Real-World Outcomes of Ledipasvir/Sofosbuvir in Treatment-Naïve Patients With Hepatitis C

May 3, 2016
Zobair M. Younossi, MD, MPH, FACG, AGAF, FAASLD
Zobair M. Younossi, MD, MPH, FACG, AGAF, FAASLD

Haesuk Park, PhD
Haesuk Park, PhD

Stuart C. Gordon, MD
Stuart C. Gordon, MD

John R. Ferguson
John R. Ferguson

Aijaz Ahmed, MD
Aijaz Ahmed, MD

Douglas Dieterich, MD
Douglas Dieterich, MD

Sammy Saab, MD, MPH
Sammy Saab, MD, MPH

Volume 22, Issue SP 6

In the treatment of hepatitis C virus, the gap between efficacy and real-world effectiveness narrows with improved tolerability and ease of use.


Objectives: Studies of hepatitis C virus (HCV) regimens have documented substantially reduced effectiveness in sustained virologic response (SVR) in the context of real-world clinical practice compared with clinical trials. Real-world and clinical trial SVR and cost-per-SVR data have not been reported for the all-oral, peginterferon-free and ribavirin (RBV)-free ledipasvir/sofosbuvir (LDV/SOF) regimen. Our objective was to compare the rates of SVR achievement and cost per SVR between pooled data from clinical studies of LDV/SOF and from real-world clinical practice.

Methods: Data were derived from the Hepatitis C Therapeutic Registry and Research Network (HCV-TARGET), a real-world, multicenter, prospective, observational study; and from the TRIO Network, a retrospective database of HCV-treated patients. The 1-year cost per SVR was calculated as the total cost of an SVR ([cost of treatment regimen, adverse events, and monitoring costs] per SVR) during the first year of treatment.

Results: After 12 weeks, the SVR rates obtained in real-world studies ranged from 94% to 98%, comparing favorably with the SVRs achieved in the ION-1 and ION-3 trials (94% and 95%-99% with 8 and 12 weeks of RBV-free therapy, respectively). A single SVR, on average, cost $84,989 among patients enrolled in the ION-3 trial, with higher costs ($101,204) among patients with compensated cirrhosis compared with noncirrhotic patients ($81,668). In the pooled TARGET/TRIO population, the average cost of an SVR was $84,770, with costs of $101,380 and $81,368 in patients with compensated cirrhosis and patients without cirrhosis, respectively.

Conclusions: Unlike the results obtained with prior HCV regimens, this study suggests that similar SVR rates are achieved with LDV/SOF in clinical trialTake-Away Points

Chronic hepatitis C virus (HCV) infection is an important cause of morbidity, mortality, and healthcare costs in the United States. According to the CDC, approximately 2.7 to 3.2 million Americans have a chronic HCV infection.1,2 Estimates made prior to the availability of direct-acting antivirals (DAAs) predicted that the death rate from HCV-related complications would double between 2010 and 2019 in the United States. Further, estimates suggested that the total direct costs of managing HCV-related liver disease would reach $6.5 billion to $13.6 billion in the same time frame.3

The management of HCV has evolved as the seriousness of long-term sequelae of HCV has become recognized, and in parallel with advancements in therapy. As a result of underdiagnosis, and with the limitations of previous therapies that used interferon-based regimens, fewer than 6% of individuals with HCV infection ultimately achieved a sustained virologic response (SVR) in real-world clinical practice.2

For more than 2 decades, recombinant interferon-α was the backbone of treatment for HCV infection.4 Pegylation of interferon, used together with other antiviral drugs, resulted in an incremental improvement in efficacy. Furthermore, interferon-based therapy is only initiated in about one-third of patients who are potential candidates for treatment because of adverse drug events and patient comorbidities.5 Even among patients who undergo treatment, with side effects, treatment duration, and complexity, there are limited real-world treatment completion rates, and thus, limited attainment of SVR.4,6

