Direct-acting antivirals for the treatment of hepatitis C virus infection
Author:
Paul J Pockros, 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: Feb 2018. | This topic last updated: Aug 24, 2017.

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 agents. 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 "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults" and "Overview of the management of chronic hepatitis C virus infection".)

Many direct-acting antivirals are in various stages of development and are not yet available. These are discussed in detail elsewhere.

VIRAL LIFE CYCLE AND REPLICATION — The main targets of the direct-acting antiviral agents are the HCV-encoded proteins that are vital to the replication of the virus (figure 1). The infectious viral structure is comprised of envelope glycoproteins in a lipid bilayer that contain the viral core protein and RNA [2]. 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. 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. 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.

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

NS3/4A PROTEASE INHIBITORS — NS3/4A protease inhibitors are inhibitors of 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.

The first generation protease inhibitors telaprevir and boceprevir were the first direct-acting antivirals available for the treatment of HCV, and were used in conjunction with peginterferon and ribavirin for the treatment of genotype 1 infection [4,5]. Following the introduction of other potent and better tolerated DAAs, the clinical importance of these agents diminished substantially because of their cumbersome administration, substantial adverse effects, drug-drug interactions, and low barrier to resistance. Subsequent-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. In addition, the newer protease inhibitors also appear to have increased efficacy against genotype 1 HCV; however, most still have limited efficacy against other genotypes [6]. Additionally, the barrier to resistance also remains relatively low (table 1).

The following are protease inhibitors available in the United States. Asunaprevir is a protease inhibitor in use in Japan.

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

Grazoprevir — Grazoprevir is a potent, pangenotypic protease inhibitor, which is only available in combination with the NS5A inhibitor elbasvir. (See 'Elbasvir-grazoprevir' below.)

Paritaprevir — Paritaprevir is an HCV protease inhibitor that is given with low dose ritonavir (a protease inhibitor that does not have anti-HCV activity) for a pharmacologic boosting effect. Paritaprevir and ritonavir are available as a fixed-dose combination with ombitasvir (an NS5A inhibitor) and usually given with the non-nucleoside NS5B inhibitor dasabuvir. (See 'Ombitasvir-paritaprevir-ritonavir with or without dasabuvir' below.)

Simeprevir — Simeprevir was the first available second-generation protease inhibitor [7]. It is used in combination with peginterferon and ribavirin or in combination with sofosbuvir with or without ribavirin for chronic genotype 1 infection. (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Simeprevir plus peginterferon and ribavirin' and "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Simeprevir plus sofosbuvir'.)

Administration and pharmacologySimeprevir 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 [8]. 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. In addition, higher exposure to simeprevir was reported in patients of East Asian ancestry, and simeprevir should be used with caution in this group [9].

Adverse effects – In general, simeprevir is well tolerated. Treatment discontinuation for adverse effects appears infrequent [10,11]. 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 interactionsSimeprevir is oxidatively metabolized by CYP3A subfamily, which consists mainly of hepatic and intestinal CYP3A4 metabolism [12]. 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 [8]. 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 is not recommended [9]. Simeprevir can be safely administered with tacrolimus or sirolimus.

For other specific drug interactions, refer to the Lexi-Interact 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 [13].

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) [14]. Preliminary data suggest that the Q80K mutation does not substantially impact response rates to the combination of simeprevir and sofosbuvir [15]. 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 [8].

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

NS5A INHIBITORS — The NS5A protein plays a role in both viral replication and the assembly of the hepatitis C virus (HCV) [16,17]. 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 SVR when given in conjunction with peginterferon and ribavirin [18]. 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 [19,20].

Daclatasvir — Daclatasvir is a NS5A inhibitor that is used mainly in combination with sofosbuvir. The clinical use of this regimen is discussed elsewhere. (See "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults", section on 'Genotype 3'.)

