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The American Journal of Managed Care Special Issue: HCV
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Real-World Outcomes of Ledipasvir/Sofosbuvir in Treatment-Naïve Patients With Hepatitis C
Zobair M. Younossi, MD, MPH, FACG, AGAF, FAASLD; Haesuk Park, PhD; Stuart C. Gordon, MD; John R. Ferguson; Aijaz Ahmed, MD; Douglas Dieterich, MD; and Sammy Saab, MD, MPH
Improving HCV Cure Rates in HIV-Coinfected Patients - A Real-World Perspective
Seetha Lakshmi, MD; Maria Alcaide, MD; Ana M. Palacio, MD, MPH; Mohammed Shaikhomer, MD; Abigail L. Alexander, MS; Genevieve Gill-Wiehl, BA; Aman Pandey, BS; Kunal Patel, BS; Dushyantha Jayaweera, MD; and Maria Del Pilar Hernandez, MD
Does Patient Cost Sharing for HCV Drugs Make Sense?
Darius N. Lakdawalla, PhD; Mark T. Linthicum, MPP; and Jacqueline Vanderpuye-Orgle, PhD
A Way Out of the Dismal Arithmetic of Hepatitis C Treatment
Jay Bhattacharya, MD, PhD, Center for Primary Care and Outcomes Research, Stanford University School of Medicine; Guest Editor-in-Chief for the HCV special issue of The American Journal of Managed
Value of Expanding HCV Screening and Treatment Policies in the United States
Mark T. Linthicum, MPP; Yuri Sanchez Gonzalez, PhD; Karen Mulligan, PhD; Gigi A. Moreno, PhD; David Dreyfus, DBA; Timothy Juday, PhD; Steven E. Marx, PharmD; Darius N. Lakdawalla, PhD; Brian R. Edlin, MD; and Ron Brookmeyer, PhD
The Wider Public Health Value of HCV Treatment Accrued by Liver Transplant Recipients
Anupam B. Jena, MD, PhD; Warren Stevens, PhD; Yuri Sanchez Gonzalez, PhD; Steven E. Marx, PharmD; Timothy Juday, PhD; Darius N. Lakdawalla, PhD; and Tomas J. Philipson, PhD
Costs and Spillover Effects of Private Insurers' Coverage of Hepatitis C Treatment
Gigi A. Moreno, PhD; Karen Mulligan, PhD; Caroline Huber, MPH; Mark T. Linthicum, MPP; David Dreyfus, DBA; Timothy Juday, PhD; Steven E. Marx, PharmD; Yuri Sanchez Gonzalez, PhD; Ron Brookmeyer, PhD; and Darius N. Lakdawalla, PhD
Coverage for Hepatitis C Drugs in Medicare Part D
Jeah Kyoungrae Jung, PhD; Roger Feldman, PhD; Chelim Cheong, PhD; Ping Du, MD, PhD; and Douglas Leslie, PhD

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

Zobair M. Younossi, MD, MPH, FACG, AGAF, FAASLD; Haesuk Park, PhD; Stuart C. Gordon, MD; John R. Ferguson; Aijaz Ahmed, MD; Douglas Dieterich, MD; and Sammy Saab, MD, MPH
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 trial
Take-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

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