Hepatitis C virus (HCV) infection is a major health burden and associated with substantial morbidity and mortality. However, the disease often remains underdiagnosed and untreated. The treatment of HCV infection has evolved dramatically with the introduction of novel, interferon-free therapies that are now able to achieve high cure rates. However, improved and more effective strategies for controlling the high costs of managing patients with HCV, especially in light of the shifting treatment paradigm, need to be developed. This article, the second in a series of 3 focused on hepatitis C, will discuss the diagnosis and management of HCV infection, including treatment recommendations from practice guidelines and emerging agents to treat HCV, and provide suggestions for incorporating these options into treatment algorithms.
Am J Manag Care. 2015;21:S86-S96As noted in article 1 of this 3-article supplement, infection with the hepatitis C virus (HCV) is highly prevalent and associated with increased morbidity and mortality, but unfortunately, the disease remains frequently underdiagnosed and undertreated.1-3 Studies suggest that 45% to 85% of approximately 3.9 million Americans infected with HCV are unaware of their infection, and only about 7% to 11% of those with HCV infection receive treatment.4,5 A lack of knowledge and awareness of HCV among healthcare providers and at-risk patients is likely to contribute to missed opportunities for early diagnosis and treatment, and subsequently, poor outcomes.6 Observational studies and surveillance data indicate that about one-third of anti-HCV antibody-positive patients had no documented follow- up HCV RNA testing.7,8 Recent therapeutic advances have demonstrated great potential to improve virologic response and liver-related outcomes associated with HCV, and so this article, the second in a series of 3 focused on HCV, will discuss the diagnosis and management of HCV infection, including treatment recommendations from practice guidelines and emerging agents to treat HCV, and provide suggestions for incorporating these options into treatment algorithms.9
Diagnosis of HCV Infection
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).9 Further, the Centers for Disease Control and Prevention (CDC) testing recommendations for HCV infection are outlined in Table 1.10
All persons recommended for HCV testing should first be tested for anti-HCV antibody using FDA-approved tests, which include laboratory-conducted assays and a point-of-care assay (ie, a rapid test for anti-HCV antibody).11 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 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 treatmentrelated viral clearance) because these individuals may be anti-HCV negative. Prior to HCV treatment initiation, quantitative RNA PCR testing is recommended to document the baseline level of viremia.
Testing for HCV genotype is useful in clinical management for predicting the likelihood of response, and for determining the optimal treatment regimen and duration of therapy.12 HCV can be classified into at least 6 major genotypes (genotypes 1 to 6). Each HCV genotype varies with respect to its nucleotide sequence, geographical distribution, and response to therapy.13 Genotype 1 (subtypes 1a and 1b) accounts for approximately 70% of cases in the United States, followed by genotypes 2 and 3.13,14 Although there is no difference in the risk of cirrhosis according to genotype, HCV genotype 1b is associated with a higher rate of hepatocellular carcinoma, and genotype 3 is associated with a higher rate of hepatic steatosis.15,16 In patients with genotype 3, hepatic steatosis is also more severe than in other genotypes, and its severity correlates with HCV replication in the serum and liver. Results of multivariable logistic regression performed on more than 3000 patients showed that steatosis was associated independently with HCV genotype 3 (OR, 4.24; P <.001).17 Recent data also show that HCV genotype 3 is associated with an increased rate of fibrosis progression with an odds ratio of 1.89 to progress more than 0.083 fibrosis units per year compared with non-3 genotypes.18 HCV genotypes 4 and 5 are predominant in the Middle East and Africa, where they account for more than 80% of HCV infections, and genotype 6 is mainly prevalent in Southeast Asia. Until the availability of newer HCV treatment regimens, genotype 1 has been considered the most difficult to treat, with a lower response (40%-50%) to interferon-based therapies than genotypes 2 and 3 (80%).19 Genotype 4 is poorly responsive (29%-55%) to interferon-based regimens.20,21
HCV Therapy: The Historical Perspective
For many years, the standard of care for HCV infection was a combination of peginterferon alfa plus ribavirin. In pivotal clinical trials, patients received peginterferon alfa-2b 180 mcg subcutaneously per week and weight-based daily ribavirin (1000 mg for <75 kg, 1200 mg for ≥75 kg), and these agents were administered for 48 weeks (HCV genotypes 1, 4, 5, and 6) or 24 weeks (HCV genotypes 2 and 3). Studies demonstrated that this drug regimen induced sustained virological response (SVR) rates of 34% to 52% in those with genotype 1 and 80% to 82% in those with genotype 2 and 3 infections.22-24 However, lower SVR rates, less than 30%, were seen among patients who have HCV genotype 1 infection and certain baseline characteristics, such as advanced fibrosis or human immunodeficiency virus (HIV) coinfection.25,26
Further, interferon-based treatment regimens have unfavorable adverse event (AE) profiles including depression and influenza-like symptoms, which have led to discontinuation rates of 7% to 14% in clinical studies.22,23 Serious AEs associated with ribavirin-based regimens include fatigue (60%-66%) and hemolytic anemia (10%- 13%).22,27 The need for improved outcomes in patients with HCV infection led to the development of specifically targeted antiviral therapy, or direct-acting antivirals (DAAs).