Administration and pharmacologyDaclatasvir 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 effectsDaclatasvir is generally well tolerated. In clinical trials of daclatasvir-containing regimens, headache, fatigue, and nausea were the most commonly reported adverse effects [20,21]. These were mild to moderate in severity.

Drug interactionsDaclatasvir 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 Lexi-Interact 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 SVR rates [21]. Among the 10 patients who had virologic failure and did not have a Y93H polymorphism at baseline, Y93H emerged in nine 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.

Elbasvir — The NS5A inhibitor elbasvir is only available as a fixed-dose combination with the protease inhibitor grazoprevir. (See 'Elbasvir-grazoprevir' below.)

Ledipasvir — Ledipasvir is 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.)

Ombitasvir — The NS5A inhibitor ombitasvir is only available as a fixed-dose combination with the protease inhibitors paritaprevir and ritonavir, which is usually given in combination with the non-nucleotide NS5B inhibitor dasabuvir. (See 'Ombitasvir-paritaprevir-ritonavir with or without dasabuvir' below.)

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

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

NS5B RNA-DEPENDENT RNA POLYMERASE INHIBITORS — 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, nucleoside polymerase inhibitors (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.

Sofosbuvir — Sofosbuvir is the first NS5B NPIs to be available in the United States. Sofosbuvir is used in various combinations with other antivirals for different indications.

Selection of sofosbuvir containing regimens for treatment of chronic HCV is discussed in detail elsewhere. (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults".)

Administration and pharmacologySofosbuvir is the only agent in this class and 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. Renal clearance is the major form of elimination, and pharmacokinetic studies with sofosbuvir suggested that no dose adjustment is required for patients with mild or moderate renal insufficiency (glomerular filtration rate greater than 30 mL/minute) [22]. Sofosbuvir exposure is increased in patients with severe renal impairment including those on dialysis. Further study in this population is warranted before dosing recommendations can be made in such patients.

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 effectsSofosbuvir 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 [23-25]. 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 [26,27].

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 [28,29].

For other specific drug interactions, refer to the Lexi-Interact 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 [30]. However, this mutation has only been clinically identified in one patient who experienced virologic relapse in trials of sofosbuvir-containing regimens [31,32]. 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.

Non-nucleoside polymerase inhibitors (NNPIs) — The four allosteric sites that act as targets for non-nucleoside polymerase inhibitors (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 [33]. 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).

Dasabuvir — Dasabuvir is administered and packaged with ombitasvir-paritaprevir-ritonavir. (See 'Ombitasvir-paritaprevir-ritonavir with or without dasabuvir' below.)

FIXED-DOSE COMBINATIONS

Elbasvir-grazoprevir — Elbasvir, an NS5A inhibitor, and grazoprevir, a NS3/4A protease inhibitor with a high barrier of resistance, are coformulated in a single tablet [34]. This regimen is administered with or without weight-based ribavirin, depending on certain patient characteristics. The clinical use of this regimen is discussed elsewhere. (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Elbasvir-grazoprevir' and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults".)

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.

Adverse effectsElbasvir-grazoprevir is well tolerated. In large trials, the most common adverse events were headache, fatigue, and nausea [35,36]. 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 [34]. 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 Lexi-Interact 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 [35,37]. 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) [38]. This suggests that salvage regimens will be necessary for the NS5A-resistant polymorphisms only.

Glecaprevir-pibrentasvir — The NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir are coformulated in a single tablet [34]. The regimen is pangenotypic and has a high barrier to resistance. The clinical use of this regimen is discussed elsewhere. (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Selection of treatment regimens' and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults", section on 'Selection of treatment regimen' and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults" and "Treatment of chronic hepatitis C infection in adults with renal impairment".)

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 Child-Pugh class B or C cirrhosis.

Adverse effectsGlecaprevir-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 [39]. 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 Lexi-Interact 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 [40]. 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 [41]. 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 "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Prior failure with an NS5A inhibitor regimen'.)

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 "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Ledipasvir-sofosbuvir' and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults".)

