Douglas Dieterich, MD

To estimate change in chronic hepatitis C virus (HCV) disease and the economic burden associated with comprehensive treatment of the chronic HCV—infected Medicaid population.

 Treatment-naïve patients with genotype 1 chronic HCV were followed over a lifetime horizon from the third-party payer perspective. Patients entered the model insured under Medicaid and were treated under state-specific restrictions by Metavir fibrosis stage (base case) or all treated (all-patient strategy) with an approved all-oral regimen (ledipasvir/sofosbuvir [LDV/SOF] for 8 weeks or 12 weeks, depending on cirrhosis status, viral load, and state-specific LDV/SOF restrictions). Untreated patients were assumed to age into Medicare at 65 years, where they were treated with LDV/SOF without restriction by fibrotic stage. 

The sustained virologic response (SVR) rate of the current Medicaid LDV/SOF restriction strategy was 75.2% versus 95.9% if all LDV/SOF-eligible patients were treated under Medicaid. Treating all eligible Medicaid patients with LDV/SOF, regardless of fibrotic stage, was projected to result in 36,752 fewer cases of cirrhosis; 1739 fewer liver transplants; 8169 fewer cases of hepatocellular carcinoma; 16,173 fewer HCV-related deaths; 0.84 additional life-years per patient; and 1.03 additional quality-adjusted life-years per patient. Treating all Medicaid patients with chronic HCV using LDV/SOF resulted in a 39.4% ($3.8 billion) savings and decreased the proportion of total costs attributable to downstream costs of care to 18.3%.

 A “treat all” strategy in a Medicaid population resulted in superior SVRs, substantial reductions in downstream negative clinical outcomes, and considerable cost savings. Current restrictive state policies regarding HCV treatment in Medicaid populations must be reassessed in light of these data. 

	A restrictive Medicaid policy in many states limits hepatitis C virus (HCV) treatment to patients with severe disease, leading to suboptimal treatment outcomes, high patient burden, and excess costs. This analysis estimated change in HCV disease and the economic burden associated with comprehensive treatment of eligible Medicaid patients with ledipasvir/sofosbuvir (LDV/SOF). A “treat all” strategy led to: 

		Increased sustained virologic response rates were 95.9% if all LDV/SOF-eligible patients were treated under Medicaid versus 75.2% under the current Medicaid LDV/SOF restriction strategy.

		Improved clinical outcomes: 36,752 fewer cases of cirrhosis; 1739 fewer liver transplants; 8169 fewer cases of hepatocellular carcinoma; 16,173 fewer HCV-related deaths; 0.84 additional life-years per patient; and 1.03 additional quality-adjusted life-years per patient. 

		A $3.8-billion overall savings in healthcare costs.

Approximately 3.5 million Americans are infected with chronic hepatitis C virus (HCV),

 with the majority born between 1945 and 1965 and considered part of the baby boomer generation. HCV is a systemic disease with both hepatic and extrahepatic clinical manifestations

 that also has negative impacts on patient-reported outcomes (PROs),

 such as fatigue and decreased work productivity.

 These manifestations are associated with significant direct and indirect costs to individuals, their families, and society that increase in parallel with disease severity and the need for liver transplantation.

Until recently, available treatments for HCV had limited efficacy and were often poorly tolerated; few patients received treatment and many remained uncured.

 A number of barriers existed to curing HCV. First, conventional treatments were less tolerable than current regimes and had low effectiveness.

 Second, risk-based screening for HCV failed to identify many patients with the disease.

 Third, linking patients who are HCV-positive to care was suboptimal, with less than 40% of diagnosed patients receiving follow-up care.

 Fourth, patients with HCV often lacked insurance coverage and frequently had psychiatric and clinical contraindications to interferon, leading to less than one-third being eligible for, and having access to, treatment.

  These factors contributed to an epidemic of advanced liver disease, cirrhosis, and hepatocellular carcinoma (HCC) in the United States that led to increases in mortality, especially among men, blacks, and those aged 55 to 64 years.

Between 1996 and 2006, the prevalence of cirrhosis and decompensated cirrhosis in patients with HCV more than doubled, and the prevalence of HCC increased more than 20-fold.

 Further, the prevalence of HCV is disproportionally higher in inner cities in the United States and among those who are eligible for Medicaid.

Data from 2012 suggest that 12.5% of liver transplant patients with HCV were covered by Medicaid. Considering that the average cost of a liver transplant due to HCV is $188,000,

 Medicaid pays an estimated $147 million annually for liver transplantation, and there is additional significant cost for posttransplant immunosuppression and management of resulting complications. These costs are likely underestimated because many patients never receive transplants and require repeated hospitalization for complications of cirrhosis and HCC.

 Furthermore, premature death of patients with HCV leads to significant societal costs.

