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Review |

Treatment of Hepatitis C:  A Systematic Review FREE

Anita Kohli, MD, MS1,2; Ashton Shaffer, BA3; Amy Sherman, MD3; Shyam Kottilil, MD, PHD3
[+] Author Affiliations
1Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland
2Critical Care Medicine Department, Clinical Research Center, National Institutes of Health, Bethesda, Maryland
3Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
JAMA. 2014;312(6):631-640. doi:10.1001/jama.2014.7085.
Text Size: A A A
Published online

Importance  Hepatitis C virus (HCV) infects more than 185 million individuals worldwide. Twenty percent of patients chronically infected with HCV progress to cirrhosis. New, simpler therapeutics using direct-acting antivirals that target various stages of the HCV life cycle are in development to eradicate HCV without concomitant interferon.

Objectives  To summarize published evidence on safety, efficacy (measured by a sustained virologic response [SVR], which is the treatment goal of undetectable plasma HCV RNA 12 or 24 weeks after therapy completion), and tolerability of current US Food and Drug Administration–approved interferon-based regimens and oral interferon-free regimens used for treating HCV infection and coinfection with human immunodeficiency virus (HIV) and HCV; to provide treatment recommendations for specialists and generalists based on published evidence.

Evidence Review  A literature search of Web of Science, Scopus, Embase, Agricola, Cochrane Library, Cinahl Plus, ClinicalTrials.gov, Conference Papers Index, Gideon, PsycINFO, Google Scholar, and Oaister was conducted from January 1, 2009, to May 30, 2014. Publications describing phase 2, 3, and 4 studies evaluating the treatment of HCV were included. Forty-one studies involving 19 063 adult patients were included. Strength of clinical data and subsequent HCV treatment recommendations were graded according to the Oxford Centre for Evidence-Based Medicine.

Findings  Patients infected with HCV genotype 1 represent 60% to 75% of HCV infections in the United States. Hepatitis C virus genotype 1 is more difficult to cure than genotype 2 or genotype 3. Patients with HCV genotype 1 should receive treatment with sofosbuvir + pegylated interferon + ribavirin because of the shorter duration of therapy and high rates of SVR (89%-90%). Simeprevir + pegylated interferon + ribavirin is an alternative for patients with HCV genotype 1 (SVR, 79%-86%). Patients with HCV genotypes 2 and 3, representing 20% to 29% of US HCV infections, should receive therapy with sofosbuvir + ribavirin alone (SVR for genotype 2, 12 weeks’ duration: 82%-93%; SVR for genotype 3, 24 weeks’ duration, 80%-95%). Patients with HIV-HCV coinfection and patients with compensated cirrhosis (ie, cirrhosis but preserved synthetic liver function) should receive the same treatment as HCV-monoinfected patients.

Conclusions and Relevance  New, short-duration, simpler therapies result in high SVR rates for HCV-infected patients. In conjunction with increased screening for HCV as suggested by recent Centers for Disease Control and Prevention guidelines, availability of new therapies may lead to the treatment of many more people with chronic HCV infection.

Figures in this Article

Hepatitis C virus (HCV) infects an estimated 185 million individuals worldwide1 and 3.4 million to 4.4 million people in the United States.2 Approximately 80% of acutely infected HCV patients progress to chronic infection, 20% of whom develop cirrhosis within 25 years, with 25% of patients with cirrhosis developing hepatocellular carcinoma and/or decompensated liver disease.3,4 Hepatitis C virus is the primary cause of liver transplantation in the United States.5

There are 6 known genotypes of HCV. The most common genotypes in the United States are genotype 1 (subtypes are 1a and 1b), genotype 2, and genotype 3, which together comprise 97% of all infections.6 Although there is no difference in the risk of cirrhosis according to genotype, genotype 3 is associated with a higher rate of hepatic steatosis7 and genotype 1b is associated with a higher rate of hepatocellular carcinoma.8 The prevalence of hepatitis C is particularly high in subpopulations of incarcerated people, homeless people, veterans, and patients infected with human immunodeficiency virus (HIV) (Table 1). Since the discovery of HCV in 1989,14 strategies to cure the infection have evolved dramatically. A cure is defined as a sustained virologic response (SVR) and consists of undetectable levels of plasma HCV RNA 12 or 24 weeks after therapy completion (Box 1).16

Table Graphic Jump LocationTable 1.  Prevalence of HCV Genotypes and of HCV Infection in the United States by Risk Factor

Box Section Ref ID

Box 1.
Definitions of Treatment Response to HCV Treatment15
  • Nonresponse: detectable HCV RNA after 12 weeks of HCV therapy

  • Partial response: >2 log decline in HCV RNA but detectable HCV RNA after 12 weeks of HCV therapy

  • Null response: ≤2 log decline in HCV RNA after 12 weeks of HCV therapy

  • Viral breakthrough: detectable HCV RNA after previously undetectable

  • Relapse: undetectable HCV RNA on therapy with detectable HCV RNA after stopping therapy

  • Sustained virologic response: undetectable HCV RNA 12 or 24 weeks after stopping therapy

HCV indicates hepatitis C virus.

Alfa interferons, which are immunomodulatory agents administered as subcutaneous injections, were the first to be used to treat HCV successfully (Table 2). Subsequently, ribavirin, an oral antiviral nucleoside analog, was added to improve cure rates.17,18 More recently, oral directly acting antivirals (DAAs) that target various stages of the HCV life cycle have been developed (Figure).

Table Graphic Jump LocationTable 2.  Mechanism of Action, Activity, and Adverse Effects of HCV Therapies
Place holder to copy figure label and caption
Figure.
Steps in the Hepatitis C Virus Life Cycle Targeted by Directly Acting Antiviral Agents

Directly acting antiviral agents (DAAs; shown in cyan) disrupt hepatitis C virus (HCV) replication by targeting critical enzymatic steps in the HCV life cycle. Antiviral drug treatment with a DAA combined with ribavirin with or without pegylated interferon, depending on HCV genotype (see Table 4), increases suppression of HCV replication compared with interferon and ribavirin alone, leading to improved sustained virologic response rates. The illustration is schematic; structures are not to scale. Question marks indicate that mechanism of action is uncertain. Abbreviations: E, envelope glycoprotein; NS, nonstructural protein; + and −, positive and negative HCV RNA strands.

aNot approved by the US Food and Drug Administration.

