has a presumptive role in the organization of the replication complex and in regulating replication. It is also involved in assembly of the viral particle that is released from the host cell. (See 'NS5A inhibitors' below.)

Direct-acting antivirals are inhibitors of the NS3/4A protease, the NS5A protein, and the NS5B polymerase.

NS3/4A protease inhibitors — Contemporary NS3/4A protease inhibitors include:

●Glecaprevir – a potent, pangenotypic protease inhibitor that is only available in combination with the NS5A inhibitor pibrentasvir. (See 'Glecaprevir-pibrentasvir' below.)

●Voxilaprevir – a potent, pangenotypic protease inhibitor that is only available in combination with the NS5B inhibitor sofosbuvir and the NS5A inhibitor velpatasvir. (See 'Sofosbuvir-velpatasvir-voxilaprevir' below.)

●Grazoprevir – a protease inhibitor that is only available in combination with the NS5A inhibitor elbasvir. (See 'Elbasvir-grazoprevir' below.)

These agents inhibit the NS3/4A serine protease, an enzyme involved in post-translational processing and replication of HCV. Protease inhibitors disrupt HCV by blocking the NS3 catalytic site or the NS3/NS4A interaction [3]. In addition to its role in viral processing, the NS3/NS4A protease blocks TRIF-mediated Toll-like receptor signaling and Cardif-mediated retinoic acid–inducible gene 1 (RIG-1) signaling, which result in impaired induction of interferons and blocking viral elimination. Thus, inhibition of the NS3/4A protease could contribute to antiviral activity through two mechanisms.

Newer-generation protease inhibitors offer several benefits over earlier protease inhibitors, including fewer drug-drug interactions, improved dosing schedules, and less frequent and less severe side effects. Additionally, they have a relatively low barrier to resistance (table 1).

Telaprevir and boceprevir were the first-generation protease inhibitors as well as the first DAAs available for the treatment of HCV, and they were used in conjunction with peginterferon and ribavirin for the treatment of genotype 1 infection but are no longer used [4,5]. Later-generation protease inhibitors that are not commonly or widely used include paritaprevir and asunaprevir. Simeprevir is another protease inhibitor that is not widely available but may be used in some parts of the world. (See 'Simeprevir' below.)

NS5A inhibitors — Contemporary NS5A inhibitors include:

●Pibrentasvir – a pangenotypic NS5A inhibitor pibrentasvir that is only available as a fixed-dose combination with the protease inhibitor glecaprevir. (See 'Glecaprevir-pibrentasvir' below.)

●Velpatasvir – a pangenotypic NS5A inhibitor velpatasvir that is only available as a fixed-dose combination with the NS5B inhibitor sofosbuvir. (See 'Sofosbuvir-velpatasvir' below.)

●Ledipasvir – the first NS5A inhibitor to be available in the United States. It is available as part of a fixed-dose combination with sofosbuvir. (See 'Ledipasvir-sofosbuvir' below.)

●Daclatasvir – an NS5A inhibitor that is available as a single drug and is used in combination with sofosbuvir. (See 'Daclatasvir' below.)

●Elbasvir – an NS5A inhibitor that is only available as a fixed-dose combination with the protease inhibitor grazoprevir. (See 'Elbasvir-grazoprevir' below.)

Ravidasvir is an NS5A inhibitor with limited availability, mainly in resource-limited settings; it is used in combination with sofosbuvir [6].

The NS5A protein plays a role in both viral replication and the assembly of the hepatitis C virus (HCV) [7,8]. However, the precise molecular mechanisms by which NS5A accomplishes these functions are uncertain. Thus, the exact mechanism of action of HCV NS5A inhibitors is unclear.

As a class, agents that inhibit NS5A are generally quite potent and are effective across all genotypes, but they have a low barrier to resistance and variable toxicity profiles (table 1). NS5A inhibitors have been shown to significantly reduce HCV RNA levels and enhance sustained virologic response (SVR) when given in conjunction with peginterferon and ribavirin [9]. They also result in very high SVR rates among patients with genotype 1 infection when given in combination with other direct-acting antivirals with or without ribavirin [10,11].

