Revolutionizing Treatment Outcomes in Hepatitis C: Managed Care Implications and Considerations-A Clinical Overview

March 23, 2015
Monica Shah, PharmD

,
Zobair M. Younossi, MD, MPH, FACG, FACP, AGAF, FAASLD

,
Yekaterina Opsha, PharmD, BCPS

Supplements and Featured Publications, Revolutionizing Treatment Outcomes in Hepatitis C: Managed Care Implications and Considerations [CME, Volume 21, Issue 5 Suppl

Chronic hepatitis C virus (HCV) infection is highly prevalent and associated with a wide range of hepatic and extrahepatic complications. The treatment landscape for HCV infection has evolved to include regimens without interferon formulations and/or ribavirin. This change simplifies therapy, improves tolerability, and decreases therapy duration, while improving virologic response rates. This article, the first in a series of 3, will provide an overview of the hepatitis C disease state, identify populations at risk for HCV, describe testing recommendations for the diagnosis of HCV infection, and distinguish new and emerging HCV therapies.

Am J Manag Care. 2015;21:S76-S85Hepatitis C virus (HCV) infection is a serious public health problem: an estimated 185 million people worldwide and 4 million individuals in the United States are chronically infected.1,2 The major burden of HCV infection comes from sequelae associated with chronic infection. An estimated 80% of acutely infected patients with HCV progress to chronic infection: 20% develop cirrhosis within 20 years, and 25% of patients with cirrhosis progress to hepatocellular carcinoma (HCC) and/or decompensated liver disease.3 The methods of treating HCV infection have evolved to management without interferon and/or ribavirin-based regimens. This strategy appears to simplify disease treatment, improve tolerability, and decrease therapy duration, while increasing virologic response. This article, the first of 3 articles in this supplement on the topic of HCV infection, will provide an overview of the hepatitis C disease state, including epidemiology and pathophysiology; identify populations at risk for HCV; and distinguish new and emerging HCV therapies.

Epidemiology

According to a recent epidemiologic study, total global viremic HCV infections were estimated at approximately 80 million (range, 64-103 million) infections, lower than previous reports.4 Certain high-risk populations (ie, persons who inject drugs, patients on hemodialysis, and patients with cancer) were excluded from this analysis because they were not representative of HCV prevalence in the general population. The study results indicate that about 30 countries account for the majority of the total viremic HCV infections, with China, Pakistan, Nigeria, Egypt, India, and Russia together accounting for more than 50% of total infections.

Because of the differences in geographical distribution, clinical presentation, disease progression, and response to therapy, determination of HCV genotype (genetic variations or strains of the virus) is crucial.5 Worldwide, genotype 1 (G1) accounts for 46% of all HCV infections among adults, followed by G3 (22%), G2 (13%), G4 (13%), G6 (2%), and G5 (1%).4 Genotype 1b is the most common subtype, accounting for 22% of all HCV infections. However, wide variations across regions and countries are seen. HCV infections in North America, Latin America, and Europe are predominantly G1 (about 60%-70%), and a high prevalence of G4 (70%) is seen in North Africa and the Middle East (primarily Egypt).4 Genotype 3a is common in the European population of persons who inject drugs (PWID), and prevalence of HCV G4 infections is increasing in this group.6

HCV infection is often prevalent among HIV-infected populations. Approximately 7 million people worldwide and one-third of human immunodeficiency virus (HIV)- infected Americans are coinfected.7 The prevalence of HCV coinfection varies, however, depending on the mode of HIV transmission. The primary route of HCV spread appears to be injection drug use; HCV coinfection rates often exceed 90% among HIV-infected PWID.8

Pathophysiology

Discovered in 1989, HCV is a positive-strand RNA virus of the Flaviviridae family.9 It encodes a polyprotein that undergoes proteolytic cleavage to 10 polypeptides, each with specific functions.10 The structural proteins consist of 2 envelope glycoproteins, which are major viral determinants of HCV entry into hepatocytes, and the core protein, which interacts with progeny viral genomes for assembly of the virus.9 The nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A, and NS5B form a complex with viral RNA to initiate viral replication in cytoplasmic membranous structure. Assembly of HCV requires close interactions with lipid droplets and lipoprotein metabolism. Mature virus is then released from cells as lipoviral particles. HCV infects primarily hepatocytes and has the ability to evade host immune response.