Graphic Jump Location

The field of HCV therapeutics is evolving to develop strategies for eradicating HCV without using interferon formulations and/or ribavirin. This change simplifies treatment, improves tolerability, and decreases therapy duration, all while maintaining or increasing rates of SVR.

This review summarizes published data on interferon-based and oral interferon-free treatment regimens for patients infected with HCV genotypes 1, 2, or 3 from published phase 2, 3, and 4 randomized clinical trials (RCTs) and cohort studies of US Food and Drug Administration (FDA)–approved medications. We provide treatment recommendations for management of patients infected with HCV genotypes 1, 2, or 3.

This systematic review was conducted according to PRISMA guidelines.19 The National Library of Medicine through PubMed was searched for the hepatitis C (MeSH) filters clinical trial, phase II; clinical trial, phase III; and clinical trial, phase IV. The search was conducted for studies published between January 1, 2009, and May 30, 2014. In addition, we searched the following databases for the terms hepatitis C AND clinical trial AND phase II OR phase III OR phase IV: Web of Science, Scopus, Embase, Agricola, Cochrane Library, Cinahl Plus, ClinicalTrials.gov, Conference Papers Index, Gideon, PsycINFO, Google Scholar, and Oaister. Our search strategy included studies published in any language from 2009 to May 30, 2014. References of identified articles were searched for additional relevant articles. Randomized clinical trials and relevant cohort studies were included if they were published in English, used FDA-approved therapies that included SVR as a primary or secondary end point, and defined treatment-experienced patients using American Association for the Study of Liver Diseases definitions.15 Studies presenting information exclusively about patients undergoing liver transplant, acute HCV, and HCV genotypes other than 1 through 3 and dose-finding studies were excluded. Data including study design, participant demographics, stage of liver disease, treatment regimens and durations, and SVR were extracted by coauthors and recorded on a standardized electronic data collection sheet. The strength of clinical data and subsequent recommendations for treatment of HCV-infected patients were graded according to the Oxford Centre for Evidence-Based Medicine levels of evidence20 by 2 authors independently, with discrepancies resolved after joint article review and discussion. Levels of evidence are as follows: level 1A, systematic reviews (with homogeneity of randomized clinical trials); level 1B, individual randomized clinical trials (with narrow confidence intervals); level 2A, systematic reviews (with homogeneity of cohort studies); and level 2B, individual cohort studies (including low-quality randomized clinical trials). Grades of recommendation are as follows: A, consistent level 1 studies; B, consistent level 2 or 3 studies or extrapolations from level 1 studies; C, level 4 studies or extrapolations from level 2 or 3 studies; and D, level 5 evidence or troublingly inconsistent or inconclusive studies of any level.

Five hundred eighty relevant studies were screened and assessed for eligibility. After applying inclusion and exclusion criteria (eFigure in the Supplement), 41 studies (33 RCTs and 8 cohort studies) with 19 063 adult patients were selected for inclusion.

Table 3 summarizes included studies’ findings and evidence levels. A full description of treatment regimens, duration, number of participants, demographics, SVR, and discontinuations for each study is available in eTables 1 through 3 in the Supplement.

Table Graphic Jump LocationTable 3.  Studies Evaluating Hepatitis C Treatment Using SVR as Outcome, 2000-2013: Summary of Systematic Review and Findings
Evidence for Use of Telaprevir or Boceprevir + Pegylated Interferon + Weight-Based Ribavirin for Patients With HCV Genotype 1

Boceprevir and telaprevir are selective HCV nonstructural protein (NS) 3/4A serine protease inhibitors. These drugs were the first DAAs developed and found to be effective in treating patients with HCV genotype 1. Based on the outcome of SVR, 7 evidence level 1B RCTs demonstrate the superiority of triple therapy using telaprevir2124,50 or boceprevir2527 with pegylated interferon + weight-based ribavirin (1 g/d for ≤75 kg and 1.2 g/d for >75 kg) for the treatment of HCV genotype 1 treatment-naive patients (SVR range, 61%-75%) compared with treatment with pegylated interferon + weight-based ribavirin (SVR range, 38%-49%).2126,28

Shortened durations (24 weeks for telaprevir- and 28 weeks for boceprevir-containing regimens) for patients who achieve rapid viral load declines within the first 12 weeks of therapy are as effective as fixed-duration therapy of 48 weeks.21,26

Four evidence level 1B RCT and 2 level 2B studies evaluated telaprevir29,30,32,33 or boceprevir26,31 + pegylated interferon + weight-based ribavirin in treatment-experienced patients. Previous partial responders and patients who relapsed had significant improvement in SVR rates when treated with telaprevir- or boceprevir-containing regimens for up to 48 weeks (SVR range, 69%-83%) compared with pegylated interferon + weight-based ribavirin alone (SVR range, 20%-29%). Previous null responders had modest increases in SVR rates with telaprevir-based therapy (SVR range, 39%-56% vs 9%-17%) (Table 3).29

Evidence for Simeprevir + Pegylated Interferon + Weight-Based Ribavirin for Patients With HCV Genotype 1

Two DAAs, simeprevir and sofosbuvir, were recently approved for treating HCV. Simeprevir, an HCV NS3/4 serine protease inhibitor, was evaluated in treatment-naive patients and patients who had relapsed in 4 evidence level 1B studies34,35 and 1 level 2B study,36 showing higher rates of SVR (79%-86%) using 12 to 24 weeks of simeprevir + 24 to 48 weeks of pegylated interferon + weight-based ribavirin compared with pegylated interferon + weight-based ribavirin alone (SVR range, 37%-65%). In one representative study, 88% of participants had an early viral load decline (HCV RNA less than quantifiable at weeks 4 and undetectable at week 12) and were eligible for a shortened total duration of therapy of 24 weeks, with 83% to 88% of patients achieving SVR.35 Patients without an early viral load decline were less likely to achieve SVR (range, 22%-32%).35