Sofosbuvir (SOF), a nucleotide analog HCV nonstructural protein 5B polymerase inhibitor, has been developed for use in combination with peginterferon and ribavirin (RBV) for genotypes 1 or 4, and in an interferon-α—free regimen with RBV for genotypes 2 and 3.7 It may also be combined with simeprevir for HCV genotype 1.8,9 Peginterferon-free and RBV-free regimens are now approved. A regimen that has been approved for broad use includes ledipasvir (LDV), a novel nonstructural protein 5A inhibitor, combined with SOF. LDV/SOF has demonstrated efficacy in clinical trials and is approved for use in HCV genotypes 1, 4, 5, and 6.10 LDV/SOF has a high barrier to resistance, improved tolerability compared with conventional regimens, and with once-daily dosing, considerably reduced treatment complexity.11,12

In ION-1, a pivotal clinical trial of LDV/SOF in HCV genotype 1, 870 previously untreated patients with and without cirrhosis were randomly allocated to LDV/SOF or LDV/SOF plus RBV for 12 or 24 weeks.12 The study demonstrated that LDV/SOF was highly efficacious in patients with HCV genotype 1 infection, with SVR rates between 97% and 99%. In addition, in ION-3, 647 previously untreated patients with noncirrhotic HCV genotype 1 infection were randomly assigned to treatment with LDV/SOF for 8 weeks, LDV/SOF plus RBV for 8 weeks, or LDV/SOF for 12 weeks.13 Treatment with LDV/SOF resulted in rates of SVR between 93% and 95%. In addition, a post hoc analysis of the ION-1 and ION-3 trial data provided guidance on the use of the LDV/SOF 8-week regimen in noncirrhotic HCV genotype 1 patients who were treatment-naïve and had a baseline HCV RNA <6 million IU/mL.12,13

Although efficacy results derived from clinical trials are the gold standard in evaluating the effects of treatments, they are conducted under necessarily controlled settings and may not be generalizable across real-world settings. Consequently, as new regimens are approved, it is critical to assess their effectiveness in real-world settings, where conditions differ significantly from the rigorously controlled context of clinical trials. The potential differential in effectiveness, depending on setting, is illustrated by recent analyses of bocepravir/telapravir therapy, in which therapy in the real-world setting was consistently associated with significant rates of premature discontinuation and SVR rates substantially below those seen in clinical trials.14-16

Previous studies have suggested that treatment of patients infected with HCV genotype 1 with all-oral LDV/SOF regimens is cost-effective.17-19 Further, a health economic study performed from a third-party payer perspective suggested that an all-oral LDV/SOF regimen was associated with more favorable short- and long-term health economic outcomes compared with conventional therapies, and with no treatment among patients with HCV-1 and mono infection with different levels of treatment experience and different levels of cirrhosis.20 The present analysis is intended to further examine the real-world effectiveness and cost-effectiveness associated with LDV/SOF—currently the most commonly used all-oral DAA regimen for HCV genotype 1.


Patient Populations

Data for this analysis were derived from 2 real-world studies. The Hepatitis C Therapeutic Registry and Research Network (HCV-TARGET) study was a multicenter, prospective, observational study evaluating treatment outcomes in a real-world cohort of patients with chronic HCV genotype 1 who were treated with LDV/SOF with or without RBV.21 In this longitudinal, observational study, which included patients from academic (n = 44) and community (n = 17) medical centers in North America and Europe, the selection of HCV treatment regimen was made by the patient’s healthcare provider and administered per local standards of care. After excluding patients lost to follow-up, the study enrolled 1270 patients, of whom 154 received 8 weeks of therapy and 627 received 12 weeks of therapy with LDV/SOF (Table 1). Demographic, clinical, adverse events (AEs), and virologic data were collected from medical records throughout treatment and during posttreatment follow-up, and were monitored systematically for completeness and accuracy.

The TRIO study obtained data through Trio Health’s Innervation Platform, a cloud-based disease-management platform, and directly from multiple specialty pharmacies.22 Data were collected for 895 treatment-naïve patients with noncirrhotic genotype 1 HCV who initiated 8 or 12 weeks of LDV/SOF between October 2014 and March 2015.23 Sixty-two percent of patients were treated in community practices; the remainder were treated at academic centers (Table 1). SVR was determined by intent-to-treat analysis and 95% CIs were calculated.