Recent efforts to develop treatment options have focused on small-molecule inhibitors of HCV infection, which are classified based on their target of action. Some antiviral agents act directly on viral targets and others target host proteins that are essential to HCV replication. Initially, the focus was on 2 viral-encoded enzymes, the NS3/4A serine protease, which cleaves the HCV polyprotein, and the NS5B RNA-dependent RNA polymerase.11-13 More recently, the NS5A viral protein has gained attention because of its importance in the assembly of the cytoplasmic membrane-bound replication complex and the high potency of its inhibitors.14

Clinical Manifestations

Increasing evidence demonstrates that the inflammatory response in HCV infection is likely pathogenically associated with the development of both hepatic manifestations (ie, fibrosis, cirrhosis, and HCC) and extrahepatic manifestations (ie, lymphoproliferative disease, atherosclerosis, cardiovascular diseases, cerebrovascular events, diabetes, and neuropsychiatric symptoms).15 The important role of several proinflammatory cytokines, including interleukin-1β (IL-1β), has been recently emphasized in HCV-induced liver inflammation and disease progression.16 Further, HCV-related proteins (NS3, NS4, and NS5) have been demonstrated to trigger human Kupffer cells to produce inflammatory cytokines such as tumor necrosis factor-a (TNF-a) and IL-1β.17

HCV infection is a major cause of liver fibrosis and ultimate progression to cirrhosis.18 A study in more than 3000 HCV-infected individuals showed that approximately 50% of patients had steatosis and 87% had fibrosis.19 Results of multivariable logistic regression showed that steatosis was independently associated with several factors, including hepatic inflammation (P = .001), HCV G3 (P <.001), fibrosis (P <.001), diabetes (P = .007), high body mass index (P <.001), ongoing alcohol abuse (P = .009), and older age (P <.001); whereas factors associated with fibrosis included steatosis (P <.001), inflammatory activity (P <.001), male sex (P = .001), and older age (P <.001). HCV G2 was associated with reduced fibrosis (OR, 0.688; 95% CI, 0.483-0.981; P = .083).19

Numerous extrahepatic manifestations, including immune-related manifestations, are also seen in up to 75% of HCV-infected patients; these extrahepatic manifestations differ in severity.20 HCV infection accounts for about 80% of the cases of mixed cryoglobulinemia (MC) vasculitis, a small vessel vasculitis involving the skin, joints, and kidney. Interferon-based regimens appear to induce clinical remission; however, the adverse effects of interferon may mimic manifestations of cryoglobulinemia.21 Although clinical data are not yet available, the use of interferon-free direct-acting antiviral (DAA) regimens may be an attractive alternative for these patients.22

In the Chronic Hepatitis Cohort Study (CHeCS), disease-specific, liver-related, and non—liver-related mortality data for HCV patients were compared with multiple cause of death (MCOD) data in 12 million death certificates in 2006 to 2010.23 Of the approximately 11,000 patients with HCV, 14% died during the study period. Most CHeCS decedents were male (68%) and born from 1945 to 1965 (75%). The mean age of death was 59 years—15 years younger than the MCOD rate. The age-adjusted mortality rate in liver disease was 12 times higher than the MCOD rate. In addition, all adjusted death rates from extrahepatic causes were higher than the national MCOD rate, particularly in deaths with genitourinary causes (RR, 3.75; 95% CI, 3.73-3.77), mental disorders (RR, 2.25; 95% CI, 2.25-2.26), and diabetes (RR, 1.77; 95% CI, 1.76-1.78) (all P <.0001). In approximately 50% of all deaths in individuals with known HCV, liver disease was listed on the death certificate. Thus, even if other diseases associated with HCV infection such as diabetes are excluded, it appears that most individuals are dying not just with HCV but from HCV. Such consideration is essential because identifying and treating HCV patients in an era of rapidly evolving and effective treatment regimens could potentially have a major health impact.