One evidence level 1B study37 of simeprevir in previous null and partial responders and relapsers showed that 12 to 48 weeks of simeprevir + pegylated interferon + weight-based ribavirin for 48 weeks resulted in high rates of SVR (67%-80%) compared with pegylated interferon + weight-based ribavirin alone (36%). Response rates to simprevir-containing therapy, however, were lower in null responders (41%-59% vs 19%) and partial responders (65%-86% vs 9%) than previous relapsers (76%-89% vs 37%) but higher compared with pegylated interferon + weight-based ribavirin. In both treatment-naive and treatment-experienced patients infected with HCV genotype 1a, those with a Q80K polymorphism in the NS3 region of hepatitis C virus responded less well to simeprevir-containing therapy (26%-31% difference in SVR).

Evidence for Use of Sofosbuvir + Pegylated Interferon + Weight-Based Ribavirin for Patients With HCV Genotype 1

Most recently, sofosbuvir, an HCV NS5b nucleotide polymerase inhibitor, has been approved for treating HCV infection. Two evidence level 1B studies38,39 and 1 level 2B study40 showed high SVR rates (89%-90%) after treatment with only 12 weeks of sofosbuvir + pegylated interferon + weight-based ribavirin in treatment-naive patients. There was no benefit to extending treatment duration to 24 weeks or use of response-guided therapy (SVR range, 89%-91%).38,39

Evidence for Use of an All-Oral Regimen of Sofosbuvir + Ribavirin in Patients With HCV Genotypes 1, 2, and 3

An evidence level 1B study40 among patients with HCV genotypes 2 and 3 demonstrated improved response to sofosbuvir + weight-based ribavirin therapy for 12 weeks compared with pegylated interferon + weight-based ribavirin for 24 weeks (97% with sofosbuvir vs 78% with pegylated interferon) in treatment-naive patients with HCV genotype 2. This high SVR rate in patients with HCV genotype 2 treated with sofosbuvir + weight-based ribavirin was confirmed in another evidence level 2B study.44 One level 1B study43 and 1 level 2B44 study showed a benefit in longer-duration therapy (12 weeks vs 16 weeks) with sofosbuvir + ribavirin for treatment-experienced patients with HCV genotype 3 (30% vs 62%) and an even larger benefit with 24 weeks of therapy in patients with HCV genotype 3 who were treatment experienced (80%) and treatment naive (95%) but not in patients with HCV genotype 2 (82% for treatment-experienced and 89% for treatment-naive).

Sofosbuvir + ribavirin for 12 to 24 weeks in HCV genotype 1 was evaluated in 2 evidence level 2B studies.41,42 Response to treatment in patients with HCV genotype 1 who were treatment naive was 68% to 84%.

Special Populations
Patients With Compensated Cirrhosis

Few patients with compensated cirrhosis (ie, without jaundice, ascites, encephalopathy, or variceal hemorrhage) have been included in clinical trials of regimens using new DAAs, and patients with signs of portal hypertension (as evidenced by a platelet count <90×103/μL) are generally excluded. In 4 studies,21,2426 treatment-naive patients with cirrhosis treated with telaprevir-containing therapy (62%-63% vs 75%) or boceprevir-containing therapy (41%-52% vs 67%-76%) had lower response rates than patients without cirrhosis. In a subanalysis of 1 study40 of sofosbuvir + pegylated interferon + weight-based ribavirin for 12 weeks, patients with cirrhosis responded less well than patients without cirrhosis (80% vs 92%). Similarly, response to sofosbuvir + weight-based ribavirin alone for 24 weeks in patients with HCV genotype 1 was lower in patients with stage 3 or 4 liver disease (54% vs 79% with stage 2 or lower diease).42 Response to treatment with simeprevir + pegylated interferon + weight-based ribavirin was lower in patients with bridging fibrosis or cirrhosis compared with those with less liver fibrosis for both treatment-naive patients (68% vs 84%) and treatment-experienced patients (73% vs 82% in previous relapsers, 67% vs 79% in partial responders, and 33% vs 66% in null responders).35,37

These differences were not observed among patients with HCV genotype 2 who were treated with 12 weeks of sofosbuvir + weight-based ribavirin (83%-94% with fibrosis vs 92%-97% without fibrosis). Extending the duration of sofosbuvir + weight-based ribavirin combination therapy for treatment-naive patients with HCV genotype 3 from 12 weeks to 24 weeks improved SVR rates for patients with cirrhosis (21% vs 92%). This extended duration also resulted in a higher response rate in treatment-experienced patients with cirrhosis (SVR, 60%); however, this rate is still lower than that seen in treatment-experienced patients without cirrhosis (SVR, 85%) who were treated for the same duration.40,43,44

Patients With HIV-HCV Coinfection

About one-third of all HIV-infected patients are also coinfected with HCV.12 Response rates to pegylated interferon + weight-based ribavirin in 2 evidence level 2B studies47,48 were poor in treatment-naive and treatment-experienced coinfected patients (36%-15%). Two evidence level 1B studies45,46 showed that the addition of telaprevir or boceprevir to pegylated interferon + weight-based ribavirin (SVR rates, 74% and 63%) was superior to pegylated interferon + weight-based ribavirin alone (SVR rates, 30% and 45%). However, sofosbuvir + weight-based ribavirin therapy for 24 weeks resulted in high response rates in patients with HCV genotypes 1, 2, and 3 (SVR range, 76%-92%) in 1 evidence level 2B study.44

In summary, the addition of DAAs to pegylated interferon + ribavirin leads to significant improvements in SVR rates. The regimen of sofosbuvir + ribavirin has high SVR rates in small studies of patients with HIV-HCV coinfection.