Several highly effective, well-tolerated targeted treatments for HCV, such as sofosbuvir (SOF)-based regimens, have been developed over the last 5 years. The cost of these more effective regimens is higher than for older regimens; however, the cost per cure is lower and the regimens are generally considered to be highly cost-effective.

 It has been well established that universal, immediate treatment with these all-oral, interferon-free highly effective targeted regimens is cost-effective and decreases downstream medical costs, due primarily to the avoidance of liver-related complications.

 Furthermore, in the United States, marketplace competition has reduced the net cost of these drugs as manufacturers provide substantial discounts for Medicaid patients. Despite these factors, a recent study from the TRIO registry found that Medicaid was the least likely payer to cover HCV treatment

; states that do cover HCV treatment under Medicaid typically subject newer regimens to reimbursement restrictions by fibrotic stage, patient characteristic (eg, not reimbursed in intravenous drug users), or prescriber type (eg, hepatologist only).

As patients with HCV reach Medicare age, the cost of care will be shifted to Medicare, where current drug discounts do not exist, but full coverage is possible. In this context, we used a decision-analytic model to estimate the reduction of disease and economic burden of immediate treatment of Medicaid patients with HCV with highly effective all-oral regimens versus delayed treatment in Medicare.

We constructed a decision-analytic Markov model, described previously,

 which followed a cohort of treatment-naïve (TN) patients with genotype 1 (GT1) mono-infected chronic HCV over a lifetime horizon from the third-party payer perspective. Patients entered the model insured under Medicaid and were treated or untreated with an approved all-oral regimen (ledipasvir/SOF [LDV/SOF] 8 weeks [W] or 12W, depending on cirrhotic status, viral load, and state-specific LDV/SOF restrictions)

 Untreated patients were assumed to age into Medicare at 65 years, after which they were treated with LDV/SOF without restriction by fibrotic stage. No retreatment of patients previously treated with an LDV/SOF regimen was permitted in Medicare.

Discounting of costs and outcomes was assumed at 3%. The model compared the health and cost consequences of treatment under current Medicaid state-specific restrictions by Metavir fibrosis stage (current situation) versus treatment in Medicaid without restriction by fibrotic stage (comparative situation).

Medicaid patients were assumed to enter the model with a mean age of 43 years.

 The number of patients with HCV covered under each state’s Medicaid program was sourced from claims analyses

 (and Gilead Sciences confidential data on file) and inflated to 2015 numbers based on the calculated growth rate of the national population (eAppendix Table A [

According to sources and Gilead Sciences internal data on file, assumptions included 70% with GT1,

 100% were aware of their infection, 60% had a viral load under 6 million copies and thus were potentially eligible for LDV/SOF 8W,

 and 83% were noncirrhotic according to internal Ipsos data on file. These inputs were assumed to apply uniformly across all state Medicaid populations.

was used to inform restrictions for LDV/SOF; restrictions for LDV/SOF were assumed to be identical to SOF restrictions. States without any data for SOF restrictions by Metavir fibrosis stage were excluded from the analysis (15.3% of state Medicaid patients) and not modeled.

Transition probabilities and utilities have been described previously

 and were obtained from the literature and hepatologist consensus. Transition probabilities and utilities were assumed to be identical for Medicaid and Medicare patients, although background mortality was age-adjusted as patients progressed through the model. These inputs are summarized in eAppendix Tables B, C, and D.

Wholesale acquisition costs (WAC) for LDV/SOF 8W and 12W were sourced from Red Book (Micromedex, Greenwood Village, Colorado

 and reported in 2014 US$. In the base case, no price increases for LDV/SOF were assumed over the time horizon of the model. A best price rebate to Medicaid of 50% of the WAC for LDV/SOF was assumed (Medicaid 8W price: $31,500; Medicaid 12W price: $47,250). To derive Medicare prices for LDV/SOF 22 years into the future, an LDV/SOF annual WAC price increase of 2.6% was assumed, which was derived from the rate of historical price increases for a market basket of 13 antivirals indicated for the treatment of HIV (5.6%), launched in the United States between 2005 and 2012, net of the annual rate of inflation over this time period (3%). Currently marketed HCV direct-acting antivirals (DAAs) have not been on the market enough time (<4 years) to robustly extrapolate price increases over a 22-year horizon. LDV/SOF’s rebate in Medicare was assumed to be 25% (Medicare future 8W price: $83,108.18; Medicare future 12W price: $124,662.26). Rebate assumptions were based on the magnitude of the rebates currently offered for LDV/SOF to Medicare and Medicaid.

Health state and monitoring costs for the Medicare population are reported in 2014 US$ and are summarized in eAppendix Table E based on our previously developed model.