Populations at Risk and Testing Recommendations for HCV Infection

HCV is primarily transmitted through percutaneous exposure to blood. An important risk for HCV infection is injection drug use, accounting for at least 60% of acute HCV infections in the United States.22 Other modes of transmission include mother-to-infant, sharing of contaminated devices for noninjection drug use, and healthcare exposures, including the receipt of blood products before 1992 and clotting factor concentrates before 1987.22

The increased risk of HCV infection among PWID, including those in the United States, has been widely reported.24,25 Investigations by local health departments and the Centers for Disease Control and Prevention (CDC) in Massachusetts and Wisconsin indicated an emergence of HCV infection, particularly among persons younger than 30 years of non-Hispanic white race who reported opioid analgesic abuse before switching to heroin. Surveillance data also suggested that the reported incidence of acute hepatitis C increased significantly in young persons (aged ≤30 years)—13% annually in nonurban counties (P = .003) versus 5% annually in urban counties (P = .028).26 Thirty (88%) of 34 reporting states and territories observed higher incidence in 2012 than 2006, especially in nonurban counties east of the Mississippi River. Of the 1200 newly reported HCV young persons, 52% were female and 85% were white. In 635 interviews, 75% of respondents reported injection drug use. Both the CDC and US Preventive Services Task Force recommend HCV testing in persons with a history of injection drug use.2,27

Over the past decade, epidemics of acute HCV due to sexual transmission in HIV-infected men who have sex with men (MSM) have also been reported.28,29 In one study, 226 HIV-positive MSM diagnosed with acute HCV infection in Europe and Australia were evaluated.29 The majority (96%) of participants were diagnosed based on anti-HCV or HCV RNA seroconversion rather than clinical and/or biochemical hepatitis (ie, acute hepatitis in those without pre-existing liver disease). The median age at HCV diagnosis was 38 years, the median CD4 count was 518 cells/μL, and 62% received highly active antiretroviral therapy (HAART). Among study participants, HCV genotypes 1a (60%) and 4d (20%) were predominant. The number of MSM reporting injection drug use in the 12 months before HCV seroconversion in mainland Europe was 2.9%; in the UK, 17%; and in Australia, 50%. However, only 1 subject (2.6%), who was from the UK, reported needle sharing. According to a recent Swiss study of 840 MSM, the seroprevalence of hepatitis C among non—HIV-diagnosed MSM appears to be low, 0.37% (95% CI, 0.12%-1.69%).30

Evidence also suggests that hepatitis C is rarely transmitted via sexual contact among HCV-serodiscordant heterosexual couples.31 A study conducted in 500 HCV-positive, HIV-negative subjects and their long-term partners estimated the risk for HCV infection among monogamous heterosexual couples. The prevalence of HCV infection among partners potentially attributable to sexual contact was 3/500 (0.6%; 95% CI, 0.0%-1.3%), assuming all HCV RNA-negative partners were discordant (minimum estimate); and 6/500 (1.2%; 95% CI, 0.2%-2.2%), assuming all HCV RNA-negative, antibody-concordant couples were concordant (maximum estimate).

Guidelines for HCV testing, management and treatment have been recently endorsed by the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA).22 Further, the CDC testing recommendations for HCV infection have also been published.32 HCV testing is recommended in select populations based on demographics, prior exposures, certain high-risk behaviors, and medical conditions. In 2012, CDC issued a recommendation that adults born from 1945 to 1965 should be tested once, without prior ascertainment of HCV risk factors.2 Testing is also advocated for persons with risk behaviors or exposures, including current or previous injection drug users, long-term hemodialysis patients, prior recipients of transfusions or organ transplants, children born to HCV-infected mothers, those with HIV infection, persons who have received a tattoo in an unregulated setting, or those who were incarcerated.22,32 Healthcare or emergency medical workers after needle sticks, sharps, or mucosal exposures to HCV-infected blood should also receive testing. Annual HCV testing is recommended for HIV-seropositive MSM who have unprotected sex.

