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Management of Hepatitis C Infection

Stefan Zeuzem, MD
Program Director
Jordan J. Feld, MD, MPH
Hemant Shah, MD, MScCH HPTE
Released: June 17, 2019

Types of Therapy

Combination therapy is necessary to optimize HCV treatment response rates. Treatment options currently approved by the FDA and/or the European Medicines Agency (EMA) include combination therapies given based on genotype, presence of cirrhosis, and/or treatment experience (Table 1).

Table 1. Approved Regimens for Patients With HCV Infection

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For a summary of current guidelines on which regimens are recommended in specific patient scenarios, click here.

HCV Viral Life Cycle

HCV enters the hepatocyte following interaction with a number of cellular entry factors, including CD81 and SRB1. Once inside the cell, the viral genome is released from the nucleocapsid and the HCV polyprotein is translated using the internal ribosome entry site. The polyprotein is then cleaved by cellular and viral proteases to yield the structural and nonstructural proteins. The core NS3 and NS5A proteins form the replication complex on lipid droplets and serve as a scaffold for the RNA polymerase to replicate the viral genome, which is then packaged in the envelope glycoproteins (E1/E2) before noncytolytic secretion of mature virions.

Combination HCV therapies such as ledipasvir/sofosbuvir, ombitasvir/paritaprevir/ritonavir plus dasabuvir, elbasvir/grazoprevir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, and glecaprevir/pibrentasvir employ multiple DAAs that inhibit several stages of the HCV life cycle. As in HIV infection, the use of DAA combination regimens aims to provide potency and to prevent the emergence of drug resistance. With combination therapy, the different agents are collectively able to suppress both wild-type and drug-resistant viral populations. Clinicians should consider the mechanisms of action of each class of drugs and past treatment history when choosing combination therapies.

Figure 1. HCV viral life cycle and DAA targets.

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Protease Inhibitors

The viral NS3/NS4A serine protease is crucial for processing the single polyprotein encoded by HCV RNA into individually active proteins, NS4A, NS4B, NS5A, and NS5B. Without these serine proteins, RNA replication could not occur and the HCV life cycle is effectively disrupted.[11] The NS3/NS4A protease also cleaves the cellular MAVS and TRIF adaptor proteins, thereby blocking RIG-I and toll-like receptor-3–initiated interferon synthesis enabling HCV infection to establish chronicity.[12] Targeting the protease may thus inhibit HCV replication directly and may also promote innate immune signaling, which may help with viral clearance. Seven approved DAAs—boceprevir, glecaprevir, grazoprevir, paritaprevir, simeprevir, telaprevir, and voxilaprevir—inhibit the NS3/NS4A serine protease as their primary mechanism of action, although the protease inhibitors boceprevir, simeprevir, and telaprevir are no longer marketed in the United States or the European Union. The NS3/NS4A serine protease inhibitors have a lower barrier to resistance than other agents, such as sofosbuvir.[11]

Use of HCV protease inhibitors presents significant potential for drug–drug interactions.[13] Before starting patients on a protease inhibitor, it is important to review all concomitant medications, both prescription and nonprescription, including herbals such as St John’s wort and supplements such as naringin, with this in mind. Patients should also be reminded to inquire about potential interactions before starting any new medications that may be prescribed by another healthcare professional during therapy. As clinical experience with these agents increases, other drug interactions may be identified, and therefore it is advisable to refer to a regularly updated data source, for example, the University of Liverpool Web site at http://www.hep-druginteractions.org/.

Paritaprevir. Paritaprevir, an HCV NS3/NS4A serine protease inhibitor, is approved by the FDA[14] and the EMA[15] as part of the coformulation, ombitasvir/paritaprevir/ritonavir plus dasabuvir for the treatment of chronic genotype 1 (with dasabuvir) and genotype 4 (without dasabuvir) HCV infection.[14] Ombitasvir/paritaprevir/ritonavir plus dasabuvir should be given with or without ribavirin depending on HCV genotype/subtype and cirrhosis status (Table 2) (Table 3). Ombitasvir/paritaprevir/ritonavir is administered as two 12.5/75/50-mg tablets once daily (morning) and dasabuvir is administered as one 250-mg tablet twice daily (morning and evening) with a meal (Table 4). A once-daily extended-release coformulation containing all 4 agents, dasabuvir/ombitasvir/paritaprevir/ritonavir, is approved by the FDA for the treatment of genotype 1 HCV infection. This coformulation should also be given with or without ribavirin depending on HCV genotype 1 subtype and cirrhosis status. Ombitasvir/paritaprevir/ritonavir plus dasabuvir is administered as three 200/8.33/50/33.33-mg tablets once daily with a meal.

This combination is contraindicated in patients with moderate to severe hepatic impairment or decompensated cirrhosis (Child-Pugh B or C).[14,15] This contraindication is based on reports of hepatic decompensation and liver failure, including some cases requiring liver transplantation or resulting in death among patients receiving ombitasvir/paritaprevir/ritonavir-containing regimens. Patients who experienced these severe outcomes had evidence of advanced cirrhosis before beginning treatment.

Patients with HCV/HIV coinfection should be receiving a suppressive HIV regimen before beginning treatment with ombitasvir/paritaprevir/ritonavir plus dasabuvir, as exposure to ritonavir alone may select for HIV drug resistance.

Table 2. FDA-Approved Regimens for Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvir and Dasabuvir/Ombitasvir/Paritaprevir/Ritonavir in Patients With Genotype 1 HCV Infection[14]

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Table 3. FDA-Approved Regimen for Ombitasvir/Paritaprevir/Ritonavir in Patients With Genotype 4 HCV Infection[16]

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Table 4. Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvir and Dasabuvir/Ombitasvir/Paritaprevir/Ritonavir: Dosing and Administration

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Drug Resistance
In cell culture with genotype 1a HCV infection, single NS3 amino acid substitutions, F43L, R155G/K/S, A156T, and D168A/E/F/H/N/V/Y all reduce the antiviral activity of paritaprevir by 7-fold to 219-fold.[14] The NS3 Q80K substitution reduces paritaprevir activity by 3-fold in cell culture but whether this is relevant clinically, particularly when paritaprevir is used with ombitasvir and dasabuvir, is unknown. Substitutions when found in combination, V36M, Y56H, or E357K with R155K or D168 reduce paritaprevir activity by 2-fold to 7-fold. In cell culture with genotype 1b infection, single NS3 amino acid substitutions A156T and D168A/H/V reduce activity by 7-fold to 159-fold. When the substitution Y56H occurs with D168 variants, paritaprevir activity is reduced an additional 16-fold to 26-fold.[14]