Minorities

Limited data have been published regarding treatment of African American and Hispanic patients using regimens that include sofosbuvir or simeprevir. One study, however, included a subanalysis of 159 African American patients and showed an improvement in SVR with boceprevir + pegylated interferon + weight-based ribavirin (SVR, 53%) over pegylated interferon + weight-based ribavirin alone (SVR, 23%).27

Recently, polymorphisms in the upstream promoter region of the IL28B gene were described that partially explained differential response rates to interferon-containing therapy for HCV genotype 1 infection among races, with individuals who carry the CC genotype (enriched in Asians or whites) more likely to respond to therapy than those with a TT genotype (enriched in African American populations).4 Subanalyses of studies in treatment-naive patients using simeprevir have shown this regimen to be more effective in patients carrying the IL28B CC polymorphism compared with those without the CC genotype (94%-97% vs 68%-58%34,35). The predictive ability of IL28B in patients treated with sofosbuvir + pegylated interferon + weight-based ribavirin or sofosbuvir + weight-based ribavirin is unclear.3840

Other Populations

Few data are available regarding the use of DAAs in patients with impaired renal function (ie, glomerular filtration rate <50) or end-stage renal disease. This group may be at an increased risk of adverse events, particularly anemia in regimens containing ribavirin, and may require dose reductions in medications. No DAAs have been studied or are approved for use in children.

Safety and Adverse Events

A major deterrent for wide use of interferon alfa + ribavirin in the treatment of HCV has been the spectrum of adverse events associated with them (Table 2). The addition of boceprevir to pegylated interferon + ribavirin regimens is further associated with an increased incidence of anemia, dysgeusia, and neutropenia compared with pegylated interferon + ribavirin alone.25,26 The addition of telaprevir to pegylated interferon + ribavirin is associated with increased fatigue, pyrexia, nausea, diarrhea, hemorrhoids, pruritus, rashes, alopecia, insomnia, and anemia.22,24 Given the diversity in adverse events reported, no formal statistical comparison of adverse events on various treatment regimens was performed in this review, but the rates of discontinuation of medications were higher in treatment groups containing telaprevir or boceprevir than pegylated interferon + ribavirin alone (ranges, 9%-26% vs 8%-25% vs 2%-16%, respectively). The addition of sofosbuvir to pegylated interferon + ribavirin is associated with increased fatigue, nausea, anemia, pyrexia, and neutropenia, with the range of patients who discontinued therapy increasing with treatment duration from 12 weeks (range, 2%-6%) to 24 to 48 weeks (range, 2%-14%).3840 During therapy with sofosbuvir + ribavirin alone, fatigue, headache, nausea, insomnia, irritability, and pruritus were the most common adverse events. Anemia occurred in up to 10% of patients receiving sofosbuvir + ribavirin; however, discontinuations of this regimen were rare (range, 0%-1%).40,41 The addition of simeprevir is associated with increased rash, transient hyperbilirubinemia, pruritus, nausea, myalgia, and dyspnea; however, discontinuation rates for simeprevir-containing regimens were similar to those seen with pegylated interferon + ribavirin (range, 2%-11% vs 1%-13%).34,35,37 Drug interactions between DAAs and other medications or other DAAs are of particular concern with the use of the protease inhibitors boceprevir and telaprevir and, to a lesser extent, simprevir and should be reviewed prior to the initiation of HCV therapy.51 Finally, no data are available regarding the teratogenicity of DAA agents, while ribavirin is a known teratogen. All patients should be counseled to use one form of contraception and those receiving ribavirin to use 2 forms of contraception during therapy and for 6 months following completion given the teratogenic effect of ribavirin.52,53 In summary, the addition of boceprevir or telaprevir to pegylated interferon + ribavirin increased overall adverse effects, while the addition of simeprevir or sofosbuvir reduced the total duration and pill burden of therapy and maintained or decreased adverse events. Sofosbuvir + ribavirin alone is well tolerated and shows promise to improve the adverse effect profile and tolerability of HCV treatment.

Treatment of HCV has evolved rapidly and has led to improved rates of SVR. Improvement in HCV therapy began with the addition of the protease inhibitors telaprevir and boceprevir to pegylated interferon + weight-based ribavirin for patients with HCV genotype 1. These have now been replaced by sofosbuvir and simeprevir, with improved efficacy and safety for treating HCV genotype 1. Sofosbuvir + weight-based ribavirin alone has replaced interferon-containing therapy for HCV genotypes 2 and 3.

Current evidence indicates that treatment for HCV genotype 1 should consist of sofosbuvir + pegylated interferon + weight-based ribavirin for 12 weeks (treatment-naive patients: grade A recommendation; treatment-experienced patients: grade B recommendation) (Table 4) because of the short duration of overall therapy. A second-line alternative in treatment-naive patients and previous relapsers is pegylated interferon + weight-based ribavirin for 24 weeks along with simeprevir for the first 12 weeks (grade A recommendation). Partial and null responders can be treated with pegylated interferon + weight-based ribavirin for 48 weeks along with simeprevir for the first 12 weeks (grade A recommendation). All therapy in patients who receive simeprevir-containing regimens should be stopped for patients with an inadequate on-treatment virologic response (ie, quantifiable HCV viral load at week 4, 12, and/or 24) (grade B recommendation). Prior to treatment with simeprevir-containing regimens, patients with HCV genotype 1a should be tested for the presence of a Q80K mutation, which reduces the likelihood of treatment success.

Table Graphic Jump LocationTable 4.  Recommended Therapy for Hepatitis C

Patients infected with HCV genotype 2 can be treated with sofosbuvir + weight-based ribavirin for 12 weeks (treatment-naive patients: grade A recommendation; treatment-experienced patients: grade B recommendation). Patients infected with HCV genotype 3 can be treated with sofosbuvir along with weight-based ribavirin for 24 weeks (treatment-naive and -experienced patients: grade B recommendation).