Diagnosis of HCV Infection

All persons recommended for HCV testing should first be tested for anti-HCV antibody using FDA-approved tests, which include laboratory-based assays and a pointof- care assay (ie, a rapid test for anti-HCV antibody).32 The anti-HCV rapid antibody test is an indirect immunoassay with a sensitivity and specificity similar to those of FDA-approved, laboratory-based anti-HCV antibody assays. The availability of a rapid test provides wider testing access to persons at risk for HCV infection and allows for use in nontraditional settings such as physician offices, community health clinics, and hospital emergency departments. A nonreactive anti-HCV antibody result indicates that no anti-HCV antibody is detected. However, a reactive result indicates one of the following: 1) current HCV infection, 2) past HCV infection that has resolved, or 3) false positivity. Therefore, an HCV nucleic acid test (NAT) to detect viremia is necessary to confirm active HCV infection and guide disease management. Similarly, if HCV RNA is detected via NAT, it indicates active HCV infection. If HCV RNA is not detected, it indicates either past, resolved HCV infection or false anti-HCV-antibody positivity. HCV RNA testing is also recommended for persons with a negative anti-HCV antibody test who are either immunocompromised (ie, persons receiving chronic hemodialysis) or who might have been exposed to HCV within the last 6 months (including those who are possibly reinfected after previous spontaneous or treatment-related viral clearance) because these individuals may be anti-HCV antibody negative.

Before initiation of HCV treatment, quantitative RNA PCR testing is recommended to document the baseline level of viremia. Testing for HCV genotype is useful in clinical management for predicting likelihood of response and determining the optimal treatment regimen and duration of therapy.33

Treatment Options for HCV Infection

In the interferon era, clinical studies of HCV treatment conventionally used a primary end point of 24-week sustained virologic response (SVR24), defined as the continued absence of detectable HCV RNA 24 weeks after completion of therapy. SVR24, a marker for virologic cure, has been shown to be durable in large prospective trials in more than 99% of patients followed up for 5 years or more.34,35 While some healthcare providers may still test SVR24 in certain patients, more recently, SVR 12 weeks after the end of therapy (SVR12) has been established as an appropriate efficacy end point in clinical and research settings and a proximate goal of HCV treatment.22 Among HCV-infected persons, SVR has been associated with an improvement in hepatic clinical manifestations, including a 40% to 70% improvement in liver fibrosis and necrosis, a 70% reduction in HCC, a decrease in symptoms and mortality from severe extrahepatic manifestations, such as cryoglobulinemic vasculitis, and reduced risk of all-cause mortality.36-38

As the clinical and economic burden of HCV infection continues to increase, there is a substantial need for highly effective, safe, short-term, and affordable HCV treatment regimens. Historically, interferon- and/ or ribavirin-based regimens were the mainstay of HCV treatment. However, limited efficacy and higher therapyrelated adverse events (AEs) have been observed in the real-world setting with treatment regimens that include interferon and first-generation DAAs.39,40 In 1 such study, 36% of patients receiving interferon-ribavirin plus protease-inhibitor (boceprevir or telaprevir) therapy experienced anemia, requiring ribavirin dose reduction.40 Further, high rates of thrombocytopenia (20%) and neutropenia (12%) also required therapy dose modifications. Fortunately, the development of new DAAs against HCV has progressed steadily, providing oral interferonfree therapies associated with improved SVR rates.

Second-Generation DAAs

As discussed earlier, 3 main therapeutic targets of HCV have been identified—NS3/4A protease, NS5B polymerase, and NS5A replication complex. A shift from traditional HCV therapies and the availability of 2 second-generation DAAs, simeprevir and sofosbuvir, have led to improved efficacy and safety for treating HCV infection.

NS3/4A Protease Inhibitor: Simeprevir

Simeprevir, a HCV NS3/4A serine protease inhibitor, has been evaluated in treatment-naïve HCV G1 patients. Treatment with simeprevir resulted in SVR rates of 74% to 92%. Simeprevir was administered for 12 to 24 weeks along with peginterferon-ribavirin for 24 to 48 weeks. By contrast, SVR rates for peginterferon-ribavirin alone range from 46% to 65%.41,42