In a pooled analysis of patients receiving ombitasvir/paritaprevir/ritonavir plus dasabuvir in phase IIb and III trials, resistance data were available for 64 individuals with virologic failure. Treatment-emergent substitutions were observed in 30 of 57 (53%) of patients with genotype 1a HCV and in 1 of 6 (17%) patients with genotype 1b HCV.[14] In a pooled analysis of patients with genotype 1a HCV receiving ombitasvir/paritaprevir/ritonavir plus dasabuvir in phase III clinical studies, the NS3 Q80K variant was detected at baseline in 38%. This variant was enriched 2-fold in patients with virologic failure compared with patients achieving SVR. It is not expected that baseline HCV polymorphisms will have a substantial impact on SVR when ombitasvir/paritaprevir/ritonavir plus dasabuvir is used as recommended, given high treatment success rates observed in clinical trials.[14]

Drug–Drug Interactions
Paritaprevir is an inhibitor of UGT1A1, OATP1B1, OATP1B3, and BCRP and requires ritonavir boosting. Ombitasvir and dasabuvir are also inhibitors of UGT1A1, and ritonavir is an inhibitor of CYP3A4. Coadministration of ombitasvir/paritaprevir/ritonavir plus dasabuvir with substrates of these enzymes may result in increased drug exposure.[14] Paritaprevir is primarily metabolized by CYP3A enzymes and is a substrate of P-gp. Coadministration of ombitasvir/paritaprevir/ritonavir plus dasabuvir with inhibitors of CYP3A or P-gp may increase the concentration of paritaprevir and ritonavir. Ombitasvir/paritaprevir/ritonavir plus dasabuvir should not be coadministered with a number of medicines, including darunavir/ritonavir, lopinavir/ritonavir, and rilpivirine. If coadministered, atazanavir should be given in the morning, without additional ritonavir.[14] See prescribing information or the University of Liverpool Web site (http://www.hep-druginteractions.org/) for a full list of potential drug–drug interactions and contraindications.

Grazoprevir. Grazoprevir, an HCV NS3/NS4A serine protease inhibitor, is approved by the FDA as part of a coformulation with elbasvir, an HCV NS5A inhibitor, for the treatment of chronic genotype 1 (Table 5) and genotype 4 (Table 6) HCV infection.[17] Elbasvir/grazoprevir should be given with or without ribavirin, depending on HCV genotype/subtype, presence of NS5A polymorphisms, and treatment history. Elbasvir/grazoprevir is administered orally as one 50/100-mg tablet once daily with or without a meal (Table 7). The same dosing recommendations apply to patients with HCV/HIV coinfection.

This combination is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B or C).[17] This contraindication is due to an expected increase in grazoprevir plasma concentration and the concomitant increased risk of ALT elevations, as well as a lack of clinical safety and efficacy experience for this regimen in HCV-infected patients with severe hepatic impairment. Specifically, a 12-fold increase in grazoprevir exposure was observed in HCV-uninfected patients with Child-Pugh C cirrhosis. However, no dosage adjustment is needed for renal impairment, including for patients on dialysis. Finally, if elbasvir/grazoprevir is administered with ribavirin, the warnings and cautions associated with ribavirin should also be considered.

Table 5. FDA-Approved Regimens for Elbasvir/Grazoprevir in Patients With Genotype 1 HCV Infection With or Without Compensated Cirrhosis[17]

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Table 6. FDA-Approved Regimens for Elbasvir/Grazoprevir in Patients With Genotype 4 HCV Infection With or Without Compensated Cirrhosis[17]

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Table 7. Elbasvir/Grazoprevir: Dosing and Administration

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Drug Resistance
HCV replicons with amino acid substitutions in NS3 demonstrating reduced susceptibility to grazoprevir have been selected in cell culture for HCV genotypes 1a, 1b, and 4.[17] In cell culture with genotype 1a HCV infection, single NS3 amino acid substitutions Y56H, R155K, A156G/T/V, and D168A/E/G/N/S/V/Y reduced antiviral activity of grazoprevir by 2-fold to 81-fold. However, V36L/M, Q80K/R, or V107I had no effect on grazoprevir activity. In cell culture with genotype 1b HCV infection, single NS3 amino acid substitutions F43S, Y56F, V107I, A156S/T/V, and D168A/G/V reduced grazoprevir antiviral activity by 1.5-fold to 375-fold. For genotype 4 HCV–infected cell culture, the NS3 D168A/V substitutions reduced grazoprevir activity by 110-fold to 320-fold. When in combination, grazoprevir resistance associated substitutions (RAS) further reduced grazoprevir antiviral activity regardless of HCV genotype.

In a pooled analysis of patients receiving elbasvir/grazoprevir with or without ribavirin in phase IIb and III clinical trials, resistance data were available for 50 individuals with virologic failure (6 on treatment; 44 post treatment).[17] Treatment-emergent NS3 substitutions were observed in 29 of 37 (78%) patients with genotype 1a HCV infection, in 2 of 8 (25%) patients with genotype 1b HCV infection, and in 2 of 5 (40%) patients with genotype 4 HCV infection. For genotype 1a HCV infection, the most common treatment-emergent NS3 substitutions were at position D168 (n = 18). Also of note was the detection of treatment-emergent substitutions to both grazoprevir (NS3 substitutions) and elbasvir (NS5A substitutions) in 23 of 37 (62%) patients with genotype 1a, 1 of 8 (13%) patients with genotype 1b, and 2 of 5 (40%) patients with genotype 4 HCV infection, with genotype 1 HCV viral populations harboring treatment-emergent NS5A RAS demonstrating greater persistence than those with NS3 substitutions. However, the long-term clinical impact of the emergence and persistence of resistance to elbasvir/grazoprevir is yet unknown.

Drug–Drug Interactions
Grazoprevir is a substrate of organic anion-transporting polypeptide OATP1B1/3 transporters.[17] Therefore, coadministration of elbasvir/grazoprevir with substrates of these enzymes may result in increased drug exposure and is contraindicated. Furthermore, both elbasvir and grazoprevir are substrates of CYP3A and P-gp. Although the role of intestinal P-gp in the absorption of these agents appears to be minimal, coadministration of elbasvir/grazoprevir with moderate or strong CYP3A inhibitors or inducers may increase and decrease plasma concentrations of these drugs, respectively, thereby impairing the therapeutic effect or resulting in increased drug exposure. Thus, coadministration of elbasvir/grazoprevir with strong CYP3A inhibitors or moderate or strong CYP3A inducers, including the HIV medication efavirenz, is contraindicated. Elbasvir/grazoprevir should not be coadministered with several other medications, including the anticonvulsants phenytoin and carbamazepine, the antimycobacterial rifampin, the antifungal ketoconazole, the antibiotic nafcillin, the endothelin antagonist bosentan, St John’s Wort, the immunosuppressant cyclosporine, and the HIV medications atazanavir, darunavir, lopinavir, saquinavir, tipranavir, and etravirine, as well as cobicistat-containing regimens.[17] See prescribing information or the University of Liverpool Web site (http://www.hep-druginteractions.org/) for a full list of potential drug–drug interactions and contraindications.

