Hepatitis C Treatment & Management

Updated: Jan 28, 2018
  • Author: Vinod K Dhawan, MD, FACP, FRCPC, FIDSA; Chief Editor: BS Anand, MD  more...
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Treatment

Approach Considerations

Please note that guidelines for the current diagnostic workup and management of hepatitis C (HCV) infection continue to rapidly evolve. Clinicians are advised to refer frequently to the most recent recommendations of the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (ISDA) at https://www.hcvguidelines.org/. Other resources can also be found at the IDSA website at http://www.idsociety.org/HCV_Clinical_Guidance/.

Spontaneous resolution of acute HCV infection may occur in 15% to 50% of patients. [1, 14, 32, 33] ​ Monitoring for spontaneous clearance for a minimum of 6 months before initiating treatment is therefore recommended. Patients with acute HCV infection appear to have an excellent chance of responding to 6 months of standard therapy with interferon (IFN). However, IFN-sparing regimens are safer and are currently recommended for the treatment of acute HCV infection as with chronic HCV infection.

Hepatitis C has become a curable disease with the use of antiviral agents (>95%). [1]  Treatment for chronic HCV is based on guidelines from the Infectious Diseases Society of America (IDSA) and the American Associations for the Study of Liver Diseases (AASLD), in collaboration with the International Antiviral Society-USA (IAS-USA). [32]  These guidelines are updated often. The guidelines propose that because all patients cannot receive treatment immediately upon the approval of new agents, priority should be given to those with the most urgent need. The recommendations include the following [32] :

  • Patients with advanced fibrosis, those with compensated cirrhosis, liver transplant recipients, and those with severe extraheptic complications are to be given the highest priority for treatment.

  • Based on available resources, patients at high risk for liver-related complications and severe extrahepatic hepatitis C complications should be given high priority for treatment.

  • Treatment decisions should balance the anticipated reduction in transmission versus the likelihood of reinfection in patients whose risk of HCV transmission is high and in whom HCV treatment may result in a reduction in transmission (eg, men who have high-risk sex with men, active injection drug users, incarcerated persons, and those on hemodialysis).

Initiating treatment earlier for patients with lower stage fibrosis may extend the benefits of sustained virologic response (SVR). In a long-term follow-up study, 820 patients with METAVIR stage F0 or F1 fibrosis confirmed by biopsy were followed for up to 20 years. The 15-year survival rate was statistically significantly better for those who experienced SVR (93%) compared to those whose treatment had failed (82%) or for those who remained untreated (88%) (P =.003). [72]

Treatment of chronic HCV infection has two goals. The first is to achieve sustained eradication of HCV (ie, SVR), which is defined as the persistent absence of HCV RNA in serum 12 weeks after completing antiviral treatment. The second goal is to prevent progression to cirrhosis, hepatocellular carcinoma (HCC), and decompensated liver disease requiring liver transplantation.

In a multicenter observational study of 583 treatment-naïve and treatment-experienced Egyptian patients with HCV genotype 4 infection, 12 weeks of simeprevir plus sofosbuvir therapy resulted in an overall SVR rate of 95.7%. [73] In a separate study of 18,378 treatment-naïve and treatment-experienced Egyptian patients with HCV genotype 4 infection and different stages of fibrosis, treatment with 12 weeks of generic daclatasvir plus sofobuvir, with or without ribavirin, resulted in an overall 95.1% SVR. [74]

In a prospective study of 158 patients with chronic HCV infection and liver cirrhosis who received interferon-free therapies with direct-acting antiviral agents (DAAs) and 184 control HCV patients with untreated liver cirrhosis, the short-term risk (1.5 years) for de novo HCC did not change. [75]

Antiviral therapy for chronic hepatitis C should be determined on a case-by-case basis. However, treatment is widely recommended for patients with elevated serum alanine aminotransferase (ALT) levels who meet the following criteria [6] :

  • Age older than 18 years
  • Positive HCV antibody and serum HCV RNA test results
  • Compensated liver disease (eg, no hepatic encephalopathy or ascites)
  • Acceptable hematologic and biochemical indices (hemoglobin at least 13 g/dL for men and 12 g/dL for women; neutrophil count >1500/mm 3, serum creatinine <1.5 mg/dL)
  • Willingness to be treated and to adhere to treatment requirements
  • No contraindications for treatment

A further criterion is liver biopsy findings consistent with a diagnosis of chronic hepatitis. However, a pretreatment liver biopsy is not mandatory. It may be helpful in certain situations, such as in patients with normal transaminase levels, particularly those with a history of alcohol dependence, in whom little correlation may exist between liver enzyme levels and histologic findings.

Viral load suppression reduces the risk of hepatitis C liver morbidity and mortality. In an observational study of Veterans Affairs (VA) HCV clinical registry data from 128,769 patients that spanned more than a decade, researchers found that those who achieved an undetectable HCV viral load had a decreased risk of subsequent liver morbidity and death. [76, 77] Viral load suppression reduced the risk for future liver events by 27% (eg, compensated/decompensated cirrhosis, HCC, or liver-related hospitalization) as well as reduced the risk of death by 45%, relative to patients who did not achieve viral load suppression. Among the entire study population, only 24% had been treated previously for HCV; of these patients, only 16% (4% of all patients) achieved an undetectable viral load. [76, 77]

Patient race/ethnicity and HCV genotypes also affected the risk of future liver events and death. The risk for all liver events and death was higher in white patients relative to black patients, and those with HCV genotype 3 had a higher risk for all study outcomes compared to patients who had HCV genotype 2 (lowest risk) or genotype 1. [76, 77]

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Interferons and Pegylated Interferons

The two most frequently used recombinant interferon (IFN) preparations in clinical trials have been IFN alfa-2b (Intron-A) and IFN alfa-2a (Roferon-A), which differ from each other by only a single amino acid residue. IFN alfacon-1 (Infergen), or consensus IFN, is a genetically engineered compound synthesized by combining the most common amino acid sequences from all 12 naturally occurring IFNs. Roferon-A was discontinued from the market in 2007 and Infergen was discontinued from the market in 2013.

The addition of propylene glycol (PEG) molecules to IFN has led to the development of long-lasting IFNs that have better sustained absorption, a slower rate of clearance, and a longer half-life than unmodified IFN, which permits more convenient once-weekly dosing. The FDA has approved PEG-IFNs for the treatment of chronic hepatitis C.

Two PEG-IFN preparations are available for the treatment of chronic hepatitis C. PEG-IFN alfa-2b (PEG-Intron) consists of IFN alfa-2b attached to a single 12-kd PEG chain; it is excreted by the kidneys. PEG-IFN alfa-2a (Pegasys) consists of IFN alfa-2a attached to a 40-kd branched PEG molecule; it is metabolized predominantly by the liver.

IFN monotherapy in acute hepatitis C

Although the short courses of standard IFN monotherapy introduced in the 1980s by Hoofnagle et al, [78] Davis et al, [9] and Di Bisceglie et al [79] led to sustained improvement in liver disease and loss of virus in less than 10% of patients, these therapies were the first to cure chronic viral hepatitis.