Sofosbuvir + weight-based ribavirin had SVR rates similar in patients with HIV-HCV coinfection to those seen in patients with HCV monoinfection for genotype 1 (76%), genotype 2 (88%), and genotype 3 (92%); however, few patients with HCV genotypes 2 and 3 were included in initial studies. The use of sofosbuvir and, to a larger extent, simeprevir, telaprevir, and boceprevir in HIV-infected patients is complicated by extensive drug interactions with HIV antiretrovirals.55,56 Hence, patients with HIV-HCV coinfection should be treated only by an experienced physician after careful assessment for potential drug interactions and using the same recommended regimens for HCV monoinfection (grade B recommendation).

Prior to HCV treatment, the stage of liver fibrosis should be assessed by liver biopsy or noninvasive markers. Patients with cirrhosis should be referred to a specialist for evaluation of sequelae (ie, hepatocellular carcinoma, hepatic decompensation)46 and HCV treatment using the same regimens for patients with compensated cirrhosis as patients without cirrhosis (grade B recommendation).

Given the prevalence of neutropenia and anemia for patients receiving interferon-containing therapy, patients should be monitored for 2 weeks after starting treatment and at least monthly thereafter for the duration of therapy.

Limitations of this review include that study populations included in RCTs of sofosbuvir and simeprevir as well as newer DAAs are not demographically reflective of all patients with HCV. In particular, only small numbers of patients with cirrhosis, patients previously treated, minority patients, and patients coinfected with HIV were included, limiting the generalizability of recommendations. Further studies are warranted to evaluate the optimal combinations of DAAs and treatment duration that maximize treatment efficacy and minimize adverse effects for all subgroups of HCV-infected patients, to assess for potential for drug interactions between DAAs and concomitant medications, and to elucidate the implications of antiviral resistance.

Changes to guidelines for treatment of HCV can be expected as new regimens, many of which do not include interferon and are not included in this review, are developed and receive FDA approval. These interferon-free regimens have shown high SVR rates with few adverse events in phase 3 trials.53,57,58 In response to these rapidly emerging results, the Infectious Diseases Society of America and the American Association for the Study of Liver Diseases jointly released in 2014 a dynamic online clinical guidance that accommodates rapid updates, which should be used as a reference.54In addition, given the recently published Centers for Disease Control and Prevention guidelines recommending birth cohort screening for HCV infection, many new HCV diagnoses can be expected in the United States.11 The burden of care in HCV treatment will likely overwhelm the capacity of US hepatologists and infectious disease physicians. Hepatitis C virus–positive patients without cirrhosis who have few comorbidities may be treated in a primary care setting using interferon-free therapy. Primary care physicians will need to be familiar with potential adverse effects of new regimens. Patients with cirrhosis, decompensated liver disease, renal insufficiency, multiple concomitant medications or comorbidities, or HIV coinfection, as well as pediatric patients, should be referred to a subspecialist for evaluation of liver disease as well as potential drug-drug interactions prior to HCV treatment. An important aspect of HCV not covered in this review is the cost of emerging DAAs. At the moment, the cost of treatment for a patient with HCV genotype 1 may be as high as $150 000, which will likely restrict wide use of novel agents.

Recent therapeutic advances are transforming chronic HCV into a routinely curable disease. Increased HCV detection combined with the availability of simple, well-tolerated treatment regimens can potentially reduce the need for liver transplantation and reduce HCV-related mortality. For patients needing treatment, there is strong evidence for the use of sofosbuvir + pegylated interferon + ribavirin for patients with HCV genotype 1 and for sofosbuvir + ribavirin alone for patients with HCV genotypes 2 and 3 (Box 2). Further studies are required to better characterize the utility of sofosbuvir and simeprevir in patients with HIV-HCV coinfection. Treatment of patients with HIV-HCV is best carried out by a specialist.

Box Section Ref ID

Box 2.
Key Points
  1. Pegylated interferons with ribavirin and sofosbuvir or simeprevir should be used to treat patients infected with HCV genotype 1.

  2. Sofosbuvir with ribavirin alone should be used to treat patients infected with HCV genotypes 2 and 3.

  3. Patients coinfected with human immunodefiency virus and HCV genotype 1 should be treated for HCV with pegylated interferons, ribavirin, and sofosbuvir by a physician with experience in treating this particular group of patients and familiar with potential drug interactions.

HCV indicates hepatitis C virus.

Section Editor: Mary McGrae McDermott, MD, Senior Editor.
Submissions:We encourage authors to submit papers for consideration as a Review. Please contact Mary McGrae McDermott, MD, at mdm608@northwestern.edu.

Corresponding Author: Shyam Kottilil, MD, PhD, Immunopathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, 10 Centre Dr, Bldg 10, Room 11N204, Bethesda, MD 20892 (skottilil@niaid.nih.gov).

Author Contributions: Drs Kohli and Kottilil had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Kottilil.

Obtained funding: Kottilil.

Administrative, technical, or material support: Kohli, Shaffer, Kottilil.

Study supervision: Kottilil.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This research was supported in part by the Intramural Research Program of the National Institutes of Health (National Institute of Allergy and Infectious Diseases and the Clinical Research Center). This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E.

Role of the Sponors: The funding organization was responsible for the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.