Voxilaprevir. Sofosbuvir/velpatasvir/voxilaprevir is approved by the FDA for a duration of 12 weeks in patients without cirrhosis or with compensated cirrhosis (Child-Pugh A) who either have genotypes 1-6 chronic HCV infection and were previously treated with an NS5A inhibitor or who have genotypes 1a or 3 chronic HCV infection and were previously treated with sofosbuvir (Table 18).[18] Sofosbuvir/velpatasvir/voxilaprevir is administered as a single 400/100/100-mg tablet once daily, with food (Table 19). There is no approved dose recommendation for patients with severe renal impairment or end-stage renal disease. The EMA has also approved sofosbuvir/velpatasvir/voxilaprevir for individuals with genotypes 1-6 HCV infection who are either DAA naive or experienced.[19] The recommended treatment duration is 8 weeks among DAA-naive individuals without cirrhosis, and an 8-week-long course may also be considered for DAA-naive patients with genotype 3 HCV infection. Among all other DAA-naive patients without cirrhosis and DAA-experienced patients with or without compensated cirrhosis, the recommended treatment duration is 12 weeks. The EMA has not approved a dose recommendation for individuals with severe renal impairment or end-stage renal disease, and does not recommend sofosbuvir/velpatasvir/voxilaprevir for those with moderate or severe hepatic impairment (Child-Pugh B or C).

Drug Resistance
In cell culture, substitutions at NS3/4A amino acid positions 41, 156, and 168 conferred reduced voxilaprevir susceptibility. In particular for NS3, A156L/T (genotype 1a), A156T/V (genotype 1b), A156L/V (genotype 2a), A156T/V (genotype 3a), and A156L/T/V (genotype 4) reduced voxilaprevir antiviral activity more than 100-fold. Moreover, combinations of these mutations were additive in their ability to reduce voxilaprevir activity.

During clinical study, in the phase III POLARIS-1 and POLARIS-4 trials, 12% to 15% of patients treated with 12 weeks of sofosbuvir/velpatasvir/voxilaprevir harbored baseline NS3/4A RAS.[18] Nevertheless, SVR rates were unaffected by baseline mutation status and ranged from 97% to 100% (Table 8). Treatment-emergent RAS were rare in these trials, with only 2 patients in POLARIS-1 demonstrating novel mutations at virologic failure, neither in NS3 (Table 9).[20] One of these patients experienced virologic breakthrough (vs relapse) and had low plasma concentrations of study drugs indicative of treatment nonadherence.

Table 8. Impact of Baseline RASs (15% Detection Threshold) on Response Rates to Sofosbuvir/Velpatasvir/Voxilaprevir in the POLARIS Trials[20]

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Table 9. Treatment-Emergent RASs in Patients Experiencing Virologic Failure With Sofosbuvir/Velpatasvir/Voxilaprevir in the POLARIS Trials[20]

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Drug–Drug Interactions
Voxilaprevir is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3.[18] Thus, as with many other DAAs used to treat HCV infection, coadministration with P-gp and/or CYP inducers such as carbamazepine or St John’s wort is not recommended because of an expected reduction in sofosbuvir/velpatasvir/voxilaprevir exposure. Voxilaprevir is also an inhibitor of P-gp, BCRP, OATP1B1, and OATP1B3, making coadministration of substrates of these transporters (eg, methotrexate) suboptimal. Simultaneous use of rifampin with sofosbuvir/velpatasvir/voxilaprevir is contraindicated. Significant drug–drug interactions may also occur when sofosbuvir/velpatasvir/voxilaprevir is coadministered with specific antiarrhythmics, anticonvulsants, antimycobacterials, HIV antiretroviral agents, HMG-CoA reductase inhibitors, or cyclosporine.

Glecaprevir. Glecaprevir, a HCV NS3/NS4A protease inhibitor, is approved by the FDA and the EMA as part of a coformulation with pibrentasvir, an HCV NS5A inhibitor, for treatment-naive patients chronically infected with genotypes 1-6 HCV; treatment-experienced patients may also be eligible for treatment with this coformulation based on the type of agent previously used and HCV genotype (Table 10).[21,22] Glecaprevir/pibrentasvir is administered orally as three 100/40-mg tablets once daily with a meal (Table 11). The same dosing recommendations apply to patients with HCV/HIV coinfection or with any degree of renal impairment, including patients on dialysis.

Glecaprevir/pibrentasvir is not recommended in patients with moderate hepatic impairment (Child-Pugh B) because of a lack of established clinical safety and efficacy data in this population; furthermore, this combination is contraindicated in patients with severe hepatic impairment (Child-Pugh C).[21,22] This contraindication is due, in part, to increased glecaprevir plasma concentration following regimen administration. Specifically, an 11-fold increase in glecaprevir exposure was observed in Child-Pugh C subjects compared with HCV-uninfected patients with normal hepatic function.

Table 10. Approved Regimens for Glecaprevir/Pibrentasvir in Patients With HCV Infection[21,22]

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Table 11. Glecaprevir/Pibrentasvir: Dosing and Administration

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Drug Resistance
In cell culture with HCV genotypes 1a, 1b, 2a, 3a, 4a, or 6a, reductions in glecaprevir antiviral activity were most pronounced, at greater than 100-fold, upon introduction of substitutions at NS3 position A156.[21] By contrast, the effect of substitution at NS3 position D/Q168 was genotype and subtype specific, with a greater than 30-fold reduction in glecaprevir antiviral activity for D168F/Y in genotype 1a, Q168R in genotype 3a, and D168A/G/H/V/Y in genotype 6a; glecaprevir antiviral activity was further reduced when D/Q168 substitutions occurred in tandem with NS3 Y56H. Finally, the NS3 Q80R substitution reduced glecaprevir antiviral activity 21-fold but only in genotype 3a, whereas other Q80 changes in genotype 1 (eg, Q80K) had no appreciable effect.

In pooled analyses of treatment-naive or peginterferon, ribavirin, and/or sofosbuvir-experienced patients receiving glecaprevir/pibrentasvir in phase II and III trials, resistance data were available for 22 individuals with virologic failure (Table 12). Treatment-emergent substitutions were observed in NS3 for 12 of 22 (55%) patients and in NS5A for 18 of 22 (82%) patients, all of whom were infected with genotype 1-3 HCV.[21] In NS3/4A and/or NS5A inhibitor–experienced patients who experienced virologic failure on glecaprevir/pibrentasvir during the phase II MAGELLAN-1 trial, treatment-emergent substitutions occurred in NS3 for 8 of 11 (73%) patients and in NS5A for 9 of 10 (90%) patients. Baseline HCV polymorphisms did not affect achievement of SVR in NS3/4A and NS5A inhibitor–naive patients with genotype 1, 2, 4, 5, or 6 HCV infection. However, in noncirrhotic, treatment-naive patients infected with genotype 3 HCV who received glecaprevir/pibrentasvir for 8 weeks, only 78% of those with baseline NS5A A30K achieved SVR.[21] Moreover, in vitro and clinical data suggest that cross resistance between glecaprevir and other HCV NS3/4A protease inhibitors is possible.