NS5B RNA-dependent RNA polymerase inhibitors — Contemporary NS5B inhibitors include:

●Sofosbuvir – The first NS5B inhibitor to be available in the United States; it is a nucleotide polymerase inhibitor, specifically. It is used in combination with various other antiviral agents and is available as a single drug as well as in fixed drug combinations. (See 'Sofosbuvir' below and 'Sofosbuvir-velpatasvir' below and 'Ledipasvir-sofosbuvir' below and 'Sofosbuvir-velpatasvir-voxilaprevir' below.)

NS5B is an RNA-dependent RNA polymerase involved in post-translational processing that is necessary for replication of HCV. The enzyme has a catalytic site for nucleoside binding and at least four other sites at which a non-nucleoside compound can bind and cause allosteric alteration. The enzyme’s structure is highly conserved across all HCV genotypes, giving agents that inhibit NS5B efficacy against all six genotypes [3].

There are two classes of polymerase inhibitors: nucleoside/ nucleotide analogues (NPIs) and non-nucleoside analogues (NNPIs). The NPIs target the catalytic site of NS5B and result in chain termination, while NNPIs act as allosteric inhibitors.

●Nucleot(s)ide polymerase inhibitors (NPIs) – Nucleotide inhibitors are activated within the hepatocyte through phosphorylation to nucleoside triphosphate, which competes with nucleotides, resulting in chain termination during RNA replication of the viral genome.

As a class, NPIs have moderate to high efficacy across all six genotypes, with equal efficacy among subtypes 1a and 1b and have a very high barrier to resistance (table 1).

Another potential advantage of NPIs is that the NS5B active site is relatively intolerant to amino acid substitutions. As a result, active site NS5B mutations that confer resistance to NPIs are more likely to also impair RNA polymerase activity compared with mutations in NNPI allosteric binding pockets, thus rendering the mutant virus less "fit" compared with wild-type virus.

However, the drug class as a whole has been plagued with toxicity problems, limiting the number of drugs that have completed late development.

●Non-nucleoside polymerase inhibitors (NNPIs) – The four allosteric sites that act as targets for NNPIs are thumb domains 1 and 2 and palm domains 1 and 2. As a class, NNPIs are less potent, are more genotype specific (all NNPIs in clinical development have been optimized for genotype 1), have a low to moderate barrier to resistance, and have variable toxicity profiles [12]. Consequently, this class of drug has been studied primarily as an adjunct to more potent compounds with higher barriers to resistance. See table for a summary of advantages and disadvantages of the four classes of drugs (table 1).

FIXED-DOSE COMBINATION AGENTS

Glecaprevir-pibrentasvir — The NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir are coformulated in a single tablet [13]. The regimen is pangenotypic and has a high barrier to resistance. The clinical use of this regimen is discussed elsewhere. (See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults" and "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults".)

●Administration and pharmacology – The combination tablet consists of 100 mg glecaprevir and 40 mg pibrentasvir. The daily dose consists of three tablets taken at the same time, administered with food.

Glecaprevir-pibrentasvir can be used in patients with any degree of renal impairment, including those on dialysis, without the need for dose modifications. The regimen is contraindicated in patients with decompensated (Child-Pugh class B or C) cirrhosis because of a risk of worsening liver function or liver failure. In contrast, it is generally safe among patients with compensated (Child-Pugh class A) cirrhosis despite a two-fold increase in glecaprevir levels in such patients [14]. Nevertheless, it is important to ensure that the liver disease is not more advanced. (See 'Protease inhibitors and hepatic decompensation' below.)

●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 who received glecaprevir-pibrentasvir, most adverse effects were mild, with headache and fatigue the most common complaints [15]. Less 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.

●Drug interactions – Glecaprevir and pibrentasvir are substrates and inhibitors of P-gp, breast cancer resistance protein (BCRP), and organic anion transporting polypeptide (OATP) 1B1/3. Coadministration is thus contraindicated with atazanavir and rifampin. Coadministration is not recommended with carbamazepine, ethinyl estradiol-containing medications (such as oral contraceptive agents), St. John's wort, efavirenz, darunavir, lopinavir, ritonavir, and certain statins (atorvastatin, lovastatin, and simvastatin).

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

●Resistance – Virologic failure with glecaprevir-pibrentasvir in patients without prior NS3 or NS5A inhibitor exposure is rare but has been associated with the emergence of various genotype-dependent substitutions in both NS3 and NS5A proteins [16]. However, among such patients, preexisting substitutions in the NS3 and NS5A proteins were not associated with treatment failure, except in treatment-experienced genotype 3-infected patients who received only 12 weeks of therapy.

