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Hepatitis C infection: A multi-faceted systemic disease with clinical, patient reported and economic consequences

      Summary

      Hepatitis C virus infection (HCV) affects approximately 170–200 million individuals globally. HCV is one of the primary causes of hepatocellular carcinoma (HCC) and cirrhosis and has been identified as the leading indication for liver transplantation in most Western countries. Because HCV is a systemic disease with hepatic, extrahepatic, economic and patient reported consequences, it is important for healthcare practitioners to understand the comprehensive and multi-faceted picture of this disease. In this context, it is important to fully appreciate the impact of HCV on the individual patient and the society. With the recent advent of the new generation of direct antiviral agents, the long standing goal of eradicating HCV in most infected patients has been accomplished. Therefore, now more than ever, it is critical to assess the total benefits of sustained virological response in a comprehensive manner. This should not be limited to the clinical benefits of HCV cure, but also to account for the improvement of patient reported health and economic outcomes of HCV cure. It is only through this comprehensive approach to HCV and its treatment that we will understand the full impact of this disease and the tremendous gains that have been achieved with the new antiviral regimens.

      Keywords

      Introduction

      The discovery of hepatitis C virus (HCV) in 1989 was the culmination of years of scientific efforts to identify one of the most challenging causes of chronic liver disease [
      • Williams I.T.
      • Bell B.P.
      • Kuhnert W.
      • Alter M.J.
      Incidence and transmission patterns of acute hepatitis C in the United States, 1982–2006.
      ,
      • Alter M.J.
      • Margolis H.S.
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      • Mares A.
      • Alexander W.J.
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      The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team.
      ]. Following the HCV discovery, efforts in the next decades focused on accurately diagnosing HCV infection, quantifying the amount of virus in the blood, determining HCV genotypes, and clarifying the natural history of chronic HCV infection [
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      Seroepidemiological studies of transfusion-associated hepatitis.
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      • Razavi H.
      Global epidemiology and genotype distribution of the hepatitis C virus infection.
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      • Hajarizadeh B.
      • Grebely J.
      • Dore G.J.
      Epidemiology and natural history of HCV infection.
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      • Leone N.
      • Rizzetto M.
      Natural history of hepatitis C virus infection: from chronic hepatitis to cirrhosis, to hepatocellular carcinoma.
      ,
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      Natural history of hepatitis C.
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      • Messina J.P.
      • Humphreys I.
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      • Brown A.
      • Cooke G.S.
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      Global distribution and prevalence of hepatitis C virus genotypes.
      ]. As a result of these advances, the total burden of HCV infections can now be accurately estimated worldwide [
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      • Razavi H.
      Global epidemiology and genotype distribution of the hepatitis C virus infection.
      ]. Additionally, there is strong evidence suggesting that HCV is one of the major causes of hepatocellular carcinoma (HCC) (especially in Western countries and Japan) and has become the leading indication for liver transplantation [
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      Global epidemiology and genotype distribution of the hepatitis C virus infection.
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      ].
      Globally, we also know that genotype 1 (GT1) is the most common (46%) genotype of HCV with a predominant geographic dispersion found in the United States, Europe, Australia, and Japan. Genotype 3 (GT3) is the second most prevalent (22%) genotype found mostly in Pakistan. Furthermore, genotype 4 (GT4,13%) is predominantly found in Egypt and North Africa [
      • Gower E.
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      • Blach S.
      • Razavi-Shearer K.
      • Razavi H.
      Global epidemiology and genotype distribution of the hepatitis C virus infection.
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      The original treatment of HCV was interferon (IFN)-based regimens. However, the efficacy of these regimens was low with approximately 10% of the eligible patients in the Western world able to receive treatment [
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      The changing landscape of hepatitis C virus therapy: focus on interferon-free treatment.
      ]. Subsequent advances in the field of HCV treatment combined IFN with ribavirin (RBV), and subsequently the first generation protease inhibitors. These regimens led to higher rates of sustained virologic response (SVR) in clinical trials but were associated with increased side effects leading to a gap between the efficacy rates from clinical trials and the effectiveness SVR rates reported from the real world practices [
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      In 2013, we witnessed the start of the “miraculous era in HCV treatment” with the next generation of direct antiviral agents (DAAs) providing SVR rates over 95% for GT1. In addition, these regimens, which are free from IFN, have better tolerability and a better safety profile [
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      Sofosbuvir and ribavirin in HCV genotypes 2 and 3.
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      Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267, ABT-333 +/− ribavirin in patients with chronic HCV GT1 infection: results from the AVIATOR study.
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      Resistance analysis of baseline and treatment-emergent variants in hepatitis C virus genotype 1 in the AVIATOR study with paritaprevir-ritonavir, ombitasvir, and dasabuvir.
      ,

      Press release: OLYSIO™ (simeprevir) receives FDA approval for combination treatment of chronic hepatitis C. Obtained from the world wide web at http://www.jnj.com/news/all/OLYSIO-simeprevir-Receives-FDA-Approval-for-Combination-Treatment-of-Chronic-Hepatitis-C Last accessed on Mar 21, 2016.

      ,
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      Efficacy and safety of sofosbuvir/ledipasvir for the treatment of patients with hepatitis C virus re-infection after liver transplantation.
      ,
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      Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial.
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      • Zeuzem S.
      • Gane E.
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      • Andreone P.
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      Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial.
      ,
      • Banerjee D.
      • Reddy K.R.
      Review article: safety and tolerability of direct-acting anti-viral agents in the new era of hepatitis C therapy.
      ,
      • Kattakuzhy S.
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      • Sidharthan S.
      • Sims Z.
      • McLaughlin M.
      • Price A.
      • et al.
      Moderate sustained virologic response rates with 6-week combination directly acting anti-hepatitis C virus therapy in patients with advanced liver disease.
      ]. In fact, a recently FDA approved pan-genotypic 12-week regimen can achieve 98% SVR for all patients without advanced liver disease regardless of HCV genotype [
      • Cornberg M.
      One pill for all HCV-genotypes?.
      ]. In addition to high efficacy, increasing evidence suggests that these newer regimens not only have high SVR rates in the clinical trial setting but also high SVR rates are reported from real world practices, closing the gap between efficacy and effectiveness of HCV treatment [
      • Cornberg M.
      One pill for all HCV-genotypes?.
      ].
      A comprehensive approach is now needed to appreciate the total burden of HCV infection in tandem with the development of highly effective treatment regimens. Clinical, patient reported, and economic outcomes of HCV and its treatment all should be included in the comprehensive approach (Fig. 1).
      Consequences of HCV infection must be assessed based on its clinical outcomes, patient-reported outcomes and economic outcomes.
      Figure thumbnail gr1
      Fig. 1How to capture the comprehensive benefits approach for measuring the burden of HCV to patients and to society. HCV, hepatitis C virus; EHM, extra-hepatic manifestations; HQRL, health-related quality of life; WP, window phase; ICER, incremental cost-effectiveness ratio; PRO, patient related outcomes.
      Each one of these outcomes represents different aspects of patients’ and societal priorities. In fact, clinical endpoints such as stage of hepatic fibrosis or SVR are surrogates for the most important clinical outcome i.e., improvement in survival. Numerous studies have shown SVR leads to a reduction in hepatic fibrosis which in turn, is an excellent predictor of liver related mortality in patients with HCV [
      • Petta S.
      • Di Marco V.
      • Bruno S.
      • Enea M.
      • Calvaruso V.
      • Boccaccio V.
      • et al.
      Impact of virus eradication in patients with compensated hepatitis C virus-related cirrhosis: competing risks and multistate model.
      ]. In contrast, patient reported outcomes (PROs) are surrogates for patients’ experience while economic endpoints (such as cost per SVR) are surrogate markers for resource utilization [
      • Lam B.P.
      • Jeffers T.
      • Younoszai Z.
      • Fazel Y.
      • Younossi Z.M.
      The changing landscape of hepatitis C virus therapy: focus on interferon-free treatment.
      ]. Therefore, the purpose of this review is to cover these respective topics in order to provide a current and more thorough understanding of multi-faceted aspects of HCV and its treatment.