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

Severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2) does not substantially affect the pharmacokinetics of ledipasvir, but because levels of sofosbuvir and its metabolite accumulate in the setting of severe renal impairment, the combination should not be used in such settings pending further data. No dose adjustment is warranted for mild or moderate 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.

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

Resistance – Virologic failure with ledipasvir-sofosbuvir has been associated with several NS5A mutations that reduce susceptibility to ledipasvir, most commonly Q30R, Y93H/N, and L31M in subtype 1a virus and Y93H in subtype 1b virus [31,42]. 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' above.)

Ombitasvir-paritaprevir-ritonavir with or without dasabuvir — The NS5A inhibitor ombitasvir, the HCV protease inhibitor paritaprevir, and the protease inhibitor ritonavir are coformulated in a single tablet. Ritonavir does not have direct anti-HCV activity but instead is included to increase levels of paritaprevir through inhibition of CYP3A-mediated metabolism. The fixed-dose combination tablet is available either alone or packaged and coadministered with an additional tablet, the non-nucleoside polymerase (NS5B) inhibitor dasabuvir.

Ombitasvir-paritaprevir-ritonavir plus dasabuvir is administered with or without weight-based ribavirin, depending on the patient population, for the treatment of chronic genotype 1 infection. Ombitasvir-paritaprevir-ritonavir with ribavirin but without dasabuvir is effective for genotype 4 infections. The clinical use of these regimens is discussed elsewhere. (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Ombitasvir-paritaprevir-ritonavir plus dasabuvir' and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults", section on 'Genotype 4'.)

Administration and pharmacology – For normal-release formulations, two combination tablets (each containing 12.5 mg ombitasvir, 75 mg paritaprevir, and 50 mg ritonavir) are administered once daily. If dasabuvir is part of the regimen, a single 250 mg dasabuvir tablet is administered twice daily. For the extended-release four-drug coformulation, three tablets (each containing 8.33 mg ombitasvir, 50 mg paritaprevir, 33.33 mg ritonavir, and 200 mg dasabuvir) are administered once daily. All of these formulations are given with food.

Renal impairment is not expected to clinically affect levels of ombitasvir-paritaprevir-ritonavir with or without dasabuvir, although the regimens have not been studied in HCV-infected individuals with severe renal insufficiency (estimated GFR <30 mL/min/1.73 m2) [43]. No dose adjustment is warranted for mild (Child Pugh Class A) hepatic impairment, but use is contraindicated in moderate to severe (Child Pugh classes B and C) hepatic impairment.

Adverse effects – The regimen of ombitasvir-paritaprevir-ritonavir with or without dasabuvir is generally well tolerated, but mild adverse effects are common and cases of hepatic decompensation in patients with underlying cirrhosis have been reported.

In trials that evaluated this regimen with ribavirin, the most common adverse effects that occurred more frequently than with placebo included nausea, pruritus, insomnia, diarrhea, and asthenia [44,45]. Fatigue and headache were the most common side effects but did not differ in frequency from placebo. Some of these symptoms may be attributable to the ribavirin component. In trials that compared the regimen with or without ribavirin, pruritus, nausea, insomnia, and rash occurred more frequently among those who received ribavirin [46,47].

When the regimen is administered with ribavirin, decreases in the hemoglobin level are common but usually limited to 2.0 to 2.5 g/dl, and severe anemia (hemoglobin <8 g/dL) is uncommon [43-47]. Mild hyperbilirubinemia also occurred more commonly when the regimen was given with ribavirin. Although increases in the alanine aminotransferase were uncommon overall, these occurred with greater frequency among women who were also taking ethinyl estradiol-containing medications.

In patients with underlying cirrhosis, use of ombitasvir-paritaprevir-ritonavir with or without dasabuvir has been associated with hepatic decompensation [48]. Most cases occurred within one to four weeks of drug initiation, and some cases resulted in need for liver transplantation or death. Patients with cirrhosis who use this regimen should be monitored closely for signs of decompensation and undergo interval transaminase and bilirubin testing after initiation.