Among patients with prior NS3 or NS5A inhibitor exposure, preexisting substitutions in either NS3 or NS5A proteins were not associated with treatment failure [17]. However, when both NS3 and NS5A substitutions were present, seen only inpatients who have prior exposure to both NS3 and NS5A inhibitors, sustained virologic response (SVR) rates were compromised. Glecaprevir-pibrentasvir should not be used in this small group of patients. (See "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults", section on 'Relapse after sofosbuvir-velpatasvir (or other sofosbuvir-NS5A combination)'.)

Sofosbuvir-velpatasvir — The pangenotypic NS5A inhibitor velpatasvir and the NS5B inhibitor sofosbuvir are coformulated in a single tablet. The clinical use of this regimen, which is effective against all genotypes, is discussed elsewhere. (See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults" and "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults".)

●Administration and pharmacology – The combination tablet consists of 100 mg velpatasvir and 400 mg sofosbuvir and is administered once daily with or without food.

No dose adjustment is warranted for any degree of renal impairment, including patients requiring dialysis or in the setting of moderate (Child Pugh Class B) or severe (Child Pugh class C) hepatic impairment.

●Adverse effects – The combination sofosbuvir-velpatasvir is well tolerated. In an analysis of three trials of sofosbuvir-velpatasvir, adverse effects were common but occurred at similar rates and severity as among patients who received placebo [18]. The most common complaints were headache, fatigue, nausea, nasopharyngitis, and insomnia. Bradycardia is a rare but serious potential adverse effect associated with sofosbuvir, usually when used with amiodarone. (See 'Sofosbuvir' below.)

●Drug interactions – Velpatasvir, like sofosbuvir, is a substrate of the P-glycoprotein (P-gp) drug transporter, so drugs that are potent intestinal P-gp inducers may decrease velpatasvir levels. Thus, coadministration of sofosbuvir-velpatasvir is not recommended with rifampin, rifabutin, rifapentine, St. John's wort, carbamazepine, phenytoin, phenobarbital, oxcarbazepine, or tipranavir/ritonavir. Coadministration is also not recommended with efavirenz, which decreases the levels of velpatasvir. In addition, as an inhibitor of P-gp, velpatasvir may increase absorption of P-gp substrates.

Increased gastric pH levels decrease absorption of velpatasvir; thus coadministration with proton pump inhibitors is ideally avoided. If a proton pump inhibitor is necessary, they can be coadministered, but it is important to follow the manufacturer's instructions: sofosbuvir-velpatasvir should be administered with food and taken four hours prior to omeprazole 20 mg (other proton pump inhibitors have not been studied) [19].

Any drugs that should not be used with sofosbuvir (such as amiodarone) should also not be used with sofosbuvir-velpatasvir (see 'Sofosbuvir' below). For other specific drug interactions, refer to the drug interactions program included with UpToDate.

●Resistance – Virologic failure in with sofosbuvir-velpatasvir has been associated with emergence of the Y93N/H mutation in the NS5A gene in genotypes 1 and 3 virus [20,21]. In patients with genotype 3 infection, the presence of preexisting resistance-associated substitutions (in particular Y93H) appears to be associated with a higher likelihood of relapse, although even those with resistance-associated substitutions achieve high SVR rates (88 versus 97 percent in those without) [20]. No virologic failures were documented in the initial trials of sofosbuvir-velpatasvir in other genotypes. Mutational analysis testing for NS5A mutations are commercially available from LabCorp and Quest Labs.

Polymorphisms associated with sofosbuvir exposure are discussed elsewhere. (See 'Sofosbuvir' below.)

Ledipasvir-sofosbuvir — The NS5A inhibitor ledipasvir and the nucleotide polymerase (NS5B) inhibitor sofosbuvir are coformulated in a single tablet. This regimen is administered with or without weight-based ribavirin, depending on the patient population. The clinical use of this regimen is discussed elsewhere. (See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults", section on 'Alternative regimens'.)

●Administration and pharmacology – The combination tablet consists of 90 mg ledipasvir and 400 mg sofosbuvir and is administered once daily with or without food.

No dose adjustment is warranted for renal insufficiency or in the setting of moderate (Child Pugh Class B) or severe (Child Pugh class C) hepatic impairment.