NS5B Polymerase Inhibitor: Sofosbuvir

In clinical studies, higher SVR rates (90%; 95% CI, 87%-93%) were seen after only 12 weeks of therapy with sofosbuvir plus peginterferon-ribavirin in 327 treatmentnaïve patients with HCV G1, G4, G5, or G6.43 The SVR rates for sofosbuvir plus peginterferon-ribavirin in previously untreated patients were 92% for those without cirrhosis and 80% for those with cirrhosis.43 The efficacy of simeprevir plus peginterferon-ribavirin was 83% to 85% in previously untreated HCV G1 patients with no cirrhosis, but only 58% to 65% in cirrhotic patients and 53% in peginterferon-ribavirin-null responders.44-46 Thus, there is a need for an interferon-free, all-oral HCV therapy that is highly effective for all HCV patient populations, including those with cirrhosis. In November 2014, the FDA approved sofosbuvir in combination with simeprevir as an all-oral, interferon- and ribavirin-free treatment option for HCV G1 infection. The recommended treatment duration of simeprevir with sofosbuvir is 12 weeks for patients without cirrhosis and 24 weeks in those with cirrhosis.22

NS5A Inhibitor: Ledipasvir

The recent approval of ledipasvir-sofosbuvir has benefited the care of HCV patients because of the combination’s improved pharmacokinetics, simplified oncedaily dosing schedule, and reduced drug interactions. Treatment with ledipasvir-sofosbuvir, with or without ribavirin, for 12 or 24 weeks in previously untreated patients (n = 865) with HCV G1 infection, including those with compensated cirrhosis (16% of total patients), demonstrated higher SVR rates (97%-99%; P <.001 for all comparisons).47 The recommended treatment duration of ledipasvir-sofosbuvir is 12 weeks for treatment-naïve patients with or without cirrhosis, 12 weeks for treatmentexperienced patients without cirrhosis, and 24 weeks for treatment-experienced individuals with cirrhosis.22

Ombitasvir, Paritaprevir, and Ritonavir Plus Dasabuvir

In December 2014, the FDA approved ombitasvir, paritaprevir, and ritonavir fixed-dose combination tablets co-packaged with dasabuvir tablets for the treatment of patients with HCV G1 infection, including those with compensated cirrhosis. The combination product may be used with or without ribavirin. The fixed-dose combination of ombitasvir (a NS5A inhibitor), paritaprevir, (formerly ABT-450, a NS3/4A protease inhibitor), and ritonavir is administered once daily, whereas dasabuvir (a NS5B RNA polymerase inhibitor) is dosed twice daily.22

The 3 DAA regimen (3D) of coformulated ABT-450/r with ombitasvir plus dasabuvir, with ribavirin, was evaluated in HCV G1-infected patients.48 The pharmacokinetic (PK) profile of the 3D regimen was evaluated in subjects with varying degrees of renal impairment, using estimated creatinine clearance (CrCl) by Cockroft- Gault equation.49 This phase 1, open-label study enrolled patients not infected with HCV or HIV. Using regression analyses to assess the effect of renal impairment on PK, results showed that no dose adjustment for ABT-450/r, ombitasvir, and dasabuvir are needed in subject with renal impairment.

For liver transplant recipients with G1 HCV infection receiving the 3D regimen, dose modifications of the immunosuppressant agents, tacrolimus and cyclosporine, are necessary.50 When administered with 3D, the prestudy total cyclosporine dose was reduced to one-fifth and given daily; for tacrolimus, a dose of 0.5 mg every 7 days or 0.2 mg every 3 days was administered. PK simulation demonstrated that these dose modifications yielded drug concentrations within the therapeutic range.

Safety data from the PEARL-II (A Study to Evaluate the Safety and Effect of the Experimental Drugs ABT- 450/Ritonavir/ABT-267 [ABT-450/r/ABT-267] and ABT-333 in People With Chronic Hepatitis C [PEARLII]), PEARL-III, and PEARL-IV trials showed that 3D was well tolerated, either with or without ribavirin.51 In these 3 studies, patients with HCV G1a and G1b infections received either 3D (n = 509) or 3D plus ribavirin (n = 401). The most common AEs seen in the 3D plus ribavirin and 3D groups were fatigue (29.9% and 26.5%, respectively) and headache (24.4% and 25.3%, respectively). The rate of discontinuation due to AEs was 0.5% or less among patients in both treatment groups. The medication adherence rate was greater than 98.5% in all treatment groups.52

Emerging Therapies for HCV Infection

Several other interferon-free HCV therapies are in the clinical pipeline, including grazoprevir (MK-5172, a HCV NS3/4A protease inhibitor), elbasvir (MK-8742, a HCV NS5A replication complex inhibitor), GS-9669 (a nonnucleotide NS5B inhibitor), and daclatasvir (a NS5A replication complex inhibitor).