      Hepatitis C virus infection – a systemic disease

      Over the past 2 decades, healthcare practitioners have developed a solid understanding of the clinical course and the hepatic consequences of HCV infection. They have found that HCV is self-limiting in 15%-25% of patients who clear the virus. Approximately 75%-85% of infected patients do not clear the virus by 6 months and thus develop chronic hepatitis. The rate of chronic HCV infection is affected by many factors, including the age at time of infection, gender, ethnicity (e.g., African American), and the development of jaundice during the acute infection stage (more symptoms increase the chance of viral clearance). Cirrhosis develops in approximately 10% to 15% of individuals with chronic HCV infection [
      • Alter M.J.
      • Margolis H.S.
      • Krawczynski K.
      • Judson F.N.
      • Mares A.
      • Alexander W.J.
      • et al.
      The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team.
      ,
      • Purcell R.H.
      • Walsh J.H.
      • Holland P.V.
      • Morrow A.G.
      • Wood S.
      • Chanock R.M.
      Seroepidemiological studies of transfusion-associated hepatitis.
      ,
      • Hajarizadeh B.
      • Grebely J.
      • Dore G.J.
      Epidemiology and natural history of HCV infection.
      ,
      • Leone N.
      • Rizzetto M.
      Natural history of hepatitis C virus infection: from chronic hepatitis to cirrhosis, to hepatocellular carcinoma.
      ,
      • Westbrook R.H.
      • Dusheiko G.
      Natural history of hepatitis C.
      ]. There are external and host factors which increases the risk of liver disease progression. Multiple studies have shown that chronic alcohol use is a major external risk factor for the progression of chronic hepatitis C to cirrhosis and HCC. Host risk factors potentially accelerating progression include older age at time of infection, male gender, coinfection with human immunodeficiency virus (HIV) or hepatitis B virus (HBV), and comorbid conditions such as immunosuppression, insulin resistance, non-alcoholic steatohepatitis (NASH), hemochromatosis, and schistosomiasis [
      • Taylor A.L.
      • Denniston M.M.
      • Klevens R.M.
      • McKnight-Eily L.R.
      • Jiles R.B.
      Association of hepatitis C virus with alcohol use among U.S. adults: NHANES 2003–2010.
      ,
      • Ortiz V.
      • Berenguer M.
      • Rayon J.M.
      • Carrasco D.
      • Berenguer J.
      Contribution of obesity to hepatitis C-related fibrosis progression.
      ,
      • D’Souza R.
      • Sabin C.A.
      • Foster G.R.
      Insulin resistance plays a significant role in liver fibrosis in chronic hepatitis C and in the response to antiviral therapy.
      ,
      • Calvaruso V.
      • Craxì A.
      Immunological alterations in hepatitis C virus infection.
      ,
      • Hung C.H.
      • Lee C.M.
      • Lu S.N.
      Hepatitis C virus-associated insulin resistance: pathogenic mechanisms and clinical implications.
      ,
      • Davis G.L.
      • Alter M.J.
      • El-Serag H.
      • Poynard T.
      • Jennings L.W.
      Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression.
      ] (Fig. 2).
      Figure thumbnail gr2
      Fig. 2HCV and progression of liver disease. HCV, hepatitis C virus; SVR, sustained virological response; HCC, hepatocellular carcinoma; USA, United States of America.
      Recent data also have shown that HCV genotype 1 might specifically interfere with a particular host genetic background altering certain intracellular insulin signaling pathways [
      • Camma C.
      • Bruno S.
      • Di Marco V.
      • et al.
      Insulin resistance is associated with steatosis in nondiabetic patients with genotype 1 chronic hepatitis C.
      ]. Geographical differences in the rate of disease progression to cirrhosis should also be considered. In the USA and Europe the rate of disease progression is approximately 15% (range 8%–24%), while in Japan it ranges between 30% and 46% [
      • Messina J.P.
      • Humphreys I.
      • Flaxman A.
      • Brown A.
      • Cooke G.S.
      • Pybus O.G.
      • et al.
      Global distribution and prevalence of hepatitis C virus genotypes.
      ]. Similarly, the percentage of HCV patients who develop HCC is 0.7%–1.3% in Western countries, but is significantly higher in the Far East and Japan where the rate ranges from 10% to 19% [
      • Lee M.H.
      • Yang H.I.
      • Lu S.N.
      • Jen C.L.
      • You S.L.
      • Wang L.Y.
      • et al.
      Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study.
      ].
      Multiple studies have attempted to measure the time interval from the time of infection to development of cirrhosis and HCC [
      • Leone N.
      • Rizzetto M.
      Natural history of hepatitis C virus infection: from chronic hepatitis to cirrhosis, to hepatocellular carcinoma.
      ,
      • Castells L.
      • Vargas V.
      • Gonzalez A.
      • Esteban J.
      • Esteban R.
      • Guardia J.
      Long interval between HCV infection and development of hepatocellular carcinoma.
      ,
      • Degos F.
      • Christidis C.
      • Ganne-Carrie N.
      • Farmachidi J.P.
      • Degott C.
      • Guettier C.
      • et al.
      Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular carcinoma and death.
      ,
      • Donato F.
      • Boffetta P.
      • Puoti M.
      A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma.
      ]. Frequently, the initial time of infection is not known, so it must be estimated unless the individuals contracted HCV through a single blood transfusion or surgery, in which case a precise time interval from infection to cirrhosis and HCC can be estimated [
      • Williams I.T.
      • Bell B.P.
      • Kuhnert W.
      • Alter M.J.
      Incidence and transmission patterns of acute hepatitis C in the United States, 1982–2006.
      ,
      • Purcell R.H.
      • Walsh J.H.
      • Holland P.V.
      • Morrow A.G.
      • Wood S.
      • Chanock R.M.
      Seroepidemiological studies of transfusion-associated hepatitis.
      ,
      • Gordon S.C.
      • Bayati N.
      • Silverman A.L.
      Clinical outcome of hepatitis C as a function of mode of transmission.
      ]. In a longitudinal U.S. study by Tong et al., the mean time of development of cirrhosis was 21 ± 10 years in chronic post-transfusion hepatitis C patients [
      • Tong M.J.
      • El-Farra N.S.
      • Reikes A.R.
      • Co R.L.
      Clinical outcomes after transfusion-associated hepatitis C.
      ]. In a European study by Castells et al., the time to development of cirrhosis and HCC was 24 years and 27 years, respectively [
      • Castells L.
      • Vargas V.
      • Gonzalez A.
      • Esteban J.
      • Esteban R.
      • Guardia J.
      Long interval between HCV infection and development of hepatocellular carcinoma.
      ].
      It is important to note that virtually all HCV-related HCC occurs among patients with cirrhosis. In a meta-analysis of 21 case-control studies, the risk for HCC was increased 17-fold in HCV-infected patients compared to HCV-negative controls [
      • Donato F.
      • Boffetta P.
      • Puoti M.
      A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma.
      ]. Once cirrhosis was established, HCC developed at an annual rate of 1% to 4% [
      • Castells L.
      • Vargas V.
      • Gonzalez A.
      • Esteban J.
      • Esteban R.
      • Guardia J.
      Long interval between HCV infection and development of hepatocellular carcinoma.
      ,
      • Degos F.
      • Christidis C.
      • Ganne-Carrie N.
      • Farmachidi J.P.
      • Degott C.
      • Guettier C.
      • et al.
      Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular carcinoma and death.
      ,
      • Donato F.
      • Boffetta P.
      • Puoti M.
      A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma.
      ,
      • Gordon S.C.
      • Bayati N.
      • Silverman A.L.
      Clinical outcome of hepatitis C as a function of mode of transmission.
      ,
      • Tong M.J.
      • El-Farra N.S.
      • Reikes A.R.
      • Co R.L.
      Clinical outcomes after transfusion-associated hepatitis C.
      ,
      • Bruno S.
      • Silini E.
      • Crosignani A.
      • Borzio F.
      • Leandro G.
      • Bono F.
      • et al.
      Hepatitis C virus genotypes and risk of hepatocellular carcinoma in cirrhosis: a prospective study.
      ,
      • Chiba T.
      • Matsuzaki Y.
      • Abei M.
      • Shoda J.
      • Aikawa T.
      • Tanaka N.
      • et al.
      Multivariate analysis of risk factors for hepatocellular carcinoma in patients with hepatitis C virus-related liver cirrhosis.
      ,
      • Fattovich G.
      • Stroffolini T.
      • Zagni I.
      • Donato F.
      Hepatocellular carcinoma in cirrhosis: incidence and risk factors.
      ]. In fact, in a prospective cohort study reported from the United States, the rate of progression to cirrhosis was found to be 7% to 16% and HCC of 0.7% to 1.3% per year [
      • Gordon S.C.
      • Bayati N.
      • Silverman A.L.
      Clinical outcome of hepatitis C as a function of mode of transmission.
      ]. In contrast, a study reported from Japan, the development of HCC ranged from 5–7% [
      • Lee M.H.
      • Yang H.I.
      • Lu S.N.
      • Jen C.L.
      • You S.L.
      • Wang L.Y.
      • et al.
      Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study.
      ].
      A number of studies suggest a significant reduction in the risk of cirrhosis and HCC in patients who achieve SVR [
      • Tada T.
      • Kumada T.
      • Toyoda H.
      • Kiriyama S.
      • Tanikawa M.
      • Hisanaga Y.
      • et al.
      Viral eradication reduces all-cause mortality in patients with chronic hepatitis C virus infection: a propensity score analysis.
      ,
      • Aleman S.
      • Rahbin N.
      • Weiland O.
      • Davidsdottir L.
      • Hedenstierna M.
      • Rose N.
      • et al.
      A risk for hepatocellular carcinoma persists long-term after sustained virologic response in patients with hepatitis C-associated liver cirrhosis.
      ]. Nevertheless, it is important to note that in patients with advanced fibrosis who achieve SVR, a residual risk of hepatocellular carcinoma remains [
      • Bruno S.
      • Di Marco V.
      • Iavarone M.
      • Roffi L.
      • Crosignani A.
      • Calvaruso V.
      • et al.
      Survival of patients with HCV cirrhosis and sustained virologic response is similar to the general population.
      ].
      The clinical progression of HCV-related liver disease (cirrhosis and HCC) significantly contributes to increased mortality worldwide [
      • Hajarizadeh B.
      • Grebely J.
      • Dore G.J.
      Epidemiology and natural history of HCV infection.
      ,
      • Leone N.
      • Rizzetto M.
      Natural history of hepatitis C virus infection: from chronic hepatitis to cirrhosis, to hepatocellular carcinoma.
      ,
      • Bruno S.
      • Di Marco V.
      • Iavarone M.
      • Roffi L.
      • Crosignani A.
      • Calvaruso V.
      • et al.
      Survival of patients with HCV cirrhosis and sustained virologic response is similar to the general population.
      ,
      • Ly K.N.
      • Hughes E.M.
      • Jiles R.B.
      • Holmberg S.D.
      Rising mortality associated with hepatitis C virus in the United States, 2003–2013.
      ,
      • D’Amico G.
      • Pasta L.
      • Morabito A.
      • D’Amico M.
      • Caltagirone M.
      • Malizia G.
      • et al.
      Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients.
      ]. In fact, in the U.S., deaths associated with chronic HCV are more likely to be caused from decompensated cirrhosis rather than HCC. The cumulative probability of an episode of clinical decompensation is 5% at year 1, and increases to 30% at 10 years from the diagnosis of cirrhosis. The development of esophageal-gastric varices and the development of any other decompensating event is associated with an additive increase in the risk for mortality [
      • Ly K.N.
      • Hughes E.M.
      • Jiles R.B.
      • Holmberg S.D.
      Rising mortality associated with hepatitis C virus in the United States, 2003–2013.
      ,
      • D’Amico G.
      • Pasta L.
      • Morabito A.
      • D’Amico M.
      • Caltagirone M.
      • Malizia G.
      • et al.
      Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients.
      ]. Once decompensated cirrhosis occurs, the 5-year survival of HCV patients can be as low as 50% [
      • D’Amico G.
      • Pasta L.
      • Morabito A.
      • D’Amico M.
      • Caltagirone M.
      • Malizia G.
      • et al.
      Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients.
      ,
      • Fattovich G.
      • Giustina G.
      • Degos F.
      • Tremolada F.
      • Diodati G.
      • Almasio P.
      • et al.
      Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients.
      ,
      • Serfaty L.
      • Aumaître H.
      • Chazouillères O.
      • Bonnand A.M.
      • Rosmorduc O.
      • Poupon R.E.
      • et al.
      Determinants of outcome of compensated hepatitis C virus-related cirrhosis.
      ,
      • Hu K.Q.
      • Tong M.J.
      The long-term outcomes of patients with compensated hepatitis C virus-related cirrhosis and history of parenteral exposure in the United States.
      ]. On the other hand, 3, 5, and 10-year survival rates of compensated cirrhosis related to HCV is estimated to be 96%, 91%, and 79%, respectively [
      • Fattovich G.
      • Giustina G.
      • Degos F.
      • Tremolada F.
      • Diodati G.
      • Almasio P.
      • et al.
      Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients.
      ,
      • Serfaty L.
      • Aumaître H.
      • Chazouillères O.
      • Bonnand A.M.
      • Rosmorduc O.
      • Poupon R.E.
      • et al.
      Determinants of outcome of compensated hepatitis C virus-related cirrhosis.
      ,
      • Hu K.Q.
      • Tong M.J.
      The long-term outcomes of patients with compensated hepatitis C virus-related cirrhosis and history of parenteral exposure in the United States.
      ].
      In addition to these important clinical outcomes, there is increasing evidence that HCV has a number of important extrahepatic manifestations (EHM) [
      • Younossi Z.
      • Park H.
      • Henry L.
      • Adeyemi A.
      • Stepanova M.
      Extra-hepatic manifestations of hepatitis C-a meta-analysis of prevalence, quality of life, and economic burden.
      ,
      • Cacoub P.
      • Comarmond C.
      • Domont F.
      • Savey L.
      • Desbois A.C.
      • Saadoun D.
      Extrahepatic manifestations of chronic hepatitis C virus infection.
      ,
      • Petta S.
      • Maida M.
      • Macaluso F.S.
      • Barbara M.
      • Licata A.
      • Craxì A.
      • et al.
      Hepatitis C virus infection is associated with increased cardiovascular mortality: a meta-analysis of observational studies.
      ,
      • Domont F.
      • Cacoub P.
      Chronic hepatitis C virus infection, a new cardiovascular risk factor?.
      ]. In a recent systematic review, the authors reported a definitive relationship between HCV and mixed type 2 cryoglobulinemic vasculitis as well as B cell lymphoma while also finding a higher prevalence of thirteen disease states in HCV positive patients when compared to non-HCV positive patients (type 2 diabetes, insulin resistance, glomerulonephritis, fatigue, depression and cardiovascular disease). In fact, an additional 11 EHMs have been potentially linked to HCV [
      • Cacoub P.
      • Comarmond C.
      • Domont F.
      • Savey L.
      • Desbois A.C.
      • Saadoun D.
      Extrahepatic manifestations of chronic hepatitis C virus infection.
      ]. In a more recent meta-analysis, the prevalence of 12 different EHMs of HCV ranged from 0.21% for end-stage renal disease to 24.5% for depression, with the odds of developing these EHMs ranging from 1.58 (1.30–1.86) for diabetes mellitus to 8.53 (4.15–17.52) for PCT (Table 1) [
      • Younossi Z.
      • Park H.
      • Henry L.
      • Adeyemi A.
      • Stepanova M.
      Extra-hepatic manifestations of hepatitis C-a meta-analysis of prevalence, quality of life, and economic burden.
      ]. Additionally, a meta-analysis on the development of cardiovascular disease (CVD) in HCV positive patients found that the odds ratio (OR) for cardiovascular disease in HCV was 1.20 (95% CI: 1.03–1.40), while the OR for stroke was 1.35 (95% CI:1.00–1.82) [
      • Petta S.
      • Maida M.
      • Macaluso F.S.
      • Barbara M.
      • Licata A.
      • Craxì A.
      • et al.
      Hepatitis C virus infection is associated with increased cardiovascular mortality: a meta-analysis of observational studies.
      ]. In addition to these EHMs of HCV, a number of other diseases (neurologic diseases, connective tissue disorders, organ-specific malignancies, etc.) have been associated with HCV. Nevertheless, the strength of these associations require publication of additional evidence.
      Table 1The extrahepatic manifestations of HCV.
      (Adapted from Younossi Z. et al. 2016)
      • Younossi Z.
      • Park H.
      • Henry L.
      • Adeyemi A.
      • Stepanova M.
      Extra-hepatic manifestations of hepatitis C-a meta-analysis of prevalence, quality of life, and economic burden.
      .
      ∗A meta-analysis on the development of cardiovascular disease in HCV + patients found that the OR for cardiovascular disease in HCV was 1.20 (95% CI: 1.03–1.40), while the OR for stroke was 1.35 (95% CI: 1.00–1.82) ∗
      • Petta S.
      • Maida M.
      • Macaluso F.S.
      • Barbara M.
      • Licata A.
      • Craxì A.
      • et al.
      Hepatitis C virus infection is associated with increased cardiovascular mortality: a meta-analysis of observational studies.
      . MC, mixed cryoglobulinemia; HCV, hepatitis C virus; CI, confidence interval; RR, relative risk, n.a., not available.
      The exact mechanism by which HCV causes these EHMs is not known, though there are suggestions that some extrahepatic manifestations are related to immune related mechanisms (such as cryovasculitis, arthritis and lymphoma) while others are related to HCV induced insulin resistance such as the development of type 2 diabetes [
      • Calvaruso V.
      • Craxì A.
      Immunological alterations in hepatitis C virus infection.
      ,
      • Hung C.H.
      • Lee C.M.
      • Lu S.N.
      Hepatitis C virus-associated insulin resistance: pathogenic mechanisms and clinical implications.
      ,
      • Huckans M.
      • Fuller B.E.
      • Olavarria H.
      • Sasaki A.W.
      • Chang M.
      • Flora K.D.
      • et al.
      Multi-analytic profile analysis of plasma immune proteins: altered expression of peripheral immune factors is associated with neuropsychiatric symptom severity in adults with and without chronic hepatitis C virus infection.
      ]. There is also a possibly that the virus itself can be pathogenic to the specific cell type. In this context, the mechanism for the increased risk of cerebrovascular and cardiovascular disease has been suggested to be a result of the chronic inflammatory state caused by HCV inducing increased cytokine activity which causes an increase in arterial plaque [
      • Cacoub P.
      • Comarmond C.
      • Domont F.
      • Savey L.
      • Desbois A.C.
      • Saadoun D.
      Extrahepatic manifestations of chronic hepatitis C virus infection.
      ]. Along with the increased risk of vascular disease in HCV positive patients, evidence has also shown an increased cardiovascular mortality risk [
      • Petta S.
      • Maida M.
      • Macaluso F.S.
      • Barbara M.
      • Licata A.
      • Craxì A.
      • et al.
      Hepatitis C virus infection is associated with increased cardiovascular mortality: a meta-analysis of observational studies.
      ,
      • Domont F.
      • Cacoub P.
      Chronic hepatitis C virus infection, a new cardiovascular risk factor?.
      ]. Finally, the mechanism of the neuropsychiatric manifestation (depression and brain fog) of HCV may be related to the virus invading both the white brain matter and brain stem, as well as the impact of circulating HCV-related cytokines on the brain [
      • Huckans M.
      • Fuller B.E.
      • Olavarria H.
      • Sasaki A.W.
      • Chang M.
      • Flora K.D.
      • et al.
      Multi-analytic profile analysis of plasma immune proteins: altered expression of peripheral immune factors is associated with neuropsychiatric symptom severity in adults with and without chronic hepatitis C virus infection.
      ,
      • Ashrafi M.
      • Modabbernia A.
      • Dalir M.
      • Taslimi S.
      • Karami M.
      • Ostovaneh M.R.
      • et al.
      Predictors of mental and physical health in non-cirrhotic patients with viral hepatitis: a case control study.
      ,
      • Adinolfi L.E.
      • Nevola R.
      • Lus G.
      • Restivo L.
      • Guerrera B.
      • Romano C.
      • et al.
      Chronic hepatitis C virus infection and neurological and psychiatric disorders: an overview.
      ,
      • Monaco S.
      • Ferrari S.
      • Gajofatto A.
      • Zanusso G.
      • Mariotto S.
      HCV-related nervous system disorders.
      ,
      • Monaco S.
      • Mariotto S.
      • Ferrari S.
      • Calabrese M.
      • Zanusso G.
      • Gajofatto A.
      • et al.
      Hepatitis C virus-associated neurocognitive and neuropsychiatric disorders: Advances in 2015.
      ]. Furthermore, the cause of chronic fatigue (both peripheral and central fatigue) observed during HCV infection is unknown but is also thought to be a result of the disruption in cellular activity caused by the effects of circulating inflammatory cytokines and chemokines [
      • Ashrafi M.
      • Modabbernia A.
      • Dalir M.
      • Taslimi S.
      • Karami M.
      • Ostovaneh M.R.
      • et al.
      Predictors of mental and physical health in non-cirrhotic patients with viral hepatitis: a case control study.
      ,
      • Monaco S.
      • Ferrari S.
      • Gajofatto A.
      • Zanusso G.
      • Mariotto S.
      HCV-related nervous system disorders.
      ].
      In summary, it is increasingly critical to acknowledge and assess both the hepatic and the extrahepatic manifestations of HCV. Together, these elements provide a more robust picture of the true systemic clinical burden of HCV infection.
      HCV causes a systemic disease with both hepatic and extrahepatic manifestation.