First-Generation DAAs: NS3/4A Protease Inhibitors
At the time of their introduction in 2011, the 2 NS3/4A protease inhibitors, boceprevir and telaprevir, shifted the standard of care for the treatment of chronic HCV infection to triple therapy with peginterferonribavirin and a protease inhibitor. Boceprevir and Telaprevir In clinical studies, the addition of boceprevir or telaprevir to a peginterferon-ribavirin regimen has been shown to increase the rates of SVR (40%-70%) in previously untreated adults with HCV genotype 1 infection.28,29 However, higher incidence of anemia has been observed among patients receiving boceprevir-containing regimens compared with peginterferon-ribavirin therapy (43% vs 20%; P <.001).30
Real-life setting data on telaprevir and boceprevirbased regimens suggest substantially lower SVR rates and high incidence of AEs. The French National Agency for Research on AIDS and Viral Hepatitis cohort 20 (ANRS CO20)—Compassionate Use of Protease Inhibitors in viral C Cirrhosis (CUPIC) study—evaluated the safety and efficacy of triple combination regimens, including telaprevir or boceprevir, in treatment-experienced cirrhotic patients in the reallife setting.31 A total of 660 patients were enrolled in 56 French centers, and 511 patients reached Week 60 of follow-up evaluation. Among 299 patients who received telaprevir, 74.2% of those who relapsed, 40% of partial responders, and 19.4% of null responders achieved SVR 12 weeks after end of treatment (SVR12) (P <.0001). In the boceprevir group (n = 212), 53.9% of those who relapsed, 38.3% of partial responders, and none of the null responders achieved SVR12 (P = .0004). During the follow-up evaluation period, a high incidence of serious AEs, including liver decompensation, was seen in 255 patients (49.9%), leading to early discontinuation of all drugs in 108 patients (21.1%). During the course of therapy, severe infections occurred in 10.4% of patients, and deaths in 2.2% of patients, mostly related to septicemia and pneumonia.
Of note, in the recent AASLD/IDSA guidance, telaprevir- or boceprevir-based regimens with or without peginterferon-ribavirin are not recommended for treatment-naïve patients or nonresponders, mainly due to relatively poor efficacy and tolerability, numerous drug interactions, and prolonged treatment duration.9 Marking a shift from traditional HCV therapies, the second- generation DAAs were introduced with the potential for improved pharmacokinetics, simplified once-daily dosing, and better tolerability.