 An inflation factor was not applied for medical costs, as, unlike for pharmacy costs, these were not assumed to increase at a rate faster than that of inflation. These were adapted to a Medicaid population by applying the national Medicaid-to-Medicare fee ratio of 0.66, sourced from the Kaiser Family Foundation.

A total of 120,980 Medicaid patients with chronic HCV were included: 60,248 receiving LDV/SOF 8W; 40,165 noncirrhotic patients receiving LDV/SOF 12W; and 20,567 compensated cirrhosis patients receiving LDV/SOF 12W. Under current Medicaid restrictions, 4.2%, 49.6%, and 6.8% of Medicaid patients with HCV GT1 could access LDV/SOF treatment only at Metavir fibrosis stages F2, F3, or F4, respectively (

In the aggregate (ie, including treated and untreated patients to calculate a weighted average), the SVR rate of the current Medicaid LDV/SOF restriction strategy was 75.2% versus 95.9% if all potentially LDV/SOF-eligible patients were treated (

). Under current restrictions, 9618 patients potentially eligible for LDV/SOF 8W were assumed to age into Medicare as compensated cirrhotics and become ineligible for 8W treatment. An additional 25,774 patients would age into Medicare with decompensated cirrhosis or hepatocellular carcinoma or as liver transplant patients (or die due to liver-related mortality) and become ineligible for LDV/SOF 12W (Table).

Relative to current restrictions, treating all eligible Medicaid patients with LDV/SOF regardless of fibrotic stage would result in 36,752 fewer cases of cirrhosis (—87%); 1739 fewer liver transplants (–81%); 8169 fewer cases of hepatocellular carcinoma (–73%); 16,173 fewer HCV-related deaths (–77%); 0.84 additional life-years per patient (+4%); and 1.03 additional quality-adjusted life-years (QALYs) per patient (+6%), given that earlier treatment with LDV/SOF universally resulted in better health outcomes (eAppendix Table F).

Under the current scenario of Medicaid LDV/SOF restrictions, the total costs of treating the HCV cohort totaled $9.7 billion, with the majority of costs (50.4%) attributable to downstream costs of care (ie, hospitalization costs, outpatient costs, and non-LDV/SOF pharmacy costs). Treating all Medicaid patients with chronic HCV using LDV/SOF led to a 39.4% ($3.8 billion) savings over the model time horizon (

) and decreased the relative proportion of total costs attributable to downstream costs of care to 18.3%.

Although the largest cost savings were attributable to downstream medical cost offsets, pharmacy costs attributable to LDV/SOF treatment decreased 2%, from $4.84 billion to $4.75 billion; this is due in part to the 9618 patients potentially eligible for LDV/SOF 8W treatment under Medicaid at the onset of the model who age into Medicare as compensated cirrhotics and can only receive treatment with the 12W regimen. Additional LDV/SOF cost savings result from treating a larger number of patients under Medicaid and the lower price for LDV/SOF under this scheme versus Medicare ($31,500 vs $83,108.18 [inflation-adjusted future price] for LDV/SOF 8W).

Under the current scenario of Medicaid LDV/SOF restrictions, the aggregate cost per SVR across the entire patient cohort—patients treated in Medicaid, patients treated in Medicare, and patients unable to be treated&mdash;was $51,809. Treating all Medicaid patients with LDV/SOF led to a 19.8% ($10,282) savings per SVR and was dominant from a cost-effectiveness (cost per life-year gained, cost per QALY gained) standpoint, given that earlier treatment with LDV/SOF resulted in better health and cost outcomes (eAppendix Tables F and G).

Access to HCV treatment under current state Medicaid programs is highly heterogeneous. Although HCV treatment qualification has become less stringent in some states, others refuse coverage, have instituted criteria for only treating patients with advanced fibrosis, or have not yet considered adding DAAs to their formularies.

 This strategy is flawed: first, patients with advanced fibrosis are more difficult to treat;

 second, fibrosis is a surrogate for liver-related mortality and fails to account for other negative impacts of HCV on patients and their well-being. In fact, evidence suggests that patients with early-stage fibrosis experience at least equivalent PROs and work productivity benefits from an HCV cure compared with those with more severe disease.

The confluence of high HCV prevalence in the Medicaid population and lack of access to treatment may result in individual and societal harm and has cost implications beyond Medicaid. Although full coverage is possible as patients with HCV age in to Medicare, Medicaid-level drug discounts are not offered, thereby increasing the acquisition cost of HCV drugs for the population not treated earlier in their disease. Further, these policies disproportionately affect economic disadvantaged populations that rely on Medicaid, creating significant health disparities for aging and minority populations.

