What the Infectious Disease Physician Needs to Know About Pegylated Interferon and Ribavirin

This review summarizes the relevant issues with pegylated interferon and ribavirin, with a particular focus on side effects profile and management, as well as their continued role in therapy given the emergence of interferon-free regimens.

Abstract

The treatment of chronic hepatitis C is rapidly evolving from triple therapy to regimens that do not require interferon or even ribavirin. However, pegylated interferon and ribavirin will remain the backbone of hepatitis C therapy for the time being. This review summarizes the pharmacokinetics of peginterferon and ribavirin with a particular emphasis on their side-effect profile and management. Finally, the continued role of peginterferon and ribavirin in future therapies will be discussed.

There has been a paradigm shift in the therapy of genotype 1 chronic hepatitis C infection following the United States Food and Drug Administration (FDA) approval of 2 oral, non-structural protein (NS3) protease inhibitors, boceprevir and telaprevir, in May 2011. Nevertheless, pegylated interferon (peginterferon) and ribavirin remain relevant in the treatment paradigm as these 2 agents form the backbone of the currently approved triple therapy regimens. In addition, peginterferon and ribavirin remain the standard of care for non-genotype-1 chronic hepatitis C infection. This review will focus on practical aspects of using peginterferon and ribavirin alone or in combination with an NS3 protease inhibitor.

PEGINTERFERON

Alfa interferons were among the first drugs used to treat chronic hepatitis C. Pegylated modification to the standard interferon molecule improved its pharmacokinetic profile and resulted in improved compliance and overall effectiveness compared to standard alfa interferon. Two formulations of peginterferon are approved for use in chronic hepatitis C: peginterferon alfa-2a (Pegasys, Roche Pharmaceuticals) and peginterferon alfa-2b (Peg-Intron, Schering-Plough Corporation). Minor differences in efficacy and safety were shown in a large, head-to-head comparison of both peginterferons in the IDEAL trial, which evaluated 3 regimens in subjects with hepatitis C virus (HCV) genotype 1: low-dose peginterferon alfa-2b (1 μg/kg/week), standard-dose peginterferon alfa-2b (1.5 μg/kg/week) and standard dose peginterferon alfa-2a (180 μg/week) plus ribavirin. The sustained virologic response (SVR) rates for the 2 FDA-approved peginterferon and ribavirin regimens were almost identical: 39.8% for peginterferon alfa-2b plus ribavirin and 40.9% for peginterferon alfa-2a with ribavirin. In addition, there were no substantial differences in efficacy between the low and high doses of peginterferon alfa-2b with ribavirin, 38% vs 39.8%, respectively [1]. A criticism of the trial design was the lower dose of ribavirin used in the peginterferon alfa-2a arm compared to the 2 peginterferon alfa-2b arms, which may explain the higher relapse rate observed in the peginterferon alfa-2a arm compared to the peginterferon alfa-2b arm, 31.5% vs 23.5% [1]. Subsequent comparisons of the 2 formulations of peginterferon, including a recent Cochrane meta-analysis of 8 trials, concluded that peginterferon alfa-2a had a small but significantly better efficacy compared to peginterferon alfa-2b (both in combination with ribavirin) in achieving SVR (47% vs 41%; risk ratio 1.11, 95% confidence interval 1.04–1.19; P = .004) but there was no significant difference in adverse events between the 2 formulations [2]. Selection of one formulation over the other involves physician experience, ease of dosing, and drug availability.

DOSING AND ADMINISTRATION

In adults, peginterferon alfa-2a is administered subcutaneously at a fixed dose of 180 µg once weekly together with oral ribavirin 1000–1200 mg daily, (infra vide for specific recommendations on ribavirin dosage). Peginterferon alfa-2a is approved for children and adolescents aged 5 to 18 years at a dose of 180 µg/1.73 m² × body surface area once weekly, to a maximum dose of 180 µg in combination with ribavirin. Dosing of peginterferon alfa-2b is weight-based: 1.5 µg/kg in combination with weight-based ribavirin 800 mg to 1400 mg daily (infra vide for specific recommendations on dosing). In pediatric patients (3 to 18 years), peginterferon alfa-2b is dosed at 60 µg/m² [3]. The duration of therapy for both preparations is 48 weeks for genotypes 1, 4–6 and 24 weeks for genotypes 2 and 3. The initial dose of peginterferon alfa-2a should be reduced to 135 μg/week in subjects with a creatinine clearance <30 mL/minute [4]. Dose reduction is also advised for peginterferon alfa-2b in patients with renal impairment.