Table 12. Treatment-Emergent Substitutions in Phase II/III Trials of Glecaprevir/Pibrentasvir[21]

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Drug–Drug Interactions
Glecaprevir is both an inhibitor and a substrate of P-gp, BCRP, and OATP 1B1/3. Thus, coadministration of glecaprevir with substrates or inhibitors of these proteins may result in increased substrate or glecaprevir exposure, respectively.[21] For instance, coadministration of glecaprevir/pibrentasvir with carbamazepine, efavirenz, or St John’s wort is not recommended, as the concentration of glecaprevir may decrease. Other agents not recommended for coadministration with glecaprevir/pibrentasvir include ethinyl estradiol–containing oral contraceptives; darunavir, lopinavir, or ritonavir; atorvastatin, lovastatin, or simvastatin; and cyclosporine > 100 mg/day. Lastly, glecaprevir/pibrentasvir coadministration with atazanavir or rifampin is contraindicated.

NS5B Polymerase Inhibitors

NS5B is the sole RNA polymerase responsible for replication of the HCV and a prime target for antiviral therapy. It is a viral protein translated en bloc with all of the other HCV proteins and is processed cotranslationally and posttranslationally into an individual polypeptide by the viral NS3/NS4A serine protease. There are 2 types of NS5B RNA polymerase inhibitors, nucleoside/nucleotide analogues that compete for the enzyme active site and nonnucleoside analogues that target allosteric sites. High conservation of the NS5B polymerase active site allows pangenotypic coverage of nucleoside/nucleotide analogues, such as sofosbuvir, with a high barrier to resistance.[11] Nonnucleoside analogue NS5B inhibitors, such as dasabuvir, on the other hand, are more genotype or subtype specific and have a low barrier to resistance. Sofosbuvir is currently the only NS5B nucleotide polymerase inhibitor approved in the United States and elsewhere for the treatment of HCV infection, and dasabuvir is the only approved nonnucleoside analogue.

As clinical experience with these agents increases, additional drug–drug interactions may be identified, and therefore, it is advisable to refer to a regularly updated data source, eg, the University of Liverpool Web site at http://www.hep-druginteractions.org/.

Sofosbuvir. Sofosbuvir is a nucleotide analogue that targets the active site of the NS5B RNA polymerase effectively blocking HCV replication. It is approved for the treatment of chronic HCV genotype 1, 2, 3, or 4 infection in the United States[23] and for treatment of genotypes 1-6 in Europe.[24] Sofosbuvir is also available in coformulations with ledipasvir, velpatasvir, or velpatasvir and voxilaprevir. Ledipasvir/sofosbuvir is approved by the FDA for the treatment of genotypes 1, 4, 5, and 6 HCV infection,[25] and by the EMA for treatment of genotypes 1, 3, and 4 HCV infection.[26] Sofosbuvir/velpatasvir is approved by the FDA and by the EMA for the treatment of genotypes 1-6 chronic HCV infection.[27,28] Sofosbuvir/velpatasvir/voxilaprevir is approved by the FDA for the retreatment of genotypes 1-6 chronic HCV infection following previous treatment failure (type of treatment failure indicated depends on HCV genotype), and is also approved by the EMA for treatment of DAA-naive and DAA-experienced patients with genotypes 1-6 HCV infection.[19] With the development of newer DAAs, multiple regimens based on combinations of sofosbuvir with ribavirin and/or peginterferon alfa are no longer commonly used for treatment of HCV infection, although these regimens are still approved for HCV treatment in the United States and in Europe.

As discussed in other sections of this module, the combination of daclatasvir plus sofosbuvir for the treatment of genotype 3 HCV infection is an approved indication in the FDA prescribing information for daclatasvir.

Table 13. Approved Regimens for Sofosbuvir in Patients With HCV Infection[23,24,27]

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Ledipasvir/sofosbuvir is approved for 12- or 24-week durations according to genotype, cirrhosis status, and other patient factors (Table 14). An 8-week treatment course can be considered in certain treatment-naive patients. Ledipasvir/sofosbuvir is administered as a single 90/400-mg tablet once daily, with or without food (Table 15). There is no approved dose recommendation for patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min) or end-stage renal disease.

Table 14. Approved Regimens for Ledipasvir/Sofosbuvir in Patients With HCV Infection[25,26]

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Table 15. Ledipasvir/Sofosbuvir: Dosing and Administration

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Sofosbuvir/velpatasvir is approved for genotypes 1-6 chronic HCV infection for a duration 12 weeks in patients without cirrhosis or with compensated cirrhosis (Child-Pugh A) or with ribavirin for 12 weeks for patients with decompensated cirrhosis (Child-Pugh B and C) (Table 16).[27,28] Sofosbuvir/velpatasvir is administered as a single 400/100-mg tablet once daily, with or without food (Table 17). There is no approved dose recommendation for patients with severe renal impairment or end-stage renal disease.

Table 16. Approved Regimens for Sofosbuvir/Velpatasvir in Patients With HCV Infection[27,28]

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Table 17. Sofosbuvir/Velpatasvir: Dosing and Administration

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Sofosbuvir/velpatasvir/voxilaprevir is approved by the FDA for a duration of 12 weeks in patients without cirrhosis or with compensated cirrhosis (Child-Pugh A) who either have genotype 1-6 chronic HCV infection and were previously treated with an NS5A inhibitor or who have genotype 1a or 3 chronic HCV infection and were previously treated with sofosbuvir (Table 18).[18] Sofosbuvir/velpatasvir/voxilaprevir is administered as a single 400/100/100-mg tablet once daily, with food (Table 19). There is no approved dose recommendation for patients with severe renal impairment or end-stage renal disease. Sofosbuvir/velpatasvir/voxilaprevir has also been approved by the EMA for individuals with genotypes 1-6 HCV infection who are either DAA naive or experienced.[19] Among DAA-naive individuals without cirrhosis, the recommended treatment duration is 8 weeks, and an 8-week-long course may also be considered for DAA-naive patients with genotype 3 HCV infection. Among all other DAA-naive patients without cirrhosis and DAA-experienced patients with or without compensated cirrhosis, the recommended treatment duration is 12 weeks. A dose recommendation was not made for individuals with severe renal impairment or end-stage renal disease. The EMA does not recommend sofosbuvir/velpatasvir/voxilaprevir for those with moderate or severe hepatic impairment (Child-Pugh B or C).