Drug interactions – Because components of ombitasvir-paritaprevir-ritonavir and dasabuvir are both substrates and inhibitors of major metabolic enzymes, drug interactions are considerable. Common drugs that should not be coadministered with ombitasvir-paritaprevir-ritonavir and dasabuvir include anticonvulsants, rifampin, St. John's wort, ethinyl estradiol-containing products (ie, certain oral contraceptives), and salmeterol [43]. Likewise, close monitoring and/or dose reductions of certain drugs, such as statins, cyclosporine, tacrolimus, and antiarrhythmics, is warranted when they are used with this regimen.

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

Resistance – Exposure to ombitasvir, paritaprevir, and dasabuvir can select for mutations in the NS5A, NS3, and NS5B, respectively, that result in decreased activity of the given agent. In clinical trials, the most common mutations that emerged during treatment or on relapse among subtype 1a infections were D168V/any in NS3, M28A/T/V and Q30E/K/R in NS5A, and S556G/R in NS5B [43-47]. There were very few virologic failures with subtype 1b infection. Although baseline prevalence of some resistance-associated mutations was slightly higher among patients who failed treatment compared with those who achieved SVR, such polymorphisms are not expected to have a clinically significant impact or prognostic value with regards to treatment response [43].

Cross resistance between class is expected. In vitro studies suggested that dasabuvir retains activity against viruses with the S282T polymorphism, which is associated with decreased susceptibility to nucleotide NS5B inhibitors.

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 "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection 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 mild or moderate renal insufficiency or in the setting of moderate (Child Pugh Class B) or severe (Child Pugh class C) hepatic impairment.

Preliminary studies suggest that severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2) does not substantially affect the pharmacokinetics of velpatasvir, but because levels of sofosbuvir and its metabolite accumulate in the setting of severe renal impairment, the combination should not be used in such settings pending further data.

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 [49]. The most common complaints were headache, fatigue, nausea, nasopharyngitis, and insomnia.

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 may decrease absorption of velpatasvir. Acid suppressing agents can be coadministered if necessary; if used with proton pump inhibitors, sofosbuvir-velpatasvir should be administered without food and taken four hours prior to a low dose of a proton pump inhibitor.

Any drugs that should not be used with sofosbuvir (such as amiodarone) should also not be used with sofosbuvir-velpatasvir (see 'Sofosbuvir' above). For other specific drug interactions, refer to the Lexi-Interact 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 [50,51]. 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) [50]. 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' above.)

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 "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Selection of treatment regimens' and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults", section on 'Selection of treatment regimen' and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults" and "Treatment of chronic hepatitis C infection in adults with renal impairment".)

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 mild or moderate renal insufficiency or in the setting of mild (Child Pugh Class A) hepatic impairment. Because levels of sofosbuvir and its metabolite accumulate in the setting of severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2), sofosbuvir-velpatasvir-voxilaprevir should not be used in such settings pending further data. This regimen is also 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.

Adverse effects – The combination is well tolerated. In trials, <1 percent of participants discontinued a 12-week regimen for adverse events [52]. The most common adverse events are headache, fatigue, diarrhea, and nausea.

Drug interactions – The same drug interactions with sofosbuvir-velpatasvir apply to sofosbuvir-velpatasvir-voxilaprevir, with the exception that 20 mg omeprazole can be used for acid suppression (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 Lexi-Interact 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 [52]. 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).

CLASS ADVERSE EFFECTS — Overall, direct-acting antiviral (DAA) regimens are extremely well tolerated, with only mild to moderate side effects. As more individuals are treated, rare adverse effects may be identified. 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 [53]. 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 [54]. It is unclear what proportion of these represent cases of 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 and that further data are needed to more clearly define it.

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 'Other monitoring' and "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'HBV coinfection'.)