In clinical practice the efficacy and safety profiles of both formulations of peginterferon are quite similar. Substituting one formulation for another during re-treatment of subjects who failed therapy usually does not lead to an improvement in the SVR rate and therefore is not advised.

SIDE EFFECTS OF PEGINTERFERON

Binding of type 1 interferon alfa to the interferon alfa receptor initiates a signal transduction pathway leading to the induction of multiple genes referred to as interferon stimulated genes (ISGs). These ISGs encode for multiple proteins that mediate the antiviral effects of interferon as well as its side effects. Side effects together with the injectable route of administration are important reasons as to why interferon is not more widely accepted. The 2 peginterferon preparations have comparable side effect profiles. In phase 3 clinical trials, nearly all patients experienced 1 or more adverse events. Serious adverse events occurred in 10% of patients treated with peginterferon alfa-2a and in 17% of patients treated with peginterferon alfa-2b, both in combination with ribavirin [5, 6]. Dose reductions due to adverse reactions were necessary in 38% of patients treated with peginterferon alfa-2a and 42% of those treated with peginterferon alfa-2b. The most common reasons for dose modifications were neutropenia (27% and 18%, respectively) and thrombocytopenia (4% and 3%, respectively). Fourteen percent and 10% of patients had to discontinue therapy due to an adverse event or laboratory abnormality, respectively. The most common reasons for discontinuing therapy were psychiatric (depression and irritability), systemic (eg, fatigue, headache), or gastrointestinal adverse events. Common side effects experienced by most patients are fatigue, fever, chills, myalgias, arthralgias, backache, headache, anorexia, nausea, diarrhea, impaired concentration, difficulty sleeping, weight loss, decreased libido, hair loss, and bone marrow suppression. These influenza-like symptoms are usually worse following the first injection of peginterferon and gradually improve over the next 3 to 4 injections. Other side effects occurring in >5% of patients with peginterferon monotherapy are listed in Table 1 [5, 6]. More serious but less common side effects (<1% to <5%) are listed in Table 1. Other serious advents events that are idiosyncratic and rare have been reported and the reader is advised to consult the package insert for each formulation of peginterferon for further information.

Table 1.

Side Effects of Pegylated Interferon and Ribavirin

Side Effects	Pegylated Interferon	Ribavirin
Common >5%	Injection site Inflammation	Anemia
	Fatigue	Pruritus
	Headache	Rash
	Chills and rigors	Fatigue and weakness
	Fever	Nausea
	Weight loss	Nasal stuffiness
	Dizziness
	Myalgia
	Arthralgia
	Musculoskeletal pain
	Nausea
	Anorexia
	Diarrhea
	Neutropenia
	Insomnia
	Depression
	Anxiety/emotional lability/irritability
	Dyspnea
	Cough
	Alopecia
	Pruritus
	Rash
	Dry skin
Serious (<1% to <5%)	Suicidal attempt	Symptomatic anemia
	Suicidal ideation	Myocardial infarction
	Severe depression	Angina pectoris
	Psychosis	Cerebrovascular accident
	Aggressive behavior	Acute gout
	Relapse of drug addiction/overdose	Gallstones
	Nerve palsy (facial, oculomotor)	Fetal loss
	Cardiomyopathy	Fetal abnormalities
	Myocardial infarction
	Angina pectoris
	Pericardial effusion
	Retinal ischemia
	Retinal artery or vein thrombosis
	Blindness
	Decreased visual acuity
	Optic neuritis
	Transient ischemic attack
	Supraventricular arrhythmias
	Syncope
	Sepsis
	Bronchiolitis obliterans
	Pleural effusion
	Gastroenteritis
	Pancreatitis
	Gout
	Hyperglycemia
	Hypothroidism/hyperthyroidism
	Autoimmune thrombocytopenia
	Rheumatoid arthritis
	Interstitial nephritis
	Lupus-like syndrome
	Sarcoidosis
	Worsening of psoriasis
	Urticaria
	Injection-site necrosis
	Vasculitis
	Phototoxicity

RIBAVIRIN

Ribavirin is a synthetic guanosine nucleoside analogue with antiviral activity against a broad range of RNA viruses. Ribavirin monotherapy has been shown to decrease and even normalize serum alanine aminotransferase levels and improve hepatic necro-inflammation in some, but has no or minimal effects on hepatic fibrosis or serum HCV-RNA levels [7].