Comparator data were derived from ION-1 and ION-3. ION-1 was a phase 3, open-label study of previously untreated patients with chronic HCV genotype 1 infection; patients were randomly allocated to LDV/SOF or LDV/SOF plus RBV for 12 or 24 weeks.12 The LDV/SOF 12-week regimen resulted in an SVR rate of 99% (95% CI, 96-100). ION-3 was a phase 3, open-label study in which 647 treatment-naïve patients with noncirrhotic HCV genotype 1 infection were randomly allocated to receive LDV/SOF for 8 weeks, LDV/SOF plus RBV for 8 weeks, or LDV/SOF for 12 weeks; the primary end point of this study was SVR at 12 weeks after the end of therapy.13 In this study, the rate of SVR was 94% (95% CI, 90-97) with 8 weeks of LDV/SOF and 95% (95% CI, 92-98) with 12 weeks of LDV/SOF.

Cost Inputs

Cost inputs were based on those identified in a cost-effectiveness study of LDV/SOF in patients with chronic HCV genotype 1 infection.20 Briefly, a decision-analytic Markov model, previously published and validated, was used to model a cohort of genotype 1 treatment-naïve patients for a 1-year period.20 Costs were sourced from real-life retrospective data or from publicly available costing sources. Costs related to HCV, including drug acquisition, monitoring, AEs, and health-state costs, were calculated in 2015 US dollars (inflated using the medical care component of the Consumer Price Index,24 where necessary). The costs of drug acquisitions were calculated using the indicated dosing, the duration of therapy, and unit drug costs. Monitoring-resource use from the American Association for the Study of Liver Diseases monitoring guidelines, consensus from a national panel of hepatologists, and unit costs were used as the basis for calculating monitoring costs. Unit costs were derived from the 2014 Resource-Based Relative Value Scale (RBRVS).25

Total monitoring costs over the treatment period were then aggregated from the weekly totals and treatment duration (including early discontinuation). AE costs were calculated based on the incidence of each event and the pharmacy costs and office visits for the management of each event. These pharmacy costs were based on drug treatment algorithms (validated by the national panel of hepatologists) and the wholesale acquisition costs.26 All AEs were assumed to be associated with 1 office visit with both a doctor and a nurse. Office visit costs were sourced from the RBRVS. Cost per SVR was calculated as the total cost of an SVR during the first year of treatment (cost of the treatment regimen + cost of AEs + monitoring costs) divided by the SVR rate.


Baseline demographics of patients enrolled in these studies are summarized in Table 1.

Comparison of SVR Rates in ION-1/ION-3 and Real-World Clinical Studies

SVR rates in HCV-TARGET and TRIO exceeded 94% across all subgroups measured (Table 2). Among patients infected with HCV genotype 1a or 1b, there was little difference in SVR rate between those who were managed with an 8-week or 12-week regimen (Table 2 [A and B]). The rates obtained in these real-world studies were consistent with the rates achieved in ION-1 and ION-3.

Cost per SVR in ION-1/ION-3 and Real-World Clinical Studies

Table 3 (A-C) presents the cost per SVR obtained in ION-1/ION-3, HCV-TARGET, TRIO, and the pooled TARGET/TRIO population. It was estimated that each SVR, on average, cost $84,989 among patients enrolled in ION-1/ION-3, with higher costs ($101,204) among patients with compensated cirrhosis compared with patients without cirrhosis ($81,668). Similar costs and patterns were seen in HCV-TARGET, TRIO, and the pooled TARGET/TRIO populations. In the latter population, the average cost of an SVR was $84,770, with costs of $101,380 and $81,368 in patients with compensated cirrhosis and patients without cirrhosis, respectively.


Second-generation (all-oral) DAAs, such as LDV/SOF, have been demonstrated in clinical trials to have high efficacy and an acceptable safety profile, combined with a simple treatment strategy. Further, data suggest that the peginterferon-free and RBV-free regimen, LDV/SOF, is associated with improvements in patient-reported outcomes and positive patient experiences during treatment and after SVR.19 However, few comparisons have been made between clinical trial and real-world outcomes with this regimen.