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

The main targets of the direct-acting antiviral agents are the HCV-encoded proteins that are vital to the replication of the virus (figure 1). Most of the direct-acting antivirals available or in late stages of development are inhibitors of the NS3/4A protease, the NS5A protein, and the NS5B polymerase (table 1). (See 'Introduction' above and 'Viral life cycle and replication' above.)

Glecaprevir, grazoprevir, simeprevir, paritaprevir, and voxilaprevir 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, and simeprevir and paritaprevir are only effective for genotype 1 infection. For simeprevir, certain viral polymorphisms are associated with resistance and decreased clinical efficacy. (See 'NS3/4A protease inhibitors' above.)

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. Unlike other candidate drugs in this class, it has not been associated with excess toxicity and is generally well tolerated. (See 'Nucleot(s)ide polymerase inhibitors (NPIs)' above.)

Dasabuvir is a non-nucleoside polymerase inhibitor. These agents are less potent and have a lower threshold for resistance than other classes; their main role will likely be as an adjunct to more potent compounds with higher barriers to resistance. (See 'Non-nucleoside polymerase inhibitors (NNPIs)' above.)

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. Elbasvir, ledipasvir, ombitasvir, pibrentasvir, velpatasvir, and daclatasvir are all well-tolerated NS5A inhibitors. For elbasvir, certain viral polymorphisms in the NS5A protein are associated with resistance and decreased clinical efficacy. (See 'NS5A inhibitors' above.)

Several direct-acting antivirals are only available as part of fixed-dose combinations. These are elbasvir-grazoprevir, glecaprevir-pibrentasvir, ledipasvir-sofosbuvir, sofosbuvir-velpatasvir, sofosbuvir-velpatasvir-voxilaprevir, and ombitasvir-paritaprevir-ritonavir, the latter of which is administered with dasabuvir for certain genotypes. (See 'Fixed-dose combinations' above.)