Table 18. Approved Regimens for Sofosbuvir/Velpatasvir/Voxilaprevir in Patients With HCV Infection[18]

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Table 19. Sofosbuvir/Velpatasvir/Voxilaprevir: Dosing and Administration

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Drug Resistance
One of the major advantages of sofosbuvir is its unique resistance profile. A substitution of a serine for a threonine at position 282 (S282T) leads to high-level sofosbuvir resistance,[30] but this substitution also markedly limits the replication fitness of the virus. Because of the poor ability of the S282T variant to replicate, it rarely emerges during sofosbuvir therapy and is likely to return to extremely low levels in the absence of drug pressure. However, data from a single-arm trial evaluating ledipasvir/sofosbuvir retreatment for 24 weeks in patients with genotype 1 HCV infection who experienced previous failure of ledipasvir/sofosbuvir for 8-12 weeks (with or without ribavirin) demonstrated that in this setting the emergence of NS5B resistance variants was relatively common, occurring in 33% of patients (4/12) with virologic failure.[31] The variants identified included S282T alone in 2 patients, L159F alone in 1 patient, and S282T plus L159F in 1 patient.

Drug–Drug Interactions
Sofosbuvir is not metabolized via CYP3A4, limiting the likelihood of drug–drug interactions with other agents. Sofosbuvir is a substrate for P-gp and should not be coadministered with potent P-gp inducers such as rifampin or St John’s wort.[23]

Dasabuvir. Dasabuvir is a nonnucleoside NS5B RNA polymerase inhibitor that targets the enzyme’s allosteric sites, effectively blocking HCV replication. It is approved by the FDA and the EMA in combination with coformulated ombitasvir/paritaprevir/ritonavir for the treatment of chronic genotype 1 HCV infection.[14,15] A once-daily extended-release coformulation containing all 4 agents, dasabuvir/ombitasvir/paritaprevir/ritonavir, is also approved by the FDA for the treatment of genotype 1 HCV infection.[32]

NS5A Inhibitors

NS5A is a viral protein with no enzymatic activity that is essential for HCV RNA replication and assembly. Its role in replication appears to be the formation of a membranous web along with viral protein NS4B, and this web provides a platform for replication. NS5A is composed of 3 domains; domains I and II are essential for HCV replication and domain III plays a role in virion assembly.[33,34] NS5A also contains phosphorylation sites, which act as regulators balancing RNA replication and downstream events.[35] NS5A inhibitors are highly potent and have lower barrier to resistance.[11]

There are currently 6 approved NS5A inhibitors: daclatasvir, elbasvir, ledipasvir, ombitasvir, pibrentasvir, and velpatasvir.[14,17,25,29] With the exception of daclatasvir, all are part of coformulations with other DAAs. Ledipasvir is approved as a coformulation with the NS5B RNA polymerase inhibitor  sofosbuvir,[25] ombitasvir is approved as a coformulation with the NS3/NS4A protease inhibitor, paritaprevir and ritonavir used in combination with the NS5B RNA polymerase inhibitor dasabuvir[14] and as a once-daily coformulation with paritaprevir/ritonavir/dasabuvir, and elbasvir is approved as a coformulation with the NS3/NS4A protease inhibitor grazoprevir.[17] Daclatasvir is approved for use in combination with sofosbuvir.[29]

As clinical experience with these agents increases, additional drug–drug interactions may be identified, and therefore it is advisable to refer to a regularly updated data source, for example, the University of Liverpool Web site at http://www.hep-druginteractions.org/.

Ledipasvir. Ledipasvir/sofosbuvir is approved for the treatment of chronic genotypes 1, 4, 5, and 6 HCV infection in the United States[25] and for the treatment of genotypes 1, 3, 4, 5, and 6 HCV infection in adults and adolescents 12 years of age or older in Europe.[26] Ledipasvir/sofosbuvir is approved for 12- or 24-week durations according to genotype and other patient factors (Table 14). An 8-week treatment course can be considered in certain treatment-naive patients. Ledipasvir/sofosbuvir is administered as a single 90/400-mg tablet once daily, with or without food (Table 15). There is no approved dose recommendation for patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min) or end-stage renal disease and it should generally be avoided in these patients. Examinations of real-world data have found SVR rates of 91.3% to 97.0% with ledipasvir/sofosbuvir-based regimens among patients with genotype 1 HCV infection.[36-38]

Drug Resistance
Approximately 15% to 20% of patients with genotype 1 HCV infection enrolled in the phase III ION-1, -2, and -3 trials of ledipasvir/sofosbuvir with or without ribavirin harbored baseline NS5A RAS (Table 20). In addition, NS5A RAS were detected in the majority of patients with virologic relapse in these studies, and in most of these cases, the variants were present at baseline.[39-41] Nevertheless, SVR rates ranged from 89% to 96% among patients with NS5A RAS at baseline, consistent with sofosbuvir remaining fully active.

Table 20. Impact of NS5A RAS on Response and Relapse Rates in the ION Trials*[39-41]

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Drug–Drug Interactions
Ledipasvir is a P-gp substrate; therefore, the same precautions and warnings for sofosbuvir should be adhered to when administering ledipasvir/sofosbuvir.[25] In addition to rifampin and St John’s wort, significant drug–drug interactions may also occur when ledipasvir/sofosbuvir is coadministered with specific acid-reducing agents, anticonvulsants, antimycobacterials, HIV antiretroviral agents, and simeprevir. In addition, ledipasvir absorption is affected by gastric pH with reduced absorption noted with increasing pH. In one multicenter, prospective, observational study, proton pump inhibitor (PPI) use at baseline was associated with a lower SVR rate vs no PPI use at baseline among patients with genotype 1 HCV infection who were treated with ledipasvir/sofosbuvir.[38] Patients receiving PPIs should either stop these agents during HCV therapy if possible or take the PPI (doses comparable to omeprazole 20 mg or lower) with ledipasvir/sofosbuvir under fasted conditions to ensure that gastric pH is at its lowest point of the day at the time of drug administration.[25]

Ombitasvir. Ombitasvir is an NS5A inhibitor that effectively blocks HCV replication. It is approved by the FDA[14] and the EMA[15] as part of the coformulation ombitasvir/paritaprevir/ritonavir plus dasabuvir for the treatment of chronic genotype 1 (with dasabuvir) and genotype 4 (without dasabuvir) HCV infection. A once-daily extended-release coformulation containing all 4 agents, dasabuvir/ombitasvir/paritaprevir/ritonavir, is also approved by the FDA for the treatment of genotype 1 HCV infection.[32] This regimen is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B or C).[14]

Drug Resistance
In cell culture with HCV genotype 1a models, several single NS5A amino acid substitutions reduce the activity of ombitasvir from 58- to 67,000-fold including M28T/V, Q30E/R, L31V, H58D, and Y93C/H/L/N.[14] In genotype 1b HCV cell culture models, amino acid substitutions L28T, L31F/V, and Y93H reduce ombitasvir by 8- to 661-fold. Combinations of such variants can further reduce ombitasvir activity.