The addition of ribavirin to interferon was the first major advancement in therapy for chronic hepatitis C, leading to a doubling in SVR rates from 13%-20% with standard interferon monotherapy to 39%–42% when administered for 48 weeks [8]. The introduction of peginterferon in combination with ribavirin further increased SVR rates to 54%–56%. Although ribavirin has been used in the clinic for >30 years, its mechanism of action is largely unknown. This has hindered the development of other ribavirin-like compounds that lack its side effect profile. There is evidence for both direct and indirect antiviral [9–11]. as well as immune-mediated mechanisms of action [9, 12].

DOSING AND ADMINISTRATION OF RIBAVIRIN

Ribavirin is administered orally in 2 divided doses. Dosing is based according to body weight, HCV genotype, and formulation of peginterferon prescribed (see Table 2 for specific dosing information).

Table 2.

Ribavirin Dosing for Chronic Hepatitis C Treatment

	In Combination With Peginterferon Alfa-2a	In Combination With Peginterferon Alfa-2b
Genotypes 1 & 4–6	Body weight ≤75 kg: 1000 mg/d	Body weight <65 kg: 800 mg/d
	Body weight >75 kg: 1200 mg/d	Body weight 65–85 kg: 1000 mg/d
		Body weight 86–105 kg: 1200 mg/d
		Body weight 106–125 kg: 1400 mg/da
Genotypes 2 & 3b	800 mg/d	800 mg/d
HIV-HCV coinfection (all genotypes)c	800 mg/d	800 mg/d
Children aged 2–17 yd	15 mg/kg/d in 2 divided doses	15 mg/kg/d in 2 divided doses

Abbreviations: HCV, hepatitis C virus; HIV, human immunodeficiency virus.

^a Based on large, post-marketing community study.

^b Some practitioners may choose to use weight-based dosing for genotype 2 and 3 patients with the goal of shortening therapy to 12–16 weeks, if a rapid virologic response (HCV RNA undetectable by treatment week 4) is achieved.

^c No benefit of higher ribavirin doses were shown in a recent study. Higher doses were associated with a higher incidence of anemia [53].

^d Available as an oral solution for children.

Ribavirin is renally excreted and can accumulate to toxic levels in patients with renal impairment. Recent changes to the peginterferon alfa-2a label advise using reduced doses of ribavirin, alternating 200 mg with 400 mg every other day in patients with chronic kidney disease and 200 mg daily in patients with creatinine clearance <30 mL/minute and on hemodialysis. These are guidelines and caution and close monitoring of hemoglobin level and/or referral to a specialist is advised when using ribavirin in patients with advanced stages of chronic kidney disease.

SIDE EFFECTS OF RIBAVIRIN THERAPY

Dose-dependent hemolytic anemia is the most common side effect of ribavirin therapy. Approximately two-thirds of patients experience anemia but <1% of patients develop severe anemia (hemoglobin <8 g/dL). Hemoglobin levels usually return to baseline within 4–12 weeks after stopping therapy. The anemia is due to accumulation of ribavirin in erythrocytes because the non-nucleated erythrocyte is unable to export ribavirin triphosphate. High intra-erythrocyte levels of ribavirin result in decreased availability of ATP, leading to a greater susceptibility to oxidative damage and intravascular hemolysis [13]. Recently, it was demonstrated that individuals with polymorphisms of the inosine triphosphatase (ITPA) gene that result in ITPA deficiency were less susceptible to ribavirin-induced hemolysis. Unfortunately, only a small proportion of individuals in the general population have the beneficial ITPA genotype [14].

Other common side effects associated with ribavirin use include pruritis or rash, fatigue, nasal stuffiness, and gastrointestinal upset. More serious side effects include acute gout, development of pigment gallstones, fetal death, and fetal abnormalities (infra vide section on pregnancy).

WHY DOES RIBAVIRIN REMAIN IMPORTANT?