Clinical-trial patients are selected using strict criteria and are closely monitored throughout treatment. Data suggest that there is a significant decrement in performance of conventional regimens in real-world clinical practice. Randomized, controlled clinical trials have demonstrated SVR rates for peginterferon and RBV regimens ranging from 54% to 63%27; however, a study conducted in urban minority patients, in which 255 patients were treated, showed an SVR of 14% in genotype 1 patients and 37% in genotype 2/3 patients, with significant differences in academic and community centers.27 Similarly, SVR rates with telapravir- or bocepravir-based regimens, in combination with peginterferon and RBV, are lower in real-world clinical practice.14 In one study utilizing records from the Northern California Kaiser Permanente Medical Care Program, SVR was achieved in 56% of patients who received a telapravir-based regimen and in 53% of those who received a bocepravir-based regimen.14 In this context, the SVR rates achieved in real-world clinical practice were lower than the 59% to 75% rates seen in clinical trials.28-31

The difference between efficacy rates reported from clinical trials and the effectiveness rates reported from the real-world setting of HCV treatment regimens has been attributed to several factors. The most important reason for the discrepancy is likely to be the side-effect profile of these regimens. In the Kaiser Permanente study, side effects resulted in premature discontinuation of 16% of the cohort, which was substantially higher than the 2% rate seen in the Serine Protease Inhibitor Therapy (SPRINT)-2 trial of bocepravir.30 The complexity of treatment management in real-world clinical practice with peginterferon- and RBV-based regimens may also contribute to suboptimal SVR rates in clinical practice.

Both clinical trials and real-world clinical studies of LDV/SOF have demonstrated a low rate of discontinuation due to AEs.21,23,32,33 In ION-3, for example, AEs were infrequent among patients who received LDV/SOF without concomitant RBV; no patients in any arm of this study discontinued treatment prematurely due to a related AE.13 Fatigue, headache, and nausea were the most common AEs and were clearly manageable for all patients in this study. Similar results were seen in HCV-TARGET and TRIO.21,23 In both, serious AEs were infrequent, with few patients discontinuing therapy.

These data support the interactions between viral eradication, low side-effect profile, and improvement in patient-reported outcomes. Substantial data suggest that treatment regimens that cause impairments in health-related quality of life and other patient-reported outcomes (eg, fatigue, work productivity) may result in differences between efficacy and effectiveness. In contrast to interferon-based regimens, LDV/SOF has been shown to improve patient-reported outcomes during treatment, potentially enhancing adherence to the treatment regimen and, therefore, reducing the gap between efficacy and effectiveness.34,35 This concept is supported by real-world data from TRIO and HCV-TARGET, indicating that SVR rates in this setting are similar to those reported for clinical trials.

In addition, 51% and 59% of patients in TRIO and HCV-TARGET, respectively, who could have qualified for 8-week treatment with LDV/SOF, received a 12-week regimen.21,23 These data may indicate potential underutilization of the 8-week regimen. In this context, appropriate use of the 8-week regimen in noncirrhotic, treatment-naïve patients with viral load <6 million IU/mL may further improve cost per SVR associated with LDV/SOF.

These data are supported by additional real-world studies. A study conducted by Backus and colleagues evaluated outcomes with LDV/SOF, with or without RBV, in treatment-naïve patients infected with HCV genotype 1 who were managed in the US Department of Veterans Affairs with LDV/SOF (n = 3763) or LDV/SOF + RBV (n = 602).32 Overall, more than 90% of patients in this difficult-to-treat population experienced an SVR; rates were similar between LDV/SOF and LDV/SOF plus RBV in key subpopulations, including African Americans, Caucasians, and patients with Fibrosis-4 scores ≤3.25 or >3.25. Only 3.6% of patients discontinued treatment before 8 weeks, contributing to the overall positive outcome of the study. Another trial evaluated the real-world effectiveness of 8 weeks of LDV/SOF.33 This study included 103 patients treated at a single center; SVR was measured after 12 weeks of follow-up. No patients in this study received RBV, and all were noncirrhotic. In this study, the rate of SVR after 12 weeks was 100%. Only 3.9% of patients were nonadherent to treatment, and no AEs led to treatment discontinuation.