      Patient reported outcomes related to HCV infection

      In addition to clinical outcomes, investigators have confirmed that HCV infection causes a tremendous impact on PROs [
      • Younossi Z.
      • Kallman J.
      • Kincaid J.
      The effects of HCV infection and management on health-related quality of life.
      ,
      • Younossi Z.M.
      Chronic liver disease and health-related quality of life.
      ,
      • Afendy A.
      • Kallman J.B.
      • Stepanova M.
      • Younoszai Z.
      • Aquino R.D.
      • Bianchi G.
      • et al.
      Predictors of health-related quality of life in patients with chronic liver disease.
      ,
      • Dan A.A.
      • Crone C.
      • Wise T.N.
      • Martin L.M.
      • Ramsey L.
      • Magee S.
      • et al.
      Anger experiences among hepatitis C patients: relationship to depressive symptoms and health-related quality of life.
      ,
      • Younossi Z.M.
      • Kanwal F.
      • Saab S.
      • Brown K.A.
      • El-Serag H.B.
      • Kim W.R.
      • et al.
      The impact of hepatitis C burden: an evidence-based approach.
      ,
      • Kallman J.
      • O’Neil M.M.
      • Larive B.
      • Boparai N.
      • Calabrese L.
      • Younossi Z.M.
      Fatigue and health-related quality of life (HRQL) in chronic hepatitis C virus infection.
      ,
      • Su J.
      • Brook R.A.
      • Kleinman N.L.
      • Corey-Lisle P.
      The impact of hepatitis C virus infection on work absence, productivity, and healthcare benefit costs.
      ,
      • Bonkovsky H.L.
      • Snow K.K.
      • Malet P.F.
      • Back-Madruga C.
      • Fontana R.J.
      • Sterling R.K.
      • et al.
      Health-related quality of life in patients with chronic hepatitis C and advanced fibrosis.
      ,
      • Younossi Z.M.
      • Boparai N.
      • Price L.L.
      • Kiwi M.L.
      • McCormick M.
      • Guyatt G.
      Health-related quality of life in chronic liver disease: the impact of type and severity of disease.
      ,
      • Spiegel B.M.
      • Younossi Z.M.
      • Hays R.D.
      • Revicki D.
      • Robbins S.
      • Kanwal F.
      Impact of hepatitis C on health related quality of life: a systematic review and quantitative assessment.
      ]. PROs are defined as measurements of a patient’s state of health as perceived by the patient and are reported directly from the patient without any modification [
      • Testa M.A.
      • Simonson D.C.
      Assessment of quality-of-life outcomes.
      ].
      Therefore, through the use of PRO instruments, clinical investigators have been able to establish that patients with HCV infection experience tremendous impairment in their health related quality of life (HRQOL) and well-being, especially in the domains of physical functioning, mental health, and work productivity as a result of the virus itself [
      • Younossi Z.
      • Kallman J.
      • Kincaid J.
      The effects of HCV infection and management on health-related quality of life.
      ,
      • Younossi Z.M.
      Chronic liver disease and health-related quality of life.
      ,
      • Afendy A.
      • Kallman J.B.
      • Stepanova M.
      • Younoszai Z.
      • Aquino R.D.
      • Bianchi G.
      • et al.
      Predictors of health-related quality of life in patients with chronic liver disease.
      ,
      • Dan A.A.
      • Crone C.
      • Wise T.N.
      • Martin L.M.
      • Ramsey L.
      • Magee S.
      • et al.
      Anger experiences among hepatitis C patients: relationship to depressive symptoms and health-related quality of life.
      ,
      • Younossi Z.M.
      • Kanwal F.
      • Saab S.
      • Brown K.A.
      • El-Serag H.B.
      • Kim W.R.
      • et al.
      The impact of hepatitis C burden: an evidence-based approach.
      ,
      • Kallman J.
      • O’Neil M.M.
      • Larive B.
      • Boparai N.
      • Calabrese L.
      • Younossi Z.M.
      Fatigue and health-related quality of life (HRQL) in chronic hepatitis C virus infection.
      ,
      • Su J.
      • Brook R.A.
      • Kleinman N.L.
      • Corey-Lisle P.
      The impact of hepatitis C virus infection on work absence, productivity, and healthcare benefit costs.
      ,
      • Bonkovsky H.L.
      • Snow K.K.
      • Malet P.F.
      • Back-Madruga C.
      • Fontana R.J.
      • Sterling R.K.
      • et al.
      Health-related quality of life in patients with chronic hepatitis C and advanced fibrosis.
      ,
      • Younossi Z.M.
      • Boparai N.
      • Price L.L.
      • Kiwi M.L.
      • McCormick M.
      • Guyatt G.
      Health-related quality of life in chronic liver disease: the impact of type and severity of disease.
      ,
      • Spiegel B.M.
      • Younossi Z.M.
      • Hays R.D.
      • Revicki D.
      • Robbins S.
      • Kanwal F.
      Impact of hepatitis C on health related quality of life: a systematic review and quantitative assessment.
      ,
      • Loria A.
      • Doyle K.
      • Weinstein A.A.
      • Winter P.
      • Escheik C.
      • Price J.
      • et al.
      Multiple factors predict physical performance in people with chronic liver disease.
      ,
      • Stewart B.
      • Mikocka-Walus A.
      • Morgan J.
      • Colman A.
      • Phelps M.
      • Harley H.
      • et al.
      Anxiety and depression in Australian chronic hepatitis C outpatients: prevalence and predictors.
      ,
      • Zalai D.
      • Sherman M.
      • McShane K.
      • Shapiro C.M.
      • Carney C.E.
      The importance of fatigue cognitions in chronic hepatitis C infection.
      ,
      • Gutteling J.J.
      • Duivenvoorden H.J.
      • Busschbach J.J.
      • de Man R.A.
      • Darlington A.S.
      Psychological determinants of health-related quality of life in patients with chronic liver disease.
      ,
      • Poynard T.
      • Cacoub P.
      • Ratziu V.
      • Myers R.P.
      • Dezailles M.H.
      • Mercadier A.
      • et al.
      Fatigue in patients with chronic hepatitis C.
      ,
      • Younossi I.
      • Weinstein A.
      • Stepanova M.
      • Hunt S.
      • Younossi Z.M.
      Mental and emotional impairment in patients with hepatitis C is related to lower work productivity.
      ]. Additionally, multivariate analyses have determined that disease severity (presence of advanced liver disease), and psychiatric co-morbidities, especially depression, are important drivers of PRO impairment [
      • Dan A.A.
      • Crone C.
      • Wise T.N.
      • Martin L.M.
      • Ramsey L.
      • Magee S.
      • et al.
      Anger experiences among hepatitis C patients: relationship to depressive symptoms and health-related quality of life.
      ,
      • Loria A.
      • Doyle K.
      • Weinstein A.A.
      • Winter P.
      • Escheik C.
      • Price J.
      • et al.
      Multiple factors predict physical performance in people with chronic liver disease.
      ,
      • Stewart B.
      • Mikocka-Walus A.
      • Morgan J.
      • Colman A.
      • Phelps M.
      • Harley H.
      • et al.
      Anxiety and depression in Australian chronic hepatitis C outpatients: prevalence and predictors.
      ,
      • Gutteling J.J.
      • Duivenvoorden H.J.
      • Busschbach J.J.
      • de Man R.A.
      • Darlington A.S.
      Psychological determinants of health-related quality of life in patients with chronic liver disease.
      ]. It is important to recognize that, in a similar fashion that the clinical outcomes are considered the surrogate markers of survival, and PROs are important surrogate markers of patient experience [
      • Dan A.A.
      • Kallman J.B.
      • Srivastava R.
      • Younoszai Z.
      • Kim A.
      • Younossi Z.M.
      Impact of chronic liver disease and cirrhosis on health utilities using SF-6D and the health utility index.
      ].
      In this context, there are a number of important reasons to measure PROs. First and foremost, these are the most important outcomes from the individual patient’s perspective and provide physicians and other health care providers the impact of their treatment regimen on their lives [
      • Younossi I.
      • Weinstein A.
      • Stepanova M.
      • Hunt S.
      • Younossi Z.M.
      Mental and emotional impairment in patients with hepatitis C is related to lower work productivity.
      ,
      • Dan A.A.
      • Kallman J.B.
      • Srivastava R.
      • Younoszai Z.
      • Kim A.
      • Younossi Z.M.
      Impact of chronic liver disease and cirrhosis on health utilities using SF-6D and the health utility index.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Nader F.
      • Lam B.
      • Hunt S.
      The patient’s journey with chronic hepatitis C from interferon plus ribavirin to interferon- and ribavirin-free regimens: a study of health-related quality of life.
      ,
      • Mulhall B.P.
      • Younossi Z.
      Impact of adherence on the outcome of antiviral therapy for chronic hepatitis C.
      ,
      • Younossi Z.
      • Henry L.
      The impact of the new antiviral regimens on patient reported outcomes and health economics of patients with chronic hepatitis C.
      ,
      • Younossi Z.
      • Henry L.
      Systematic review: patient-reported outcomes in chronic hepatitis C–the impact of liver disease and new treatment regimens.
      ,
      • Vera-Llonch M.
      • Martin M.
      • Aggarwal J.
      • Donepudi M.
      • Bayliss M.
      • Goss T.
      • et al.
      Health-related quality of life in genotype 1 treatment-naïve chronic hepatitis C patients receiving telaprevir combination treatment in the ADVANCE study.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Sulkowski M.
      • Naggie S.
      • Puoti M.
      • Orkin C.
      • et al.
      Sofosbuvir and ribavirin for treatment of chronic hepatitis C in patients coinfected with hepatitis C virus and HIV: the impact on patient-reported outcomes.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Henry L.
      • Gane E.
      • Jacobson I.M.
      • Lawitz E.
      • et al.
      Minimal impact of sofosbuvir and ribavirin on health related quality of life in chronic hepatitis C (CH-C).
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Zeuzem S.
      • Dusheiko G.
      • Esteban R.
      • Hezode C.
      • et al.
      Patient-reported outcomes assessment in chronic hepatitis C treated with sofosbuvir and ribavirin:the VALENCE study.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Nader F.
      • Jacobson I.M.
      • Gane E.
      • Nelson D.
      • et al.
      Patient-reported outcomes in chronic hepatitis C patients with cirrhosis treated with sofosbuvir containing regimens.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Marcellin P.
      • Afdhal N.
      • Kowdley K.V.
      • Zeuzem S.
      • et al.
      Treatment with ledipasvir and sofosbuvir improves patient-reported outcomes: results from the ION-1, 2 and 3 clinical trials.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Henry L.
      • Gane E.
      • Jacobson I.M.
      • Lawitz E.
      • et al.
      Effects of sofosbuvir-based treatment, with and without interferon, on outcome and productivity of patients with chronic hepatitis C.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Chan H.L.
      • Lee M.H.
      • Yu M.L.
      • Dan Y.Y.
      • et al.
      Patient-reported outcomes in Asian patients with chronic hepatitis C treated with ledipasvir and sofosbuvir.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Nader F.
      • Henry L.
      Patient-reported outcomes of elderly adults with chronic hepatitis C treated with interferon- and ribavirin-free regimens.
      ,
      • Marcellin F.
      • Demoulin B.
      • Spire B.
      • Suzan-Monti M.
      • Roux P.
      • Protopopescu C.
      • et al.
      Spontaneous and post-treatment HCV clearance: relationships with health-related quality of life in HIV infection (ANRS-VESPA2 study).
      ,
      • Gerber L.
      • Estep M.
      • Stepanova M.
      • Escheik C.
      • Weinstein A.
      • Younossi Z.M.
      Effects of viral eradication with ledipasvir and sofosbuvir, with or without ribavirin, on measures of fatigue in patients with chronic hepatitis C virus infection.
      ,
      • Che Y.H.
      • You J.
      • Chongsuvivatwong V.
      • Li L.
      • Sriplung H.
      • Yan Y.Z.
      • et al.
      Dynamics and liver disease specific aspects of quality of life among patients with chronic liver disease in Yunnan, China.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Pol S.
      • Bronowicki J.P.
      • Carrieri M.P.
      • Bourlière M.
      The impact of ledipasvir/sofosbuvir on patient-reported outcomes in cirrhotic patients with chronic hepatitis C: the SIRIUS study.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Feld J.
      • Zeuzem S.
      • Jacobson I.
      • Agarwal K.
      • et al.
      Sofosbuvir/velpatasvir improves patient-reported outcomes in HCV patients: results from ASTRAL-1 Placebo-Controlled Trial.
      ,
      • Younossi Z.M.
      • Jiang Y.
      • Smith N.J.
      • Stepanova M.
      • Beckerman R.
      Ledipasvir/sofosbuvir regimens for chronic hepatitis C infection: Insights from a work productivity economic model from the United States.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Afdhal N.
      • Kowdley K.V.
      • Zeuzem S.
      • Henry L.
      • et al.
      Improvement of health-related quality of life and work productivity in chronic hepatitis C patients with early and advanced fibrosis treated with ledipasvir and sofosbuvir.
      ,
      • Smith-Palmer J.
      • Cerri K.
      • Valentine W.
      Achieving sustained virologic response in hepatitis C: a systematic review of the clinical, economic and quality of life benefits.
      ]. In addition to representing patient’s perspective, improvement of population’s quality of life can be an important policy priority for the society. In fact, policy goals for a healthy country in the United States have led to development of “Healthy People 2020”. This policy document not only emphasizes the enhancement of improved health and better access to care, but strives to improve the quality of life in the U.S. population [