In a pooled analysis of patients receiving ombitasvir/paritaprevir/ritonavir plus dasabuvir in phase IIb and III trials, resistance data were available for 64 individuals with virologic failure. Treatment-emergent substitutions were observed in 30 of 57 (53%) of patients with genotype 1a HCV and in 1 of 6 (17%) patients with genotype 1b HCV.[14] In an analysis of genotype 1a–infected patients with treatment-emergent RAS following receipt of ombitasvir/paritaprevir/ritonavir plus dasabuvir in phase II clinical studies, NS5A variants persisted in all 24 assessed patients at posttreatment Week 24 and in all 18 assessed patients at posttreatment Week 48. It is not expected that baseline HCV variants will have a substantial impact on SVR when ombitasvir/paritaprevir/ritonavir plus dasabuvir is used as recommended.[14]

Drug–Drug Interactions
Ombitasvir is a substrate of UGT1A1, P-gp, and BCRP. Paritaprevir and dasabuvir are also inhibitors of UGT1A1, and ritonavir is an inhibitor of CYP3A4. Coadministration of ombitasvir/paritaprevir/ritonavir plus dasabuvir with substrates of these enzymes may result in increased drug exposure.[14] Ombitasvir is primarily metabolized by amide hydrolysis and less so by CYP enzymes.[14] Ombitasvir/paritaprevir/ritonavir plus dasabuvir should not be coadministered with a number of medicines, including darunavir/ritonavir, lopinavir/ritonavir, and rilpivirine. If coadministered, atazanavir should be given in the morning, without additional ritonavir.[14] See prescribing information for a full list of potential drug–drug interactions and contraindications.

Daclatasvir. Daclatasvir was approved by the FDA in 2015 for the treatment of genotype 3 HCV infection in combination with sofosbuvir, and the indication for this combination has since been expanded to include genotype 1 HCV infection. In the United States, daclatasvir plus sofosbuvir is indicated for 12 weeks with or without ribavirin depending on cirrhosis status (Table 21).

Table 21. FDA-Approved Regimens for Daclatasvir in Patients With HCV Infection[29]

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Daclatasvir was also approved by the EMA in 2014 for use in combination with other drugs for the treatment of chronic genotype 1, 3, or 4 HCV infection (Table 22) (Table 23).[42] According to European prescribing information, daclatasvir with sofosbuvir is indicated for 12 weeks in patients with genotype 1 or 4 HCV infection in the absence of cirrhosis. This combination can also be taken without ribavirin in patients with genotype 1 or 4 HCV infection and cirrhosis if the treatment duration is extended to 24 weeks. In patients with compensated cirrhosis and genotype 3 HCV infection, the recommended regimen is daclatasvir with sofosbuvir with or without ribavirin for 24 weeks. No dose adjustments are required for patients with Child-Pugh B or C disease. Daclatasvir is also approved in Japan in combination with the NS3/4A protease inhibitor, asunaprevir, for patients with genotype 1 chronic HCV infection who are ineligible for or have failed on interferon-based therapy.

Table 22. EMA-Approved Regimens for Daclatasvir in Patients With HCV Infection[42]

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Table 23. Daclatasvir: Dosing and Administration

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Drug Resistance
NS5A amino acid substitutions that have been associated with resistance to daclatasvir in cell-based replicon systems include M28T, Q30E/H/R, L31V, and Y93C/H/N for genotype 1a HCV infection and L31V and Y93H for genotype 1b HCV infection.[42] In clinical trials of daclatasvir, A30K/S, L31I, S62A/L/P/T, and Y93H NS5A variants have been detected at the time of virologic failure in patients with genotype 3 HCV infection.[29]         

Drug–Drug Interactions
Daclatasvir is metabolized by CYP3A4 and moderately inhibits OATP1B1, P-gp, and BCRP.[29,42] A study evaluating pharmacokinetic drug–drug interactions between daclatasvir and several antiretroviral agents demonstrated reduced daclatasvir exposure when coadministered with efavirenz and increased exposure when coadministered with atazanavir/ritonavir.[43] The prescribing information advises that daclatasvir is contraindicated in combination with strong CYP3A4 inducers because of the potential for decreased daclatasvir exposure and consequent reduced efficacy.[29] In addition, daclatasvir dose should be decreased to 30 mg/day when coadministered with strong CYP3A4 inhibitors and should be increased to 90 mg/day when coadministered with moderate CYP3A4 inducers.

Elbasvir. Elbasvir is an inhibitor of HCV NS5A, a protein that is required for HCV replication. It is approved by the FDA as part of a coformulation with the NS3/NS4A protease inhibitor grazoprevir for the treatment of chronic genotype 1 (Table 5) and genotype 4 (Table 6) HCV infection.[17] Elbasvir/grazoprevir should be given with or without ribavirin depending on HCV genotype/subtype, mutational status, and treatment history. It is administered orally as one 50/100-mg tablet once daily with or without a meal (Table 7). When in combination with ribavirin, the recommended dosage of ribavirin is weight-based administered in 2 divided doses with food.

The combination of elbasvir/grazoprevir is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B or C). However, no dosage adjustment is needed for renal impairment, including for patients on dialysis. [17]

Drug Resistance
HCV replicons with resistance associated amino acid substitutions in NS5A and reduced susceptibility to elbasvir have been selected in cell culture for genotypes 1a, 1b, and 4 HCV.[17] In cell culture infected with genotype 1a HCV, several single NS5A amino acid substitutions were shown to reduce the activity of elbasvir by 1.5-fold to 2000-fold, including M28A/G/T, Q30D/E/H/K/R, L31M/V, H58D, and Y93C/H/N. In genotype 1b HCV cell culture models, 2-fold to 17-fold reductions in elbasvir antiviral activity were observed for the single NS5A substitutions L28M, L31F, and Y93H. For genotype 4 HCV, the single NS5A substitutions L30S, M31V, and Y93H reduced elbasvir antiviral activity by 3-fold to 23-fold. Combinations of these variants can further reduce elbasvir activity regardless of HCV genotype.

In a pooled analysis of patients receiving elbasvir/grazoprevir in phase IIb and III trials, resistance data were available for 50 individuals with virologic failure (6 on treatment; 44 post treatment) and available sequence data.[17] Treatment-emergent NS5A substitutions were observed in 30 of 37 (81%) patients with genotype 1a HCV infection, 7 of 8 (88%) patients with genotype 1b HCV infection, and 5 of 5 (100%) patients with genotype 4 HCV infection. The most common treatment-emergent NS5A substitutions in genotype 1a HCV were at position Q30 (n = 22). In an analysis of genotype 1a HCV–infected patients, NS5A RAS persisted at detectable levels in 95% (35/37) of patients at 12 weeks post treatment and in all 9 patients assessed at posttreatment Week 24. For genotype 1b HCV–infected patients, NS5A RAS persisted in 100% of patients at both posttreatment Weeks 12 and 24. Overall, NS5A RAS showed more persistence than viral populations with NS3 resistance- associated substitutions. However, the long-term clinical impact of the emergence and persistence of resistance to elbasvir/grazoprevir is yet unknown.