Second-Generation DAAs: Simeprevir
Similarly to other HCV NS3/4A protease inhibitors, simeprevir acts by inhibiting the protease-mediated cleavage of several of the nonstructural proteins of HCV from the polypeptide encoded by the viral genome.32 The usual simeprevir dose is 150 mg orally once daily with food. The use of simeprevir has not been studied in patients with moderate to severe hepatic impairment or in individuals of East Asian ancestry.33 Simeprevir should be administered with sofosbuvir for 12 weeks for treatment-naïve or treatment-experienced patients without cirrhosis or for 24 weeks in those with cirrhosis.33 Like other DAAs, there are a number of potential drug interactions between simeprevir and other medication classes, including antiarrhythmics, anticonvulsants, antibiotics, antifungals, herbal products, and HIV medications, that should be considered prior to initiation of HCV therapy.33
The safety, efficacy, and tolerability of simeprevir in combination with interferon alfa and ribavirin in treatment-naïve patients with HCV genotype 1 infection was evaluated in a multicenter trial, conducted in Australia, Europe, North America, and New Zealand.34 In QUEST-1 (A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy, Safety and Tolerability of TMC435 vs Placebo as Part of a Treatment Regimen Including Peginterferon a-2a and Ribavirin in Treatment-naïve, Genotype 1 Hepatitis C-infected Subjects), 394 patients with HCV genotype 1 infection received simeprevir (150 mg once daily) plus peginterferon-alfa 2a plus weight-based ribavirin for 12 weeks, followed by peginterferon-alfa 2a plus ribavirin (simeprevir group), or placebo plus peginterferon-alfa 2a plus ribavirin for 12 weeks, followed by peginterferonalfa 2a plus ribavirin (placebo group). Treatment duration was 24 weeks or 48 weeks in the simeprevir group, according to criteria for response-guided therapy, and 48 weeks in the placebo group. The primary efficacy end point was SVR12 and was assessed with an intentto- treat analysis. Study results showed that SVR12 was higher in the simeprevir group (n = 264) than the placebo group (n = 130) (80% vs 50%), and the difference stratified by HCV genotype 1 and interleukin-28B (IL28B) genotype was significant (29.3%; 95% CI, 20.1-38.6; P <.0001). During the first 12 weeks, the most common AEs in the simeprevir and placebo groups were fatigue (40% vs 38%, respectively) and headache (31% vs 37%, respectively). The incidence of rash was similar in both groups (simeprevir 27%, placebo 25%).
Similar results were seen in another phase 3 study conducted in Europe and North and South Americas.35 In QUEST-2, the safety and efficacy of the combination of simeprevir versus placebo, plus peginterferon alfa 2a or 2b plus ribavirin in treatment-naïve patients with HCV genotype 1 infection were evaluated. The primary efficacy end point was the proportion of patients achieving SVR12, defined as HCV RNA concentration of less than 25 IU/mL undetectable at end of treatment and less than 25 IU/mL detectable or undetectable 12 weeks after end of treatment. In the simeprevir group, 81% (209/257) of patients and 50% (67/134) of patients in the placebo group achieved SVR12 (adjusted difference, 32.3%; 95% CI, 23.3- 41.2; P <.0001). The adjusted difference weighted by HCV subtype, IL28B genotype, and peginterferon type as stratification factors was 32.2% (95% CI, 23.3-41.2; P <.0001). NS3/4A protease inhibitor-based regimens pose several treatment challenges, including safety concerns, potential for drug interactions, and complex regimens with high pill burden, and a low genetic barrier to the development of resistance.36
NS5B Polymerase Inhibitor: Sofosbuvir
The availability of the NS5B polymerase inhibitor sofosbuvir shifted the treatment care of chronic HCV patients to allow for a simplified once-daily dosing schedule, improved pharmacokinetics, and fewer drug interactions. Sofosbuvir is a prodrug of a nucleotide analogue inhibitor of the HCV NS5B RNA-dependent polymerase, a key component in viral replication. Consistent with its mechanism of action and high genetic barrier to resistance, virologic breakthrough has not been observed during therapy with sofosbuvir.37 The usual sofosbuvir dose is 400 mg orally once daily.38 No dose adjustment of sofosbuvir is required for patients with mild to moderate renal impairment. There are no available sofosbuvir dose recommendations for patients with severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2) or end-stage renal disease. Sofosbuvir is a substrate of the drug transporter P-gp and breast cancer resistance protein. There are a number of potentially significant drug interactions with sofosbuvir and concomitant medications, including anticonvulsants, antimycobacterials, herbal products, and HIV protease inhibitors.38
The Combination of Simeprevir and Sofosbuvir in HCV-infected patients (COSMOS) study evaluated the safety and efficacy of simeprevir and sofosbuvir, with or without ribavirin, in patients with HCV genotype 1 infections who had previously not responded to or not received peginterferon-ribavirin therapy.39 In this openlabel US trial, 168 patients were randomized to receive 150 mg of simeprevir and 400 mg of sofosbuvir daily for 24 weeks with ribavirin (group 1), or without ribavirin (group 2), or for 12 weeks with (group 3) or without (group 4) ribavirin. There were 2 cohorts: previous nonresponders with Metavir scores F0 to F2 (cohort 1) and previous nonresponders and treatment-naïve patients with Metavir scores F3 to F4 (cohort 2). The primary end point was SVR 12 weeks after discontinuing treatment. SVR12 was achieved in 72 of 80 patients (90%; 95% CI, 81-96) in cohort 1, and 82 of 87 (94%; 95% CI, 87-98) in cohort 2. The pooled data from both cohorts showed that the most common AEs were fatigue (31%), headache (20%), and nausea (16%). Of note, on the basis of interim data from this study, the AASLD/IDSA guidance shifted to recommend sofosbuvir plus simeprevir once daily, with or without ribavirin, for patients with HCV genotype 1 infection who do not respond to peginterferon or ribavirin or who are treatment-naïve.40 In November 2014, the FDA approved sofosbuvir in combination with simeprevir as an all-oral, interferon- and ribavirin-free treatment option for HCV genotype 1 infection.