●Adverse effects – The combination of ledipasvir and sofosbuvir is well tolerated. Although the majority of patients in trials of ledipasvir-sofosbuvir reported adverse effects of any kind, the vast majority were mild or moderate. The most common adverse effects reported are fatigue, headache, nausea, and insomnia. Bradycardia is a rare but serious potential adverse effect associated with sofosbuvir, usually when used with amiodarone. (See 'Sofosbuvir' below.)

●Drug interactions – Ledipasvir, like sofosbuvir, is a substrate of the P-glycoprotein (P-gp) drug transporter, so drugs that are potent intestinal P-gp inducers may decrease ledipasvir levels. Thus, coadministration of ledipasvir-sofosbuvir is not recommended with rifampin, rifabutin, rifapentine, St. John’s wort, carbamazepine, phenytoin, phenobarbital, oxcarbazepine, or tipranavir/ritonavir. In addition, ledipasvir is an inhibitor of P-gp and may increase absorption of P-gp substrates.

Increased gastric pH levels may decrease absorption of ledipasvir. Acid suppressing agents can be coadministered if necessary, but low doses or spaced out administration should be used.

Any drugs that should not be used with sofosbuvir (such as amiodarone) should also not be used with ledipasvir-sofosbuvir (see 'Sofosbuvir' below). Clinical management of interactions with antiretroviral agents are discussed elsewhere (see "Treatment of chronic hepatitis C virus infection in the patient with HIV", section on 'Ledipasvir-sofosbuvir'). For other specific drug interactions, refer to the drug interactions program included with UpToDate.

●Resistance – Virologic failure with ledipasvir-sofosbuvir has been associated with several NS5A inhibitor mutations that reduce susceptibility to ledipasvir, most commonly Q30R, Y93H/N, and L31M in subtype 1a virus and Y93H in subtype 1b virus [22,23]. Although approximately 20 percent of genotype 1 viruses harbor polymorphisms that confer reduced susceptibility to ledipasvir, such preexisting resistance-associated polymorphisms did not appear to affect efficacy of ledipasvir-sofosbuvir in treatment-naïve patients. Further data are needed, but the presence of NS5A mutations does not require adjustment of duration or dosing, even though it may attenuate efficacy in treatment-experienced patients treated for 12 weeks. Mutational analysis testing for NS5A mutations are now commercially available from LabCorp and Quest Labs.

Polymorphisms associated with sofosbuvir exposure are discussed elsewhere. (See 'Sofosbuvir' below.)

Sofosbuvir-velpatasvir-voxilaprevir — This combination adds the NS3/4A inhibitor voxilaprevir to the NS5B inhibitor sofosbuvir and the NS5A inhibitor velpatasvir. This regimen is pangenotypic and mainly reserved for patients who have prior failure on DAA (and predominantly NS5A inhibitor-containing) regimens. The clinical use of this regimen is discussed elsewhere. (See "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults".)

●Administration and pharmacology – The combination tablet consists of 400 mg sofosbuvir, 100 mg velpatasvir, and 100 mg voxilaprevir, and is administered once daily with food.

No dose adjustment is warranted for renal insufficiency (including patients on dialysis) or in the setting of mild (Child Pugh Class A) hepatic impairment. This regimen is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C) due to higher exposures of voxilaprevir seen in these patients. (See 'Protease inhibitors and hepatic decompensation' below.)

●Adverse effects – The combination is well tolerated. In trials, <1 percent of participants discontinued a 12-week regimen for adverse events [24]. The most common adverse events are headache, fatigue, diarrhea, and nausea. Bradycardia is a rare but serious potential adverse effect associated with sofosbuvir, usually when used with amiodarone. (See 'Sofosbuvir' below.)

●Drug interactions – The same drug interactions with sofosbuvir-velpatasvir apply to sofosbuvir-velpatasvir-voxilaprevir (see 'Sofosbuvir-velpatasvir' above). Additionally, coadministration is contraindicated with rifampin and is not recommended with atazanavir, lopinavir, certain statins (rosuvastatin and pitavastatin), and cyclosporine.

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

●Resistance – Although virologic failure with sofosbuvir-velpatasvir-voxilaprevir has been associated with emergence of substitutions in the NS3 and NS5A proteins, preexisting substitutions in these proteins or in the NS5B protein are not associated with lower SVR rates [24]. No data are available to guide management of patients who have failed this regimen in the setting of prior NS5A or NS3 resistance-associated substitutions (7 of 445 patients in two trials).