      Healthy People 2020 Goals: Health-Related Quality of Life & Well-Being. Obtained from the world wide web at: https://www.healthypeople.gov/2020/topics-objectives/topic/health-related-quality-of-life-well-being. Last accessed on March 20,2016.

      ]. It is also important to note that measuring PROs also provide clues about the prognosis by predicting mortality in HCV-related cirrhotics [
      • Younossi Z.
      • Henry L.
      The impact of the new antiviral regimens on patient reported outcomes and health economics of patients with chronic hepatitis C.
      ,
      • Smith-Palmer J.
      • Cerri K.
      • Valentine W.
      Achieving sustained virologic response in hepatitis C: a systematic review of the clinical, economic and quality of life benefits.
      ].
      Treatment success must also be assessed not only in the context of clinical outcomes (SVR, improvement in survival, resolution of extrahepatic manifestations) but also according to patient-reported outcomes and economic outcomes.
      Finally, PROs can be added to the clinical outcomes of a clinical trial to assess the comprehensive impact of a new treatment. In this context, the combination of the efficacy and the safety of treatment intervention can determine whether the intervention can reduce the risk of death leading to increases in the quantity of life. If the clinical trials also include PROs such as health-related quality of life (HRQOL), one can capture the positive or negative impact of intervention on patients’ well-being. An intervention with lots of side effects would negatively affect patient adherence, which could affect the clinical outcome assessed in the efficacy trials. On the other hand, if the intervention leads to improvement of quality of life, the benefit of treatment can be even more profound. By combining both quantity of life and quality of life, the actual net benefit of treatment can be estimated [
      • Dan A.A.
      • Kallman J.B.
      • Srivastava R.
      • Younoszai Z.
      • Kim A.
      • Younossi Z.M.
      Impact of chronic liver disease and cirrhosis on health utilities using SF-6D and the health utility index.
      ].
      However, PROs reside in a bi-directional relationship between HRQOL and the efficacy/safety of any drug intervention. As noted previously, treatment regimens with high side effects can negatively impact patients’ HRQOL which, in turn, can influence adherence to the treatment regimen [
      • Lam B.P.
      • Jeffers T.
      • Younoszai Z.
      • Fazel Y.
      • Younossi Z.M.
      The changing landscape of hepatitis C virus therapy: focus on interferon-free treatment.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Nader F.
      • Lam B.
      • Hunt S.
      The patient’s journey with chronic hepatitis C from interferon plus ribavirin to interferon- and ribavirin-free regimens: a study of health-related quality of life.
      ,
      • Mulhall B.P.
      • Younossi Z.
      Impact of adherence on the outcome of antiviral therapy for chronic hepatitis C.
      ]. Non-adherence to the prescribed treatment regimen affects the effectiveness of the treatment intervention. In contrast, regimens which improve patients’ HRQOL could potentially improve adherence and thus, maximize treatment effectiveness in the real world. The most relevant example of this discrepancy between efficacy and effectiveness was shown with the use of triple combination of IFN + RBV and the first generation protease inhibitors. Although randomized clinical trials showed an efficacy rate of 60–65% (SVR), the high rate of associated side effects led to poor adherence and effectiveness with SVR rates as low as 30% in real world practices [
      • Lam B.P.
      • Jeffers T.
      • Younoszai Z.
      • Fazel Y.
      • Younossi Z.M.
      The changing landscape of hepatitis C virus therapy: focus on interferon-free treatment.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Nader F.
      • Lam B.
      • Hunt S.
      The patient’s journey with chronic hepatitis C from interferon plus ribavirin to interferon- and ribavirin-free regimens: a study of health-related quality of life.
      ,
      • Mulhall B.P.
      • Younossi Z.
      Impact of adherence on the outcome of antiviral therapy for chronic hepatitis C.
      ]. In contrast, the most recent data with the use of all oral agents for HCV in real world practices show similar SVR rates to those reported from clinical trials. Therefore, one can argue that the influence of treatment on PROs such as HRQOL can explain the gap between efficacy rates from clinical trials and the effectiveness rates from real world practices. As the side effect profiles of these regimens improve and HRQOL during treatment is not negatively impacted, the gap between SVR rates from the efficacy trials and the effectiveness rates from real world setting will be diminished [
      • Lam B.P.
      • Jeffers T.
      • Younoszai Z.
      • Fazel Y.
      • Younossi Z.M.
      The changing landscape of hepatitis C virus therapy: focus on interferon-free treatment.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Nader F.
      • Lam B.
      • Hunt S.
      The patient’s journey with chronic hepatitis C from interferon plus ribavirin to interferon- and ribavirin-free regimens: a study of health-related quality of life.
      ,
      • Mulhall B.P.
      • Younossi Z.
      Impact of adherence on the outcome of antiviral therapy for chronic hepatitis C.
      ].

      The clinical, PRO and economic implications of new anti-HCV treatment

      The recent availability of all oral DAA regimens for HCV has increased the efficacy rates to 98% with an excellent tolerability profile and relatively simple administration schedules [
      • Jacobson I.M.
      • Gordon S.C.
      • Kowdley K.V.
      • Yoshida E.M.
      • Rodriguez-Torres M.
      • Sulkowski M.S.
      • et al.
      Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options.
      ,
      • Afdhal N.
      • Zeuzem S.
      • Kwo P.
      • Chojkier M.
      • Gitlin N.
      • Puoti M.
      • et al.
      Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection.
      ,
      • Afdhal N.
      • Reddy K.R.
      • Nelson D.R.
      • Lawitz E.
      • Gordon S.C.
      • Schiff E.
      • et al.
      Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection.
      ,
      • Zeuzem S.
      • Dusheiko G.M.
      • Salupere R.
      • Mangia A.
      • Flisiak R.
      • Hyland R.H.
      • et al.
      Sofosbuvir and ribavirin in HCV genotypes 2 and 3.
      ,
      • Kowdley K.V.
      • Gordon S.C.
      • Reddy K.R.
      • Rossaro L.
      • Bernstein D.E.
      • Lawitz E.
      • et al.
      Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis.
      ,
      • Dalgard O.
      • Bjøro K.
      • Ring-Larsen H.
      • Bjornsson E.
      • Holberg-Petersen M.
      • Skovlund E.
      • et al.
      Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid virological response.
      , ,
      • Nachega J.B.
      • Parienti J.
      • Olalekan J.
      • Uthman A.
      • Gross R.
      • Dowdy D.W.
      • et al.
      Lower pill burden and once-daily antiretroviral treatment regimens for HIV infection: a meta-analysis of randomized controlled trials.
      ,
      • Kowdley K.V.
      • Lawitz E.
      • Poordad F.
      • et al.
      Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267, ABT-333 +/− ribavirin in patients with chronic HCV GT1 infection: results from the AVIATOR study.
      ,
      • Krishnan P.
      • Tripathi R.
      • Schnell G.
      • Reisch T.
      • Beyer J.
      • Irvin M.
      • et al.
      Resistance analysis of baseline and treatment-emergent variants in hepatitis C virus genotype 1 in the AVIATOR study with paritaprevir-ritonavir, ombitasvir, and dasabuvir.
      ,

      Press release: OLYSIO™ (simeprevir) receives FDA approval for combination treatment of chronic hepatitis C. Obtained from the world wide web at http://www.jnj.com/news/all/OLYSIO-simeprevir-Receives-FDA-Approval-for-Combination-Treatment-of-Chronic-Hepatitis-C Last accessed on Mar 21, 2016.