Two phase 3 studies evaluated the safety and efficacy of 12 weeks of therapy with sofosbuvir-containing regimens in previously untreated patients with HCV infection.37 The NEUTRINO (A Phase 3, Multicenter, Open-Label Study to Investigate the Efficacy and Safety of GS-7977 With Peginterferon Alfa 2a and Ribavirin for 12 Weeks in Treatment-Naive Subjects With Chronic Genotype 1, 4, 5, or 6 HCV Infection) trial was a single group, open-label study of sofosbuvir plus peginterferonribavirin in 327 patients with HCV genotype 1, 4, 5, or 6 (of whom 98% had genotype 1 or 4). All patients received sofosbuvir 400 mg once daily plus daily weight-based ribavirin (1000 mg for <75-kg patients and 1200 mg for ≥75- kg patients), and peginterferon-alfa 2a was administered subcutaneously once weekly at a dose of 180 mcg. In the FISSION (A Phase 3, Multicenter, Randomized, Active- Controlled Study to Investigate the Safety and Efficacy of PSI-7977 and Ribavirin for 12 Weeks Compared to Pegylated Interferon and Ribavirin for 24 Weeks in Treatment-Naïve Patients With Chronic Genotype 2 or 3 HCV Infection) study, 499 patients with HCV genotype 2 or 3 infection were randomly assigned to receive sofosbuvir plus ribavirin for 12 weeks or peginterferonalfa 2a plus ribavirin for 24 weeks. In both studies, the primary efficacy end point was SVR, defined as HCV RNA level below the lower limit of quantification, at 12 weeks after the end of treatment. In the NEUTRINO trial, 295 of the 327 patients (90%; 95% CI, 87-93) with HCV genotype 1, 4, 5, or 6 achieved the defined SVR 12 weeks after treatment, compared with an adjusted historical response rate of 60% (P <.001). SVR12 rates for patients with HCV genotype 1 was 89.4% (95% CI, 85.3-92.7) and 97.1% (95% CI, 85.1-99.9) for genotypes 4, 5, and 6.
In the FISSION study, SVR was achieved in 67.2% of patients in the sofosbuvir-ribavirin group and 66.7% in the peginterferon alfa 2a-ribavirin group (95% CI, —7.5 to 8.0). In patients with HCV genotype 2, SVR12 occurred in 97.1% of those in the sofosbuvir-ribavirin group, compared with 77.6% in the peginterferon-ribavirin group (95% CI, 8.4-31.5). In HCV genotype 3 patients, SVR12 was achieved in 55.7% of those in the sofosbuvir-ribavirin group, compared with 62.5% in the peginterferon-ribavirin group (95% CI, –17.1 to 3.5). Response rates in the sofosbuvir-ribavirin group were higher among patients with genotype 2 infection than those with genotype 3 (97.1% vs 55.7%, P <.001). The incidence of AEs was lower in the sofosbuvir-ribavirin group than the peginterferonribavirin group: fatigue (36% vs 55%), headache (25% vs 44%), nausea (18% vs 29%), and neutropenia (0% vs 12%).
Ledipasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication.41 In October 2014, ledipasvir-sofosbuvir, the first fixed-dose combination (FDC) agent was FDA approved for the treatment of chronic HCV genotype 1 infection.42 The single FDC tablet contains 90 mg of ledipasvir and 400 mg of sofosbuvir. The recommended dose is 1 tablet taken orally once daily with or without food. For treatment-naïve patients with or without cirrhosis and treatment-experienced patients without cirrhosis, the recommended therapy duration is 12 weeks; however, longer therapy duration of 24 weeks is recommended for treatment-experienced patients with cirrhosis.