Though the mechanism by which ribavirin exerts its antiviral activity is unclear, ribavirin remains critical for the success of therapy for chronic hepatitis C. Its major clinical effect is the prevention of virologic relapse and it also has a small, but significant antiviral activity [15]. In the peginterferon alfa-2a phase 3 trial, patients who received peginterferon alfa-2a plus ribavirin had a 10% higher end of treatment response than those who received peginterferon alone, 69% vs 59%, respectively. More importantly, patients who received peginterferon plus ribavirin had significantly higher SVR rates (56%) compared to those who received peginterferon alone (29%), highlighting the critical role of ribavirin in reducing virologic relapse.

In the era of direct-acting antivirals, ribavirin still appears to be relevant in preventing relapse and the development of antiviral resistance. This was first shown in the PROVE 2 study, which compared 2 ribavirin-containing triple drug regimens (telaprevir, peginterferon, and ribavirin for 12 weeks followed by peginterferon and ribavirin for an additional 12 weeks or 24 weeks) to a ribavirin-free regimen (telaprevir and peginterferon for 12 weeks followed by 12 weeks of peginterferon) and standard of care (peginterferon and ribavirin for 48 weeks). The SVR rate in the ribavirin free arm was only 36% compared to 60% and 69% in the 2 ribavirin-containing arms [16]. Virologic breakthrough was 1% and 5% in patients who received ribavirin compared to 24% in the non-ribavirin-containing arm. A more recent study that evaluated an interferon-free regimen using a NS3 protease inhibitor with a non-nucleoside polymerase inhibitor for chronic hepatitis C demonstrated that the addition of ribavirin dramatically reduced the emergence of antiviral resistance from 87% to 15% [17]. Thus, ribavirin is likely to be part of direct-acting antiviral regimens in the foreseeable future, particularly for interferon resistant patients (partial and null responders), serving to prevent virologic relapse and development of antiviral resistance. However, it is possible the combination of several potent direct-acting antivirals against multiple viral and/or host targets might negate the need for ribavirin in treatment-naive patients [17–19].

MANAGEMENT OF PEGINTERFERON AND RIBAVIRIN SIDE EFFECTS—WHEN TO DOSE REDUCE AND WHEN TO USE GROWTH FACTORS?

In our experience, hematologic and neuro-psychiatric side-effects during therapy are the most troublesome and difficult to manage. Interferon is a potent suppressor of bone marrow function and cytopenias tend to be more common in patients with hypertension and elevated serum creatinine levels [20]. Anemia usually results from peginterferon-related bone marrow suppression and ribavirin-induced hemolysis. In the phase 3 studies of peginterferon and ribavirin, 9% to 16% of subjects experienced a decline in hemoglobin level to <10 g/dL with a maximal drop in hemoglobin of 3.7 g/dL, and dose modification was required in 9%–13% of subjects [21, 22]. The largest decline in hemoglobin usually occurs within the first 4–8 weeks of therapy. Erythropoiesis-stimulating agents (ESAs) such as erythropoietin and darbepoietin have been used to manage the anemia during therapy with peginterferon and ribavirin. Their use has been associated with an improved sense of well-being and less requirement for ribavirin dose reduction, but not with improved SVR rates [23–25]. While generally safe, erythropoietin and darbepoietin use has been associated with serious side effects including hypertension, venous thromboembolism, pure red cell aplasia, and death [26, 27]. As a consequence, clinical guidelines recommend dose reduction of ribavirin as the first-line response to anemia. The ribavirin dose should be reduced in increments of 200 mg/day once the hemoglobin levels falls below 10 g/dL and both peginterferon and ribavirin should be discontinued if the hemoglobin level drops below 8.5 g/dL [5, 6]. For patients with a history of cardiac disease, the peginterferon dose should be reduced by half and the ribavirin dose cut by 200 mg/day if a >2 g/dL decrease in hemoglobin is observed during any 4-week period [5, 6].