The C-WORTHY (A Phase II Randomized Clinical Trial to Study the Efficacy and Safety of the Combination Regimen MK-5172 and MK-8742 ± Ribavirin [RBV] in Subjects With Chronic Hepatitis C Virus Infection) study assessed the efficacy and safety of MK-5172 and MK-8742 in treatment-naïve, noncirrhotic G1 HCV monoinfected and HIV/HCV coinfected patients.53,54 A total of 159 monoinfected and 59 coinfected patients were enrolled. Monoinfected patients received 8 or 12 weeks of MK-5172 (100 mg once daily) plus MK-8742 (20 or 50 mg once daily), with or without ribavirin. Coinfected patients received both agents for 12 weeks, with or without ribavirin; all were on stable antiretroviral regimens. SVR12 rates for monoinfected and coinfected patients treated for 12 weeks, with or without ribavirin, were 95% (123/129 patients) and 93% (50/54), respectively. Among monoinfected patients with GT1a infection treated with 8 or 12 weeks with MK-5172 and MK-8742 plus ribavirin, SVR12 rates were 80% (24/30) and 94% (49/52), respectively, and 96% (23/24) for coinfected patients treated for 12 weeks. Overall, high SVR12 (95%) was seen with 12-week regimens of MK-5172 and MK-8742, with or without ribavirin (173/183), with low virologic failure (3.3%, 6/183 patients). The most common AEs were fatigue, headache, nausea, insomnia, and asthenia. No patient discontinued therapy because of an AE or laboratory abnormality. Virologic resistance analysis, from a phase 2 study in treatmentnaïve HCV G1-infected patients, showed that virologic failure occurred uncommonly (2.3%, 6/266 patients) in MK-5172/peginterferon/ribavirin recipients.55

A recent study evaluated whether ledipasvir-sofosbuvir, with either ribavirin or GS-9669, would allow cirrhotic patients with HCV G1 infection to achieve high SVR rates when administered for a shorter duration (8 weeks).56 Patients were randomized in equal proportions to receive either ledipasvir-sofosbuvir plus ribavirin (n = 35), ledipasvir-sofosbuvir plus GS-9669 250 mg (n = 32), or ledipasvir-sofosbuvir plus GS-9669 500 mg (n = 33) daily for 8 weeks. SVR12 was seen in 89% of patients in the ledipasvir-sofosbuvir plus ribavirin group, in 91% of the ledipasvir-sofosbuvir plus GS-9669 250-mg group, and in 82% of the ledipasvir-sofosbuvir plus GS-9669 500-mg cohort. Study results suggested that coadministration of GS-9669 did not appear to provide additional efficacy compared with ribavirin; a more potent agent or one with a complimentary mechanism of action may be needed to shorten therapy duration or achieve higher SVR rates.

Recent evidence suggests that HCV G3 may be less responsive to treatment than other genotypes.43 The only currently available all-oral regimen requires 24-week treatment that includes ribavirin. Newer ribavirin-free regimens are being investigated to shorten treatment duration. The efficacy and safety of daclatasvir, a pangenotypic NS5A inhibitor, plus sofosbuvir were evaluated in 152 patients with HCV G3 infection.57 Two cohorts, treatment-naïve and treatment-experienced patients, received daclatasvir 60 mg daily plus sofosbuvir for 12 weeks. Overall, SVR 4 weeks at the end of therapy (SVR4) was seen in 91% and 86% of treatment-naïve (n = 101) and treatment-experienced (n = 51) patients, respectively. SVR12 was achieved in 90% of treatment-naïve and 86% of treatment-experienced patients. One patient had detectable HCV RNA at the end of therapy, and 15 had a relapse post treatment (mostly cirrhotic patients). The most common AEs were headache (20%), fatigue (18%), and nausea (12%).