The efficacy of ledipasvir-sofosbuvir was evaluated in 3 phase 3 trials: ION-1, ION-2, and ION-3. In the ION-1 (A Phase 3, Multicenter, Randomized, Open-Label Study to Investigate the Efficacy and Safety of Sofosbuvir/ GS-5885 Fixed-Dose Combination [FDC] +/- Ribavirin for 12 and 24 Weeks in Treatment-Naive Subjects With Chronic Genotype 1 HCV Infection) study, the efficacy and safety of ledipasvir-sofosbuvir FDC, with or without ribavirin, was evaluated in previously untreated patients (n = 865) with chronic HCV genotype 1 infection, including those with compensated cirrhosis (n = 136, 16% of total patients).43 The protocol specified that patients with cirrhosis could account for about 20% of the study population. In this study, conducted at 99 US and European sites, patients were randomly assigned to 1 of 4 treatment groups: ledipasvir-sofosbuvir (n = 214) for 12 weeks, ledipasvir-sofosbuvir plus ribavirin (n = 217) for 12 weeks, ledipasvir-sofosbuvir (n = 217) for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin (n = 217) for 24 weeks. The primary efficacy end point was SVR12. Overall, 67% of patients had HCV genotype 1a infection, and 12% were African American. In patients treated for 12 weeks, the SVR rates were 99% (95% CI, 96-100) in the ledipasvirsofosbuvir group and 97% (95% CI, 94-99) in the ledipasvir- sofosbuvir plus ribavirin group. In those treated for 24 weeks, the SVR rates were 98% (95% CI, 95-99) in the ledipasvir-sofosbuvir group and 99% (95% CI, 97-100) in the ledipasvir-sofosbuvir plus ribavirin group. The rates of SVR in all 4 treatment groups were superior to the historical rate of 60% (P <.001 for all comparisons). According to the intention-to-treat analysis, SVR in the 4 treatment groups was 94% to 100% in patients with cirrhosis, 97% to 99% in those with HCV genotype 1a infection, and 91% to 100% among African American patients. This study, however, was not designed or powered to formally evaluate rates of response among these subgroups.
The ION-2 (A Phase 3, Multicenter, Randomized, Open-Label Study to Investigate the Efficacy and Safety of Sofosbuvir/GS-5885 Fixed-Dose Combination +/- Ribavirin for 12 and 24 Weeks in Treatment-Experienced Subjects With Chronic Genotype 1 HCV Infection) study was conducted in 440 patients with HCV genotype 1 infection who did not achieve SVR following treatment with peginterferon-ribavirin, with or without a protease inhibitor.44 Overall, 52% of study patients had received prior treatment with a protease inhibitor (telaprevir, boceprevir, or other). A total of 20% of patients in each of the 4 treatment groups had cirrhosis. In this study, conducted at 64 US sites, patients were randomly assigned to 1 of 4 treatment groups: ledipasvir-sofosbuvir (n = 109) for 12 weeks, ledipasvir-sofosbuvir plus ribavirin (n = 111) for 12 weeks, ledipasvir-sofosbuvir (n = 109) for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin (n = 111) for 24 weeks. The primary efficacy end point was SVR12. The SVR12 was 94% (95% CI, 87-97) with 12 weeks of ledipasvir-sofosbuvir, 96% (95% CI, 91-99) with 12 weeks of ledipasvir-sofosbuvir plus ribavirin, 99% (95% CI, 95-100) with 24 weeks of ledipasvir-sofosbuvir, and 99% (95% CI, 95-100) with 24 weeks of ledipasvirsofosbuvir plus ribavirin. The rates of SVR in all 4 treatment groups were superior to the adjusted historical rate of 25% (P <.001 for all comparisons). Among patients with cirrhosis who received 12 weeks of treatment, the SVR rates were 86% in the ledipasvir-sofosbuvir group and 82% in the ledipasvir-sofosbuvir plus group. The SVR rates among patients without cirrhosis were 95% and 100%, respectively. In the 24-week treatment group, the SVR rates were similar in patients with cirrhosis (100% in both regimens) and those without cirrhosis (99% in both regimens). However, the study was not powered for intergroup comparisons.