      ,
      • Ciesek S.
      • Proske V.
      • Otto B.
      • Pischke S.
      • Costa R.
      • Lüthgehetmann M.
      • et al.
      Efficacy and safety of sofosbuvir/ledipasvir for the treatment of patients with hepatitis C virus re-infection after liver transplantation.
      ,
      • Jacobson I.M.
      • Dore G.J.
      • Foster G.R.
      • Fried M.W.
      • Radu M.
      • Rafalsky V.V.
      • et al.
      Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial.
      ,
      • Forns X.
      • Lawitz E.
      • Zeuzem S.
      • Gane E.
      • Bronowicki J.P.
      • Andreone P.
      • et al.
      Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial.
      ,
      • Banerjee D.
      • Reddy K.R.
      Review article: safety and tolerability of direct-acting anti-viral agents in the new era of hepatitis C therapy.
      ,
      • Kattakuzhy S.
      • Wilson E.
      • Sidharthan S.
      • Sims Z.
      • McLaughlin M.
      • Price A.
      • et al.
      Moderate sustained virologic response rates with 6-week combination directly acting anti-hepatitis C virus therapy in patients with advanced liver disease.
      ]. With the publication of the ASTRAL trial results, having a pan-genotypic regimen for all stages of HCV related liver disease brings an additional advancement to the field of HCV treatment [
      • Jacobson I.M.
      • Gordon S.C.
      • Kowdley K.V.
      • Yoshida E.M.
      • Rodriguez-Torres M.
      • Sulkowski M.S.
      • et al.
      Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options.
      ,
      • Afdhal N.
      • Zeuzem S.
      • Kwo P.
      • Chojkier M.
      • Gitlin N.
      • Puoti M.
      • et al.
      Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection.
      ,
      • Afdhal N.
      • Reddy K.R.
      • Nelson D.R.
      • Lawitz E.
      • Gordon S.C.
      • Schiff E.
      • et al.
      Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection.
      ,
      • Zeuzem S.
      • Dusheiko G.M.
      • Salupere R.
      • Mangia A.
      • Flisiak R.
      • Hyland R.H.
      • et al.
      Sofosbuvir and ribavirin in HCV genotypes 2 and 3.
      ,
      • Kowdley K.V.
      • Gordon S.C.
      • Reddy K.R.
      • Rossaro L.
      • Bernstein D.E.
      • Lawitz E.
      • et al.
      Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis.
      ,
      • Dalgard O.
      • Bjøro K.
      • Ring-Larsen H.
      • Bjornsson E.
      • Holberg-Petersen M.
      • Skovlund E.
      • et al.
      Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid virological response.
      , ,
      • Nachega J.B.
      • Parienti J.
      • Olalekan J.
      • Uthman A.
      • Gross R.
      • Dowdy D.W.
      • et al.
      Lower pill burden and once-daily antiretroviral treatment regimens for HIV infection: a meta-analysis of randomized controlled trials.
      ,
      • Kowdley K.V.
      • Lawitz E.
      • Poordad F.
      • et al.
      Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267, ABT-333 +/− ribavirin in patients with chronic HCV GT1 infection: results from the AVIATOR study.
      ,
      • Krishnan P.
      • Tripathi R.
      • Schnell G.
      • Reisch T.
      • Beyer J.
      • Irvin M.
      • et al.
      Resistance analysis of baseline and treatment-emergent variants in hepatitis C virus genotype 1 in the AVIATOR study with paritaprevir-ritonavir, ombitasvir, and dasabuvir.
      ,

      Press release: OLYSIO™ (simeprevir) receives FDA approval for combination treatment of chronic hepatitis C. Obtained from the world wide web at http://www.jnj.com/news/all/OLYSIO-simeprevir-Receives-FDA-Approval-for-Combination-Treatment-of-Chronic-Hepatitis-C Last accessed on Mar 21, 2016.

      ,
      • Ciesek S.
      • Proske V.
      • Otto B.
      • Pischke S.
      • Costa R.
      • Lüthgehetmann M.
      • et al.
      Efficacy and safety of sofosbuvir/ledipasvir for the treatment of patients with hepatitis C virus re-infection after liver transplantation.
      ,
      • Jacobson I.M.
      • Dore G.J.
      • Foster G.R.
      • Fried M.W.
      • Radu M.
      • Rafalsky V.V.
      • et al.
      Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial.
      ,
      • Forns X.
      • Lawitz E.
      • Zeuzem S.
      • Gane E.
      • Bronowicki J.P.
      • Andreone P.
      • et al.
      Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial.
      ,
      • Banerjee D.
      • Reddy K.R.
      Review article: safety and tolerability of direct-acting anti-viral agents in the new era of hepatitis C therapy.
      ,
      • Kattakuzhy S.
      • Wilson E.
      • Sidharthan S.
      • Sims Z.
      • McLaughlin M.
      • Price A.
      • et al.
      Moderate sustained virologic response rates with 6-week combination directly acting anti-hepatitis C virus therapy in patients with advanced liver disease.
      ,
      • Feld J.J.
      • Jacobson I.M.
      • Hézode C.
      • Asselah T.
      • Ruane P.J.
      • Gruener N.
      • et al.
      Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection.
      ,
      • Foster G.R.
      • Afdhal N.
      • Roberts S.K.
      • Bräu N.
      • Gane E.J.
      • Pianko S.
      • et al.
      Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection.
      ,
      • Curry M.P.
      • O’Leary J.G.
      • Bzowej N.
      • Muir A.J.
      • Korenblat K.M.
      • Fenkel J.M.
      Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis.
      ]. Therefore, it is now critical to understand the benefits of these high cure rates on PROs compared to the prior HCV treatments which were associated with a tremendous negative HRQOL burden.
      In a recent systematic review, the results clearly documented that treatment with IFN caused severe HRQOL impairment which persisted up to 12 weeks post treatment regardless of the patients’ SVR status [
      • Lam B.P.
      • Jeffers T.
      • Younoszai Z.
      • Fazel Y.
      • Younossi Z.M.
      The changing landscape of hepatitis C virus therapy: focus on interferon-free treatment.
      ,
      • Younossi Z.
      • Henry L.
      Systematic review: patient-reported outcomes in chronic hepatitis C–the impact of liver disease and new treatment regimens.
      ]. Furthermore, the use of RBV-containing regimens without IFN also were associated with a modest but reversible HRQOL decrements, especially in the physical functioning aspect [
      • Younossi Z.M.
      • Stepanova M.
      • Nader F.
      • Lam B.
      • Hunt S.
      The patient’s journey with chronic hepatitis C from interferon plus ribavirin to interferon- and ribavirin-free regimens: a study of health-related quality of life.
      ]. In contrast, the use of the new interferon- and ribavirin-free all oral regimens for HCV treatment have resulted in significant improvement in patients’ HRQOL scores as early as 2 weeks into the treatment, especially in those domains most affected by the hepatitis C virus [physical functioning, work productivity (presenteeism), social functioning, activity]. In fact, by the end of treatment with the DAA’s many of the significantly improved scores closely approximated or surpassed the HRQOL scores of the general population without HCV [
      • Younossi Z.
      • Henry L.
      The impact of the new antiviral regimens on patient reported outcomes and health economics of patients with chronic hepatitis C.
      ,
      • Younossi Z.
      • Henry L.
      Systematic review: patient-reported outcomes in chronic hepatitis C–the impact of liver disease and new treatment regimens.
      ,
      • Vera-Llonch M.
      • Martin M.
      • Aggarwal J.
      • Donepudi M.
      • Bayliss M.
      • Goss T.
      • et al.
      Health-related quality of life in genotype 1 treatment-naïve chronic hepatitis C patients receiving telaprevir combination treatment in the ADVANCE study.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Sulkowski M.
      • Naggie S.
      • Puoti M.
      • Orkin C.
      • et al.
      Sofosbuvir and ribavirin for treatment of chronic hepatitis C in patients coinfected with hepatitis C virus and HIV: the impact on patient-reported outcomes.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Henry L.
      • Gane E.
      • Jacobson I.M.
      • Lawitz E.
      • et al.
      Minimal impact of sofosbuvir and ribavirin on health related quality of life in chronic hepatitis C (CH-C).
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Zeuzem S.
      • Dusheiko G.
      • Esteban R.
      • Hezode C.
      • et al.
      Patient-reported outcomes assessment in chronic hepatitis C treated with sofosbuvir and ribavirin:the VALENCE study.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Nader F.
      • Jacobson I.M.
      • Gane E.
      • Nelson D.
      • et al.
      Patient-reported outcomes in chronic hepatitis C patients with cirrhosis treated with sofosbuvir containing regimens.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Marcellin P.
      • Afdhal N.
      • Kowdley K.V.
      • Zeuzem S.
      • et al.
      Treatment with ledipasvir and sofosbuvir improves patient-reported outcomes: results from the ION-1, 2 and 3 clinical trials.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Henry L.
      • Gane E.
      • Jacobson I.M.
      • Lawitz E.
      • et al.
      Effects of sofosbuvir-based treatment, with and without interferon, on outcome and productivity of patients with chronic hepatitis C.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Chan H.L.
      • Lee M.H.
      • Yu M.L.
      • Dan Y.Y.
      • et al.
      Patient-reported outcomes in Asian patients with chronic hepatitis C treated with ledipasvir and sofosbuvir.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Nader F.
      • Henry L.
      Patient-reported outcomes of elderly adults with chronic hepatitis C treated with interferon- and ribavirin-free regimens.
      ,
      • Marcellin F.
      • Demoulin B.
      • Spire B.
      • Suzan-Monti M.
      • Roux P.
      • Protopopescu C.
      • et al.
      Spontaneous and post-treatment HCV clearance: relationships with health-related quality of life in HIV infection (ANRS-VESPA2 study).
      ,
      • Gerber L.
      • Estep M.
      • Stepanova M.
      • Escheik C.
      • Weinstein A.
      • Younossi Z.M.
      Effects of viral eradication with ledipasvir and sofosbuvir, with or without ribavirin, on measures of fatigue in patients with chronic hepatitis C virus infection.
      ,
      • Che Y.H.
      • You J.
      • Chongsuvivatwong V.
      • Li L.
      • Sriplung H.
      • Yan Y.Z.
      • et al.
      Dynamics and liver disease specific aspects of quality of life among patients with chronic liver disease in Yunnan, China.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Pol S.
      • Bronowicki J.P.
      • Carrieri M.P.
      • Bourlière M.
      The impact of ledipasvir/sofosbuvir on patient-reported outcomes in cirrhotic patients with chronic hepatitis C: the SIRIUS study.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Feld J.
      • Zeuzem S.
      • Jacobson I.
      • Agarwal K.
      • et al.
      Sofosbuvir/velpatasvir improves patient-reported outcomes in HCV patients: results from ASTRAL-1 Placebo-Controlled Trial.
      ,
      • Younossi Z.M.
      • Jiang Y.
      • Smith N.J.
      • Stepanova M.
      • Beckerman R.
      Ledipasvir/sofosbuvir regimens for chronic hepatitis C infection: Insights from a work productivity economic model from the United States.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Afdhal N.
      • Kowdley K.V.
      • Zeuzem S.
      • Henry L.
      • et al.
      Improvement of health-related quality of life and work productivity in chronic hepatitis C patients with early and advanced fibrosis treated with ledipasvir and sofosbuvir.
      ]. These PRO gains have also been observed in patients with both early and advanced fibrosis [
      • Younossi Z.M.
      • Stepanova M.
      • Nader F.
      • Jacobson I.M.
      • Gane E.
      • Nelson D.
      • et al.
      Patient-reported outcomes in chronic hepatitis C patients with cirrhosis treated with sofosbuvir containing regimens.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Pol S.
      • Bronowicki J.P.
      • Carrieri M.P.
      • Bourlière M.
      The impact of ledipasvir/sofosbuvir on patient-reported outcomes in cirrhotic patients with chronic hepatitis C: the SIRIUS study.
      ]. In fact, the PRO score changes between patients with advanced fibrosis and early fibrosis were not only similar during treatment but also after achieving SVR. These data suggest that regarding PRO scores, patients with early liver disease and advanced liver disease should be considered in a similar fashion. Further, these PRO gains hold true even in the co-infected populations (HCV-HIV) and the hard to treat patients (treatment failures and retreatment) [
      • Younossi Z.M.
      • Stepanova M.
      • Nader F.
      • Lam B.
      • Hunt S.
      The patient’s journey with chronic hepatitis C from interferon plus ribavirin to interferon- and ribavirin-free regimens: a study of health-related quality of life.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Sulkowski M.
      • Naggie S.
      • Puoti M.
      • Orkin C.
      • et al.
      Sofosbuvir and ribavirin for treatment of chronic hepatitis C in patients coinfected with hepatitis C virus and HIV: the impact on patient-reported outcomes.
      ].
      In summary, the current data suggest that significant PRO gains occur with the new DAA treatment regimens regardless of the patient population (co-infected, advanced fibrosis, retreatments, and treatment failures) with the largest gains noted in those patients who obtain SVR [
      • Younossi Z.
      • Henry L.
      The impact of the new antiviral regimens on patient reported outcomes and health economics of patients with chronic hepatitis C.
      ,
      • Younossi Z.
      • Henry L.
      Systematic review: patient-reported outcomes in chronic hepatitis C–the impact of liver disease and new treatment regimens.
      ,
      • Vera-Llonch M.
      • Martin M.
      • Aggarwal J.
      • Donepudi M.
      • Bayliss M.
      • Goss T.
      • et al.
      Health-related quality of life in genotype 1 treatment-naïve chronic hepatitis C patients receiving telaprevir combination treatment in the ADVANCE study.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Sulkowski M.
      • Naggie S.
      • Puoti M.
      • Orkin C.
      • et al.
      Sofosbuvir and ribavirin for treatment of chronic hepatitis C in patients coinfected with hepatitis C virus and HIV: the impact on patient-reported outcomes.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Henry L.
      • Gane E.
      • Jacobson I.M.
      • Lawitz E.
      • et al.
      Minimal impact of sofosbuvir and ribavirin on health related quality of life in chronic hepatitis C (CH-C).
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Zeuzem S.
      • Dusheiko G.
      • Esteban R.
      • Hezode C.
      • et al.
      Patient-reported outcomes assessment in chronic hepatitis C treated with sofosbuvir and ribavirin:the VALENCE study.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Nader F.
      • Jacobson I.M.
      • Gane E.
      • Nelson D.
      • et al.
      Patient-reported outcomes in chronic hepatitis C patients with cirrhosis treated with sofosbuvir containing regimens.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Marcellin P.
      • Afdhal N.
      • Kowdley K.V.
      • Zeuzem S.
      • et al.
      Treatment with ledipasvir and sofosbuvir improves patient-reported outcomes: results from the ION-1, 2 and 3 clinical trials.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Henry L.
      • Gane E.
      • Jacobson I.M.
      • Lawitz E.
      • et al.
      Effects of sofosbuvir-based treatment, with and without interferon, on outcome and productivity of patients with chronic hepatitis C.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Chan H.L.
      • Lee M.H.
      • Yu M.L.
      • Dan Y.Y.
      • et al.
      Patient-reported outcomes in Asian patients with chronic hepatitis C treated with ledipasvir and sofosbuvir.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Nader F.
      • Henry L.
      Patient-reported outcomes of elderly adults with chronic hepatitis C treated with interferon- and ribavirin-free regimens.
      ,
      • Marcellin F.
      • Demoulin B.
      • Spire B.
      • Suzan-Monti M.
      • Roux P.
      • Protopopescu C.
      • et al.
      Spontaneous and post-treatment HCV clearance: relationships with health-related quality of life in HIV infection (ANRS-VESPA2 study).
      ,
      • Gerber L.
      • Estep M.
      • Stepanova M.
      • Escheik C.
      • Weinstein A.
      • Younossi Z.M.
      Effects of viral eradication with ledipasvir and sofosbuvir, with or without ribavirin, on measures of fatigue in patients with chronic hepatitis C virus infection.
      ,
      • Che Y.H.
      • You J.
      • Chongsuvivatwong V.
      • Li L.
      • Sriplung H.
      • Yan Y.Z.
      • et al.
      Dynamics and liver disease specific aspects of quality of life among patients with chronic liver disease in Yunnan, China.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Pol S.
      • Bronowicki J.P.
      • Carrieri M.P.
      • Bourlière M.
      The impact of ledipasvir/sofosbuvir on patient-reported outcomes in cirrhotic patients with chronic hepatitis C: the SIRIUS study.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Feld J.
      • Zeuzem S.
      • Jacobson I.
      • Agarwal K.
      • et al.
      Sofosbuvir/velpatasvir improves patient-reported outcomes in HCV patients: results from ASTRAL-1 Placebo-Controlled Trial.
      ,
      • Younossi Z.M.
      • Jiang Y.
      • Smith N.J.
      • Stepanova M.
      • Beckerman R.
      Ledipasvir/sofosbuvir regimens for chronic hepatitis C infection: Insights from a work productivity economic model from the United States.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Afdhal N.
      • Kowdley K.V.
      • Zeuzem S.
      • Henry L.
      • et al.
      Improvement of health-related quality of life and work productivity in chronic hepatitis C patients with early and advanced fibrosis treated with ledipasvir and sofosbuvir.
      ,
      • Smith-Palmer J.
      • Cerri K.
      • Valentine W.
      Achieving sustained virologic response in hepatitis C: a systematic review of the clinical, economic and quality of life benefits.
      ]. Therefore, regardless of the treatment needed, SVR should be the goal, not only to improve clinical outcomes, but also to improve patients’ experience as documented by improving PRO scores. In fact, these data suggest that the improvement of PRO scores may also improve adherence to the treatment regimens which would close the gap between SVR rates from efficacy trials and the SVR rates from effectiveness trials or assessments in real world practices.