Jaeckel et al reported that treatment with IFN alfa-2b prevented chronic infection in 98% of a group of 44 German patients with acute hepatitis C. [80] In this study, patients received 5 million U/day of IFN alfa-2b subcutaneously for 4 weeks and then three times per week for another 20 weeks; the IFN alfa-2b was well tolerated in all patients but one. [80]

Because it has the poorest safety profile of all the HCV antiviral agentss, with few exceptions PEG-IFN is no longer recommended in combination regimens. Spontaneous resolution of acute HCV infection may occur in 15% to 50% of patients. [1, 14, 32, 33]  Monitoring for spontaneous clearance for a minimum of 6 months before initiating any treatment is therefore recommended.

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Interferons and Ribavirin

A major advance in the treatment of chronic hepatitis C was the addition of the oral nucleoside analogue ribavirin to the interferon (IFN) regimen. As reported in the landmark 1998 studies by McHutchison et al [81] and Poynard et al, [82] IFN alfa-2b and ribavirin combination therapy for 6-12 months resulted in sustained eradication rates of 30%-40%. However, patients with HCV genotype 1 who were treated for 12 months had a much less favorable response than patients infected with genotypes 2 and 3 who received a 6-month course of therapy.

PEG-IFN therapy with ribavirin

The addition of ribavirin to PEG-IFN heralded a new era in the treatment of chronic HCV. The benefits of combination therapy were documented in three landmark trials: Manns et al in 2001, [83] Fried et al in 2002, [84] and Hadziyannis et al in 2004. [85]

Manns et al reported a significantly higher sustained virologic response (SVR) rate in patients given higher-dose PEG-IFN alfa-2b plus ribavirin than in patients given lower-dose PEG-IFN alfa-2b plus ribavirin or those who received IFN alfa-2b plus ribavirin. [83] Adverse-effect profiles in the three treatment groups were similar. Secondary analyses identified body weight and HCV RNA viral load less than 1 million copies/mL as important predictors of SVR. (See the image below.)

Pegylated interferon alfa-2b plus ribavirin therap Pegylated interferon alfa-2b plus ribavirin therapy for chronic hepatitis C.

Fried at al found that patients who received PEG-IFN alfa-2a plus ribavirin had a significantly higher SVR rate than patients who received IFN alfa-2b plus ribavirin (56% vs 44%) or PEG-IFN alfa-2a alone (56% vs 29%). [84] The SVR rates for patients with HCV genotype 1 were 46%, 36%, and 21%, respectively, for the three regimens.

Hadziyannis et al reported that in patients infected with HCV genotype 1, 48 weeks of treatment was statistically superior to 24 weeks, and standard-dose ribavirin was statistically superior to low-dose ribavirin. [85] In this study, 1311 persons were randomized to PEG-IFN alfa-2a at 180 mcg/wk for 24 or 48 weeks plus a low dose (800 mg/day) or standard weight-based dose (1000 or 1200 mg/day) of ribavirin. [85] In patients with HCV genotypes 2 or 3, there were no statistically significant differences in SVR rates in the four treatment groups.

In a study of ribavirin in combination with either PEG-IFN alfa-2b or PEG-IFN alfa-2a for the treatment of chronic HCV infection, Ascione et al reported a higher SVR rate with PEG-IFN alfa-2a (68%) than with PEG-IFN alfa-2b (54.4%). [86] SVR rates were not statistically different in patients with a baseline HCV RNA of 500,000 IU/mL or below or in those with cirrhosis. [86]

In a similar trial, Rumi et al reported that treatment with ribavirin plus PEG-IFN alfa-2a resulted in a significantly higher SVR rate than ribavirin plus PEG-IFN alfa-2b. The two regimens showed a similar safety profile. [87]

In a study of patients coinfected with HCV and human immunodeficiency virus (HIV) with compensated cirrhosis, Mira et al found that SVR to PEG-IFN plus ribavirin significantly reduced the incidence of liver-related decompensations and overall mortality. [88] The probability of hepatic decompensation was 0% at 1 year and 4% at 3 years for SVR patients, compared with 15% and 32%, respectively, for non-SVR patients. The probability of overall mortality was 0% at 1 year and 4% at 3 years for SVR patients, compared with 12% and 20%, respectively, for non-SVR patients. [88]

In conclusion, treatment with PEG-IFN alfa-2a and ribavirin may be individualized by genotype. Patients with HCV genotype 1 require treatment for 48 weeks and a standard dose of ribavirin; those with HCV genotype 2 or 3 seem to be adequately treated with a low dose of ribavirin for 24 weeks. [89]

Response to therapy of HCV genotype 1 (ie, achievement of SVR) can be predicted by identifying the single neoceotide polymorphisms (SNPs) located in the region of interleukin (IL)-28B gene through genome-wide association studies (GWAS). Patients with the CC genotype of the IL-28B have a much more favorable response as compared to the CT or TT genotype (70% vs 25%-30%). Testing for IL-28B genotype is thus a useful tool in the management of patients. [90]

Adverse effects

Adverse effects are common with IFN and ribavirin combination therapy. Approximately 75% of patients experience one or more adverse effects.

Adverse effects of IFN include the following:

  • Hematologic complications (ie, neutropenia, thrombocytopenia)
  • Neuropsychiatric complications (ie, memory and concentration disturbances, visual disturbances, headaches, depression, irritability)
  • Flulike symptoms
  • Metabolic complications (ie, hypothyroidism, hyperthyroidism, low-grade fever)
  • Gastrointestinal complications (ie, nausea, vomiting, weight loss)
  • Dermatologic complications (ie, alopecia)
  • Pulmonary complications (ie, interstitial fibrosis)

Adverse effects of ribavirin include the following:

  • Hematologic complications (ie, hemolytic anemia)
  • Reproductive complications (ie, birth defects)
  • Metabolic complications (ie, gout)

Because of the risk of reproductive complications from ribavirin, it is recommended that patients and their partners not become pregnant while either is on therapy as well as for 6 months after the completion of treatment.

Growth factors, such as granulocyte-stimulating factor (GSF) and erythropoietin, are frequently used to counteract the adverse hematologic effects of IFN and ribavirin, respectively. Despite the encouraging early results reported by Afdhal et al [91] and Van Thiel et al, [92]  the cost-effectiveness data supporting the routine use of these agents as a means of avoiding IFN and ribavirin dose reductions are insufficient.

In November 2012, the FDA approved eltrombopag (Promacta), an oral thrombopoietin agonist, for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of IFN-based therapy. The approval was based on results from the phase 3 ltrombopag to Iitiate and Maintain Interferon ntiviral Treatment to enefit Subjects with Hepatitis C related iver Diseas (ENABLE) 1 and 2 trials, which showed eltrombopag significantly reduced the time to the first IFN dose reduction compared with placebo. [93, 94]

Because of this, a significant improvement in virologic response was observed in the eltrombopag group compared with placebo. These randomized, double-blind, placebo-controlled, multicenter studies collectively enrolled 1521 patients with platelet counts less than 75,000/mcL. ENABLE 1 utilized PEG-IFN alfa-2a plus ribavirin for antiviral treatment and ENABLE 2 utilized PEG-IFN alfa-2b plus ribavirin.