In ION-3 (A Phase 3, Multicenter, Randomized, Open-Label Study to Investigate the Efficacy and Safety of Sofosbuvir/Ledipasvir Fixed-Dose Combination +/- Ribavirin for 8 Weeks and Sofosbuvir/Ledipasvir Fixed Dose Combination for 12 Weeks in Treatment-Naïve Subjects With Chronic Genotype 1 HCV Infection) study, 647 previously untreated patients with HCV genotype 1 infection without cirrhosis were evaluated.45 The SVR12 was 94% (95% CI, 90-97) with 8 weeks of ledipasvir-sofosbuvir, 93% (95% CI, 89-96) with 8 weeks of ledipasvir-sofosbuvir plus ribavirin, and 95% (95% CI, 92-98) with 12 weeks of ledipasvir-sofosbuvir. In all 3 treatment groups, the SVR rates were superior to the adjusted historical control rate of 60% (P <.001 for all comparisons). None of the patients who had received 8 weeks of only ledipasvir-sofosbuvir discontinued treatment because of AEs.
In clinical trials, the most common AEs seen with ledipasvir- sofosbuvir were fatigue (~20%), headache (~15%), insomnia (~5%), and nausea (~7%).43-45 Patients who received ledipasvir-sofosbuvir plus ribavirin had higher rates of events known to be associated with ribavirin, including fatigue (~35%), insomnia (~21%), rash (~10%), pruritus (~10%), and anemia (~10%).43 Notable drug interactions associated with ledipasvir-sofosbuvir include P-gp inducers (ie, rifampin or St. John’s wort), which may decrease ledipasvir and sofosbuvir plasma concentrations; therefore, concomitant use of these agents is not recommended.42
Ombitasvir, Paritaprevir, and Ritonavir Plus Dasabuvir
In December 2014, the FDA approved ombitasvir, paritaprevir, and ritonavir FDC tablets copackaged with dasabuvir tablets for the treatment of patients with HCV genotype 1 infection, including those with compensated cirrhosis. The combination product may be used with or without ribavirin. The FDC 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.9
The PEARL-1 (A Randomized, Open-Label Study to Evaluate the Safety and Efficacy of Coadministration of ABT-450 With Ritonavir [ABT-450/r] and ABT-267 in Adults With Chronic Hepatitis C Virus Infection) study evaluated the safety and efficacy of an oral, interferonfree regimen of ombitasvir and ABT-450 plus ritonavir (ABT-450/r) with or without ribavirin in treatmentnaïve and peginterferon/ribavirin-experienced noncirrhotic patients with HCV genotype 4 infection.46 Patients received once-daily ombitasvir 25 mg and ABT-450/r 150/100 mg, with or without weight-based twice-daily ribavirin. In treatment-naïve patients, a SVR12 rate of 90.9% was seen in the ombitasvir and ABT-450/r group (n = 44) and 100% in the ombitasvir and ABT-450/r plus ribavirin group (n = 42). In treatment-experienced patients, a SVR12 rate of 100% was seen in ombitasvir and ABT-450/r plus ribavirin group (n = 41). Most commonly reported AEs (in any group) were headache (27%- 33%), asthenia (24%-33%), fatigue (7%-18%), and nausea (9%-17%).
The efficacy of a combination regimen of 3 directacting antiviral (3D) agents (ombitasvir, ABT-450/r, and dasabuvir) with or without ribavirin was assessed in HCV genotype 1b-infected patients, who were null responders to previous peginterferon-ribavirin.47 Patients (n = 209) received the coformulated ombitasvir/ABT-450/r (25 mg/150 mg/100 mg once daily) and dasabuvir 250 mg twice daily, with or without ribavirin. SVR12 was achieved in 95.7% of all patients, and similar SVR12 rates were seen in genotype 1a and 1b null responders (95.4% and 95.9%, respectively). All 32 genotype 1b—infected patients who received 3D without ribavirin achieved SVR12. The most common AEs (occurring in ≥10% of patients) included headache, fatigue, nausea, and asthenia.
The efficacy of ombitasvir-ABT-450/r, dasabuvir, and ribavirin was evaluated in 380 HCV genotype 1b— infected patients with compensated cirrhosis in an openlabel study.48 Among patients (n = 208) who received treatment for 12 weeks, 91.8% (97.5% CI, 87.6-96.1) had an SVR at post treatment Week 12. Among patients (n = 172) who were treated for 24 weeks, 95.9% (97.5% CI, 92.6-99.3) had an SVR at post treatment Week 12. The difference in SVR rates between the 2 groups was not significant (P = .09). In both treatment groups, the primary efficacy end points met the prespecified criteria for noninferiority and superiority to the historical rate with telaprevir plus peginterferon-ribavirin in those with HCV genotype 1 infection and cirrhosis.