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Germer  JJ, Mandrekar  JN, Bendel  JL, Mitchell  PS, Yao  JD.  Hepatitis C virus genotypes in clinical specimens tested at a national reference testing laboratory in the United States. J Clin Microbiol. 2011;49(8):3040-3043.
PubMed   |  Link to Article
Smith  BD, Morgan  RL, Beckett  GA,  et al; Centers for Disease Control and Prevention.  Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep. 2012;61(RR-4):1-32.
PubMed
Sherman  KE, Rouster  SD, Chung  RT, Rajicic  N.  Hepatitis C virus prevalence among patients infected with human immunodeficiency virus: a cross-sectional analysis of the US adult AIDS Clinical Trials Group. Clin Infect Dis. 2002;34(6):831-837.
PubMed   |  Link to Article
Backus  LI, Boothroyd  D, Deyton  LR.  HIV, hepatitis C and HIV/hepatitis C virus co-infection in vulnerable populations. AIDS. 2005;19(suppl 3):S13-S19.
PubMed   |  Link to Article
Choo  QL, Kuo  G, Weiner  AJ, Overby  LR, Bradley  DW, Houghton  M.  Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science. 1989;244(4902):359-362.
PubMed   |  Link to Article
Ghany  MG, Nelson  DR, Strader  DB, Thomas  DL, Seeff  LB; American Association for Study of Liver Diseases.  An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54(4):1433-1444.
PubMed   |  Link to Article
Swain  MG, Lai  MY, Shiffman  ML,  et al.  A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin. Gastroenterology. 2010;139(5):1593-1601.
PubMed   |  Link to Article
McHutchison  JG, Gordon  SC, Schiff  ER,  et al; Hepatitis Interventional Therapy Group.  Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med. 1998;339(21):1485-1492.
PubMed   |  Link to Article
Poynard  T, Marcellin  P, Lee  SS,  et al; International Hepatitis Interventional Therapy Group.  Randomised trial of interferon α2b plus ribavirin for 48 weeks or for 24 weeks vs interferon α2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet. 1998;352(9138):1426-1432.
PubMed   |  Link to Article
Moher  D, Liberati  A, Tetzlaff  J, Altman  DG; PRISMA Group.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264-269, W64.
PubMed   |  Link to Article
Oxford Centre for Evidence-Based Medicine—levels of evidence (March 2009).http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/. Accessed March 3, 2014.
Sherman  KE, Flamm  SL, Afdhal  NH,  et al; ILLUMINATE Study Team.  Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med. 2011;365(11):1014-1024.
PubMed   |  Link to Article
McHutchison  JG, Everson  GT, Gordon  SC,  et al; PROVE1 Study Team.  Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 2009;360(18):1827-1838.
PubMed   |  Link to Article
Kumada  H, Toyota  J, Okanoue  T, Chayama  K, Tsubouchi  H, Hayashi  N.  Telaprevir with peginterferon and ribavirin for treatment-naive patients chronically infected with HCV of genotype 1 in Japan. J Hepatol. 2012;56(1):78-84.
PubMed   |  Link to Article
Jacobson  IM, McHutchison  JG, Dusheiko  G,  et al; ADVANCE Study Team.  Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364(25):2405-2416.
PubMed   |  Link to Article
Kwo  PY, Lawitz  EJ, McCone  J,  et al; SPRINT-1 Investigators.  Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet. 2010;376(9742):705-716.
PubMed   |  Link to Article
Bacon  BR, Gordon  SC, Lawitz  E,  et al; HCV RESPOND-2 Investigators.  Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13):1207-1217.
PubMed   |  Link to Article
Poordad  F, McCone  J  Jr, Bacon  BR,  et al; SPRINT-2 Investigators.  Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13):1195-1206.
PubMed   |  Link to Article
Pallier  C, Rodriguez  C, Brillet  R, Nordmann  P, Hézode  C, Pawlotsky  JM.  Complex dynamics of hepatitis B virus resistance to adefovir. Hepatology. 2009;49(1):50-59.
PubMed   |  Link to Article
Zeuzem  S, Andreone  P, Pol  S,  et al; REALIZE Study Team.  Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364(25):2417-2428.
PubMed   |  Link to Article
McHutchison  JG, Manns  MP, Muir  AJ,  et al; PROVE3 Study Team.  Telaprevir for previously treated chronic HCV infection. N Engl J Med. 2010;362(14):1292-1303.
PubMed   |  Link to Article
Flamm  SL, Lawitz  E, Jacobson  I,  et al.  Boceprevir with peginterferon alfa-2a-ribavirin is effective for previously treated chronic hepatitis C genotype 1 infection. Clin Gastroenterol Hepatol. 2013;11(1):81-U216.
PubMed   |  Link to Article
Hayashi  N, Okanoue  T, Tsubouchi  H, Toyota  J, Chayama  K, Kumada  H.  Efficacy and safety of telaprevir, a new protease inhibitor, for difficult-to-treat patients with genotype 1 chronic hepatitis C. J Viral Hepat. 2012;19(2):e134-e142.
PubMed   |  Link to Article
Muir  AJ, Poordad  FF, McHutchison  JG,  et al.  Retreatment with telaprevir combination therapy in hepatitis C patients with well-characterized prior treatment response. Hepatology. 2011;54(5):1538-1546.