In patients who are at risk of depression or who develop depression during treatment, any antidepressant is better than none. Because available evidence suggests that all antidepressants will have an effect, Schaefer et al reported that treatment must be individualized on the basis of the adverse effect profile, drug-to-drug interactions, and general considerations (eg, speed of onset, efficacy). [95]

Fatigue is common in patients with chronic hepatitis C, but it is poorly associated with biochemical parameters. Sustained response is accompanied by substantial improvement of fatigue. [96]

With the availability of newer directly acting agents (DAAs), and due to the poor safety profile of PEG-IFN, PEG-IFN is no longer recommended in combination regimens. However, in resource-limited settings, PEG-IFN alfa-2a continues to have a role in the management of acute and chronic HCV, as well as in those with end-stage renal disease and individuals who don't have access to or who are not candidates for DAA therapy. [97]

Ribavirin continues to be used in combination with sofosbuvir alone or other combinations.

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Direct-Acting Antiviral Agents (DAAs)

Relatively recently, several antiviral agents have been developed to specifically target various sites of hepatitis C (HCV) viral replication. Similar to the antiretroviral drugs, these agents have been approved by FDA in various combinations to interrupt HCV replication at different sites, with reported  90%-95% sustained virologic response (SVR) rates in treated patients versus 50%-70% in those completing treatment with dual-therapy pegylated interferon (PEG-IFN) plus ribavirin. [98]  However, clinicians should be aware that baseline resistance-associated substitutions (RASs) may impair treatment response to direct-acting antiviral agents (DAAs), particularly baseline NS5A resistance in DAA-naïve HCV patients. [99]

Currently available agents and their target sites are outlined below.

NS3/4 targeting protease inhibitors

  • Boceprevir
  • Telaprevir
  • Simeprevir
  • Pratiprevir
  • Grazoprevir

NS5B targeting polymerase inhibitors

  • Nucleotide: Sofosbuvir
  • Non-nucleotide: Dasabuvir

NS5A targeting agents

  • Ledipasvir
  • Declatasvir
  • Ombitasvir
  • Elbasvir
  • Velpatasvir

NS3/4 targeting protease inhibitors

These agents target the NS3/4 serine protease to inhibit HCV replication. In 2011, boceprevir 800 mg every 7 to 9 hours and telaprevir 1125 mg twice daily were approved to treat genotype 1 HCV infection. However, treatment with either of these two agents is no longer recommended. Their use has been superseded by the more recently approved protease inhibitors active against a broader range of viruses. 

Simeprevir (Olysio) was FDA approved in November 2013. The QUEST 1 and QUEST 2 phase 3 trials assessed the efficacy of simeprevir in 785 adult, treatment-naïve patients with chronic HCV genotype 1. Results showed that 80% and 81% of patients treated with simeprevir (plus PEG-IFN alfa and ribavirin) achieved SVR at 12 weeks (SVR12) compared with the PEG-IFN alfa and ribavirin control groups (50%). [100]

In the PROMISE study, 393 patients who had previous relapse after completing HCV treatment with PEG-IFN and ribavirin, were randomized to receive either 150 mg of once-daily simeprevir for 12 weeks plus PEG-IFN and ribavirin for 24 or 48 weeks based on response guided treatment criteria (simeprevir group) or PEG-IFN and ribavirin alone for 48 weeks (control group). In this study, the SVR12 was 79% in the simeprevir treatment group compared to 37% with PEG-IFN and ribavirin alone. [100]

The presence of the Q80K HCV genotype (GT) 1a polymorphism (commonly found in GT1a patients in the United States) at baseline had a substantial impact on the efficacy of simeprevir. In the pooled trials, the differences in SVR12 rates in GT1a patients with the Q80K polymorphism were not statistically significant between the treatment (58%) and control (55%) groups. [101] In the HPC3007 trial of HCV, the SVR12 rates for those with the Q80K polymorphism were 47% in the treatment group and 30% in the control group. [101]

Simeprevir was approved by the FDA for the treatment of HCV genotype 4 monoinfected and HCV/human immunodeficiency virus (HIV)-coinfected patients as a component of a combination antiviral treatment regimen that includes PEG-IFN and ribavirin. [102] The open-label, single-arm study (RESTORE) included 107 patients with HCV GT4 infection. Treatment included simeprevir 150 mg once daily plus PEG-IFN and ribavirin for 12 weeks, followed by PEG-IFN and ribavirin alone (12 or 36 weeks, response guided). Overall, 65.4% of patients achieved SVR12 (82.9% treatment naïve; 86.4% prior relapsers; 60% prior partial responders; 40% prior null responders). In treatment-naïve and prior relapser patients fulfilling response-guided criteria for 24 weeks of treatment (88.6% and 90.9%), SVR12 rates were high: 93.5% and 95.0%, respectively. These results were similar to previous reports for HCV GT1. [102]  As discussed later, simeprevir is used in combination with other agents for the treatment of HCV infection.

Paritaprevir given in combination with ritonavir and ribavirin to patients with hepatitis C genotype 1 for 12 weeks resulted in an SVR of 95% at 24 weeks after treatment discontinuation. [103]  Paritaprevir is a component of Viekira Pak and Technivie as discussed below.

Grazoprevir is active against a range of HCV genotypes, including some that are resistant to the most currently used antiviral medications. It is used in combination with the NS5A replication complex inhibitor elbasvir under the trade name Zepatier, either with or without ribavirin.

Asunaprevir, another agent in this class, is currently not available in the United States.

NS5B targeting polymerase inhibitors

HCV NS5B polymerase plays an essential role in HCV replication. Sofosbuvir (Sovaldi) is a NS5B polymerase inhibitor that results in suppression of HCV replication and life cycle. Sofosbuvir received FDA approval in December 2013 for treatment of chronic HCV infection with genotypes 1, 2, 3, and 4 as part of a combination antiviral regimen, including those with hepatocellular carcinoma (HCC) meeting Milan criteria (awaiting liver transplantation) to prevent HCV recurrence and those with HCV/HIV-1 coinfection.

Approval for sofosbuvir was supported by data from several phase 3 studies that evaluated 12 or 16 weeks of treatment with the drug combined with either ribavirin or ribavirin plus PEG-IFN alfa. Three of these studies evaluated sofosbuvir plus ribavirin in genotype 2 or 3 patients who were either treatment-naïve, [104] treatment-experienced [105] or PEG-IFN intolerant, ineligible, or unwilling. [105] The fourth study evaluated sofosbuvir in combination with PEG-IFN/ribavirin in treatment-naïve patients with genotypes 1, 4, 5 or 6. [104]

In these studies, sofosbuvir-based therapy was found to be superior to historical controls [104] or to placebo, [105] or noninferior to currently available treatment options [104] based on the proportion of patients who had a SVR12 after completing therapy. Patients who achieve SVR12 are considered cured of HCV. Trial participants taking sofosbuvir-based therapy achieved SVR12 rates of 50%-90%.

