Eric G. Meissner

Sofosbuvir and Ribavirin for Hepatitis C Genotype 1 in Patients With Unfavorable Treatment Characteristics: A Randomized Clinical Trial

IMPORTANCE The efficacy of directly acting antiviral agents in interferon-free regimens for the treatment of chronic hepatitis C infections needs to be evaluated in different populations. OBJECTIVE To determine the efficacy and safety of sofosbuvir with weight-based or low-dose ribavirin among a population with unfavorable treatment characteristics. DESIGN, SETTING, AND PATIENTS Single-center, randomized, 2-part, open-label phase 2 study involving 60 treatment-naive patients with hepatitis C virus (HCV) genotype 1 enrolled at the National Institutes of Health (October 2011-April 2012). INTERVENTIONS In the studys first part, 10 participants with early to moderate liver fibrosis were treated with 400 mg/d of sofosbuvir and weight-based ribavirin for 24 weeks. In the second part, 50 participants with all stages of liver fibrosis were randomized 1:1 to receive 400 mg of sofosbuvir with either weight-based or low-dose 600 mg/d of ribavirin for 24 weeks. MAIN OUTCOMES AND MEASURES The primary study end point was the proportion of participants with undetectable HCV viral load 24 weeks after treatment completion (sustained virologic response of 24 weeks [SVR24]). RESULTS In the first part of the study, 9 participants (90%; 95% CI, 55%-100%) achieved SVR24. In the second part, 7 participants (28%) in the weight-based group and 10 (40%) in the low-dose group relapsed after treatment completion leading to SVR24 rates of 68% (95% CI, 46%-85%) in the weight-based group and 48% (95% CI, 28%-69%; P = .20) in the low-dose group. Twenty individuals participated in a pharmacokinetic-viral kinetic substudy, which demonstrated a slower loss rate of infectious virus in relapsers than in participants who achieved SVR (clearance, 3.57/d vs 5.60/d; P = .009). The most frequent adverse events were headache, anemia, fatigue, and nausea. There were 7 grade 3 events including anemia, neutropenia, nausea, hypophosphatemia, and cholelithiasis or pancreatitis. No one discontinued treatment due to adverse events. CONCLUSION AND RELEVANCE In a population of patients with a high prevalence of unfavorable traditional predictors of treatment response, a 24-week regimen of sofosbuvir and weight-based or low-dose ribavirin resulted in SVR24 rates of 68% and 48%, respectively. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01441180.

Virologic Response Following Combined Ledipasvir and Sofosbuvir Administration in Patients With HCV Genotype 1 and HIV Co-infection

IMPORTANCE There is an unmet need for interferon- and ribavirin-free treatment for chronic hepatitis C virus (HCV) infection in patients co-infected with human immunodeficiency virus (HIV). OBJECTIVE To evaluate the rates of sustained virologic response (SVR) and adverse events in previously untreated patients with HCV genotype 1 and HIV co-infection following a 12-week treatment of the fixed-dose combination of ledipasvir and sofosbuvir. DESIGN, SETTING, AND PARTICIPANTS Open-label, single-center, phase 2b pilot study of previously untreated, noncirrhotic patients with HCV genotype 1 and HIV co-infection conducted at the Clinical Research Center of the National Institutes of Health, Bethesda, Maryland, from June 2013 to September 2014. Patients included those receiving antiretroviral therapy with HIV RNA values of 50 copies/mL or fewer and a CD4 T-lymphocyte count of 100 cells/mL or greater or patients with untreated HIV infection with a CD4 T-lymphocyte count of 500 cells/mL or greater. Serial measurements of safety parameters, virologic and host immune correlates, and adherence were performed. INTERVENTIONS Fifty patients with HCV genotype 1 never before treated for HCV were prescribed a fixed-dose combination of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily for 12 weeks. MAIN OUTCOMES AND MEASURES The primary study outcome was the proportion of patients with sustained viral response (plasma HCV RNA level <12 IU/mL) 12 weeks after end of treatment. RESULTS Forty-nine of 50 participants (98% [95% CI, 89% to 100%]) achieved SVR 12 weeks after end of treatment, whereas 1 patient experienced relapse at week 4 following treatment. In the patient with relapse, deep sequencing revealed a resistance associated mutation in the NS5A region conferring resistance to NS5A inhibitors, such as ledipasvir. The most common adverse events were nasal congestion (16% of patients) and myalgia (14%). There were no discontinuations or serious adverse events attributable to study drug. CONCLUSIONS AND RELEVANCE In this open-label, uncontrolled, pilot study enrolling patients co-infected with HCV genotype 1 and HIV, administration of an oral combination of ledipasvir and sofosbuvir for 12 weeks was associated with high rates of SVR after treatment completion. Larger studies that also include patients with cirrhosis and lower CD4 T-cell counts are required to understand if the results of this study generalize to all patients co-infected with HCV and HIV. TRIAL REGISTRATION clinicaltrials.gov Identifier:NCT01878799.

Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study

BACKGROUND Direct-acting antiviral drugs have a high cure rate and favourable tolerability for patients with hepatitis C virus (HCV). Shorter courses could improve affordability and adherence. Sofosbuvir and ledipasvir with ribavirin have high efficacy when taken for 8 weeks but not for 6 weeks. We assessed whether the addition of a third direct-acting antiviral drug to sofosbuvir and ledipasvir would allow a shorter treatment duration. METHODS In this single-centre, open-label, phase 2A trial, we sequentially enrolled treatment-naive patients with HCV genotype 1 infection into three treatment groups: 12 weeks of sofosbuvir and ledipasvir; 6 weeks of sofosbuvir, ledipasvir, and GS-9669; or 6 weeks of sofosbuvir, ledipasvir, and GS-9451. Patients and investigators were not masked to treatment assignment. The primary endpoint was the propotion of patients with sustained viral response at 12 weeks after treatment completion (SVR12), assessed by serum HCV RNA concentrations lower than 43 IU/mL (the lower limit of quantification). We did an intention-to-treat analysis for the primary endpoint and adverse events. This study is registered with ClinicalTrials.gov, number NCT01805882. FINDINGS Between Jan 11, 2013, and Dec 17, 2013, we enrolled 60 patients, and sequentially assigned them into three groups of 20. We noted an SVR12 in all 20 patients (100%, 95% CI 83-100) allocated to sofosbuvir and ledipasvir for 12 weeks; in 19 (95%, 75-100) of the 20 patients allocated to sofosbuvir, ledipasvir, and GS-9669 for 6 weeks (one patient relapsed 2 weeks after completion of treatment); and in 19 (95%, 75-100%) of the 20 patients allocated to sofosbuvir, ledipasvir, and GS-9451 for 6 weeks (one patient was lost to follow-up after reaching sustained viral response at 4 weeks). Most adverse events were mild and no patients discontinued treatment. Two serious adverse events occurred (pain after a post-treatment liver biopsy and vertigo), both unrelated to study drugs. INTERPRETATION In this small proof-of-concept study, two different three-drug regimens that were given for 6 weeks resulted in high cure rates for HCV infection with excellent tolerability. Addition of a third potent direct-acting antiviral drug can reduce the duration of treatment required to achieve sustained viral response in patients with chronic HCV genotype 1 infection without cirrhosis. FUNDING National Institute of Allergy and Infectious Diseases (NIAID), National Cancer Institute and Clinical Center Intramural Program, German Research Foundation, National Institutes of Health, Gilead Sciences.

Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome

BACKGROUND. Hepatitis C virus (HCV) infects approximately 170 million people worldwide and may lead to cirrhosis and hepatocellular carcinoma in chronically infected individuals. Treatment is rapidly evolving from IFN-α-based therapies to IFN-α-free regimens that consist of directly acting antiviral agents (DAAs), which demonstrate improved efficacy and tolerability in clinical trials. Virologic relapse after DAA therapy is a common cause of treatment failure; however, it is not clear why relapse occurs or whether certain individuals are more prone to recurrent viremia. METHODS. We conducted a clinical trial using the DAA sofosbuvir plus ribavirin (SOF/RBV) and performed detailed mRNA expression analysis in liver and peripheral blood from patients who achieved either a sustained virologic response (SVR) or relapsed. RESULTS. On-treatment viral clearance was accompanied by rapid downregulation of IFN-stimulated genes (ISGs) in liver and blood, regardless of treatment outcome. Analysis of paired pretreatment and end of treatment (EOT) liver biopsies from SVR patients showed that viral clearance was accompanied by decreased expression of type II and III IFNs, but unexpectedly increased expression of the type I IFN IFNA2. mRNA expression of ISGs was higher in EOT liver biopsies of patients who achieved SVR than in patients who later relapsed. CONCLUSION. These results suggest that restoration of type I intrahepatic IFN signaling by EOT may facilitate HCV eradication and prevention of relapse upon withdrawal of SOF/RBV. TRIAL REGISTRATION. ClinicalTrials.gov NCT01441180.