Elbasvir-grazoprevir — Elbasvir, an NS5A inhibitor, and grazoprevir, an NS3/4A protease inhibitor with a high barrier of resistance, are coformulated in a single tablet [13]. This regimen is effective against genotypes 1 and 4 infection and is administered with or without weight-based ribavirin, depending on certain patient characteristics. Elbasvir-grazoprevir is no longer frequently used in the United States.

●Administration and pharmacology – The combination tablet consists of 50 mg elbasvir and 100 mg grazoprevir and is administered once daily with or without food.

Prior to administration of elbasvir-grazoprevir, patients with genotype 1a infection should be tested for the presence of NS5A resistance associated substitutions (RASs) and all patients should have documentation of baseline aminotransferases.

Elbasvir-grazoprevir can be used in patients with any degree of renal impairment, including those on dialysis, without the need for dose modifications. The regimen is contraindicated in patients with Child-Pugh class B or C cirrhosis. (See 'Protease inhibitors and hepatic decompensation' below.)

●Adverse effects – Elbasvir-grazoprevir is well tolerated. In large trials, the most common adverse events were headache, fatigue, and nausea [25,26]. Serious adverse events occurred rarely and at the same rate as with placebo. Approximately 1 percent of patients developed late aminotransferase elevations greater than five times the upper limit of normal (ULN) without associated bilirubin increases that resolved once the regimen was stopped. Aminotransferase monitoring at baseline and at week 8 of therapy (and at week 12, if the total duration is 16 weeks) is recommended [13]. The regimen should be discontinued if aminotransferase elevations are accompanied by other signs or symptoms of hepatic injury (eg, jaundice, increasing bilirubin or INR).

●Drug interactions – Elbasvir and grazoprevir are primarily metabolized through CYP3A metabolism and should not be given with moderate and strong inducers or strong inhibitors of this enzyme (table 2). Grazoprevir is a substrate of OATP1B1/3 transporters and should not be given with drugs that inhibit this enzyme. Coadministration is thus contraindicated with rifampin, phenytoin, carbamazepine, St. John's wort, cyclosporine, and certain antiretroviral agents (protease inhibitors and efavirenz). Coadministration is not recommended with nafcillin, ketoconazole, etravirine, cobicistat, and modafinil.

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

●Resistance – Preexisting polymorphisms in the NS5A protein that are associated with resistance to elbasvir and lower SVR rates with elbasvir-grazoprevir in genotype 1a patients are at positions M28, Q30, L31, and Y93 [25,27]. Approximately 11 percent of genotype 1a viruses are estimated to harbor one of these polymorphisms. Patients with genotype 1a virus should be tested these polymorphisms prior to using elbasvir-grazoprevir; in patients with one of these present, SVR rates can be improved by adding weight-based ribavirin and extending the treatment course. The presence of these polymorphisms do not appear to significantly affect SVR rates with genotype 1b virus. Mutational analysis testing for NS5A mutations is commercially available from LabCorp and Quest Labs.

Polymorphisms in the NS3 protein, including the Q80L polymorphism in genotype 1a virus, do not appear to impact treatment response to elbasvir-grazoprevir. NS3/4 polymorphisms that emerge after failure on the elbasvir-grazoprevir regimen tend to disappear after 100 to 200 days, whereas emergent NS5A polymorphisms tend to persist for as long as the patients are followed (beyond 900 days) [28]. This suggests that salvage regimens will be necessary for the NS5A-resistant polymorphisms only.

SINGLE-DRUG AGENTS

Sofosbuvir — Sofosbuvir is the first NS5B nucleoside polymerase inhibitor to be available in the United States. Sofosbuvir is used in various combinations with other antivirals for different indications. It is usually used as part of a fixed-dose combination, but is also available as a single drug, usually used in combination with daclatasvir. (See 'Fixed-dose combination agents' above and 'Daclatasvir' below.)

Selection of sofosbuvir-containing regimens for treatment of chronic HCV is discussed in detail elsewhere. (See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults" and "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults".)

●Administration and pharmacology – Sofosbuvir is easily administered:

•Sofosbuvir 400 mg orally once daily with or without food (available as 400 mg tablet)

Sofosbuvir should not be used without other antiviral agents, and the dose of sofosbuvir should not be decreased. Although renal clearance is the major form of elimination of sofosbuvir and exposure is increased in patients with severe renal impairment, including those on dialysis, studies suggest safe use without dose adjustment in this population. In the United States, the drug is FDA approved for use in patients with chronic kidney disease classes 4 and 5. (See "Treatment of chronic hepatitis C infection in adults with kidney function impairment", section on 'Direct-acting antivirals'.)