PubMed   |  Link to Article
Fried  MW, Buti  M, Dore  GJ,  et al.  Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naive genotype 1 hepatitis C: the randomized PILLAR study. Hepatology. 2013;58(6):1918-1929.
PubMed   |  Link to Article
Olysio full prescribing information, QUEST 1 data. Titusville, NJ: Jannsen Therapeutics; 2013.
Hayashi  N, Seto  C, Kato  M, Komada  Y, Goto  S.  Once-daily simeprevir (TMC435) with peginterferon/ribavirin for treatment-naive hepatitis C genotype 1-infected patients in Japan: the DRAGON study. J Gastroenterol. 2014;49(1):138-147.
PubMed   |  Link to Article
Zeuzem  S, Berg  T, Gane  E,  et al.  Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology. 2014;146(2):430, e6.
PubMed   |  Link to Article
Lawitz  E, Lalezari  JP, Hassanein  T,  et al.  Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis. 2013;13(5):401-408.
PubMed   |  Link to Article
Kowdley  KV, Lawitz  E, Crespo  I,  et al.  Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet. 2013;381(9883):2100-2107.
PubMed   |  Link to Article
Lawitz  E, Mangia  A, Wyles  D,  et al.  Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878-1887.
PubMed   |  Link to Article
Gane  EJ, Stedman  CA, Hyland  RH,  et al.  Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013;368(1):34-44.
PubMed   |  Link to Article
Osinusi  A, Meissner  EG, Lee  YJ,  et al.  Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. JAMA. 2013;310(8):804-811.
PubMed   |  Link to Article
Jacobson  IM, Gordon  SC, Kowdley  KV,  et al; POSITRON Study; FUSION Study.  Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368(20):1867-1877.
PubMed   |  Link to Article
Sovaldi full prescibing information, Valence data. Foster City, CA: Gilead Sciences; 2013.
Sulkowski  M, Pol  S, Mallolas  J,  et al; P05411 Study Investigators.  Boceprevir vs placebo with pegylated interferon alfa-2b and ribavirin for treatment of hepatitis C virus genotype 1 in patients with HIV: a randomised, double-blind, controlled phase 2 trial. Lancet Infect Dis. 2013;13(7):597-605.
PubMed   |  Link to Article
Sulkowski  MS, Sherman  KE, Dieterich  DT,  et al.  Combination therapy with telaprevir for chronic hepatitis C virus genotype 1 infection in patients with HIV: a randomized trial. Ann Intern Med. 2013;159(2):86-96.
PubMed
Vachon  ML, Factor  SH, Branch  AD,  et al.  Insulin resistance predicts re-treatment failure in an efficacy study of peginterferon-α-2a and ribavirin in HIV/HCV co-infected patients. J Hepatol. 2011;54(1):41-47.
PubMed   |  Link to Article
Neukam  K, Barreiro  P, Rivero-Juárez  A,  et al.  Pegylated interferon plus ribavirin is suboptimal in IL28B CC carriers without rapid response. J Infect. 2013;67(1):59-64.
PubMed   |  Link to Article
Rodriguez-Torres  M, Jeffers  LJ, Sheikh  MY,  et al; Latino Study Group.  Peginterferon alfa-2a and ribavirin in Latino and non-Latino whites with hepatitis C. N Engl J Med. 2009;360(3):257-267.
PubMed   |  Link to Article
Hézode  C, Forestier  N, Dusheiko  G,  et al; PROVE2 Study Team.  Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. 2009;360(18):1839-1850.
PubMed   |  Link to Article
Kiser  JJ, Burton  JR  Jr, Everson  GT.  Drug-drug interactions during antiviral therapy for chronic hepatitis C. Nat Rev Gastroenterol Hepatol. 2013;10(10):596-606.
PubMed   |  Link to Article
Flamm  SL, Lawitz  E, Jacobson  IM,  et al.  Overall safety profile of boceprevir (boc) plus peginterferon alfa-2a/ribavirin in genotype 1 previous non-responders and relapsers to peginterferon/ribavirin. Hepatology. 2011;54:838A.
Kumada  H, Suzuki  Y, Ikeda  K,  et al.  Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology. 2014;59(6):2083-2091.
PubMed   |  Link to Article
American Association for the Study of Liver Diseases/Infectious Diseases Society of America. Recommendations for Testing, Managing, and Treating Hepatitis C.2014. http://www.hcvguidelines.org/full-report-view. Accessed June 9, 2014.
Seden  K, Back  D.  Directly acting antivirals for hepatitis C and antiretrovirals: potential for drug-drug interactions. Curr Opin HIV AIDS. 2011;6(6):514-526.
PubMed   |  Link to Article
Wilby  KJ, Greanya  ED, Ford  JA, Yoshida  EM, Partovi  N.  A review of drug interactions with boceprevir and telaprevir: implications for HIV and transplant patients. Ann Hepatol. 2012;11(2):179-185.
PubMed
Afdhal  N, Zeuzem  S, Kwo  P,  et al; ION-1 Investigators.  Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370(20):1889-1898.
PubMed   |  Link to Article
Feld  JJ, Kowdley  KV, Coakley  E,  et al.  Treatment of HCV with ABT-450/r–ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370(17):1594-1603.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure.
Steps in the Hepatitis C Virus Life Cycle Targeted by Directly Acting Antiviral Agents