IFNL4-ΔG Genotype Is Associated With Slower Viral Clearance in Hepatitis C, Genotype-1 Patients Treated With Sofosbuvir and Ribavirin

Response to pegylated interferon-alpha and ribavirin (IFN-α/RBV) treatment for chronic hepatitis C virus (HCV) infection is influenced by host genetic factors, but their role for IFN-α-free, direct-acting antiviral (DAA) regimens is unclear. An exonic deletion allele (IFNL4-ΔG) bolsters the established association with IFN-α/RBV therapy treatment outcome of another IFNL4 variant, rs12979860, which is located upstream of IFNL3 (IL28B). We report that in patients treated with the DAA sofosbuvir along with RBV, IFNL4-ΔG is associated with slower early viral decay, due to slower loss of free virus (P = .039) and decreased drug efficacy (P = .048), suggesting functional relevance of IFN-λ4 in IFN-α-free DAA therapies.

Effect of sofosbuvir and ribavirin treatment on peripheral and hepatic lipid metabolism in chronic hepatitis C virus, genotype 1-infected patients.

Hepatitis C virus (HCV) modulates intrahepatic cholesterol biosynthetic pathways to promote viral replication. Chronic HCV infection is associated with altered metabolism, including dyslipidemia and insulin resistance (IR), which contributes to disease progression and influences response to therapy. To further understand the impact of HCV infection on host metabolism, we examined changes in serum lipid profiles and intrahepatic expression of lipid‐related genes during interferon (IFN)‐free treatment of chronic HCV, genotype 1 infection with sofosbuvir and ribavirin (RBV), and explored associations with treatment outcome. Serum lipids (total cholesterol, low‐density lipoprotein [LDL], high‐density lipoprotein [HDL], and triglycerides [TGs]) and hemoglobin A1C (HbA1C) were measured during treatment, while gene expression of lipid‐related genes was assessed using paired pre‐ and end‐of‐treatment (EOT) liver biopsies from 8 patients (n = 7 sustained virologic response [SVR]; n = 1 relapse) and unpaired EOT liver biopsies from 25 patients (n = 17 SVR; n = 8 relapse). Serum LDL concentration and particle size increased early in therapy, whereas TG concentration and very‐low‐density lipoprotein particle size decreased concomitantly, irrespective of treatment outcome. Whereas LDL increased in patients regardless of treatment outcome, average LDL concentration was lower at baseline and post‐treatment in patients who relapsed. Analysis of paired liver biopsies revealed altered expression of genes associated with lipid transport, assembly, and signaling. In unpaired EOT liver biopsies, intrahepatic expression of fatty acid metabolism and lipid transport genes was lower in patients who experienced treatment relapse. Conclusion: Clearance of HCV using an IFN‐free antiviral regimen results in rapid changes in peripheral and intrahepatic metabolic pathways, implicating a direct effect of HCV replication on lipid homeostasis. (Hepatology 2015;61:790–801)

Re-treatment of chronic hepatitis C virus genotype 1 infection after relapse: an open-label pilot study.