When used in patients with cirrhosis, no dose adjustment has been needed in patients with moderate (Child Pugh Class B) or severe (Child Pugh class C) hepatic impairment.

●Adverse effects – Sofosbuvir is well tolerated with no significant side effects beyond what is seen with peginterferon and ribavirin. In clinical trials, the most commonly reported adverse effects of sofosbuvir and ribavirin, with or without peginterferon, are fatigue, headache, nausea, insomnia, and anemia [29-31]. Rare cases of symptomatic bradycardia have been reported following the initiation of sofosbuvir-containing regimens; most, but not all, have been in the context of concomitant use with amiodarone [32,33].

●Drug interactions – Drug interactions with sofosbuvir are substantially less than those observed with the HCV protease inhibitors. Sofosbuvir is a substrate of the P-glycoprotein (P-gp) drug transporter, so drugs that are potent intestinal P-gp inducers may decrease sofosbuvir levels. Thus, coadministration of sofosbuvir is not recommended with rifampin, rifabutin, rifapentine, St. John’s wort, carbamazepine, phenytoin, phenobarbital, oxcarbazepine, or tipranavir/ritonavir. Coadministration of sofosbuvir and amiodarone is also not recommended because of reports of symptomatic bradycardia and a fatal cardiac arrest among patients taking amiodarone who initiated a sofosbuvir-containing regimen [34,35].

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

●Resistance – Resistant polymorphisms within the NS5B polymerase have been reported with in vitro exposure to sofosbuvir, although their clinical significance is uncertain. These polymorphisms include S282T, L159F, and E341D. In particular, the S282T polymorphism is associated with reduced susceptibility to sofosbuvir [36]. However, this mutation has only been clinically identified in one patient who experienced virologic relapse in trials of sofosbuvir-containing regimens [22,37]. Other substitutions have been identified in patients who were exposed to up to 48 weeks of sofosbuvir plus ribavirin while awaiting liver transplantation, but the clinical significance of these substitutions is unknown.

Daclatasvir — Daclatasvir is an NS5A inhibitor that is used mainly in combination with sofosbuvir. Daclatasvir is now infrequently used in the United States but is used in other parts of the world.

●Administration and pharmacology – Daclatasvir is given as a 60 mg oral dose once daily with or without food. Daclatasvir is only used in combination with other DAA agents.

No dose adjustments are required for renal or hepatic impairment. Dose modifications are warranted when used with certain other medications, as below.

●Adverse effects – Daclatasvir is generally well tolerated. In clinical trials of daclatasvir-containing regimens, headache, fatigue, and nausea were the most commonly reported adverse effects [11,38]. These were mild to moderate in severity.

●Drug interactions – Daclatasvir is primarily metabolized through CYP3A metabolism and should not be given with strong inducers of this enzyme. Coadministration of daclatasvir is thus not recommended with rifampin, phenytoin, carbamazepine, and St. John's wort. A dose reduction to 30 mg once daily is recommended when daclatasvir is used with strong CYP3A inhibitors (such as ritonavir-boosted atazanavir, some azole agents, and clarithromycin). A dose increase to 90 mg once daily is recommended when daclatasvir is used with moderate CYP3A inducers (such as efavirenz, etravirine, dexamethasone, and nafcillin).

Daclatasvir is an inhibitor of P-glycoprotein transporter (P-gp), organic anion transporting polypeptide (OATP) 1B1 and 1B3, and breast cancer resistance protein (BCRP). Dose adjustments of digoxin may be warranted when used with daclatasvir.

For other specific drug interactions, refer to the drug interactions program included with UpToDate. Interactions with sofosbuvir should also be considered when daclatasvir is used in combination with sofosbuvir.

●Resistance – Polymorphisms in the NS5A protein that are associated with resistance to daclatasvir in vitro include polymorphisms at M28, A30, L31, and Y93; mutations at the Y93 site appear to be the most clinically relevant. A baseline Y93H polymorphism was detected in 13 of 148 genotype 3-infected patients in a clinical trial of daclatasvir plus sofosbuvir and was associated with lower sustained virologic response (SVR) rates [38]. Among the 10 patients who had virologic failure and did not have a Y93H polymorphism at baseline, Y93H emerged in 9 of them. Other polymorphisms were not associated with worse clinical response. Mutational analysis testing for NS5A mutations is commercially available from LabCorp and Quest Labs.