To our knowledge, this is the first study to estimate the HCV burden to both Medicare and Medicaid resulting from Medicaid HCV treatment restrictions. This study provides evidence that the current Medicaid strategy is flawed in providing treatment to different patients based on their state of residence. The current Medicaid strategy is estimated to result in 27,000 excess cases of cirrhosis and almost 10,000 excess cases of decompensated cirrhosis, leading to over 1700 liver transplants, over 8000 cases of HCC, and over 16,000 HCV-related deaths. This analysis likely underestimates the burden of HCV infection because it does not account for the negative impact of HCC-related extrahepatic diseases and PROs.

Curing Medicaid patients with HCV using an extended “treat all” strategy could reduce the risk of complications, cirrhosis, HCC, the need for liver transplantation, and liver-related deaths. Given the large number of patients with HCV, we acknowledge that such a strategy would require up-front investment in the context of state Medicaid budget constraints; however, this strategy would ultimately lead to cost savings for CMS by reducing the future burden to Medicare and the costs associated with HCV morbidity and mortality. Additionally, we believe that an HCV cure will lead to substantial improvement in PROs and work productivity. Most critically, a “treat all” strategy will reduce the health disparities caused by the current Medicaid strategy, which primarily affects minorities and baby boomers who are approaching Medicare age.

This analysis was conducted conservatively, excluding 15% of Medicaid patients for whom the restriction status of LDV/SOF was not publically available; this potentially underestimates the full impact of lifting Medicaid coverage restrictions. The restriction status of LDV/SOF was inferred from published restrictions of SOF, which may lead to uncertainty. This analysis used clinical trial data rather than real-world data as model inputs for SVR rates; however, recent studies (ie, HCV-TARGET38) have shown that real-world and clinical trial SVR rates with all-oral ribavirin-free regimens like LDV/SOF are similar. Our model structure only allowed for patients to receive treatment in Medicaid once as they entered the model and did not allow for potential treatment at subsequent time points in Medicaid as patients continued to be monitored and progress to more severe fibrosis stages; thus, the number of patients ineligible to receive treatment in Medicare may be overestimated. Finally, this analysis assumed that all chronic HCV Medicaid patients eligible for treatment were aged 43 years and aged into Medicare at 65 years, which may not reflect real-world demographics and coverage dynamics (eg, dual-eligible patients).

Institution of a less restrictive “treat all” strategy in Medicaid patients was associated with clinical outcome and cost benefits. Based on these data, we believe it is time to develop a national strategy to eradicate HCV from the United States regardless of payer status. Such a strategy requires collaboration among private payers, governmental payers (including Medicaid), healthcare providers, drug manufacturers, and patients.

The authors thank John R. Ferguson for editorial assistance in preparing this manuscript.

 Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital (ZY), Falls Church, VA; Betty and Guy Beatty Center for Integrated Research, Inova Health System (ZY), Falls Church, VA; Henry Ford Hospital (SCG), Detroit, MI; Stanford University School of Medicine (AA), Stanford, CA; Icahn School of Medicine at Mount Sinai (DD), New York, NY; University of California—Los Angeles (SS), Los Angeles, CA; Maple Health Group, LLC (RB), New York, NY.

Articles

Hepatitis C virus treatment is often restricted in Medicaid patients. This analysis evaluates the clinical and cost impacts of treating all Medicaid patients versus the current status quo.

Treating Medicaid Patients With Hepatitis C: Clinical and Economic Impact

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.

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.

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.

Unlike the results obtained with prior HCV regimens, this study suggests that similar SVR rates are achieved with LDV/SOF in clinical trial

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.

 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.

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.

For more than 2 decades, recombinant interferon-α was the backbone of treatment for HCV infection.

 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.

 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.

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.

 It may also be combined with simeprevir for HCV genotype 1.

 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.

 LDV/SOF has a high barrier to resistance, improved tolerability compared with conventional regimens, and with once-daily dosing, considerably reduced treatment complexity.

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.

 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.

 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.

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.

Previous studies have suggested that treatment of patients infected with HCV genotype 1 with all-oral LDV/SOF regimens is cost-effective.

 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.

 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.

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.

 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 (

). 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.

 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.

 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.

 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.

 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 were based on those identified in a cost-effectiveness study of LDV/SOF in patients with chronic HCV genotype 1 infection.

 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.

 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,

 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).

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.

 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 (

). 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

 (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.

 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%

; 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.

 Similarly, SVR rates with telapravir- or bocepravir-based regimens, in combination with peginterferon and RBV, are lower in real-world clinical practice.

 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.

 In this context, the SVR rates achieved in real-world clinical practice were lower than the 59% to 75% rates seen in clinical trials.

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.

 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.

 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.

 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.

 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.

 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.

 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).

 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.

 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.

 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.

 This study was funded by Gilead Sciences, Inc, Foster City, CA.

 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.

 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).

 Zobair Younossi, MD, MPH, Beatty Center for Integrated Research, 3300 Gallows Road, Falls Church, VA 22042. E-mail: zobair.younossi@inova.org.

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

Douglas Dieterich, MD

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