During the FDA’s review, data from two additional phase 3 studies were added to the new drug application (NDA) as a result of the "Breakthrough Designation" status. In the first study, patients with genotype 3 HCV infection were treated with sofosbuvir and ribavirin for 24 weeks. Eighty-four percent of patients in this trial achieved SVR12. [106] The second study evaluated sofosbuvir and ribavirin for 12 weeks in patients with genotype 2 HCV infection coinfected with HIV-1. [107]

The efficacy of combined simeprevir and sofosbuvir was investigated in the COSMOS study, an open-label, randomized phase II clinical trial. [108] For all patients (treatment-naïve and treatment-experienced, with or without cirrhosis), 93% achieved an SVR12 after 12 weeks of treatment, and 97% achieved SVR12 after 24 weeks of treatment. [108]

The open-label (ALLY-1) study assessed the safety and efficacy of a 60-mg once-daily dosage of daclatasvir in combination with sofosbuvir at 400 mg once daily and ribavirin at 600 mg/day for 12 weeks in two cohorts of patients with chronic HCV infection of any genotype (1, 2, 3, 4, and 6 were represented) and either compensated/decompensated cirrhosis (n = 60) or posttransplantation recurrence (n = 53). [109]  Eighty-two percent of patients with cirrhosis and genotype 1 infection achieved SVR12, compared to 80% in those with genotype 2, 83% with genotype 3, and 100% with genotype 4; the highest SVR12 rates were in patients with Child-Pugh class A or B (93%) versus class C (56%). In transplant recipients, 95% with genotype 1 achieved SVR12 compared to 91% of patients with genotype 3 infection. No treatment-related serious adverse events were noted. [109]

In a separate trial (ALLY-2) of previously untreated HIV-HCV coinfected patients, daclatasvir plus sofosbuvir treatment produced an SVR across all genotypes of 97.0% after 12 weeks of treatment and 76.0% after 8 weeks. [110]  

In an all-oral treatment with daclatasvir plus sofosbuvir in patients with HCV genotype 3 infection (ALLY-3 phase III study), a 12-week regimen achieved SVR12 in 96% of patients with genotype 3 infection without cirrhosis and was well tolerated. [111]

Dasabuvir is approved by the FDA only for use in combination with ombitasvir/paritaprevir/ritonavir. In the United States, this combination is sold as Viekira Pak.

NS5A targeting agents

Several agents are available for NS5A target inhibition in the replication cycle of HCV. These include ledipasvir, declatasvir, ombitasvir, elbasvir, and velpatasvir. These are all approved as part of combination products as discussed below.

Combination products

Several anti-hepatitis C agents are currently approved by FDA for treatment as described below.

◊ Ledispasvir/sofosbuvir (Harvoni)

Harvoni is a combination oral product containing ledipasvir, an NS5A protein inhibitor, and sofosbuvir that was approved by the FDA in October 2014 for the treatment of HCV genotype 1. Since its original approval in the United States, the indication has been expanded to include genotypes 1, 4, 5, and 6. It is administered once daily and does not need to be administered with IFN. Some regimens may require ribavirin. Studies have shown a high SVR (94%-99%) in all treatment groups (ie, treatment naïve or treatment experienced, with or without cirrhosis, and liver transplant recipients). [112, 113, 114]

This fixed-dose combination drug demonstrated efficacy in refractory cirrhotic hepatitis C. In a study of 154 patients with cirrhotic chronic HCV infection whose condition had failed previous protease inhibitor–based therapy, treatment with the fixed-dose combination of ledipasvir and sofosbuvir with or without ribavirin led to SVR in the majority of patients. [115, 116]  Study subjects received either ledipasvir and sofosbuvir plus placebo for 24 weeks or placebo for 12 weeks followed by ledipasvir and sofosbuvir plus ribavirin for 12 weeks. SVR12 was seen in 96% of the 24-week combination group and 97% of the 12-week combination plus ribavirin group. Three patients in the 12-week group and two patients in the 24-week group experienced relapses. [115, 116]

For treatment-naïve noncirrhotic patients, with chronic HCV and a viral load below 6 million international units/mL (IU/mL), treatment duration is generally 8 weeks. However, with a viral load above 6 million IU/mL or  with cirrhosis, ledispasvir/sofosbuvir is given for 12 weeks. In patients with and without cirrhosis, this therapy results in SVR rates greater than 95%. [108, 117]

In a trial of 20 patients with acute hepatitis C genotype 1 monoinfection, a 6-week treatment regimen with ledipasvir plus sofosbuvir resulted in SVR in all patients. [118] Treatment was well tolerated; there were no drug-related serious adverse events.

 

◊ Elbasvir/grazoprevir (Zepatier)

The fixed-dose HCV NS5A and NS3/4A protease inhibitor, elbasvir/grazoprevir (Zepatier) was approved in January 2016 for use with or without ribavirin for adults with HCV genotypes 1 or 4 infection. Elbasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly. Grazoprevir is an inhibitor of HCV NS3/4A protease, which is necessary for the proteolytic cleavage of the HCV-encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is also essential for viral replication.

Efficacy of elbasvir/grazoprevir was evaluated in clinical trials that included nearly 1400 patients. The overall SVR rates ranged from 94% to 97% for genotype 1 and 97% to 100% for genotype 4 across trials. [119, 120] The approved dosage regimens are specific to the characteristics of the patients and their virus genotype. Prior to initiating therapy, patients with HCV genotype 1a should be tested for NS5A resistance-associated substitutions (RASs) to determine the dosage regimen and duration. Those without RASs are treated for 12 weeks, but treatment is given for 16 weeks with weight-based ribavirin in those with RASs. For patients with subtype 1b infection, the regimen is given for 12 weeks without ribavirin. Duration of treatment is the same in patients with and without cirrhosis with SVR rates greater than 95%. [121]  However, this regimen is contraindicated in those with Child-Pugh classes B and C cirrhosis.

 

◊ Ombitasvir/paritaprevir/ritonavir/dasabuvir (Viekira Pak)

On December 19, 2014, the FDA approved the combination of ombitasvir/paritaprevir/ritonavir and dasabuvir (Viekira Pak) for the treatment of genotype 1 chronic hepatitis C infection in adults, including patients with compensated cirrhosis. Studies were conducted using two tablets of ombitasvir/paritaprevir/ritonavir tablet once daily (in the morning) plus one tablet of dasabuvir 250 mg tablet twice daily (morning and evening) with a meal with ribavirin (up to six pills divided into two daily doses) for 12 weeks (no cirrhosis) or 24 weeks (compensated cirrhosis) with the cure rates summarized below. [122, 123, 124, 125, 126]

HCV genotype 1a infection cure rates for the ombitasvir/paritaprevir/ritonavir and dasabuvir combination included the following:

  • No cirrhosis: SVR12 rates were 95% for 12 weeks of treatment with ribavirin (SAPPHIRE-I study) [122] ; SVR12 was 97% for 12 weeks of treatment with ribavirin but 90% without ribavirin (PEARL-IV study) [125]
  • Cirrhosis: SVR12 rates were 89% in the 12-week arm and 95% in the 24-week arm; prior treatment null responders had lower SVR rates (TURQOUISE-II study) [126]

HCV genotype 1b infection cure rates for the ombitasvir/paritaprevir/ritonavir and dasabuvir combination included the following:

  • No cirrhosis: SVR12 rates were 99% for 12 weeks of treatment with ribavirin (PEARL-III Study) [125]
  • Cirrhosis: SVR12 rates were 98.5% in the 12-week arm (with ribavirin) and 100% in the 24-week arm; prior treatment null responders had lower SVR rates (TURQOUISE-II Study) [126]

For treatment-naïve patients with HCV 1a infection, the regimen is given with ribavirin (daily dose 1000 mg for those <75 kg and 1200 mg for those ≥75 kg) for 12 weeks in patients without cirrhosis and for 24 weeks in patients with cirrhosis. For patients with subtype 1b infection, the regimen is given without ribavirin for 12 weeks, regardless of the presence of cirrhosis. This regimen is contraindicated in Child-Pugh classes B and C cirrhosis.