Context The treatment of hepatitis C virus is changing rapidly with the introduction of interferon-free regimens that include direct-acting antiviral drugs, such as sofosbuvir. Although treatment generally results in sustained viral response, some patients have relapse after initial treatment. Contribution In a small, nonrandomized study, 14 patients who had relapse after treatment with sofosbuvir plus ribavirin were re-treated with sofosbuvir plus ledipasvir for 12 weeks. All patients, including those with advanced liver disease, achieved a sustained virologic response. The combination was generally well-tolerated. Implication Treatment with sofosbuvir plus ledipasvir may be efficacious in patients who have relapse after initial therapy for hepatitis C virus. Larger randomized studies of this promising combination are warranted. The Editors Chronic hepatitis C virus (HCV) infection is a major cause of chronic liver disease and hepatocellular carcinoma and the leading indication for liver transplantation in Western countries (1, 2). Until recently, HCV treatment consisted of combination therapy with pegylated interferon (IFN) and ribavirin, with the addition of an HCV protease inhibitor (boceprevir or telaprevir) in recent years. In 2013, the U.S. Food and Drug Administration approved sofosbuvir plus ribavirin as the first IFN-free treatment of HCV genotype 2 or 3 and for patients with genotype 1 (GT-1) who are IFN-ineligible (37). Although sofosbuvir (an NS5B inhibitor) plus ribavirin is well-tolerated and effective with sustained virologic response (SVR) rates from 68% to 76% in patients with HCV GT-1 (8, 9), modest rates of relapse in patients with advanced liver disease and transplant recipients have been seen (8, 10, 11). Recent studies using sofosbuvir combined with ledipasvir (an NS5A inhibitor) for 12 weeks demonstrated high SVR rates (95% to 99%) in treatment-naive patients with HCV GT-1 (1215). Ledipasvir has potent antiviral activity against the S282T resistance-associated variant, known to reduce susceptibility to sofosbuvir in vitro (16). As previously reported, 17 of 54 patients treated with sofosbuvir plus ribavirin for 24 weeks in the National Institute of Allergy and Infectious Diseases (NIAID) SPARE study had relapse after treatment (8). We hypothesized that the combination of a second potent direct-acting antiviral agent (DAA) with sofosbuvir could result in SVR, even in patients with relapse after sofosbuvir plus ribavirin therapy and who may harbor the S282T mutation. To test this hypothesis, we re-treated those patients with sofosbuvir plus ledipasvir for 12 weeks. Methods Design Overview All patients who had relapse after 24 weeks of treatment with sofosbuvir plus ribavirin in the NIAID SPARE study (8) were offered re-treatment with sofosbuvir plus ledipasvir in the ongoing, phase 2a, open-label NIAID SYNERGY study (ClinicalTrials.gov: NCT01805882). Of the 17 eligible patients, 3 did not participate in the study. Fourteen patients enrolled and were treated with 400 mg of sofosbuvir and 90 mg of ledipasvir, administered daily as a single combination tablet, for 12 weeks. Setting and Patients The trial was conducted at the National Institutes of Health (NIH) in Bethesda, Maryland, and at community clinics that are part of the District of Columbia Partnership for HIV/AIDS Progress in Washington, DC. Written informed consent, which was approved by the NIAID Institutional Review Board, was obtained from all study patients. Eligibility criteria included documented HCV GT-1 infection and relapse in the NIAID SPARE study (8). Liver fibrosis stage was determined by biopsy within 3 years of enrollment in the NIAID SPARE study. The study was approved by the NIAID Institutional Review Board. It was conducted in adherence to the Good Clinical Practice guidelines and with regulatory requirements consistent with the Declaration of Helsinki. Outcomes and Follow-up Efficacy Assessments Plasma HCV RNA levels were measured using the Abbott RealTime HCV assay, with a lower limit of quantification of 12 IU/mL and a lower limit of detection of 3 IU/mL, or the Roche Cobas TaqMan HCV assay, version 2.0, with a lower limit of quantification of 43 IU/mL and a lower limit of detection of 15 IU/mL. Safety Assessments Patients were closely monitored for adverse events. Clinical laboratory results were assessed while receiving therapy (4, 8, and 12 weeks) and afterward (2, 4, 8, and 12 weeks after treatment). Adverse events were graded from 1 (mild) to 4 (severe), according to the NIAID Division of AIDS Toxicity Table (version 1.0). Interleukin-28B Genotyping Interleukin-28B genotype (rs12979860) was determined as previously described (8). Clinical End Points The primary end point was the proportion of patients with unquantifiable plasma HCV viral load 12 weeks after treatment completion. Safety end points included frequency and severity of adverse events, discontinuations due to adverse events, and safety laboratory changes. Statistical Analysis Primary safety and efficacy data were analyzed by intention-to-treat (all patients who initiated study medication). Missing virologic data were imputed if data from preceding and