      Economic burden of HCV

      There is also substantive and increasing evidence that HCV places a significant economic burden to society [
      • Su J.
      • Brook R.A.
      • Kleinman N.L.
      • Corey-Lisle P.
      The impact of hepatitis C virus infection on work absence, productivity, and healthcare benefit costs.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Mishra A.
      • Venkatesan C.
      • Henry L.
      • Hunt S.
      The impact of chronic hepatitis C on resource utilisation and in-patient mortality for Medicare beneficiaries between 2005 and 2010.
      ,
      • DiBonaventura Md.
      • Wagner J.S.
      • Yuan Y.
      • L’Italien G.
      • Langley P.
      • Ray Kim W.
      The impact of hepatitis C on labor force participation, absenteeism, presenteeism and non-work activities.
      ,
      • Marcellusi A.
      • Viti R.
      • Capone A.
      • Mennini F.S.
      The economic burden of HCV-induced diseases in Italy. A probabilistic cost of illness model.
      ,
      • El Khoury A.C.
      • Wallace C.
      • Klimack W.K.
      • Razavi H.
      Economic burden of hepatitis C-associated diseases: Europe, Asia Pacific, and the Americas.
      ,
      • McAdam-Marx C.
      • McGarry L.J.
      • Hane C.A.
      • Biskupiak J.
      • Deniz B.
      • Brixner D.I.
      All-cause and incremental per patient per year cost associated with chronic hepatitis C virus and associated liver complications in the United States: a managed care perspective.
      ]. The economic issues of HCV can be divided into four categories: 1) economic burden of HCV-related liver disease, 2) economic burden of HCV-related EHM, 3) economic burden of work productivity loss due to HCV infection, and 4) economic benefit of HCV treatment. The following paragraphs will summarize these four aspects of HCV-related economic burden.

      Economic burden of HCV-related liver disease

      In recent years, there has been a great deal of effort in trying to estimate the economic burden of HCV-related liver disease [
      • Su J.
      • Brook R.A.
      • Kleinman N.L.
      • Corey-Lisle P.
      The impact of hepatitis C virus infection on work absence, productivity, and healthcare benefit costs.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Mishra A.
      • Venkatesan C.
      • Henry L.
      • Hunt S.
      The impact of chronic hepatitis C on resource utilisation and in-patient mortality for Medicare beneficiaries between 2005 and 2010.
      ,
      • DiBonaventura Md.
      • Wagner J.S.
      • Yuan Y.
      • L’Italien G.
      • Langley P.
      • Ray Kim W.
      The impact of hepatitis C on labor force participation, absenteeism, presenteeism and non-work activities.
      ,
      • Marcellusi A.
      • Viti R.
      • Capone A.
      • Mennini F.S.
      The economic burden of HCV-induced diseases in Italy. A probabilistic cost of illness model.
      ,
      • El Khoury A.C.
      • Wallace C.
      • Klimack W.K.
      • Razavi H.
      Economic burden of hepatitis C-associated diseases: Europe, Asia Pacific, and the Americas.
      ,
      • McAdam-Marx C.
      • McGarry L.J.
      • Hane C.A.
      • Biskupiak J.
      • Deniz B.
      • Brixner D.I.
      All-cause and incremental per patient per year cost associated with chronic hepatitis C virus and associated liver complications in the United States: a managed care perspective.
      ]. These studies have taken into consideration the costs associated with HCV-related early liver disease as well as the costs associated with advanced liver disease, HCC and liver transplantation [
      • Younossi Z.M.
      • Stepanova M.
      • Mishra A.
      • Venkatesan C.
      • Henry L.
      • Hunt S.
      The impact of chronic hepatitis C on resource utilisation and in-patient mortality for Medicare beneficiaries between 2005 and 2010.
      ,
      • DiBonaventura Md.
      • Wagner J.S.
      • Yuan Y.
      • L’Italien G.
      • Langley P.
      • Ray Kim W.
      The impact of hepatitis C on labor force participation, absenteeism, presenteeism and non-work activities.
      ,
      • Marcellusi A.
      • Viti R.
      • Capone A.
      • Mennini F.S.
      The economic burden of HCV-induced diseases in Italy. A probabilistic cost of illness model.
      ,
      • El Khoury A.C.
      • Wallace C.
      • Klimack W.K.
      • Razavi H.
      Economic burden of hepatitis C-associated diseases: Europe, Asia Pacific, and the Americas.
      ,
      • McAdam-Marx C.
      • McGarry L.J.
      • Hane C.A.
      • Biskupiak J.
      • Deniz B.
      • Brixner D.I.
      All-cause and incremental per patient per year cost associated with chronic hepatitis C virus and associated liver complications in the United States: a managed care perspective.
      ]. In 2011, the total economic burden of HCV-related liver disease in the United States was estimated to be 6.1 billion dollars annually [
      • DiBonaventura Md.
      • Wagner J.S.
      • Yuan Y.
      • L’Italien G.
      • Langley P.
      • Ray Kim W.
      The impact of hepatitis C on labor force participation, absenteeism, presenteeism and non-work activities.
      ]. Similar studies from Italy, Europe and Asia have shown the tremendous economic burden of HCV in other parts of the world [
      • Marcellusi A.
      • Viti R.
      • Capone A.
      • Mennini F.S.
      The economic burden of HCV-induced diseases in Italy. A probabilistic cost of illness model.
      ,
      • El Khoury A.C.
      • Wallace C.
      • Klimack W.K.
      • Razavi H.
      Economic burden of hepatitis C-associated diseases: Europe, Asia Pacific, and the Americas.
      ]. Additionally, most of these studies have provided convincing evidence that the cost of treating HCV increases substantially with the progression of liver disease [
      • Younossi Z.M.
      • Stepanova M.
      • Mishra A.
      • Venkatesan C.
      • Henry L.
      • Hunt S.
      The impact of chronic hepatitis C on resource utilisation and in-patient mortality for Medicare beneficiaries between 2005 and 2010.
      ,
      • DiBonaventura Md.
      • Wagner J.S.
      • Yuan Y.
      • L’Italien G.
      • Langley P.
      • Ray Kim W.
      The impact of hepatitis C on labor force participation, absenteeism, presenteeism and non-work activities.
      ]. In one such study, the annual cost of care for non-cirrhotic HCV treatment was 17,277 USD compared to 59,995 USD for treatment of HCV patients with advanced liver disease, while the cost of care for HCV patients with HCC was almost 7 times the cost at 112,537 USD [
      • McAdam-Marx C.
      • McGarry L.J.
      • Hane C.A.
      • Biskupiak J.
      • Deniz B.
      • Brixner D.I.
      All-cause and incremental per patient per year cost associated with chronic hepatitis C virus and associated liver complications in the United States: a managed care perspective.
      ]. As patients with HCV become older, it is expected that they will develop more advanced liver disease which will, correspondingly, increase the total cost of HCV-related liver disease [
      • Golabi P.
      • Otgonsuren M.
      • Suen W.
      • Koenig A.B.
      • Noor B.
      • Younossi Z.M.
      Predictors of inpatient mortality and resource utilization for the elderly patients with chronic hepatitis C (CH-C) in the United States.
      ].