 

◊ Ombitasvir/paritaprevir/ritonavir (Technivie)

Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin was studied in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I). [127]  In previously untreated patients, SVR12 rates were 100% (42/42) in the ribavirin-containing regimen and 90.9% (40/44) in the ribavirin-free regimen. All treatment-experienced patients achieved SVR12 (49/49). In the ribavirin-free group, 2 of 42 (5%) treatment-naïve patients had virologic relapse, and 1 of 44 (2%) had virologic breakthrough; no virologic failures were recorded in the ribavirin-containing regimen. [127]

The combination product ombitasvir/paritaprevir/ritonavir (Technivie) was FDA approved in July 2015 for the treatment of genotype 4 chronic HCV without cirrhosis. [128] It is recommended to be used in conjunction with ribavirin.

 

◊ Sofosbuvir/velpatasvir (Epclusa)

On June 28, 2016, the FDA approved the fixed-dose combination tablet containing sofosbuvir and velpatasvir as the first agent to treat all six major forms of HCV in adults with chronic hepatitis C with and without cirrhosis. [129, 130]  The safety and efficacy of Epclusa for 12 weeks was evaluated in three phase III clinical trials of 1558 subjects without cirrhosis or with compensated cirrhosis. [129] Cure was noted in 95%-99% of patients. The safety and efficacy of sofosbuvir/velpatasvir was also evaluated in a clinical trial of 267 subjects with decompensated cirrhosis, of whom 87 subjects received this agent in combination with ribavirin for 12 weeks, with 94% cure rates. [129]

For patients with decompensated cirrhosis, sofosbuvir-velpatasvir is approved for use in combination with the drug ribavirin. For treatment-naïve patients, sofosbuvir-velpatasvir is given for 12 weeks, regardless of the presence of cirrhosis. This regimen results in SVR rates of approximately 98%-99%. The most common side effects of sofosbuvir-velpatasvir include headache and fatigue. Coadministration of amiodarone with combination sofosbuvir-velpatasvir is not recommended due to the possibility of symptomatic bradycardia.

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Treatment Recommendations for Chronic Hepatitis C Infection

Although quite effective, regimens for the treatment of hepatitis C remain very expensive. In a study of treatment-naïve US veterans with genotype 1 hepatitis C, ombitasvir-based therapy was considered to be the most economically efficient strategy. [131]

The following recommendations are based on guidelines from the American Association for the Study of Liver Diseases [AASLD], the Infectious Disease Society of America [ISDA], and the International Antiviral Society-USA [IAS-USA]. [32]  They are updated frequently and available at http://www.hcvguidelines.org/full-report-view.

Treatment-naïve patients

I. Genotype 1

◊ HCV genotype 1a treatment-naïve patients without cirrhosis

Recommended regimens

  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks if no baseline NS5A resistance-associated substitutions (RASs) for elbasvir are detected
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 8 weeks for non-black patients, non-HIV-infected persons, and those whose HCV RNA level is below 6 million IU/mL
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Alternative regimens 

  • Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) with dasabuvir (600 mg) for 12 weeks as part of an extended-release regimen or plus twice-daily dosed dasabuvir (250 mg), with weight-based ribavirin 
  • Daily simeprevir (150 mg) plus sofosbuvir (400 mg) for 12 weeks
  • Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 12 weeks
  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) with weight-based ribavirin for 16 weeks in patients who have baseline NS5A RASs for elbasvir

 

◊ HCV genotype 1a treatment-naïve patients with compensated cirrhosis

Recommended regimens

  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks in those with no baseline NS5A RASs for elbasvir
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Alternative regimen

  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) with weight-based ribavirin for 16 weeks in patients with baseline NS5A RASs for elbasvir

 

◊ HCV genotype 1b treatment-naïve patients without cirrhosis

Recommended regimens 

  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 8 weeks for non-black persons, non-HIV-infected patients, and those whose HCV RNA level is below 6 million IU/mL
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Alternative regimens

  • Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) for 12 weeks as part of an extended-release regimen or plus twice-daily dosed dasabuvir (250 mg)
  • Daily simeprevir (150 mg) plus sofosbuvir (400 mg) for 12 weeks
  • Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 12 weeks

 

◊ HCV genotype 1b treatment-naïve patients with compensated cirrhosis

Recommended regimens 

  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Alternative regimen 

  • Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) with dasabuvir (600 mg) for 12 weeks as part of an extended-release regimen or plus twice-daily dosed dasabuvir (250 mg)

 

II. Genotype 2

◊ HCV genotype 2 treatment-naïve patients without cirrhosis

Recommended regimens

  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Alternative regimen

  • Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 12 weeks

 

◊ HCV genotype 2 treatment-naïve patients with compensated cirrhosis

Recommended regimens

  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

Alternative regimen

  • Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 16 to 24 weeks

 

III. Genotype 3

◊ HCV genotype 3 treatment-naïve patients without cirrhosis

Recommended regimens 

  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Alternative regimen

  • Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 12 weeks

 

◊ HCV genotype 3 treatment-naïve patients with compensated cirrhosis:

Recommended regimens

  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Alternative regimens

  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) when Y93H is present
  • Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 24 weeks with or without weight-based ribavirin

 

IV. Genotype 4

◊ HCV genotype 4 treatment-naïve patients without cirrhosis

Recommended regimens 

  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks
  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks

Alternative regimen

  • Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based ribavirin for 12 weeks 

 

◊ HCV genotype 4 treatment-naïve patients with compensated cirrhosis

Recommended regimens 

  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks
  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks

Alternative regimen

  • Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based ribavirin for 12 weeks

 

V. Genotype 5 or 6

◊ HCV genotype 5 or 6 treatment-naïve patients with and without compensated cirrhosis

Recommended regimens 

  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks in those without cirrhosis or for 12 weeks in those with cirrhosis
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks, regardless of cirrhosis status
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks, regardless of cirrhosis status.