Drug–Drug Interactions
Both elbasvir and grazoprevir are substrates of CYP3A and P-gp. Although the role of intestinal P-gp in the absorption of these agents appears to be minimal, coadministration of elbasvir/grazoprevir with moderate or strong CYP3A inhibitors or inducers may increase or decrease plasma concentrations of these drugs, respectively, thereby impairing the therapeutic effect or resulting in increased drug exposure. Thus, coadministration of elbasvir/grazoprevir with strong CYP3A inhibitors or moderate or strong CYP3A inducers, including the HIV medication efavirenz, is contraindicated. Furthermore, grazoprevir is a substrate of OATP1B1/3 transporters.[17] Therefore, coadministration of elbasvir/grazoprevir with substrates of these enzymes may result in increased drug exposure and are contraindicated. Elbasvir/grazoprevir also should not be coadministered with a number of medicines, including the anticonvulsants phenytoin and carbamazepine, the antimycobacterial rifampin, the antifungal ketoconazole, the antibiotic nafcillin, the endothelin antagonist bosentan, St John’s Wort, the immunosuppressant cyclosporine, and the HIV medications atazanavir, darunavir, lopinavir, saquinavir, tipranavir, and etravirine, as well as cobicistat-containing regimens.[17] See prescribing information or the University of Liverpool Web site (http://www.hep-druginteractions.org/) for a full list of potential drug–drug interactions and contraindications.

Velpatasvir. Velpatasvir is an inhibitor of HCV NS5A, a protein that is required for HCV replication. It is approved by the FDA as part of 2 coformulations. The first approved coformulation is the combination of velpatasvir with sofosbuvir, a NS5B polymerase inhibitor, for the treatment of chronic HCV infection from genotypes 1-6 HCV infection (Table 16).[27] Sofosbuvir/velpatasvir should be given with ribavirin in patients with decompensated cirrhosis (Child-Pugh B or C). It is administered orally as one 400/100-mg tablet once daily with or without a meal (Table 17). No dosage recommendations can be made for patients with severe renal impairment or end-stage renal disease.[27] The second approved coformulation is the combination of velpatasvir with sofosbuvir and voxilaprevir, an NS3/4A protease inhibitor, for a 12-week retreatment of individuals without cirrhosis or with compensated cirrhosis (Child-Pugh A) who have either genotype 1-6 HCV infection following failure of an NS5A inhibitor–containing regimen or who have genotype 1a or 3 HCV infection following failure of a sofosbuvir-containing regimen (Table 18).[18] Sofosbuvir/velpatasvir/voxilaprevir is administered orally as one 400/100/100-mg tablet once daily with food (Table 19). No dosage recommendations are approved for patients with severe renal impairment or end-stage renal disease.

Drug Resistance
In cell culture, replicon variants with reduced susceptibility to velpatasvir were found in HCV genotypes 1a, 1b, 2a, 3a, 4a, 5a, and 6a.[27] Amino acid substitutions at NS5A positions 24, 28, 30, 31, 32, 58, 92, and 93 are associated with resistance. Substitutions associated with a > 100-fold reduction in velpatasvir susceptibility include single and double combinations of L31V and Y93H/N in genotype 1a, L31V and Y93H in genotype 1b, Y93H/S in genotype 3a, and L31V and P32A/L/Q/R in genotype 6. Single mutants F28S and Y93H in genotype 2 result in 91-fold and 46-fold reduction in velpatasvir susceptibility, respectively. The Y93H mutant results in a 3-fold reduced susceptibility in genotype 4a.

In a pooled analysis of phase III trials evaluating sofosbuvir/velpatasvir, ASTRAL-1, ASTRAL-2, and ASTRAL-3 in patients without cirrhosis or with compensated cirrhosis, 12 patients experienced virologic failure (2 with genotype 1 and 10 with genotype 3a).[27] The 2 patients with genotype 1 HCV infection had emergent resistance mutants, Y93N in 1 patient, and Y93H plus low-level K24M/T plus L31I/V in the other patient at virologic failure. Neither patient had sofosbuvir NS5B RAS at failure. Of the 10 patients with genotype 3a HCV infection who experienced virologic failure, all 10 had Y93H mutations (7 emerged posttreatment, 3 had Y93H at baseline and posttreatment). Sofosbuvir NS5B resistance mutations L314F/I were observed at a frequency of ≥ 15%, and L314P at a frequency of < 4% of patients with genotype 3a HCV infection who relapsed. In the ASTRAL-4 trial of patients with decompensated cirrhosis, 3 patients with virologic failure qualified for resistance analysis.[27] The 1 patient with genotype 1 HCV infection did not have any NS5A or NS5B resistance mutations at failure, and the 2 patients with genotype 3a HCV infection had the Y93H mutation as well as either low-level M28V or S38P mutations at failure. No patients with genotype 2, 4, 5, or 6 HCV infection experienced virologic failure in any of the phase III ASTRAL trials. In the phase III POLARIS-1 and POLARIS-4 trials evaluating sofosbuvir/velpatasvir/boxilaprevir, treatment-emergent RASs were rare, with only 2 patients in POLARIS-1 demonstrating novel mutations in NS5A at virologic failure (Table 9).[20] One of these patients experienced a virologic breakthrough and had low plasma concentrations of study drugs suggestive of treatment nonadherence.

The persistence and long-term clinical impact of sofosbuvir or velpatasvir RAS is unknown.[27]

Drug–Drug Interactions
Both sofosbuvir and velpatasvir are drug transporter P-gp and BCRP substrates, whereas the GS-331007 sofosbuvir metabolite is not.[27] Slow metabolic turnover of velpatasvir by CYP2B6, BYP2C8, and CYP3A4 was observed in vitro, and drugs that induce these enzymes may decrease plasma concentrations of sofosbuvir or velpatasvir resulting in a reduced therapeutic effect. Such agents are not recommended for use with sofosbuvir/velpatasvir. Velpatasvir is an inhibitor of drug transporters P-gp, BCRP, OATP1B1, OATP1B3, and OATP2B1, and coadministration of sofosbuvir/velpatasvir with drugs that are substrates of these transporters may increase exposure to these agents.

Pibrentasvir. Pibrentasvir, a HCV NS5A inhibitor, is approved by the FDA and the EMA as part of a coformulation with glecaprevir, an HCV NS3/4A inhibitor, for treatment-naive patients chronically infected with genotypes 1-6 HCV. Treatment-experienced patients may also be eligible for treatment with this coformulation based on the type of agent previously used and HCV genotype (Table 10).[21,22] Glecaprevir/pibrentasvir is administered orally as three 100/40-mg tablets once daily with a meal (Table 11). The same dosing recommendations apply to patients with HCV/HIV coinfection or with any degree of renal impairment, including patients on dialysis.