      Economic burden of HCV-related extrahepatic manifestation

      HCV infection negatively impact patient-reported outcomes and places significant economic burden to the society.
      As noted previously, HCV is associated with a number of EHM. These EHMs not only affect clinical and PROs but also affect the economic burden of HCV [
      • Younossi Z.
      • Park H.
      • Henry L.
      • Adeyemi A.
      • Stepanova M.
      Extra-hepatic manifestations of hepatitis C-a meta-analysis of prevalence, quality of life, and economic burden.
      ]. In a recent study which only included HCV-related extrahepatic diseases which are common and have relatively robust evidence for their associations, found the cost of the EHM of HCV in the United States was estimated to be around 1.5 billion per year [
      • Younossi Z.
      • Park H.
      • Henry L.
      • Adeyemi A.
      • Stepanova M.
      Extra-hepatic manifestations of hepatitis C-a meta-analysis of prevalence, quality of life, and economic burden.
      ]. In a separate meta-analysis on the economic burden of EHM, the risk of developing chronic renal disease was found to be considerable and may be underestimated in the total economic burden contributing to HCV-related liver disease [
      • Park H.
      • Adeyemi A.
      • Henry L.
      • Stepanova M.
      • Younossi Z.
      A meta-analytic assessment of the risk of chronic kidney disease in patients with chronic hepatitis C virus infection.
      ]. Though these studies had a significant bias towards the United States, reports from other countries suggest that EHM’s add considerably to the economic burden of HCV [
      • Chhatwal J.
      • He T.
      • Lopez-Olivo M.A.
      Systematic review of modelling approaches for the cost effectiveness of hepatitis C treatment with direct-acting antivirals.
      ].

      Economic burden of work productivity loss due to HCV infection

      HCV infection is associated with reduced work productivity (WP) [
      • Su J.
      • Brook R.A.
      • Kleinman N.L.
      • Corey-Lisle P.
      The impact of hepatitis C virus infection on work absence, productivity, and healthcare benefit costs.
      ,
      • Younossi Z.
      • Henry L.
      The impact of the new antiviral regimens on patient reported outcomes and health economics of patients with chronic hepatitis C.
      ,
      • Younossi Z.
      • Henry L.
      Systematic review: patient-reported outcomes in chronic hepatitis C–the impact of liver disease and new treatment regimens.
      ,
      • McHutchison J.G.
      • Ware Jr, J.E.
      • Bayliss M.S.
      • Pianko S.
      • Albrecht J.K.
      • Cort S.
      • et al.
      The effects of interferon alpha-2b in combination with ribavirin on health related quality of life and work productivity.
      ]. HCV appears to affect absenteeism from work leading to substantial economic burden to employers. HCV infection is also associated with increased rates of presenteeism [
      • Su J.
      • Brook R.A.
      • Kleinman N.L.
      • Corey-Lisle P.
      The impact of hepatitis C virus infection on work absence, productivity, and healthcare benefit costs.
      ,
      • Younossi Z.
      • Henry L.
      The impact of the new antiviral regimens on patient reported outcomes and health economics of patients with chronic hepatitis C.
      ,
      • McHutchison J.G.
      • Ware Jr, J.E.
      • Bayliss M.S.
      • Pianko S.
      • Albrecht J.K.
      • Cort S.
      • et al.
      The effects of interferon alpha-2b in combination with ribavirin on health related quality of life and work productivity.
      ,
      • Baran R.W.
      • Samp J.C.
      • Walker D.R.
      • Smeeding J.E.
      • Young J.W.
      • Kleinman N.L.
      • et al.
      Costs and absence of HCV-infected employees by disease stage.
      ]. The indirect economic burden of WP loss in the U.S. has been estimated to be approximately 7.1 billion USD per year while the WP loss from 5 major European countries (France, Germany, Spain, Italy and United Kingdom) has been estimated to be 2.6 billion Euros per year [
      • Baran R.W.
      • Samp J.C.
      • Walker D.R.
      • Smeeding J.E.
      • Young J.W.
      • Kleinman N.L.
      • et al.
      Costs and absence of HCV-infected employees by disease stage.
      ,
      • Vietri J.
      • Prajapati G.
      • El Khoury A.C.
      The burden of hepatitis C in Europe from the patients’ perspective: a survey in 5 countries.
      ]. Furthermore, WP loss from Asia (Hong Kong, South Korea, Singapore and Taiwan) has been estimated to be over half a billion dollars per year with treatment resulting in a gain of USD 208.9 million per year [

      Younossi ZM, Chan HLY, Dan YY, Lee MH, Lim Y, Kruger E, et al. Impact of ledipasvir/sofosbuvir on the work productivity of chronic hepatitis C patients in Asia. (Abstract) Asian pacific study of liver disease; 2016 (Tokyo, Japan).

      ].

      Economic benefit of HCV treatment

      There are several different ways to evaluate the economic impact of HCV treatment. The first is the partial economic analysis, more commonly known as a budgetary cost analysis, where treatment is examined without considering treatment outcomes (SVR, treatment side effects, clinical and economic consequences). Results from this type of analyses may lead to the false perception that cheaper drugs are economically better. A second type of analysis is a full economic analysis which considers drug costs, treatment monitoring costs, and clinical outcomes. This type of analysis provides the true net benefit or loss of the treatment program [

      Marseille E, Larson B, Kazi DS, Kahn JG, Rosen S. Thresholds for the cost–effectiveness of interventions: alternative approaches. Bulletin of the World Health Organization. Obtained from the world wide web at http://www.who.int/bulletin/volumes/93/2/14-138206/en/. Last accessed on 10 June 2016.

      ]. In cost-benefit analysis, both costs and outcomes are provided in monetary terms.
      In reality, the outcomes of treatment cannot easily be reflected in a monetary value. Therefore, a more realistic analysis for HCV is a cost-effective analysis where the outcome provided is a relevant clinical outcome such as HCV cure or SVR (cost per SVR). However, the most robust outcome is to quantify the number of quality-adjusted years of life gained due to the treatment [

      Marseille E, Larson B, Kazi DS, Kahn JG, Rosen S. Thresholds for the cost–effectiveness of interventions: alternative approaches. Bulletin of the World Health Organization. Obtained from the world wide web at http://www.who.int/bulletin/volumes/93/2/14-138206/en/. Last accessed on 10 June 2016.

      ]. This type of economic analysis, which is called a cost-utility analysis, is considered the gold standard. These types of analyses assess the cost of treatment per quality adjusted years of life gained in USD or other currency ($/QALY). In fact, by including, costs, outcomes and quality, this type of economic analysis brings in the concept of value-based medicine to the treatment of HCV. In this type of analysis, the quality adjustment of outcome is determined through societal estimation for willingness to pay threshold (WTP) which indicates the amount society is willing to pay for achieving an additional quality adjusted year of life [

      Marseille E, Larson B, Kazi DS, Kahn JG, Rosen S. Thresholds for the cost–effectiveness of interventions: alternative approaches. Bulletin of the World Health Organization. Obtained from the world wide web at http://www.who.int/bulletin/volumes/93/2/14-138206/en/. Last accessed on 10 June 2016.

      ,
      • Neumann P.J.
      • Cohen J.T.
      • Weinstein M.C.
      Updating cost-effectiveness — the curious resilience of the $50,000-per-QALY threshold.
      ,
      • Braithwaite R.S.
      • Meltzer D.O.
      • King Jr, J.T.
      • Leslie D.
      • Roberts M.S.
      What does the value of modern medicine say about the $50,000 per quality-adjusted life-year decision rule?.
      ]. Historically, in the United States, a WTP threshold of $50,000 per QALY has been used [

      Marseille E, Larson B, Kazi DS, Kahn JG, Rosen S. Thresholds for the cost–effectiveness of interventions: alternative approaches. Bulletin of the World Health Organization. Obtained from the world wide web at http://www.who.int/bulletin/volumes/93/2/14-138206/en/. Last accessed on 10 June 2016.

      ,
      • Neumann P.J.
      • Cohen J.T.
      • Weinstein M.C.
      Updating cost-effectiveness — the curious resilience of the $50,000-per-QALY threshold.
      ,
      • Braithwaite R.S.
      • Meltzer D.O.
      • King Jr, J.T.
      • Leslie D.
      • Roberts M.S.
      What does the value of modern medicine say about the $50,000 per quality-adjusted life-year decision rule?.
      ]. In reality, this value is arbitrary and outdated as it was originally established in the 1970s based on the coverage consideration of renal dialysis by Medicare [
      • Neumann P.J.
      • Cohen J.T.
      • Weinstein M.C.
      Updating cost-effectiveness — the curious resilience of the $50,000-per-QALY threshold.
      ,
      • Braithwaite R.S.
      • Meltzer D.O.
      • King Jr, J.T.
      • Leslie D.
      • Roberts M.S.
      What does the value of modern medicine say about the $50,000 per quality-adjusted life-year decision rule?.
      ]. Different WTP thresholds may now be appropriate for the treatment of different diseases within the context of the economics of each country. In this respect, the World Health Organization considers the WTP threshold to be less than 3–5 times the gross domestic product of a country [
      • Braithwaite R.S.
      • Meltzer D.O.
      • King Jr, J.T.
      • Leslie D.
      • Roberts M.S.
      What does the value of modern medicine say about the $50,000 per quality-adjusted life-year decision rule?.
      ].
      As we examine the economic impact of anti-HCV treatment, these concepts must remain at the forefront of the discussion. In this context, shortly after the introduction of the new generation of DAAs, the economic issues of HCV treatment became quite controversial due to the price of the drugs. Unfortunately, conversations about the economics of HCV have been misleading, focusing primarily on the budgetary cost of treatment. These types of analyses show that the new drugs are more expensive on a cost-per-pill basis than the older regimens. Although this is quite accurate, this type of analysis ignores the low cure rates of the older IFN-based regimens, the four times longer duration of treatment, and the substantial side effects which all lead to additional costs associated with their management as well as subsequent economic burdens of treatment failures [
      • McEwan P.
      • Ward T.
      • Bennett H.
      • Kalsekar A.
      • Webster S.
      • Brenner M.
      Yuan. Estimating the clinical and economic benefit associated with incremental improvements in sustained virologic response in chronic hepatitis C.
      ]. In contrast, when the analyses focused on the cost per SVR or cost per HCV cure of the new regimens, costs for treatment has been shown to be significantly lower for the newer regimens as compared to the older regimens [
      • Younossi Z.M.
      • Park H.
      • Saab S.
      • Ahmed A.
      • Dieterich D.
      • Gordon S.C.
      Cost-effectiveness of all-oral ledipasvir/sofosbuvir regimens in patients with chronic hepatitis C virus genotype 1 infection.
      ,
      • Chhatwal J.
      • Kanwal F.
      • Roberts M.S.
      • Dunn M.A.
      Cost-effectiveness and budget impact of hepatitis C virus treatment with sofosbuvir and ledipasvir in the United States.
      ,
      • Najafzadeh M.
      • Andersson K.
      • Shrank W.H.
      • Krumme A.A.
      • Matlin O.S.
      • Brennan T.
      • et al.
      Cost-effectiveness of novel regimens for the treatment of hepatitis C virus.
      ,
      • Tice J.A.
      • Chahal H.S.
      • Ollendorf D.A.
      Comparative clinical effectiveness and value of novel interferon-free combination therapy for hepatitis C genotype 1 summary of California technology assessment forum report.
      ,
      • Younossi Z.M.
      • Park H.
      • Saab S.
      • Ahmed A.
      • Dieterich D.
      • Gordon S.C.
      Cost-effectiveness of all-oral ledipasvir/sofosbuvir regimens in patients with chronic hepatitis C virus genotype 1 infection.
      ,
      • Bickerstaff C.
      The cost-effectiveness of novel direct acting antiviral agent therapies for the treatment of chronic hepatitis C.
      ,
      • Chahal H.S.
      • Marseille E.A.
      • Tice J.A.
      • Pearson S.D.
      • Ollendorf D.A.
      • Fox R.K.
      • et al.
      Cost-effectiveness of early treatment of hepatitis C virus genotype 1 by stage of liver fibrosis in a US treatment-naive population.
      ]. Additionally, using the cost-utility method of analysis shows that these new regimens are highly cost-effective from the societal perspective with incremental cost-effectiveness ratios below WTP thresholds in most of the Western countries [
      • Younossi Z.M.
      • Park H.
      • Saab S.
      • Ahmed A.
      • Dieterich D.
      • Gordon S.C.
      Cost-effectiveness of all-oral ledipasvir/sofosbuvir regimens in patients with chronic hepatitis C virus genotype 1 infection.
      ,
      • Chhatwal J.
      • Kanwal F.
      • Roberts M.S.
      • Dunn M.A.
      Cost-effectiveness and budget impact of hepatitis C virus treatment with sofosbuvir and ledipasvir in the United States.
      ,
      • Najafzadeh M.
      • Andersson K.
      • Shrank W.H.
      • Krumme A.A.
      • Matlin O.S.
      • Brennan T.
      • et al.
      Cost-effectiveness of novel regimens for the treatment of hepatitis C virus.
      ,
      • Tice J.A.
      • Chahal H.S.
      • Ollendorf D.A.
      Comparative clinical effectiveness and value of novel interferon-free combination therapy for hepatitis C genotype 1 summary of California technology assessment forum report.
      ,
      • Younossi Z.M.
      • Park H.
      • Saab S.
      • Ahmed A.
      • Dieterich D.
      • Gordon S.C.
      Cost-effectiveness of all-oral ledipasvir/sofosbuvir regimens in patients with chronic hepatitis C virus genotype 1 infection.
      ,
      • Bickerstaff C.
      The cost-effectiveness of novel direct acting antiviral agent therapies for the treatment of chronic hepatitis C.
      ,
      • Chahal H.S.
      • Marseille E.A.
      • Tice J.A.
      • Pearson S.D.
      • Ollendorf D.A.
      • Fox R.K.
      • et al.
      Cost-effectiveness of early treatment of hepatitis C virus genotype 1 by stage of liver fibrosis in a US treatment-naive population.
      ].
      Despite these economic data, the cost of HCV treatment remains controversial, with different stakeholders lobbying to maximize their profits, leaving patients and clinicians trapped in the middle. Unfortunately, these misperceptions about the value of novel treatments have led to barriers to access which is exemplified by different Medicaid programs in the United States with some programs virtually denying coverage for HCV treatment [
      • Barua S.
      • Greenwald R.
      • Grebely J.
      • Dore G.J.
      • Swan T.
      Restrictions for medicaid reimbursement of sofosbuvir for the treatment of hepatitis C virus infection in the United States.
      ,