succeeding time points were obtained. Baseline demographics were described using frequency statistics. Comparisons were calculated using either nonparametric tests or t tests with GraphPad Prism, version 6.0 (GraphPad Software). Role of the Funding Source This study was funded in part by the National Cancer Institute, the intramural programs of the NIH Clinical Center and NIAID, and a Collaborative Research and Development Agreement between the NIH and Gilead Sciences. The study sponsor was the Regulatory Compliance and Human Participants Protection Branch of the NIAID. The sponsor reviewed the study and provided oversight. However, it did not play a role in designing the study; collecting, analyzing, or interpreting the data; or the preparation, review, approval, or submission of the manuscript for publication. All study medications were provided by Gilead Sciences, which did not have a role in the design or conduct of the study, writing of the manuscript, or the decision to submit the manuscript for publication. Results Baseline Characteristics of Patients Most study patients were black men with an unfavorable interleukin-28B non-CC genotype (Table 1). There was a high representation of patients with HCV GT-1a infection, increased baseline HCV viral load (>800000 IU/mL), increased body mass index (>30 kg/m2), and advanced liver disease (Knodell Histology Activity Index score of 3 or 4) (17). Table 1. Baseline Characteristics of Study Patients Presence of S282T Mutation At the time of relapse after sofosbuvir plus ribavirin treatment in the SPARE trial, 13 of 14 patients had wild-type virus by population sequencing (Supplement). The 1 exception achieved unquantifiable HCV RNA levels by week 2 of therapy in SPARE and the virus remained undetectable through the end of treatment. He missed his visit at 26 weeks (2 weeks after treatment), but at 28 weeks (4 weeks after treatment), his HCV viral load was 374 IU/mL and the S282T mutation was readily detected by population sequencing. By 36 weeks (12 weeks after treatment), his HCV viral load was 81286 IU/mL and the S282T mutation was no longer detectable. He initiated sofosbuvir plus ledipasvir treatment 50 weeks after relapse. Supplement. HCV Resistance Mutations Virologic Response Each of the 14 patients treated with sofosbuvir plus ledipasvir had HCV RNA levels below the lower limit of quantification by 4 weeks (Roche Cobas TaqMan HCV Assay, version 2.0), which was maintained through the end of treatment (12 weeks). All patients achieved SVR 12 weeks after completion of treatment. Changes in Hemoglobin Levels No significant change in hemoglobin levels during sofosbuvir plus ledipasvir treatment was seen, in contrast to the decrease seen with sofosbuvir plus ribavirin. The mean hemoglobin level change was 0.07 g/L versus 11.70 g/L at 4 weeks (P=0.01), 0.5 g/L versus 12.6 g/L at 8 weeks (P=0.01), and 3.1 g/L versus 12.1 g/L at 12 weeks (P=0.06) with sofosbuvir plus ledipasvir and sofosbuvir plus ribavirin, respectively. No participant had a decrease in hemoglobin level of 15.0 g/L or greater with sofosbuvir plus ledipasvir compared with 8 of 14 (57%) with sofosbuvir plus ribavirin. Changes in Renal Function Renal variables did not change significantly over the course of treatment, although a single participant with grade 2 renal insufficiency at baseline (estimated glomerular filtration rate, 54 mL/min/1.73 m2) developed a grade 3 event. After 6 weeks of receiving study medications, he had received amoxicillin in the context of a dental procedure and continued preenrollment medications (benazepril, telmisartan, and simvastatin). In this context, his estimated glomerular filtration rate decreased to 29 mL/min/1.73 m2 (grade 3 toxicity); however, it improved (grade 2) within 1 week of withdrawing amoxicillin, returned to baseline within 3 weeks, and remained stable thereafter. He received study drugs without interruption. Safety All patients completed treatment, and no grade 4 adverse events or laboratory abnormalities occurred. The most common adverse events were myalgia and hypophosphatemia, and most adverse events were mild (Table 2). Four grade 3 events occurred (increased creatinine levels described above [n=1], hypercholesterolemia [n=1], and hypophosphatemia [n=2]). Table 2. Treatment Discontinuations, Adverse Events, and Laboratory Abnormalities Discussion In this study, we demonstrate that patients with HCV GT-1 who have viral relapse after sofosbuvir plus ribavirin therapy can be successfully re-treated with sofosbuvir plus ledipasvir. Seven (50%) of the patients in this study had advanced liver disease, which has been shown to be associated with relapse after sofosbuvir plus ribavirin therapy (8, 10, 11). In addition to having a high prevalencBackground The interferon (IFN)-free regimen of sofosbuvir and ribavirin for 24 weeks was recently approved to treat chronic hepatitis C virus (HCV), genotype-1 (GT-1) infection for interferon-ineligible patients . However, sofosbuvir/ribavirin therapy is associated with treatment relapse in 15-30% of HCV GT-1 study subjects. Neither the mechanism of relapse nor the optimal retreatment strategy for these subjects is defined.

Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial

Chronic liver injury can result in fibrosis that may progress over years to end‐stage liver disease. The most effective anti‐fibrotic therapy is treatment of the underlying disease, however when not possible, interventions to reverse or slow fibrosis progression are needed.

Four-Week Direct-Acting Antiviral Regimens in Noncirrhotic Patients With Hepatitis C Virus Genotype 1 Infection: An Open-Label, Nonrandomized Trial

BACKGROUND Treatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) for 6 weeks achieves sustained virologic response (SVR) rates of 95% in some patients. If effective, shorter therapeutic courses could improve adherence and treatment costs. OBJECTIVE To determine factors predictive of SVR to 4 weeks of DAA treatment in patients with stage F0 to F2 liver fibrosis. DESIGN Open-label, nonrandomized, phase 2a trial. (Clinical Trials.gov: NCT01805882). SETTING Single-center. PATIENTS 50 treatment-naive and predominantly African American patients with HCV genotype 1 infection and early-stage liver fibrosis were sequentially enrolled into 2 treatment groups. INTERVENTION 25 participants received a 3-drug regimen consisting of ledipasvir and sofosbuvir plus GS-9451 for 4 weeks, and 25 received a 4-drug regimen consisting of ledipasvir, sofosbuvir, GS-9451, and GS-9669 for 4 weeks. MEASUREMENTS The primary efficacy end point was SVR12 (HCV RNA level below the lower limit of quantification at posttreatment week 12). RESULTS Forty percent (10 of 25) (95% CI, 21% to 61%) of patients in the 3-drug group and 20% (5 of 25) (CI, 7% to 41%) of those in the 4-drug group achieved SVR12. Exploratory analysis suggested that lower baseline HCV viral load, younger age, and HCV genotype 1b were associated with SVR12. Ten patients had baseline HCV variants conferring greater than 20-fold resistance in vitro to at least 1 study DAA; all had viral relapse. Forty-eight percent (12 of 25) of patients receiving the 3-drug regimen and 72% (18 of 25) of those receiving the 4-drug regimen had adverse events, most of which were mild. One participant was lost to follow-up. LIMITATION Nonrandomized study design and small sample of patients with early-stage fibrosis. CONCLUSION Combination DAA therapy with 3 or 4 drugs for 4 weeks was well-tolerated but resulted in limited cure rates. PRIMARY FUNDING SOURCE National Institute of Allergy and Infectious Diseases, National Cancer Institute, and Clinical Center Intramural Program; supported in part by a cooperative research and development agreement between the National Institutes of Health and Gilead Sciences.

Achieving sustained virologic response after interferon-free hepatitis C virus treatment correlates with hepatic interferon gene expression changes independent of cirrhosis.

Chronic hepatitis C virus (HCV) infection can now be treated with oral directly acting antiviral agents, either with or without ribavirin (RBV). Virologic relapse after treatment can occur, and in some studies was more common in cirrhotic subjects. We previously observed changes in hepatic immunity during interferon (IFN)‐free therapy that correlated with favourable outcome in subjects with early liver disease. Here, we compared changes in endogenous IFN pathways during IFN‐free, RBV‐free therapy between cirrhotic and noncirrhotic subjects. mRNA and microRNA (miRNA) expression analyses were performed on paired pre‐ and post‐treatment liver biopsies from genotype‐1 HCV subjects treated with sofosbuvir/ledipasvir (SOF/LDV) for 12 weeks (n = 4, 3 cirrhotics) or SOF/LDV combined with GS‐9669 or GS‐9451 for 6 weeks (n = 6, 0 cirrhotics). Nine of ten subjects achieved a sustained virologic response (SVR), while one noncirrhotic subject relapsed. Hepatic IFN‐stimulated gene expression decreased with treatment in the liver of all subjects, with no observable impact of cirrhosis. Hepatic gene expression of type III IFNs (IFNL1, IFNL3, IFNL4‐ΔG) similarly decreased with treatment, while IFNA2 expression, undetectable in all subjects pretreatment, was detected post‐treatment in three subjects who achieved a SVR. Only the subject who relapsed had detectable IFNL4‐ΔG expression in post‐treatment liver. Other IFNs had no change in gene expression (IFNG, IFNB1, IFNA5) or could not be detected. Although expression of multiple hepatic miRNAs changed with treatment, many miRNAs previously implicated in HCV replication and IFN signalling had unchanged expression. In conclusion, favourable treatment outcome during IFN‐free HCV therapy is associated with changes in the host IFN response regardless of cirrhosis.