 

Treatment-experienced patients with previous treatment failure

IA. Genotype 1a

◊ HCV genotype 1a peginterferon (PEG-IFN)/ribavirin treatment-experienced patients without cirrhosis

Recommended regimens

  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks if no baseline NS5A RASs for elbasvir are detected
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks 

Alternative regimens 

  • Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) with dasabuvir (600 mg) as part of an extended-release regimen or plus twice-daily dasabuvir (250 mg, and weight-based ribavirin for 12 weeks
  • Daily simeprevir (150 mg) plus sofosbuvir (400 mg) for 12 weeks
  • Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 12 weeks
  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) with weight-based ribavirin for 16 weeks for patients with baseline NS5A RASs for elbasvir

 

◊ HCV genotype 1a PEG-IFN/ribavirin treatment-experienced patients with compensated cirrhosis

Recommended regimens 

  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks if no baseline NS5A RASs for elbasvir are detected
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

Alternative regimens 

  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) plus weight-based ribavirin for 12 weeks
  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) with weight-based ribavirin for 16 weeks in patients who have baseline NS5A RASs for elbasvir

 

IB. Genotype 1b

◊ HCV genotype 1b PEG-IFN/ribavirin treatment-experienced patients without cirrhosis

Recommended regimens

  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Alternative regimens

  • Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) with dasabubir (600 mg) for 12 weeks as part of an extended-release regimen or plus twice-daily dosed dasabuvir (250 mg) for 12 weeks
  • Daily simeprevir (150 mg) plus sofosbuvir (400 mg) for 12 weeks
  • Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 12 weeks

 

◊ HCV genotype 1b PEG-IFN/ribavirin treatment-experienced with compensated cirrhosis

 Recommended regimens

  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

Alternative regimens 

  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) plus weight-based ribavirin for 12 weeks
  • Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) with dasabubir (600 mg) for 12 weeks as part of an extended-release regimen or plus twice-daily dosed dasabuvir (250 mg)

 

◊ HCV genotype 1 nonstructural protein 3 (NS3) protease inhibitor (telaprevir, boceprevir, or simeprevir) plus PEG-IFN/ribavirin treatment-experienced patients without cirrhosis

Recommended regimens 

  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

Alternative regimens

  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) with weight-based ribavirin for 12 weeks for all genotype 1b patients, and genotype 1a patients without baseline NS5A RASs for elbasvir. Extend this treatment to 16 weeks for genotype 1a patients who have baseline NS5A RASs for elbasvir.

 

◊ HCV genotype 1 NS3 protease inhibitor (telaprevir, boceprevir, or simeprevir) plus PEG-IFN/ribavirin treatment-experienced patients with compensated cirrhosis

Recommended regimens

  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

Alternative regimens

  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) plus weight-based ribavirin for 12 weeks
  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) with weight-based ribavirin for 12 weeks for all genotype 1b patients, and genotype 1a patients without baseline NS5A RASs for elbasvir. Extend this treatment to 16 weeks for genotype 1a patients who have baseline NS5A RASs for elbasvir.

 

◊ HCV genotype 1 non-NS5A inhibitor, sofosbuvir-containing treatment-experienced patients without cirrhosis

Recommended regimens

  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) for 12 weeks for genotype 1a patients
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks, regardless of HCV subtype
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks for genotype 1b patients

Alternative regimen

  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) plus weight-based ribavirin, except in simeprevir failures, for 12 weeks

 

◊ HCV genotype 1 non-NS5A inhibitor, sofosbuvir-containing treatment-experienced patients with compensated cirrhosis

Recommended regimens

  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) for 12 weeks for genotype 1a patients
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks, regardless of HCV subtype
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks for genotype 1b patients

◊ HCV genotype 1 NS5A inhibitor, direct-acting antiviral agent (DAA) treatment-experienced patients with or without compensated cirrhosis

Recommended regimen

  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) for 12 weeks

Alternative regimen

  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg), except NS3/4 protease inhibitor inclusive DAA combination regimens, for 16 weeks

 

II. Genotype 2

◊ HCV genotype 2 PEG-IFN/ribavirin treatment-experienced patients without cirrhosis

Recommended regimens

  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Alternative regimen

  • Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 12 weeks

 

◊ HCV genotype 2 PEG-IFN/ribavirin treatment-experienced patients with compensated cirrhosis

Recommended regimens

  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

Alternative regimen

  • Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 16 to 24 weeks

 

◊ HCV genotype 2 sofosbuvir plus ribavirin treatment-experienced patients with or without compensated cirrhosis

Recommended regimens

  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

 

III. Genotype 3

◊ HCV genotype 3 PEG-IFN/ribavirin treatment-experienced patients without cirrhosis

Recommended regimen 

  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Alternative regimens

  • Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 12 weeks
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 16 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) for 12 weeks when RAS testing shows Y93H

 

◊ HCV genotype 3 PEG-IFN/ribavirin treatment-experienced patients with compensated cirrhosis

Recommended regimens 

  • Daily fixed-dose elbasvir (50 mg)/grazoprevir (100 mg) plus sofosbuvir (400 mg) for 12 weeks
  • aily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) for 12 weeks

Alternative regimens

  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) with weight-based ribavirin for 12 weeks
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 16 weeks

 

◊ HCV genotype 3 DAA treatment (including NS5A inhibitors)-experienced patients with or without compensated cirrhosis

Recommended regimens

  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) for 12 weeks
  • Weight-based ribavirin for 12 weeks is recommended for individuals with prior NS5A inhibitor failure and cirrhosis

 

IV. Genotype 4

◊ HCV genotype 4 PEG-IFN/ribavirin treatment-experienced patients without cirrhosis

Recommended regimens

  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks
  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks for patients who had virologic relapse after previous PEG-IFN/ribavirin treatment
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks

Alternative regimens

  • Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based ribavirin for 12 weeks
  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) plus weight-based ribavirin for 16 weeks patients with previous on-treatment virologic failure (failure to suppress or breakthrough) while on PEG-IFN/ribavirin

 

◊ HCV genotype 4 PEG-IFN/ribavirin treatment-experienced patients with compensated cirrhosis

Recommended regimens

  • Daily fixed-dose combination of sofosbuvir (400 mg)velpatasvir (100 mg) for 12 weeks
  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks for individuals who had virologic relapse after previous PEG-IFN/ribavirin treatment
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

Alternative regimens

  • Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based ribavirin for 12 weeks
  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) plus weight-based ribavirin for 16 weeks for patients with previous on-treatment virologic failure (failure to suppress or breakthrough) while on PEG-IFN/ribavirin
  • Daily ledipasvir (90 mg)/sofosbuvir (400 mg) plus weight-based ribavirin for 12 weeks

 

◊ HCV genotype 4 DAA treatment (including NS5A inhibitors)-experienced patients with or without compensated cirrhosis

Recommended regimen

  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) for 12 weeks

 

V. Genotype 5 and 6

◊ HCV genotype 5 or 6 PEG-IFN/ribavirin treatment-experienced patients with or without compensated cirrhosis

Recommend regimens

  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks for patients without cirrhosis or for 12 weeks for patients with compensated cirrhosis
  • Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

 

◊ HCV genotype 5 or 6 DAA treatment (including NS5A inhibitors)-experienced patients with or without compensated cirrhosis

Recommended regimen

  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) for 12 weeks
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HIV-HCV Coinfection

Patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are at risk for accelerated liver fibrosis and should usually be offered antiviral treatment. HIV/HCV-coinfected persons should be treated the same as those without HIV infection. With the availability of newer agents, the efficacy of treatments for coinfected persons is similar to that for their HIV-uninfected counterparts. [132, 133]  However, several important points related to drug interactions with antiretroviral medications need to be emphasized, as follows [32] :

  • Daclatasvir in combination with other antiviral agents: Reduce daclatasvir to 30 mg/day with ritonavir-boosted atazanavir and with cobicistat-boosted atazanavir; increase daclatasvir to 90 mg/day with efavirenz and with etravirine.

  • Fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg): This combination should be used with antiviral agents with which it doesn't have clinically significant interactions, such as abacavir, emtricitabine, enfuvirtide, lamivudine, raltegravir, dolutegravir, rilpivirine, and tenofovir.

  • Fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg): As with combination elbasvir/grazoprevir, combination glecaprevir/pibrentasvir should be used with antiviral agents with which it doesn't have clinically significant interactions, such as abacavir, emtricitabine, enfuvirtide, lamivudine, raltegravir, dolutegravir, rilpivirine, and tenofovir. Monitor for hepatic toxicity.

  • Simeprevir in combination with other antiviral agents: Use simeprevir with antiviral agents with which it doesn't have clinically significant interactions, such as abacavir, emtricitabine, enfuvirtide, lamivudine, maraviroc, raltegravir, dolutegravir, rilpivirine, and tenofovir.

  • Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg): This combination should not be used with efavirenz, etravirine, or nevirapine. Because velpatasvir may increase tenofovir levels, concomitant use of these agents mandates consideration of the creatinine clearance (CrCl) rate; avoid their use in those with a CrCl level below 60 mL/min.

  • Fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg): Because ledipasvir increases tenofovir levels, concomitant use of these agents mandates consideration of the CrCl rate; avoid their use in those with a CrCl level below 60 mL/min. Because potentiation of this effect is expected when tenofovir is used with ritonavir-boosted HIV protease inhibitors, avoid using ledipasvir with this combination unless the antiretroviral regimen cannot be changed and the urgency of treatment is high.

  • For combination agents expected to increase tenofovir levels, baseline and ongoing assessment for tenofovir nephrotoxicity is recommended.

  • Paritaprevir/ritonavir/ombitasvir plus dasabuvir should be used with antiretroviral drugs with which they do not have substantial interactions, such as atazanavir, dolutegravir, emtricitabine, enfuvirtide, lamivudine, raltegravir, and tenofovir.

  • The dose of ritonavir used for boosting atazanavir should be held when administered with paritaprevir/ritonavir/ombitasvir plus dasabuvir; restore the dose when the HCV treatment is completed. Atazanavir should be administered at the same time as the fixed-dose HCV combination.

  • Sofosbuvir/velpatasvir/voxilaprevir should be used with antiretroviral drugs with which they do not have substantial interactions, such as dolutegravir, emtricitabine, enfuvirtide, lamivudine, rilpivirine, and raltegravir. Monitor for hepatic toxicity. This drug combination may increase tenofovir levels. Thus, concomitant use of these agents mandates consideration of the CrCl rate; avoid their use in those with a CrCl level below 60 mL/min. Monitor renal function.

  • Avoid interrupting antiretroviral therapy to allow HCV treatment.

  • Avoid the use of elbasvir/grazoprevir or simeprevir with cobicistat, efavirenz, etravirine, nevirapine, or any HIV protease inhibitor.

  • Avoid the use of glecaprevir/pibrentasvir with with atazanavir, ritonavir-containing antiretroviral regimens, efavirenz, or etravirine.

  • Avoid the use of sofosbuvir/velpatasvir with efavirenz, etravirine, or nevirapine.

  • Avoid the use of sofosbuvir/velpatasvir/voxilaprevir with ritonavir-boosted atazanavir, efavirenz, etravirine, or nevirapine.

  • Avoid the use of sofosbuvir-based regimens with tipranavir.

  • Avoid the use of paritaprevir/ritonavir/ombitasvir plus cobicistat, dasabuvir with darunavir, efavirenz, etravirine, nevirapine, rilpivirine, ritonavir-boosted lopinavir, or ritonavir-boosted tipranavir.

  • Avoid the use of paritaprevir/ritonavir/ombitasvir, with or without dasabuvir, in HIV/HCV-coinfected individuals who are not taking antiretroviral therapy.

  • Avoid the use of ribavirin with didanosine, stavudine, or zidovudine.

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Hepatitis C and B Coinfection

Coinfection with hepatitis C virus (HCV) and hepatitis B virus (HBV), in the absence of human immunodeficiency virus (HIV) infection, is relatively uncommon in the United States, and optimal treatment regimens have not been established. However, a few important studies are worth mentioning.

Villa et al reported that 9 million U of standard interferon (IFN) three times weekly for 3 months could clear HCV in 31% of patients with HCV-HBV coinfection. [134]  Using standard IFN and ribavirin, Liu et al discovered that sustained HCV eradication was achieved at rates comparable to those in patients with HCV alone and, interestingly, up to 21% of their patients lost the hepatitis B surface antigen. [135]

Given the superior efficacy of pegylated IFN (PEG-IFN) over standard IFN, Liu et al subsequently conducted a multicenter study using PEG-IFN and ribavirin in HCV-HBC coinfected patients. This regimen proved equally effective in patients with HCV monoinfection and in those with chronic HCV-HBV coinfection. [136]

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Management of Acute HCV Infection

Acute hepatitis C virus (HCV) infection is defined as presenting within 6 months of the exposure. During this time, there is a 15% to 50% chance of spontaneous resolution of infection. [1, 14, 32, 33]  Monitoring for spontaneous clearance for a minimum of 6 months before initiating treatment is recommended. In the past, interferon (IFN)-based treatment was used with high cure rates of acute infection. However, IFN-sparing regimens are safer and are currently recommended for the treatment of acute HCV infection. [32]

When the decision is made to initiate treatment after 6 months, the same regimens that are recommended for chronic HCV infection are recommended for acute infection. [32]

The following recommendations are based on guidelines from the American Association for the Study of Liver Diseases [AASLD], the Infectious Disease Society of America [ISDA], and the International Antiviral Society-USA [IAS-USA]. [32] They are available at http://www.hcvguidelines.org/full-report-view.

Medical management and monitoring of acute HCV infection

Recommendations

  • Regular laboratory monitoring in the setting of acute HCV infection. In addition, monitoring of HCV RNA (eg, every 4-8 weeks) for 6 to 12 months to determine spontaneous clearance versus persistence of HCV infection
  • Counseling for patients with acute HCV infection to avoid hepatotoxic insults, including hepatotoxic drugs (eg, acetaminophen) and alcohol consumption, and to reduce the risk of HCV transmission to others
  • Referral to an addiction medicine specialist for patients with acute HCV infection related to substance use
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Recurrence After Liver Transplantation

Recurrent hepatitis C viral (HCV) infection is universal after liver transplantation, can lead to cirrhosis in 30% of patients within 5 years, and is emerging as the most common cause of retransplantation in the United States. [137]  Interferon (IFN) is contraindicated after organ transplantation because of its high risk of precipitating rejection, in part due to upregulation of the human leukocyte antigen (HLA) system by IFN. Liver transplantation is a possible exception, however, as allograft rejection is uncommon in liver transplant recipients with recurrent HCV infection who are treated with IFN-based therapies.

The following recommendations are based on guidelines from the American Association for the Study of Liver Diseases [AASLD], the Infectious Disease Society of America [ISDA], and the International Antiviral Society-USA [IAS-USA]. [32]  They are  subject to change and available at http://www.hcvguidelines.org/full-report-view.