      Medicaid drug rebate program notice- Release No. 172-Assuring Medicaid beneficiaries access to hepatitis c (HCV) drugs. Accessed from the world wide web at: https://www.medicaid.gov/Medicaid-CHIP-Program-Information/By-Topics/Benefits/Prescription-Drugs/Downloads/Rx-Releases/State-Releases/state-rel-172.pdf. Last accessed on 21 March 2016.

      ]. On the other hand, as the numbers of highly effective regimens become more clinically available, some payers have negotiated significant discounts for these drugs, lowering the price for these regimens [

      Kime P. VA extends hepatitis C treatment to all patients with the virus. Obtained from the world wide web at: http://www.militarytimes.com/story/veterans/2016/03/09/va-expands-hepatitis-c-treatment-all-patients-virus/81547558/. Last accessed on 10 June 2016.

      ,
      • Zoulim F.
      • Liang T.J.
      • Gerbes A.L.
      • Aghemo A.
      • Deuffic-Burban S.
      • Dusheiko G.
      • et al.
      Hepatitis C virus treatment in the real world-optimising treatment and access to therapies.
      ]. Hopefully, as the number of regimens broadens, the market competitiveness and price negotiations will make these regimens more affordable [
      • Harris R.J.
      • Thomas B.
      • Griffiths J.
      • Costella A.
      • Chapman R.
      • Ramsay M.
      • et al.
      Increased uptake and new therapies are needed to avert rising hepatitis C-related end stage liver disease in England: modelling the predicted impact of treatment under different scenarios.
      ,
      • Martin N.K.
      • Vickerman P.
      • Dore G.J.
      • Grebely J.
      • Miners A.
      • Cairns J.
      • et al.
      Prioritization of HCV treatment in the direct-acting antiviral era: An economic evaluation.
      ].
      In addition to a formal cost-effectiveness analysis per patient, it is important to consider the economic value of cure to the society. With the advent of highly effective and well tolerated regimens, eradicating HCV from the United States, Europe and the rest of the world is an achievable goal. However, this approach requires the adoption of a long-term societal perspective where substantial initial investments are needed to identify, link to care, and then treat all patients who are eligible for treatment. In a recent Markov decision analytic model for the United States, it was estimated that after a substantial initial investment, the long-term societal savings was estimated to be over $250 billion [
      • Chahal H.S.
      • Marseille E.A.
      • Tice J.A.
      • Pearson S.D.
      • Ollendorf D.A.
      • Fox R.K.
      • et al.
      Cost-effectiveness of early treatment of hepatitis C virus genotype 1 by stage of liver fibrosis in a US treatment-naive population.
      ]. This already impressive figure may be an underestimation given that the model only considers HCV GT1 and a WTP threshold of $50,000 per QALY and does not include savings potentially gained from improvement in WP and improvements in treating the EHM of HCV.
      A final economic concept to consider in the treatment of HCV requires a novel approach to assess the value of drug innovation for HCV. This approach considers the fact that with each new treatment innovation for HCV, the cost of treatment may be seen as an increase. In this context, it is important to know what economic benefit the new treatment brings to the society. For example, if the current standard for treatment of disease X is drug A, assuming that drug A costs $1000 and produces 1 additional QALY, it has an outcome worth of about $50,000. Now, let’s consider that innovation leads to the development of drug B that costs $3,000 which is three times more expensive than drug A. Purely on the basis of cost, the new drug will lead to a 300% increase in the price. However, if the new drug B leads to 2 additional QALYs, the outcome is now worth about $100,000 and the quality adjusted cost of care for the new drug decreases by $48,000. Applying this concept to the treatment of HCV, a recent study compared the historical treatment of HCV (PR) with the most recent treatment regimens [
      • McEwan P.
      • Ward T.
      • Bennett H.
      • Kalsekar A.
      • Webster S.
      • Brenner M.
      Yuan. Estimating the clinical and economic benefit associated with incremental improvements in sustained virologic response in chronic hepatitis C.
      ]. The investigators determined that when they compared the old regimen of PR, the cost of the new all oral regimens for HCV increased by $45,359. On the other hand, the significantly higher efficacy of the new all oral regimens for HCV increased the outcomes by 1.622 QALYs which is valued at $81,080 (WTP = $50,000 per QALY). Based on this analysis, the quality adjusted cost of care of the new regimen will lead to a $32,730 improvement for each treated patient [
      • McEwan P.
      • Ward T.
      • Bennett H.
      • Kalsekar A.
      • Webster S.
      • Brenner M.
      Yuan. Estimating the clinical and economic benefit associated with incremental improvements in sustained virologic response in chronic hepatitis C.
      ]. This analysis illustrates that one needs to consider not only the cost of the new innovative drug but also the value of these drugs in terms of long-term outcomes providing society with a better comprehensive understanding of the economic value of these new regimens.
      For the rest of the world, difficulties remain, especially in the low to middle income countries, which are struggling to find acceptable ways to identify and screen all at risk patients [
      • Zoulim F.
      • Liang T.J.
      • Gerbes A.L.
      • Aghemo A.
      • Deuffic-Burban S.
      • Dusheiko G.
      • et al.
      Hepatitis C virus treatment in the real world-optimising treatment and access to therapies.
      ,
      • Harris R.J.
      • Thomas B.
      • Griffiths J.
      • Costella A.
      • Chapman R.
      • Ramsay M.
      • et al.
      Increased uptake and new therapies are needed to avert rising hepatitis C-related end stage liver disease in England: modelling the predicted impact of treatment under different scenarios.
      ]. So until these issues are identified, the cost of the drugs is a secondary issue, though some ideas are being suggested to help offset the cost of drugs once a screening and identification mechanism is in place [
      • Martin N.K.
      • Vickerman P.
      • Dore G.J.
      • Grebely J.
      • Miners A.
      • Cairns J.
      • et al.
      Prioritization of HCV treatment in the direct-acting antiviral era: An economic evaluation.
      ]. These issues bring up the importance of a national strategy to deal with HCV on a country-by-country basis. The solution for eradicating HCV from the Western countries are most likely very different from the solutions offered in the low income countries. Nevertheless, developing national and global policies to eradicate HCV must be considered by all nations.

      Ethical issues in treatment of hepatitis C

      In spite of the miraculous advances in the field of HCV treatment, the new treatment regimens have stirred up a number of important ethical issues. Healthcare providers are increasingly being asked to make “difficult” ethical decisions becoming part of a process that could deny potentially life-saving treatments [
      • Povar G.J.
      • Blumen H.
      • Daniel J.
      • Daub S.
      • Evans L.
      • Holm R.P.
      • et al.
      Ethics in practice: managed care and the changing health care environment: medicine as a profession managed care ethics working group statement.
      ].
      Therefore, to help health care providers make decisions, an ethical framework is necessary. When considering an ethical framework from the patient’s perspective, one must consider the ethical principles of autonomy (a patient’s right to accept or refuse treatment), beneficence (acting for or in the patients’ best interest) and non-maleficence (to do no harm) (Table 2). Since, as discussed, there is now strong evidence that the current HCV treatment does no harm and is actually associated with substantial patient-specific benefits (clinical, PRO and economic), denying access to these treatments may actually harm our patients and denies patients a role in the decision making on whether to undergo treatment with the new regimens [
      • Povar G.J.
      • Blumen H.
      • Daniel J.
      • Daub S.
      • Evans L.
      • Holm R.P.
      • et al.
      Ethics in practice: managed care and the changing health care environment: medicine as a profession managed care ethics working group statement.
      ,
      • Snyder J.
      American college of physicians ethics manual.
      ].
      Table 2Ethical issues surrounding prescribing the new direct acting antiviral agents from the patient and the societal perspectives.
      ∗Reference
      • Younossi Z.
      What is the ethical responsibility of a provider when prescribing the new direct-acting antiviral agents to patients with hepatitis C infection?.
      .
      If one were to use an ethical framework from a societal perspective, one would consider the ethical principles of justice (fairness and equity in the distribution of health resources regardless of socioeconomic power), stewardship (the duty to protect resources) and parsimony (to choose the most economical treatment among similarly effective treatments whenever it is practical and feasible). Since a large number of HCV patients belong to minorities or those who are in the lower socioeconomic segments of society, denying access would disproportionately affect these vulnerable populations and justice would not be served. When considering the principle of stewardship, there is substantial evidence that curing HCV will protect healthcare economic resources over the long-term. When observing the ethical principle of parsimony, there is substantial evidence now which suggests that the new anti-HCV regimens are more practical and feasible (significant clinical, PRO and economic improvement) when compared with the older anti-HCV regimens [
      • Snyder J.
      American college of physicians ethics manual.
      ]. In fact, with our knowledge of the now irrefutable outcomes, choosing the older regimens will violate all the ethical principles from both the patient and the societal perspectives [
      • Younossi Z.
      What is the ethical responsibility of a provider when prescribing the new direct-acting antiviral agents to patients with hepatitis C infection?.
      ].
      Therefore, regardless of what ethical framework is applied (clinical or societal), it is apparent that clinicians have an obligation to prescribe the intervention that would be most beneficial to the patient and to their society. In other words, the intervention that improves the patients’ quantity and quality of life as well as WP should be the guide that assists clinicians in making their treatment decisions. In this context, one can argue that not providing the recommended HCV treatment or creating barriers to obtaining access to these highly effective treatments is unethical from both the patient and the societal perspectives.
      A comprehensive approach to the multifaceted aspects of HCV will provide a better understanding of the impact of HCV burden and the benefit of HCV cure.

      Conclusions

      In summary, this review clearly documents that HCV infection is a multi-faceted systemic disease with important clinical, PRO, and economic burden. It is critical that the entire spectrum of the disease burden of HCV be assessed to fully comprehend its impact on the patient and the society. Furthermore, it is also important that treatment regimens for HCV are also assessed in a comprehensive manner. This approach will help patients, health care providers and policy makers reach better informed decisions about this important disease, and its treatment to better benefit the patient and the society. Nevertheless, a number of challenges in treating HCV patients remain which center on the identification, linkage to care and providing treatment with these highly effective drug regimens.

      Conflict of interest

      ZMY has received research grants or serve as a consultant to Gilead, BMS, Abbvie and Intercept. Other authors have nothing to disclose.

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