Simeprevir — Simeprevir was the first available second-generation protease inhibitor [39]. Simeprevir is not used in the United States but may be used in other parts of the world.

●Administration and pharmacology – Simeprevir is easily administered:

•Simeprevir 150 mg orally once daily with food (available in 150 mg capsules)

Simeprevir should not be used without other antiviral agents, and the dose of simeprevir should not be decreased. No dose adjustment is required in the setting of renal impairment. The elimination of simeprevir is by the liver [40]. Simeprevir cannot be recommended in patients with moderate (Child Pugh Class B) or severe (Child Pugh class C) hepatic impairment because of increases in exposure of two- to fivefold (see 'Protease inhibitors and hepatic decompensation' below). In addition, higher exposure to simeprevir was reported in patients of Eastern Asian ancestry, and simeprevir should be used with caution in this group [41].

●Adverse effects – In general, simeprevir is well tolerated. Treatment discontinuation for adverse effects appears infrequent [42,43]. Photosensitivity and rash were reported in the simeprevir program with some serious reactions requiring hospitalization. Patients should be cautioned about this risk and instructed to use sun protective measures and limit sun exposure. If a severe rash or photosensitivity reaction occurs, simeprevir should be discontinued.

In addition, transient, mild elevations in bilirubin have been observed with simeprevir due to decreased bilirubin elimination related to inhibition of the hepatic transporters OATP1B1 and MRP2, but no pattern to suggest liver toxicity has been observed. Pruritus and nausea have also been associated with simeprevir use.

●Drug interactions – Simeprevir is oxidatively metabolized by CYP3A subfamily, which consists mainly of hepatic and intestinal CYP3A4 metabolism [44]. Therefore, coadministered drugs that are significant inducers or inhibitors of CYP3A4 are expected to alter concentrations of simeprevir (table 2). This effect on simeprevir has been confirmed for several CYP3A4 inhibitors and inducers [40]. Simeprevir, in turn, may affect the levels of other agents. As an example, simeprevir also inhibits OATP1B1/3, and substrates of OATP1B1/3 such as rosuvastatin and atorvastatin are increased.

Among the HIV antiretrovirals, simeprevir is not recommended with ritonavir, HIV protease inhibitors, and the non-nucleoside reverse transcriptase inhibitors efavirenz and nevirapine. Simeprevir can be administered without dose adjustments with rilpivirine, raltegravir, maraviroc, and all nucleos(t)ide reverse transcriptase inhibitors, including tenofovir.

In post-liver transplant patients with HCV infection, coadministration of simeprevir and cyclosporine resulted in significantly elevated simeprevir levels, so it is not recommended [41]. Simeprevir can be safely administered with tacrolimus or sirolimus.

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

●Resistance – Many of the second-generation protease inhibitors are macrocyclic molecules, which have been shown to be generally more potent. Additionally, depending on the location of the macrocycle, they are able to retain activity against resistant variants. Common wild-type and drug-resistant polymorphisms of the NS3 protein include Q80K, R155K, V36M/R155K, A156T, and D168A [45].

Several mutations in the NS3/4A protease are associated with reduced susceptibility to simeprevir. One of the most prevalent and clinically relevant mutations is the substitution Q80K. Among patients in clinical trials of simeprevir plus peginterferon and ribavirin, this polymorphism was present at baseline in 30 percent of patients with genotype 1a and was associated with a lower SVR rate (58 versus 84 percent if the Q80K was not present) [46]. Preliminary data suggest that the Q80K mutation does not substantially impact response rates to the combination of simeprevir and sofosbuvir [47]. In the United States, testing for this polymorphism is available at LabCorp.

Resistance mutations that emerge during unsuccessful treatment with first-generation protease inhibitors, such as R155K and A156T/V, are also associated with decreased in vitro susceptibility to simeprevir and are expected to impact clinical response to simeprevir [40].

CLASS ADVERSE EFFECTS — Overall, direct-acting antiviral (DAA) regimens are extremely well tolerated, with only mild to moderate side effects. In a retrospective study of over 30,000 patients with HCV infection seen at three health systems in the United States between 2012 and 2017, DAA exposure was associated with a lower rate of death (11 versus 34 events per 1000 person-years) and various other severe adverse events, including multiple organ failure, hepatic decompensation, liver cancer, acute myocardial infarction, and stroke [48].