Treatment-naïve and treatment-experienced patients

I. Genotype 1, 4, 5, or 6 post liver transplantation

◊ HCV genotype 1, 4, 5, or 6 allograft patients without cirrhosis, regardless of treatment experience

Recommended regimens

  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) with weight-based ribavirin for 12 weeks

 

◊ HCV genotype 1, 4, 5, or 6 allograft patients with compensated cirrhosis, regardless of treatment experience

Recommended regimen

  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) with weight-based ribavirin for 12 weeks

 

◊ HCV genotype 1, 4, 5, or 6 allograft patients with or without compensated cirrhosis, regardless of treatment experience

Alternative regimens

  • Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) with a low initial dose of ribavirin (600 mg; increase as tolerated) for 12 weeks
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks
  • Genotype 1 or 4 infection only: Daily simeprevir (150 mg) plus sofosbuvir (400 mg) with or without weight-based ribavirin for 12 weeks

 

◊ HCV genotype 1, 4, 5, or 6 allograft patients with decompensated cirrhosis, regardless of treatment experience

Recommended regimen

  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) with a low initial dose of ribavirin (600 mg; increase as tolerated) for 12 weeks

 

II. Genotype 2 or 3 post liver transplantation

◊ HCV genotype 2 or 3 allograft patients without cirrhosis, regardless of treatment experience

Recommended regimens

  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks
  • Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) with a low initial dose of ribavirin (600 mg; increase as tolerated) for 12 weeks

 

◊ HCV genotype 2 or 3 allograft patients with compensated cirrhosis, regardless of treatment experience

Recommended regimen

  • Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) with a low initial dose of ribavirin (600 mg; increase as tolerated) for 12 weeks

Alternative regimens

  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) with weight-based ribavirin for 12 weeks

 

◊ HCV genotype 2 or 3 allograft patients with decompensated cirrhosis, regardless of treatment experience

Recommended regimens

  • Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) with a low initial dose of ribavirin (600 mg; increase as tolerated) for 12 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) with weight-based ribavirin for 12 weeks
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Patients Using Alcohol or Injection Drugs

In 1998, Wiley et al reported that significant alcohol use (>40 g alcohol/day in women and >60 g of alcohol/day in men for >5 years) in patients infected with hepatitis C virus (HCV) resulted in a two- to three-fold greater risk of liver cirrhosis and decompensated liver disease. In addition, cirrhosis developed more rapidly in alcohol users. [138] Because of the risk that alcohol use poses for rapid liver fibrosis, hepatoma, and deleterious effects on treatment response, complete alcohol abstinence is recommended during treatment.

Practice guidelines from the American Association for the Study of Liver Diseases (AASLD) have recommended that HCV treatment not be withheld from patients who use illicit drugs or who are on a methadone maintenance program, provided they are willing to maintain close monitoring, including practicing contraception. [32, 139] However, the guidelines have also noted that "It is important to consider the individual issues that may affect the risks and benefits of treatment of HCV infection in persons who use illicit drugs, rather than to make categorical recommendations." [140]

The complexity of HCV treatment in these patients is aided by a multidisciplinary team approach composed of physicians, nurses, and substance abuse and mental health professionals.

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Deterrence/Prevention

Currently, no products are available to prevent hepatitis C virus (HCV) infection. The development of immunoprophylaxis for this disease is proving difficult; an effective neutralizing immune response has not been demonstrated.

Patients with hepatitis C should be advised to abstain from alcohol use; they should also be advised to use barrier protection during sexual intercourse. Screening high-risk patients and initiating appropriate treatment may decrease the prevalence of cirrhosis and hepatocellular carcinoma (HCC).

In an ongoing prospective study of prevention of HCV infection in injection-drug users, researchers recommended six measures that can be used to prevent the spread of hepatitis C [141, 142] :

  • Reducing risk from shared ancillary drug preparation equipment, such as containers, rinse water, and filters, in addition to shared syringes

  • Using a new rapid test at the point of care that offers results in 20 minutes; it can detect infection before seroconversion occurs and, combined with counseling, can help to stem transmission

  • Addressing social and relational contexts of injecting can encourage uninfected individuals to take precautions when injecting drugs with infected sex partners

  • Encouraging "taking a break" from injecting drugs

  • Developing models to guide delivery of new prevention strategies, including already-available approaches such as increasing syringe availability and future strategies such as direct-acting antivirals that can be used prophylactically, as well as vaccines

  • Combining interventions in synergistic ways, such as needle exchange and methadone maintenance programs

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Consultations and Long-Term Monitoring

Consultation with a gastroenterologist and hepatologist is recommended in the treatment of hepatitic C virus (HCV) infection. Consultation with a psychiatrist may be helpful before and during treatment in patients at risk of depression or other psychiatric illnesses. Patients with cirrhosis should be referred for liver transplantation evaluation after decompensation or when their Model for End-Stage Liver Disease (MELD) score rises (online calculator available at www.hepatitisc.uw.edu/page/clinical-calculators/meld).

HCV RNA tested at about week 4 after the initiation of therapy should almost always be undetected or detectable only at the limit of the quantification. Higher values at this point in time suggest suboptimum adherence.

At week 12 of treatment, the patient should be evaluated for an early virologic response by repeating the quantitative HCV RNA and interferon (IFN)-associated thyroid dysfunction screening. If the HCV RNA level is undetectable or if a greater than 2-log-fold reduction in HCV RNA level is present, therapy should be continued because, according to Fried et al, up to 65% of patients go on to develop a sustained virologic response (SVR). [84]

Conversely, if an early virologic response is not present, treatment should be stopped, because the chance of developing a sustained response of HCV eradication is less than 3%. Poynard et al reported that the one exception is in the context of clinical trials or treatment of recurrent HCV infection in liver transplant recipients [143] ; improved fibrosis scores have been reported in patients in whom the virus has not been eradicated, thus identifying a subgroup of patients who may benefit from maintenance therapy.

The HCV RNA level should be rechecked 6 months after the completion of treatment; if HCV RNA is detectable, the patient has had a relapse of the disease and an alternative treatment should therefore be considered. If HCV RNA is undetectable and test results remain negative, the patient has developed an SVR.

Patients with HCV infection should be monitored closely for adverse effects as well as response to therapy. Tests to help monitor drug toxicity include the following:

  • Complete blood cell count with differential
  • Renal function testing
  • Liver function tests (including alanine aminotransferase [ALT] level)
  • Thyrotropin level

Although measurement of ALT levels is useful for monitoring the effectiveness of therapy for HCV infection, ALT levels can fluctuate. Consequently, a single value in the reference range does not rule out active infection, progressive liver disease, or cirrhosis. ALT normalization with therapy is not proof of cure.

Patients with cirrhosis should be screened for hepatocellular carcinoma

and esophageal varices. They should also be monitored for the development of decompensated liver disease. Vaccination against hepatitis A virus (HAV) and hepatitis B virus (HBV) before or after completing HCV treatment has been recommended. [144] Patients should be offered vaccination for HAV and HBV before they develop decompensated liver disease (otherwise, if they are vaccinated after decompensation, they may be less likely to mount an immune response).

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