The study has several limitations, mainly related to the exclusion of patients with advanced cirrhosis from clinical trials (included in the exclusionary criteria for ION-1 and ION-3) and very few such patients treated in the real-world setting. Second, there are some differences in the clinico-demographic profile of patients included in the clinical trials versus in the real-world setting. Despite these differences, however, it is important to note that SVR rates and cost-effectiveness remain similar between those reported from clinical trials and from the real-world setting of clinical practice. Lastly, this study only examines short-term economic outcomes (ie, cost per SVR). Future studies are required to examine the impact of treatment with LDV/SOF in real-world settings using quality-adjusted life expectancy over a longer time horizon.


To our knowledge, this study is the first to show the cost-effectiveness of new interferon-free LDV/SOF regimens in the real-world setting. Our data suggest that cost per SVR is similar between clinical trials and real-world clinical practice among treatment-naïve patients infected with HCV genotype 1. Given that SVR rates are quite favorable for 8-week regimens of LDV/SOF in real-world clinical practice, the appropriate use of this shorter regimen may further enhance cost per SVR rates. Finally, the data support the economic value of interferon-free regimens relative to interferon-containing regimens in both the clinical trial setting and real-world clinical practice.34Author Affiliations: Department of Medicine, Center for Liver Diseases, Inova Fairfax Hospital (ZMY), Falls Church, VA; Betty and Guy Beatty Center for Integrated Research, Inova Health System (ZMY), Falls Church, VA; University of Florida College of Pharmacy (HP), Gainesville, FL; Henry Ford Hospital (SCG, AA), Detroit, MI; Independent medical writer (JRF), New Paltz, NY; Icahn School of Medicine at Mount Sinai (DD), New York, NY; University of California, Los Angeles (SS), Los Angeles, CA.

Source of Funding: This study was funded by Gilead Sciences, Inc, Foster City, CA.

Author Disclosures: Dr Younossi has received unrelated grant/research support from AbbVie Pharmaceuticals, Bristol-Myers Squibb (BMS), and Gilead Pharmaceuticals. He is also a consultant/adviser for AbbVie Pharmaceuticals, BMS, Intercept, Gilead Pharmaceuticals, and GSK. Dr Gordon has received grant/research support from AbbVie Pharmaceuticals, BMS, Conatus, CymaBay, Exalenz, Gilead Pharmaceuticals, Intercept Pharmaceuticals, and Merck. He is also a consultant/adviser for AbbVie Pharmaceuticals, BMS, Intercept, CVS Caremark, Gilead Pharmaceuticals, and Merck; and has done speaking/teaching engagements for Gilead and Intercept. Dr Park received a grant from Gilead Science and has attended meetings by the American Association for the Study of Liver Disease, partially funded by Gilead. Dr Ahmed is a consultant for Gilead, AbbVie, and Janssen; he has also received a grant from Gilead. Dr Dieterich is a consultant for Gilead, BMS, AbbVie, Merck, and Janssen, and has received honoraria and lecture fees for speaking at the invitation of a commercial sponsor. Dr Saab is a consultant for BMS, Gilead, Merck, and AbbVie, and has received honoraria and lecture fees for speaking at the invitation of a commercial sponsor; he has grants pending from Merck and Gilead. Mr Ferguson reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (ZMY, SCG, HP, AA, SS); acquisition of data (AA); analysis and interpretation of data (ZMY, SCG, HP, AA, DD, SS); drafting of the manuscript (ZMY, JRF, AA); critical revision of the manuscript for important intellectual content (ZMY, JRF, SCG, HP, AA, DD, SS); obtaining funding (HP); administrative, technical, or logistic support (JRF); and supervision (ZMY).


Address correspondence to: Zobair Younossi, MD, MPH, Beatty Center for Integrated Research, 3300 Gallows Road, Falls Church, VA 22042. E-mail:

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