Nevertheless, rare severe adverse events can occur.

HBV reactivation — As an example, reactivation of hepatitis B virus (HBV) infection, in some cases with fulminant liver failure, has been described during DAA treatment of (HCV) infection [49]. A subsequent review identified 524 cases of liver failure reported to the US Food and Drug Administration (FDA) over the course of one year, with an estimated 250,000 individuals treated over a similar time frame [50]. Reactivation may be due to diminished hepatic interferon response following HCV clearance [51]. However, it is unclear what proportion of these cases represent HBV reactivation or complications in patients with existing advanced liver disease (including inappropriate use of protease inhibitors in patients with decompensated disease), situations in which the risk of liver failure is higher than the general population. Patients should understand that this risk is overall very low.

Monitoring for and managing HBV reactivation in the setting of HCV treatment is discussed elsewhere. (See "Overview of the management of chronic hepatitis C virus infection", section on 'Monitoring for toxicity' and "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'HBV coinfection'.)

Protease inhibitors and hepatic decompensation — Cases of hepatic decompensation or failure, including events with fatal outcomes, have been reported in patients who received HCV protease inhibitor-containing regimens [52]. Many of the cases were in patients with decompensated (Child class B or C) cirrhosis, among whom these agents are not recommended. However, some of the cases were in patients who were labeled as having no cirrhosis or compensated (Child class A) cirrhosis. Details of these cases are lacking, and many of those without a diagnosis of decompensated cirrhosis had evidence of more advanced liver impairment, such as decreased platelet levels or increased portal pressure. Some also had other potential contributors to liver disease, such as liver cancer and alcohol use disorder. Pending further data, we check endoscopy in patients with platelet counts <150,000/microL or with a transient elastography score >20 kPa prior to antiviral treatment and avoid protease inhibitor-containing regimens in those with evidence of any esophageal varices.

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".)

SUMMARY

●Antiviral targets – The main targets of the direct-acting antiviral (DAA) agents are the HCV-encoded proteins that are vital to the replication of the virus (figure 1). Available DAAs are inhibitors of the NS3/4A protease, the NS5A protein, or the NS5B polymerase (table 1). (See 'Introduction' above and 'Viral life cycle and replication overview' above.)

•Protease inhibitors – Glecaprevir, voxilaprevir, and grazoprevir are HCV protease inhibitors that offer several benefits over earlier protease inhibitors (such as telaprevir and boceprevir), including fewer drug-drug interactions, improved dosing schedules, and less frequent and less severe side effects. Nevertheless, few significant drug-drug interactions may limit their use. (See 'NS3/4A protease inhibitors' above.)

•NS5A inhibitors – Agents that inhibit NS5A are generally quite potent and are effective across genotypes, but they have a low barrier to resistance and variable toxicity profiles. Velpatasvir, ledipasvir, daclatasvir, and elbasvir are all well-tolerated NS5A inhibitors. (See 'NS5A inhibitors' above.)

•NS5B inhibitors – The NS5B protein is an RNA-dependent RNA polymerase; inhibitors are either nucleoside or non-nucleoside polymerase inhibitors. Sofosbuvir is a nucleoside polymerase inhibitor with high potency across all six genotypes, a very high barrier to resistance, and few expected drug-drug interactions. Non-nucleoside polymerase inhibitors have a lower threshold for resistance than other classes; no clinically available antiviral agent is in this class. (See 'NS5B RNA-dependent RNA polymerase inhibitors' above.)

●Fixed-dose combination regimens – Several DAAs are only available as part of fixed-dose combinations. These are glecaprevir-pibrentasvir, ledipasvir-sofosbuvir, sofosbuvir-velpatasvir, sofosbuvir-velpatasvir-voxilaprevir, and elbasvir-grazoprevir, the latter of which is administered with dasabuvir for certain genotypes. (See 'Fixed-dose combination agents' above.)

●Class adverse effects – Overall, DAAs are safe and well tolerated, although there have been sporadic reports of worsening liver disease in patients with hepatitis B virus coinfection and in patients with decompensated cirrhosis who received protease inhibitor-containing regimens (which are contraindicated). (See 'Class adverse effects' above.)