Directly acting antiviral agents (DAAs; shown in cyan) disrupt hepatitis C virus (HCV) replication by targeting critical enzymatic steps in the HCV life cycle. Antiviral drug treatment with a DAA combined with ribavirin with or without pegylated interferon, depending on HCV genotype (see Table 4), increases suppression of HCV replication compared with interferon and ribavirin alone, leading to improved sustained virologic response rates. The illustration is schematic; structures are not to scale. Question marks indicate that mechanism of action is uncertain. Abbreviations: E, envelope glycoprotein; NS, nonstructural protein; + and −, positive and negative HCV RNA strands.

aNot approved by the US Food and Drug Administration.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Prevalence of HCV Genotypes and of HCV Infection in the United States by Risk Factor
Table Graphic Jump LocationTable 2.  Mechanism of Action, Activity, and Adverse Effects of HCV Therapies
Table Graphic Jump LocationTable 3.  Studies Evaluating Hepatitis C Treatment Using SVR as Outcome, 2000-2013: Summary of Systematic Review and Findings
Table Graphic Jump LocationTable 4.  Recommended Therapy for Hepatitis C

References

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PubMed   |  Link to Article
Manos  MM, Shvachko  VA, Murphy  RC, Arduino  JM, Shire  NJ.  Distribution of hepatitis C virus genotypes in a diverse US integrated health care population. J Med Virol. 2012;84(11):1744-1750.
PubMed   |  Link to Article
Germer  JJ, Mandrekar  JN, Bendel  JL, Mitchell  PS, Yao  JD.  Hepatitis C virus genotypes in clinical specimens tested at a national reference testing laboratory in the United States. J Clin Microbiol. 2011;49(8):3040-3043.
PubMed   |  Link to Article
Smith  BD, Morgan  RL, Beckett  GA,  et al; Centers for Disease Control and Prevention.  Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep. 2012;61(RR-4):1-32.
PubMed
Sherman  KE, Rouster  SD, Chung  RT, Rajicic  N.  Hepatitis C virus prevalence among patients infected with human immunodeficiency virus: a cross-sectional analysis of the US adult AIDS Clinical Trials Group. Clin Infect Dis. 2002;34(6):831-837.
PubMed   |  Link to Article
Backus  LI, Boothroyd  D, Deyton  LR.  HIV, hepatitis C and HIV/hepatitis C virus co-infection in vulnerable populations. AIDS. 2005;19(suppl 3):S13-S19.
PubMed   |  Link to Article
Choo  QL, Kuo  G, Weiner  AJ, Overby  LR, Bradley  DW, Houghton  M.  Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science. 1989;244(4902):359-362.
PubMed   |  Link to Article
Ghany  MG, Nelson  DR, Strader  DB, Thomas  DL, Seeff  LB; American Association for Study of Liver Diseases.  An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54(4):1433-1444.
PubMed   |  Link to Article
Swain  MG, Lai  MY, Shiffman  ML,  et al.  A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin. Gastroenterology. 2010;139(5):1593-1601.
PubMed   |  Link to Article
McHutchison  JG, Gordon  SC, Schiff  ER,  et al; Hepatitis Interventional Therapy Group.  Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med. 1998;339(21):1485-1492.
PubMed   |  Link to Article
Poynard  T, Marcellin  P, Lee  SS,  et al; International Hepatitis Interventional Therapy Group.  Randomised trial of interferon α2b plus ribavirin for 48 weeks or for 24 weeks vs interferon α2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet. 1998;352(9138):1426-1432.
PubMed   |  Link to Article
Moher  D, Liberati  A, Tetzlaff  J, Altman  DG; PRISMA Group.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264-269, W64.
PubMed   |  Link to Article
Oxford Centre for Evidence-Based Medicine—levels of evidence (March 2009).http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/. Accessed March 3, 2014.
Sherman  KE, Flamm  SL, Afdhal  NH,  et al; ILLUMINATE Study Team.  Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med. 2011;365(11):1014-1024.
PubMed   |  Link to Article
McHutchison  JG, Everson  GT, Gordon  SC,  et al; PROVE1 Study Team.  Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 2009;360(18):1827-1838.
PubMed   |  Link to Article
Kumada  H, Toyota  J, Okanoue  T, Chayama  K, Tsubouchi  H, Hayashi  N.  Telaprevir with peginterferon and ribavirin for treatment-naive patients chronically infected with HCV of genotype 1 in Japan. J Hepatol. 2012;56(1):78-84.
PubMed   |  Link to Article
Jacobson  IM, McHutchison  JG, Dusheiko  G,  et al; ADVANCE Study Team.  Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364(25):2405-2416.
PubMed   |  Link to Article
Kwo  PY, Lawitz  EJ, McCone  J,  et al; SPRINT-1 Investigators.  Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet. 2010;376(9742):705-716.
PubMed   |  Link to Article
Bacon  BR, Gordon  SC, Lawitz  E,  et al; HCV RESPOND-2 Investigators.  Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13):1207-1217.
PubMed   |  Link to Article
Poordad  F, McCone  J  Jr, Bacon  BR,  et al; SPRINT-2 Investigators.  Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13):1195-1206.
PubMed   |  Link to Article
Pallier  C, Rodriguez  C, Brillet  R, Nordmann  P, Hézode  C, Pawlotsky  JM.  Complex dynamics of hepatitis B virus resistance to adefovir. Hepatology. 2009;49(1):50-59.
PubMed   |  Link to Article
Zeuzem  S, Andreone  P, Pol  S,  et al; REALIZE Study Team.  Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364(25):2417-2428.
PubMed   |  Link to Article
McHutchison  JG, Manns  MP, Muir  AJ,  et al; PROVE3 Study Team.  Telaprevir for previously treated chronic HCV infection. N Engl J Med. 2010;362(14):1292-1303.
PubMed   |  Link to Article
Flamm  SL, Lawitz  E, Jacobson  I,  et al.  Boceprevir with peginterferon alfa-2a-ribavirin is effective for previously treated chronic hepatitis C genotype 1 infection. Clin Gastroenterol Hepatol. 2013;11(1):81-U216.
PubMed   |  Link to Article
Hayashi  N, Okanoue  T, Tsubouchi  H, Toyota  J, Chayama  K, Kumada  H.  Efficacy and safety of telaprevir, a new protease inhibitor, for difficult-to-treat patients with genotype 1 chronic hepatitis C. J Viral Hepat. 2012;19(2):e134-e142.
PubMed   |  Link to Article
Muir  AJ, Poordad  FF, McHutchison  JG,  et al.  Retreatment with telaprevir combination therapy in hepatitis C patients with well-characterized prior treatment response. Hepatology. 2011;54(5):1538-1546.
PubMed   |  Link to Article
Fried  MW, Buti  M, Dore  GJ,  et al.  Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naive genotype 1 hepatitis C: the randomized PILLAR study. Hepatology. 2013;58(6):1918-1929.
PubMed   |  Link to Article
Olysio full prescribing information, QUEST 1 data. Titusville, NJ: Jannsen Therapeutics; 2013.
Hayashi  N, Seto  C, Kato  M, Komada  Y, Goto  S.  Once-daily simeprevir (TMC435) with peginterferon/ribavirin for treatment-naive hepatitis C genotype 1-infected patients in Japan: the DRAGON study. J Gastroenterol. 2014;49(1):138-147.
PubMed   |  Link to Article
Zeuzem  S, Berg  T, Gane  E,  et al.  Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology. 2014;146(2):430, e6.
PubMed   |  Link to Article
Lawitz  E, Lalezari  JP, Hassanein  T,  et al.  Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis. 2013;13(5):401-408.
PubMed   |  Link to Article
Kowdley  KV, Lawitz  E, Crespo  I,  et al.  Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet. 2013;381(9883):2100-2107.
PubMed   |  Link to Article
Lawitz  E, Mangia  A, Wyles  D,  et al.  Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878-1887.
PubMed   |  Link to Article
Gane  EJ, Stedman  CA, Hyland  RH,  et al.  Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013;368(1):34-44.
PubMed   |  Link to Article
Osinusi  A, Meissner  EG, Lee  YJ,  et al.  Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. JAMA. 2013;310(8):804-811.
PubMed   |  Link to Article
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PubMed   |  Link to Article
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eTable 1. Randomized Controlled Trials and Cohort Studies of HCV Treatment in HCV Genotype 1 Infected Patients

eTable 2. Randomized Controlled Trials and Cohort Studies of HCV Treatment in Genotype 2 and 3 Infected Patients

eTable 3. Randomized Controlled Trials and Cohort Studies of HCV Treatment in HIV/HCV Co-infected Patients

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