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REFERENCES

  1. Poordad F, Dieterich D. Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents. J Viral Hepat 2012; 19:449.
  2. Scheel TK, Rice CM. Understanding the hepatitis C virus life cycle paves the way for highly effective therapies. Nat Med 2013; 19:837.
  3. Pockros PJ. New direct-acting antivirals in the development for hepatitis C virus infection. Therap Adv Gastroenterol 2010; 3:191.
  4. US Food and Drug Administration. Approval of Victrelis (boceprevir) a direct acting antiviral drug (DAA) to treat hepatitis C virus (HCV). http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/ucm255413. (Accessed on August 1, 2013).
  5. US Food and Drug Administration. Approval of Incivek (telaprevir) a direct-acting antiviral (DAA) to treat hepatitis C virus (HCV) infection. http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=201917.
  6. Hunt D, Pockros P. What are the promising new therapies in the field of chronic hepatitis C after the first-generation direct-acting antivirals? Curr Gastroenterol Rep 2013; 15:303.
  7. Prescribing Information for OLYSIOTM (simeprevir): Janssen Therapeutics, Division of Janssen Products, LP, Titusville NJ 08560. Issued November 2013.
  8. Olysio (simeprevir). US FDA approved product information. National Library of Medicine. Available online at http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=1816fd68-0ed7-4a37-84bb-e298c5ab6e28 (Accessed on November 17, 2014).
  9. FDA. Olysio U.S. prescribing information http://www.accessdata.fda.gov/drugsatfda (Accessed on October 15, 2014).
  10. Jacobson IM, Dore, GJ, Foster GR, et al. Simeprevir (TMC435) with peginterferon/ribavirin for chronic hCV genotype 1 infection in treatment-naïve patients: results from QUEST-1, a phase III trial. Presented at the 48th annual meeting of the European Association for the Study of the Liver, Amsterdam, The Netherlands, April 24-28, 2013. Abstract 1425.
  11. Manns M, Marcellin P, Poordad F, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatment-naive patients: results from QUEST-2, a phase III trial. Presented at the 48th annual meeting of the European Association for the Study of the Liver, Amsterdam, The Netherlands, April 24-28, 2013. Abstract 1413.
  12. Williams JA, Ring BJ, Cantrell VE, et al. Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. Drug Metab Dispos 2002; 30:883.
  13. Ali A, Aydin C, Gildemeister R, et al. Evaluating the role of macrocycles in the susceptibility of hepatitis C virus NS3/4A protease inhibitors to drug resistance. ACS Chem Biol 2013; 8:1469.
  14. Lenz O, Fevery B, Verbinnen T, et al. Resistance analyses of HCV isolates from patients treated with simeprevir in phase 2b/3 studies. Presented at the 64th annual meeting of the American Association for the Study of Liver Diseases, Washington, DC, November 1-5, 2013. Abstract #1101.
  15. Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet 2014; 384:1756.
  16. Evans MJ, Rice CM, Goff SP. Phosphorylation of hepatitis C virus nonstructural protein 5A modulates its protein interactions and viral RNA replication. Proc Natl Acad Sci U S A 2004; 101:13038.
  17. Tellinghuisen TL, Foss KL, Treadaway J. Regulation of hepatitis C virion production via phosphorylation of the NS5A protein. PLoS Pathog 2008; 4:e1000032.
  18. Gao M, Nettles RE, Belema M, et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 2010; 465:96.
  19. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014; 370:1879.
  20. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014; 370:211.
  21. Nelson DR, Cooper JN, Lalezari JP, et al. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology 2015; 61:1127.
  22. Sovaldi (sofosbuvir). US FDA approved product information; Foster City, CA: Gilead Sciences; December 2013.
  23. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368:1878.
  24. Lawitz E, Lalezari JP, Hassanein T, et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis 2013; 13:401.
  25. Kowdley KV, Lawitz E, Crespo I, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet 2013; 381:2100.
  26. Fontaine H, Lazarus A, Pol S, et al. Bradyarrhythmias Associated with Sofosbuvir Treatment. N Engl J Med 2015; 373:1886.
  27. Brainard DM, McHutchison JG. Bradyarrhythmias Associated with Sofosbuvir Treatment. N Engl J Med 2015; 373:1888.
  28. FDA Hepatitis Update - Important safety information: Harvoni and Sovaldi. March 21, 2015. http://content.govdelivery.com/accounts/USFDA/bulletins/f97c71 (Accessed on March 30, 2015).
  29. Renet S, Chaumais MC, Antonini T, et al. Extreme bradycardia after first doses of sofosbuvir and daclatasvir in patients receiving amiodarone: 2 cases including a rechallenge. Gastroenterology 2015; 149:1378.