HCV/HIV Coinfection

Because of the shared routes of transmission, HIV coinfection is common among HCV-positive patients.58 Historically, optimal treatment of HCV/HIV coinfection has often been difficult, primarily because of poor response with interferon-based regimens, increased risk of drug-related AEs, fewer treatment options owing to potential drug interactions, and the lack of clinical trials evaluating newer interferon-free HCV therapies in this population.59 The combination of sofosbuvir with ribavirin in HCV/HIV coinfected patients resulted in high SVR rates; however, anemia—seen in up to 20% of patients—along with relapse, remains a challenge.60 However, emerging data suggest that interferon-free therapies may be equally effective in patients with HCVmonoinfection or HCV/HIV coinfection. One such study reported the safety and efficacy of the ribavirinfree regimen of ledipasvir-sofosbuvir in HCV G1/HIV coinfected patients.61 Fifty patients were treated with once-daily ledipasvir-sofosbuvir for 12 weeks in 2 groups: antiretroviral therapy (ART)-naïve HIV long-term nonprogressors, and patients permitted on ART (tenofovir, emtricitabine, efavirenz, raltegravir, rilpivirine, with HIV suppression). Preliminary data showed that in ARTnaïve patients, SVR4 was 100% (12 of 12 patients) and SVR12 was 100% (10/10). In ART-treated patients, SVR4 was 100% (22 of 22 patients).

The TURQUOISE-I (Safety and efficacy of ABT- 450/r/Ombitasvir, Dasabuvir, and Ribavirin in patients co-infected with hepatitis C and HIV-1) study evaluated a 12- or 24-week regimen of 3D plus ribavirin in adults with HCV G1/HIV-1 coinfection.62 The trial included HCV treatment-naïve or interferon-ribavirin-experienced patients, with or without cirrhosis, CD4 count greater than 200 cells/mm3, and plasma HIV-1 RNA suppressed on stable atazanavir- or raltegravir-included antiretroviral regimen. Among patients treated with 3D plus ribavirin for 12 weeks, 93.5% (29/31) achieved SVR12, and 96.9% (31/32) of those treated for 24 weeks achieved end-of-treatment response. The most commonly reported AEs were fatigue, insomnia, and nausea, and no discontinuations due to AEs were reported.

Impact of HCV Regimens on Patient-Reported Outcomes

To evaluate the full impact of HCV burden, including clinical, economic, and patient-reported outcomes, an expert panel recently convened to provide evidencebased recommendations.63 The panel reviewed several studies, including one that assessed the health-related quality of life (HRQOL) and sexual health in patients with advanced chronic HCV, who had fibrosis or cirrhosis.64 HRQOL was evaluated using the 36-item Short-Form Health Survey (SF-36), a self-administered questionnaire including 8 physical and mental health domains and 2 physical and mental summary scales. The SF-36 scales, a validated tool that measures patientreported change in health status over time, has been used in other HCV therapeutic trials.65 Baseline comparison of HRQOL scores for the 8 SF-36 domains among patients with cirrhosis (n = 432) and those with bridging fibrosis (n = 712) demonstrated that those with cirrhosis had significantly lower scores for 7 of 8 HRQOL domains— physical functioning (P = .005), role-physical (P = .003), bodily pain (P = .001), general health (P = .03), vitality (P = .04), social functioning (P <.001), and role-emotional (P = .004).64 Other important determinants of HRQOL scores included the use of antidepressant and anxiolytic medications, cigarette smoking, and higher depression severity scores. Changes from baseline in these HRQOL parameters in patients who achieved SVR (n = 178) were compared with those who tested HCV RNA-positive before week 72 (relapsers, n = 76). In the SVR group, scores were significantly improved in 4 of 8 HRQOL domains: rolephysical (P = .003), general health (P <.0001), vitality (P <.0001), and role-emotional (P = .03). Multivariate linear regression analyses were performed to evaluate factors associated with changes in summary score. The major predictor of improvement in physical summary scores was SVR achievement (P = .0003). Patients without diabetes were more likely to have improvements in physical summary scores (P = .0007). Improvements in sexual summary scores were associated with SVR (P = .03).