Evidence-Based Treatment Guidelines
The treatment goals for HCV-infected persons are to reduce all-cause mortality and liver-related complications, including end-stage liver disease and hepatocellular carcinoma, by achieving SVR (virologic cure). The AASLD/IDSA guidelines provide initial therapy regimens for treatment-naïve patients or those who have failed previous treatment, including prior peginterferonalfa/ ribavirin therapy.9
Current treatment recommendations for treatmentnaïve patients with HCV infection are listed by HCV genotype in Table 2.9 Recommendations for retreatment of persons who have failed prior therapy are summarized in Table 3.9 In clinical practice, the preferred therapy for treatment-naïve patients with HCV genotype 1 infection appears to be 12 weeks of ledipasvir/ sofosbuvir.
Emerging Therapies for HCV Infection
Several HCV agents are currently in development, including GS-5816 (a pan-genotypic NS5A protein inhibitor). A phase 2 study evaluated the efficacy of sofosbuvir plus GS-5816, with or without ribavirin, for 8 weeks in 377 treatment-naïve, noncirrhotic patients with HCV genotypes 1 to 6.49 In Part A of the study, patients were randomized to sofosbuvir plus GS-5816 (25 mg) or sofosbuvir plus GS-5816 (100 mg) for 12 weeks. In Part B, genotype 1 and 2 HCV-infected patients were randomized to sofosbuvir plus GS-5816 (25 mg), sofosbuvir plus GS-5816 (25 mg) with ribavirin, sofosbuvir plus GS-5816 (100 mg), or sofosbuvir plus GS-5816 (100 mg) with ribavirin for 8 weeks. SVR rates of 77% to 90% were seen with 8 weeks of treatment, and 91% to 100% with 12 weeks of treatment. Ribavirin did not appear to enhance SVR rates. SVR12 was achieved in 100% of genotype 1- and 2-infected patients who received sofosbuvir plus GS-5816 (100 mg) for 12 weeks.
Impact of New HCV Treatment Regimens on Patient- Reported Outcomes
Evidence suggests that sustained responders to antiviral therapy for HCV infection have improved quality of life and productivity compared with those who do not respond to treatment.50 Interferon-related AEs have been associated with a substantial negative impact on health-related quality of life and other patient-reported outcomes (PROs).50,51 The approval of new HCV therapies, including interferon-free regimens, has not only led to improved efficacy, but also has provided patients with a more tolerable treatment option. A recent study assessed the association of cirrhosis and PROs in patients treated with sofosbuvir-containing regimens.52 In this study, HCV patients with cirrhosis showed an impairment of PROs before initiation of therapy. During treatment, patients with cirrhosis treated with interferonfree regimens showed a moderate decline in their PRO scores (0.6%-5.2% on a normalized scale of the summary scores; P >.02 for all).52 However, patients with cirrhosis treated with interferon-containing regimens experienced a decline in PRO scores that ranged from 3.4% to 16% (P <.005 for all). Another study evaluated PROs in 1431 treatment-naïve HCV patients treated with ledipasvirsofosbuvir, with or without ribavirin.53 Throughout treatment, PRO scores related to fatigue, activity, and work productivity were superior for ribavirin-free regimens (by up to 13.1%; P ≤5 to P <.0001). During therapy with ribavirin-containing regimens, significant decreases in PROs were seen from baseline scores (up to —8.1%; P <.0001), while PROs for ribavirin-free regimens improved (up to +6.1%; P <.0001).
The treatment of HCV infection has evolved dramatically in recent years with the introduction of pivotal novel therapies that are now able to achieve cure rates, defined by SVR, that are higher than 95%. However, there has been substantial focus on the economic burden associated with the high costs of these new HCV medications. Some leaders of retail pharmacies and pharmacy benefits management companies suggest that new drug approvals may create market competition and help restrain prices.54 However, it will likely involve narrower formularies in which physician choice of a particular therapy is limited by the contracts negotiated by insurers and pharmacy benefits managers. Improved and effective strategies for controlling the high costs of managing patients with HCV, especially in light of the shifting treatment paradigm, need to be developed. Table 4 provides a list of resources to help professionals stay abreast of new developments in the management of hepatitis C. Both managed care professionals and healthcare professionals must stay abreast of emerging data for HCV therapies in light of the weighty implications for therapeutic and formulary contracting 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).
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