  30. Rajyaguru S, Xu S, Hebner C, et al. Sofosbuvir selects the NS5B S282T mutation in vitro in genotype 1-6 replicons and is not cross-resistant to resistance associated variants selected by other classes of antiviral inhibitors. Presented at the 64th annual meeting of the American Association for the Study of Liver Diseases, Washington, DC, November 1-5, 2013. Abstract #1094.
  31. Harvoni (ledipasvir-sofosbuvir). US FDA approved product information. National Library of Medicine.
  32. Svarovskaia ES, Dvory-Sobol H, Parkin N, et al. Infrequent development of resistance in genotype 1-6 hepatitis C virus-infected subjects treated with sofosbuvir in phase 2 and 3 clinical trials. Clin Infect Dis 2014; 59:1666.
  33. Au JS, Pockros PJ. Novel therapeutic approaches for hepatitis C. Clin Pharmacol Ther 2014; 95:78.
  34. Zepatier (elbasvir and grazoprevir). US FDA approved product information; Whitehouse Station, NJ: Merck and Co, Inc; January 2016.
  35. Zeuzem S, Ghalib R, Reddy KR, et al. Grazoprevir-Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection: A Randomized Trial. Ann Intern Med 2015; 163:1.
  36. Lawitz E, Gane E, Pearlman B, et al. Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial. Lancet 2015; 385:1075.
  37. Thompson A, Zeuzem S, Rockstroh J, Kwo P, et al. The combination of elbasvir and grazoprevir ± RBV is highly effective for the treatment of GT1a-infected patients. Presented at the American Association for the Study of Liver Diseases Liver Meeting, San Francisco CA, November 13-17, 2015.
  38. Lahser F, Galloway A, Hwang P, et al. Interim analysis of a 3-year follow-up study of NS5A and NS3 resistance-associated variants (RAVs) after treatment with grazoprevir-containing regimens in patients with chronic hepatitis C virus (HCV) infection. Hepatology 2016; 64:32A.
  39. Dufour JF, Zuckerman E, Zadeikis N, et al. Safety of Glecaprevir/Pibrentasvir in Adults With Chronic Genotype 1-6 Hepatitis C Virus Infection: An Integrated Analysis. Presented at the 52nd Annual Meeting of the European Association for the Study of the Liver (EASL), Amsterdam, The Netherlands, April 19-23, 2017.
  40. Krishnan P, Schnell G, Tripathi R, et al. Pooled resistance analysis in HCV genotype 1-6 infected patients treated with glecaprevir/pibrentasvir in phase 2 and 3 clinical trials. Presented at the 52nd Annual Meeting of the European Association for the Study of the Liver (EASL), Amsterdam, The Netherlands, April 19-23, 2017.
  41. Poordad F, Pol S, Asatryan A, et al. MAGELLAN-1, Part 2: Glecaprevir/pibrentasvir for 12 or 16 weeks in patients with chronic HCV genotype 1 or 4 and prior direct-acting antiviral treatment failure. Presented at the 52nd Annual Meeting of the European Association for the Study of the Liver (EASL), Amsterdam, The Netherlands, April 19-23, 2017.
  42. Wyles D, Dvory-Sobol H, Svarovskaia ES, et al. Post-treatment resistance analysis of hepatitis C virus from phase II and III clinical trials of ledipasvir/sofosbuvir. J Hepatol 2017; 66:703.
  43. VIEKIRA PAK (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets). US FDA approved product information. National Library of Medicine. www.dailymed.nlm.nih.gov (Accessed on January 01, 2015).
  44. Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014; 370:1594.
  45. Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014; 370:1604.
  46. Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med 2014; 370:1983.
  47. Andreone P, Colombo MG, Enejosa JV, et al. ABT-450, ritonavir, ombitasvir, and dasabuvir achieves 97% and 100% sustained virologic response with or without ribavirin in treatment-experienced patients with HCV genotype 1b infection. Gastroenterology 2014; 147:359.
  48. FDA Drug Safety Communication: FDA warns of serious liver injury risk with hepatitis C treatments Viekira Pak and Technivie. October 22, 2015. http://www.fda.gov/Drugs/DrugSafety/ucm468634.htm (Accessed on October 22, 2015).
  49. Jacobson IM, Brau N, Bourgeois S, et al. The tolerability of sofosbuvir/velpatasvir for 12 Weeks in >1000 patients treated in the ASTRAL-1, ASTRAL-2, and ASTRAL-3 studies: An integrated safety analysis. Presented at the 51st Annual Meeting of the European Association for the Study of the Liver (EASL), Barcelona, Spain, April 13-17, 2016.
  50. Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection. N Engl J Med 2015; 373:2608.
  51. Feld JJ, Jacobson IM, Hézode C, et al. Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med 2015; 373:2599.
  52. Bourlière M, Gordon SC, Flamm SL, et al. Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection. N Engl J Med 2017; 376:2134.
  53. FDA Drug Safety Communication: FDA warns about the risk of hepatitis B reactivating in some patients treated with direct-acting antivirals for hepatitis C http://www.fda.gov/Drugs/DrugSafety/ucm522932.htm (Accessed on October 05, 2016).
  54. QuaterWatch: Monitoring FDA MedWatch Reports. Institute For Safe Medication Practices. January 25, 2017. http://www.ismp.org/quarterwatch/pdfs/2016Q2.pdf.
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