Anemia is more frequent with triple therapy regimens compared to combination therapy. Data from the phase 3 boceprevir and telaprevir studies in treatment-naive subjects reported that anemia, defined as a hemoglobin level <10 g/dL, occurred in 49% and in 36% of patients, respectively [28, 29]. In both phase 3 trials, significant anemia (hemoglobin <8.5 g/dL) occurred in 9% of subjects [28, 29]. Retrospective analyses of both phase 3 trials indicated that the dose of ribavirin can be reduced as early as 4 weeks and to as low as 400 mg daily without having a significant impact on SVR rates [30]. ESA use can be considered in patients with severe (persistently ≤10 g/dL), symptomatic, or progressive anemia, despite a reduced dose of ribavirin and in cirrhotics but this should be on an individual basis depending on how well the patient is tolerating therapy and the response to treatment. It is important to note that the dose of protease inhibitors cannot be reduced. If the anemia becomes severe enough to require cessation of ribavirin, boceprevir or telaprevir must be stopped as well. ESA agents are an unlabeled indication for management of anemia during HCV therapy and should be discontinued once the hemoglobin level is ≥12 g/dL.

The incidence of neutropenia is higher with peginterferon compared to standard interferon. Neutropenia was a frequent laboratory abnormality in the phase 3 peginterferon registration trials, occurring in 18% to 20% of subjects [5, 6]. It was the most common laboratory disorder resulting in peginterferon dose reduction. Severe neutropenia (absolute neutrophil count [ANC] <500 cells/µL) occurred in <1% of subjects [5, 6]. Despite the decline in the neutrophil count, serious infections were uncommon [31]. Constitutional neutropenia (common among African Americans) may worsen with interferon therapy but is not a contraindication to therapy [31]. In the phase 3 trials, peginterferon dose was reduced 50% for an ANC of ≤750 cells/µL and permanently discontinued for an ANC of <500 cells/µL. There is no role for prophylactic antibiotics except perhaps in those with advanced cirrhosis (Child-Turcotte-Pugh class B and C). Serious infections resulting in death have been reported, so infections should be treated expeditiously; consideration should be given to discontinuing therapy particularly in patients with cirrhosis. Several small studies have evaluated the use of granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor to improve white blood cell counts in patients receiving peginterferon and ribavirin but like ESA use, they generally do not lead to better SVR rates and significantly increase the cost of treatment [32–34].

Thrombocytopenia is usually due to bone marrow suppression related to peginterferon. Platelet counts decrease in approximately 20% of patients receiving peginterferon and ribavirin and thrombocytopenia is more common in cirrhotic patients. Despite the occurrence of thrombocytopenia, bleeding events are uncommon and usually do not occur until the platelet count falls below 50 000/µL. Moderate thrombocytopenia (platelets 51 000–80 000/µL) should be managed by reducing the peginterferon dose by 50%. Severe thrombocytopenia (platelets <50 000/µL) should lead to permanent discontinuation of peginterferon and ribavirin [5, 6]. In clinical practice, the threshold for discontinuing peginterferon for severe thrombocytopenia may differ from that used in clinical trials and the FDA recommendations. Thus, some practitioners may choose to dose reduce depending on the response to therapy, but these decisions should be individualized after an informed discussion with the patient.

Eltrombopag, a small molecule agonist of c-mpl receptor, the physiologic target of thrombopoietin, has been evaluated in chronic hepatitis C patients with thrombocytopenia [35, 36]. Therapy with eltrombopag resulted in improvement in platelet counts enabling patients to remain on therapy resulting in better SVR rates compared to those who received placebo (23% vs 14%) [36]. However, the FDA has issued a safety alert for use of eltrombopag in patients with chronic liver disease due to a high incidence of portal vein thrombosis [37].

Psychiatric side effects are particularly challenging to manage and are a frequent reason for dose reduction or discontinuation of treatment. Significant depressive symptoms occur in 21% to 58% of interferon-treated patients. Persons with psychiatric disorders are thought to be at higher risk for these side effects [38]. Early identification of depression, by direct questioning of the patient or through use of self-reported questionnaires, is important to subsequent management. Mild to moderate depression can be managed with the use of anti-depressants, particularly selective serotonin re-uptake inhibitors (paroxetine and escitalopram were the most used in trials related to interferon treatment in chronic hepatitis C) [39, 40] and antiviral treatment continued with or without dose reduction depending on the severity of symptoms. On the other hand, treatment should be stopped immediately and the patient referred to a mental health professional for patients with suicidal ideation or suicide attempt. Use of prophylactic antidepressants is controversial [41, 42]. However, 2 recent studies have shown prophylactic escitalopram to be effective in reducing the incidence and severity of interferon-induced depression in patients with no prior psychiatric disease [43, 44]. Escitalopram use has been associated with QT prolongation and caution is advised in patients with bradyarrhthymias or congestive heart failure (most of whom would be excluded from treatment with peginterferon and ribavirin). Thus, use of antidepressants should be on an individual basis taking into consideration the risks and side effects of each agent. Patients with other psychiatric disorders should be evaluated by a psychiatrist to determine treatment eligibility. Many patients may be successfully treated with a multi-disciplinary approach to management of neuropsychiatric side effects and can achieve SVR rates that are similar to those of patients without psychiatric disorders [45].