Results of another HRQOL study in HCV patients also showed that all 8 SF-36 domain scores among the cirrhosis group were significantly lower than those of the viral-clearance group (P <.05).66 Further, marital status, income, and comorbidity significantly affected all scores (P <.05).

Although select patient data gathered from clinical trials have shown a major improvement in HRQOL after achieving SVR, it is uncertain whether these results can be extrapolated to the real-life setting. A study focusing on clinic population examined whether differences in quality of life (QOL) between sustained responders and those without treatment response persist long term.67 Persons with advanced liver disease (decompensated cirrhosis, HCC, liver transplant) were excluded from the study. A total of 235 patients (133 responders, 102 nonresponders) completed the questionnaires at an average 3.7 years after the end of treatment. Compared with sustained responders, those who experienced treatment failure had lower scores on each SF-36 domain (including generic and disease specific) and on all utility measures. All of the differences between the 2 groups were significant (P <.05), with the exception of the positive well-being scale (P = .06). Nonresponders had lower QOL and utility scores than the population norms (P <.0001). Sustained responders had similar bodily pain (P = .1) and physical component summary scores (P = .21) compared with population norms, but scored significantly lower on all other measures (P <.05). The observed differences were also seen after adjustment for factors known to be associated with QOL—age, sex, ethnicity, marital status, comorbidities, and severity of physical impairments. Based on these study results of patients assessed at an average of 3.7 years after antiviral therapy, it appears that QOL improvements demonstrated in clinical studies translate to a real-world clinic setting, and that these benefits are maintained long term.

Recent study results demonstrate that most of the PRO scores, including those related to HRQOL, fatigue, and work productivity, were more favorable for ribavirin- free regimens (with ledipasvir-sofosbuvir) compared with ribavirin-containing regimens.68 These important results indicate the improved tolerability of these new regimens, which may potentially lead to enhanced treatment compliance with low drop-out rates due to AEs. The increase in compliance may have contributed to the high SVR rates seen in clinical trials with interferon- and ribavirin-free regimens.

Economic Burden of HCV Infection

According to a recent analysis, the overall HCV prevalence in the United States is declining because of lower incidence.69 However, the prevalence of advanced liver diseases, number of liver-related deaths, and healthcare costs are projected to increase. The authors estimated that in 2011, the total healthcare cost associated with HCV was $6.5 billion (range, $4.3-$8.2 billion), and that the total cost is anticipated to peak in 2024 at $9.1 billion (range, $6.4-$13.3 billion). Most expenditures will be attributable to more advanced liver diseases—decompensated cirrhosis (46%), compensated cirrhosis (20%), and HCC (16%), and the costs associated with these HCV sequelae are expected to peak in the next decade at approximately $1.4 to $4.2 billion.

Conclusion

Chronic HCV infection is associated with substantial morbidity, mortality, and costs related to treatment. However, HCV infection is frequently underdiagnosed and untreated.70,71 Increased awareness of the disease and its consequences is needed among both clinicians and patients. As the next article of this supplement will further discuss, the approval of second-generation DAAs and emergence of highly effective and safer interferonfree HCV treatments have the potential to dramatically change the approach to HCV management. However, the costs for cure are considerably higher for these pioneering therapies. Both healthcare professionals and managed care professionals must stay knowledgeable of evolving data for HCV in order to make informed treatment decisions.Author affiliation: Pharmacy Department, Monmouth Medical Center, Long Branch, NJ (MS); Betty and Guy Beatty Center for Integrated Research, Liver and Obesity Research Center, Department of Medicine, Inova Health System, Falls Church, VA (ZMY).

Funding source: The activity is supported by educational grants from Bristol-Myers Squibb and Gilead Sciences Inc.

Author disclosure: Dr Younossi has disclosed serving as a consultant for AbbVie, Bristol-Myers Squibb, Enterome, GlaxoSmithKline, Gilead Sciences, Intercept, and Salix; he has also served as an advisory board member for Janssen, Salix, and Vertex. Dr Shah has no relevant commercial financial relationships or affiliations to disclose.

Authorship information: Concept and design (ZMY); analysis and interpretation of data (MS, ZMY); drafting of the manuscript (MS); and critical revision of the manuscript for important intellectual content (MS, ZMY).

Address correspondence to: monicashah23@gmail.com.References

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