Glecaprevir/pibrentasvir is not recommended in patients with moderate hepatic impairment (Child-Pugh B) because of a lack of established clinical safety and efficacy data in this population. Furthermore, this combination is contraindicated in patients with severe hepatic impairment (Child-Pugh C).[21,22] This contraindication is due, in part, to increased pibrentasvir plasma concentration following regimen administration. Specifically, the pibrentasvir area under the concentration curve was 114% higher in Child-Pugh C subjects compared with HCV-uninfected patients with normal hepatic function.

Drug Resistance
In cell culture, reductions in pibrentasvir antiviral activity occurred with emergence of several NS5A changes, including Q30D/deletion or (Y93D/H/N or H58D + Y93H) in genotype 1a, (F28S + M31I) or (P29S + K30G) in genotype 2a, and Y93H in genotype 3a.[21] In particular, the M28G, Q30D, and P32-deletion RAS reduced pibrentasvir susceptibility by approximately 100- to 1000-fold.

Drug–Drug Interactions
Pibrentasvir is an inhibitor and/or substrate of P-gp, BCRP, and OATP 1B1/3. Thus, coadministration of pibrentasvir with substrates or inhibitors of these proteins may result in increased substrate or glecaprevir exposure, respectively.[21] For instance, coadministration of glecaprevir/pibrentasvir with carbamazepine, efavirenz, or St John’s wort is not recommended, as the concentration of pibrentasvir may decrease. Other agents not recommended for coadministration with glecaprevir/pibrentasvir include ethinyl estradiol–containing oral contraceptives; darunavir, lopinavir, or ritonavir; atorvastatin, lovastatin, or simvastatin; and cyclosporine > 100 mg/day. Lastly, glecaprevir/pibrentasvir coadministration with atazanavir or rifampin is contraindicated.

Ribavirin

Ribavirin is approved for the treatment of chronic hepatitis C when used in combination with standard or pegylated interferon or with DAAs. Ribavirin, a guanosine analogue, improves viral clearance, decreases relapse rates, and improves rates of SVR when used in combination with peginterferon compared with peginterferon alone. Despite its use in patients with HCV for more than 20 years, the precise mechanism(s) by which ribavirin improves outcomes is unknown. Suggested mechanisms include inhibition of inosine monophosphate dehydrogenase, promotion of a Th1 immune response, mutagenesis, and interferon-stimulated gene induction.[44] Ribavirin remains an important component of HCV therapy, even in the age of DAA therapy.[45,46] Early studies with telaprevir and boceprevir showed that inclusion of ribavirin reduces the emergence of resistant variants and markedly improves rates of SVR. However, sofosbuvir plus simeprevir can be used without ribavirin, and the US indications for ledipasvir/sofosbuvir do not include ribavirin for most patients (although it may be considered for treatment-experienced patients with genotype 1 HCV infection and cirrhosis).[25] Whether ribavirin use will be necessary with future DAAs is not known.

Historical Strategies

With the advent of newer DAAs, multiple strategies are no longer widely used for treatment of HCV infection. These historical treatment strategies include regimens based on simeprevir, sofosbuvir, and peginterferon. Although no longer common in clinical practice, these regimens are still approved for HCV treatment in the United States and in Europe.

Simeprevir
Simeprevir is an NS3/NS4A protease inhibitor approved for the treatment of genotype 1 or 4 HCV in the United States[47] and in Europe.[48] Simeprevir is approved for use in combination regimens and must always be coadministered with other HCV therapies. Pretreatment screening for the NS3 Q80K polymorphism is recommended in patients with genotype 1a HCV infection who are being considered for treatment with simeprevir plus peginterferon/ribavirin due to reduced efficacy. By contrast, pretreatment screening for baseline NS3 Q80K is not necessary when considering treatment with simeprevir plus sofosbuvir. The phase III OPTIMIST-1 trial showed that efficacy rates with 12 weeks of simeprevir plus sofosbuvir did not differ substantially in noncirrhotic patients with genotype 1a HCV infection with vs without the NS3 Q80K polymorphism at baseline; patients with the NS3 Q80K polymorphism achieved a SVR rate of 96% vs 97% in those without the polymorphism.[49]

An analysis of patients who did not achieve SVR while receiving simeprevir plus peginterferon/ribavirin in controlled phase IIb and III studies found that NS3 mutations emerged in 180 of 197 (91%) patients, of which most are associated with reduced susceptibility to simeprevir in vitro.[47] The predominant emergent mutation in patients with genotype 1a infection was R155K and D168V in patients with genotype 1b infection. Among patients treated with simeprevir in combination with peginterferon and ribavirin in phase III trials, the most common adverse events were low-grade rash, pruritus, nausea, myalgia, and dyspnea. Rash is most common in the first month of treatment and may include photosensitivity, necessitating sun protection measures during treatment. When simeprevir was combined with sofosbuvir for 12 or 24 weeks in the COSMOS trial, the most frequent adverse events were fatigue, headache, nausea, insomnia, pruritus, dizziness, and diarrhea.

Sofosbuvir With Peginterferon/Ribavirin
Sofosbuvir is a nucleotide analogue NS5B polymerase inhibitor that must be given in combination with other HCV therapies (peginterferon alfa plus ribavirin or ribavirin alone, or simeprevir, or daclatasvir depending on HCV genotype) and should be discontinued if these therapies are permanently discontinued. The approvals for sofosbuvir differ between the United States and Europe, in that the FDA indication for sofosbuvir only includes genotypes 1-4 HCV infection,[23] whereas the EMA indication encompasses all 6 HCV genotypes. The most common adverse events seen in phase III trials evaluating use of sofosbuvir in combination with peginterferon and ribavirin were fatigue, headache, nausea, insomnia, and anemia.[23] When sofosbuvir was studied with ribavirin alone, the most common adverse events were fatigue and headache. With either regimen, most events were mild, other than anemia and neutropenia, and discontinuation for toxicity was infrequent. Pancytopenia (anemia, neutropenia, thrombocytopenia) may also occur, particularly in patients receiving peginterferon.

Peginterferon
Both peginterferon alfa-2a and peginterferon alfa-2b are approved for the treatment of HCV by the FDA and the EMA.[50-53] Interferon alpha is a naturally occurring cytokine that has antiviral, immune modulatory, and antiinflammatory properties.[44] Its exact mechanism of action against HCV is not known, but it is presumed to involve activation of so-called interferon-stimulated genes, which are the natural host defense against viral infections. Some of the induced interferon-stimulated genes presumably clear HCV, but others likely account for the numerous adverse events associated with this therapy. Compared with interferon alfa-2a, the pegylated form provides less-frequent dosing and improved efficacy. Common adverse events associated with peginterferon/ribavirin include influenzalike symptoms after injection, dermatologic reactions (eg, hair loss, rash), neuropsychiatric effects such as depression and mania, gastrointestinal effects, and anemia.

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