ROUTINE LAB TESTING WHILE ON THERAPY

Laboratory testing is required prior to starting therapy and periodically thereafter to monitor for adverse effects, to establish response to treatment and to implement stopping rules. Each regimen has different monitoring schedules and the reader is referred to treatment guidelines for more in-depth information.

PREGNANCY

Ribavirin is designated as a Category X drug and is absolutely contraindicated in pregnant females. Teratogenecity has been reported from animal studies at doses equivalent to about 0.01 times the maximum recommended human dose. The ribavirin pregnancy registry has also reported a 4%–6% incidence of birth defects among documented exposures to ribavirin in pregnant mothers [46]. A negative pregnancy test is required prior to initiation of ribavirin and monthly thereafter while on therapy for women and female partners of male patients of childbearing potential. It is advised that females of childbearing age, female partners of male patients, and/or male patients with female partners of childbearing potential use 2 reliable methods of contraception while on therapy and until 6 months after completion of treatment. Interferon is designated a pregnancy Category C drug, and there is no evidence to suggest that telaprevir or boceprevir is teratogenic.

COMORBIDITIES OF CONCERN WHEN CONSIDERING PEGINTERFERON AND RIBAVIRIN

The presence of underlying medical conditions should be sought as part of the evaluation process prior to initiating therapy with peginterferon and ribavirin. Some medical conditions are absolute whereas others are relative contraindications to starting therapy. Absolute contraindications include decompensated liver disease (Child-Turcotte-Pugh score >6), active coronary artery disease, active infection, poorly controlled seizure disorder, active inflammatory bowel disease, end-stage kidney disease, active psychosis or drug use, major depression, cytopenia, or any poorly controlled medical condition that could be worsened by therapy. Medical conditions that may pose as relative contraindications include poorly controlled diabetes, depression, underlying rheumatological conditions, or active medical conditions whose course could be worsened by peginterferon or ribavirin such as patients with hemoglobinopathies. Individuals with risk factors for coronary heart disease should undergo stress testing because development of anemia can precipitate ischemic events. Similarly, patients with a history of diabetes and hypertension should undergo a baseline ophthalmologic and otological examination due to a higher rate of ophthalmic and auditory complications. Patients with comorbidities that are relative contraindications to treatment with peginterferon and ribavirin should be managed by a multi-disciplinary team in order to obtain best possible outcomes and to prevent serious complications.

There is need for caution and proper drug selection when peginterferon and ribavirin are administered to human immunodeficiency virus/HCV co-infected subjects who are receiving highly active antiretroviral therapy (HAART) due to the interactions or additive toxicities between these agents and ribavirin. Mitochondrial toxicity associated with didanosine leading to hepatic decompensation or pancreatitis [47, 48] or exacerbation of weight loss with stavudine [49] are problematic. Use of zidovudine enhances the risk of ribavirin-associated anemia and should be avoided [50]. Finally, there is a concern that use of abacavir may interfere with response to ribavirin due to competition for the phosphorylation pathway required for formation of the active metabolite [51, 52]. This issue has been largely overcome by using weight-based ribavirin instead of the fixed 800-mg daily dose. Significant drug–drug interactions are known to occur between HAART and telaprevir or boceprevir, and the product label or informative websites should be consulted before initiating therapy with these agents.

SUMMARY

In the rapidly changing treatment landscape, peginterferon and ribavirin will continue to play an important role in therapy of chronic hepatitis C, particularly in direct acting antiviral regimens for treatment-experienced subjects. Prescribing physicians must be aware of their side effects and how to manage them. Such knowledge is crucial in preventing and treating life-threatening complications due to these drugs. Despite their long history in therapy of chronic hepatitis C, the ultimate goal is to develop interferon-free regimens for both treatment-naive and -experienced subjects and special populations.