Aug 1, 2011 Formulary |
Abstract
Hepatitis C is an infection of the liver that may lead to cirrhosis and hepatocellular carcinoma and ultimately result in end-stage liver disease and death. The treatment for hepatitis C infection for the past decade included only interferon or pegylated interferon with or without ribavirin. These medications demonstrate moderate effectiveness in eradicating the hepatitis C virus (HCV) and are not free of adverse effects, which may require treatment discontinuation. Several new agents for the treatment of hepatitis C have been approved that have demonstrated higher cure rates for those patients with hepatitis C genotype 1 disease. This article reviews the current pharmacologic agents for the treatment of chronic hepatitis C with a focus on the newly approved HCV protease inhibitor agents boceprevir and telaprevir. (Formulary. 2011;46:314–338.)
Hepatitis C is an infection primarily transmitted via contaminated blood with the hepatitis C virus (HCV). The most common risk factors for HCV include injection drug use and blood transfusion, although the latter is less likely to be the cause today because routine screening of the blood supply from donors with multiantigen testing was implemented in 1992.1 Other risk factors associated with HCV and those who should be screened for the infection are listed in Table 1.1,2
According to the World Health Organization (WHO), this single-stranded RNA blood-borne virus has infected approximately 3% of the world's population.2 It is estimated that 3.2 million persons in the United States have chronic HCV infection, while acute HCV infection goes largely unreported.3 Despite the reported prevalence and incidence of HCV, these numbers may be underestimating the true burden of hepatitis C disease.4 In fact, WHO has estimated that 170 million persons have chronic HCV worldwide, defining a group that is sufficiently large enough for the disease to persist.2 Further, this slowly progressing disease may take several decades before it results in cirrhosis. Up to 25% of patients with cirrhosis secondary to HCV will develop hepatic failure, making it the leading and primary indication for liver transplantation.2,5
Diagnosing hepatitis C may be difficult because 60% to 70% of patients present with minimal to no complaints or symptoms affecting quality of life.1 If symptoms are present, they may include flu-like symptoms, fatigue, abdominal pain, nausea, vomiting, decrease or loss of appetite, weight loss, or arthralgias. Patients with risk factors should be screened for anti-HCV, the specific antibody to the hepatitis C virus (Table 1).1,2,5,6 Having a positive anti-HCV does not confirm chronic hepatitis C infection. Individuals should be referred for further medical evaluation to determine if they are chronically infected with HCV by testing for HCV-RNA levels.5 A positive anti-HCV and elevated HCV-RNA level indicate chronic hepatitis C infection.
Table 1 Risk factors for hepatitis C infection
Genotyping is extremely useful in predicting the likelihood of therapeutic response and dictates the duration of therapy.5,6 Eleven genotypes numbered 1 to 11 with several subtypes labeled as genotype 1a, 1b, 2a, 3b, etc., are unique to hepatitis C.2 The most common genotype in the United States is genotype 1, followed by genotype 2 and genotype 3. Individuals with HCV genotype 1 disease are less likely to respond to standard-of-care HCV medications. These include pegylated interferon (PegIFN) with or without ribavirin.2,5,6 With the newly approved agents for the treatment of hepatitis C genotype 1 disease, however, therapeutic efficacy is much more significant when used as a triple combination regimen with PegIFN and ribavirin.7,8
THERAPEUTIC OUTCOMES AND DEFINITIONS
Treatment outcomes for hepatitis C include preventing the spread of the disease; treating symptoms; preventing the development of cirrhosis, hepatocellular carcinoma, and end-stage liver disease; and decreasing morbidity and preventing mortality. Additionally, the primary goals of therapy are to normalize hepatic aminotransferases and improve histology, and ultimately to suppress and have undetectable viral replication by sustained virologic response (SVR) 24 weeks following treatment discontinuation.5,6
Several other virologic responses have been defined in the era of the newly approved agents for the treatment of hepatitis C. These important time points during the course of therapy determine whether treatment should be continued or discontinued. At week 4 of therapy, an HCV RNA level demonstrating a sensitivity of less than 50 IU/mL should be obtained to determine if the patient achieved a rapid virologic response (RVR). If RVR is achieved by week 4, the chance of SVR is approximately 90%. This time point may be used to predict the likelihood to attain an excellent treatment response.5,9 HCV-RNA levels at week 4 also may be used in response-guided therapy (RGT), when the duration of HCV therapy is adjusted based on the HCV-RNA level at weeks 4 and 12. Using the RGT approach to treat patients infected with HCV may prevent drug resistance with the new hepatitis C agents. This individualized treatment approach also may be used to identify patients who may be treated with a short or prolonged duration of therapy and to either minimize adverse effects or maximize the treatment response. Patients who do not achieve RVR, however, may still achieve SVR.
The clinician should not consider discontinuing the treatment based on RVR results.10 For patients who do not achieve RVR, HCV treatment may be continued and an early virologic response (EVR) assessed at week 12. This may result in either a complete EVR (cEVR) or a partial EVR (pEVR).10 Achieving cEVR indicates that the 12-week HCV-RNA level is undetectable. Achieving pEVR indicates that although there has been a 2 log10 IU/mL drop or more, HCV-RNA levels are still detectable after 12 weeks of therapy. Patients who continue to have detectable HCV-RNA levels during the course of therapy are considered nonresponders. Nonresponders may be characterized as having a null response, defined as HCV-RNA levels not decreasing more than 1 log10 IU/mL after 4 weeks of therapy when compared to baseline, or as having a partial response, defined as HCV-RNA levels with a greater than 2 log10 IU/mL drop but never becoming undetectable at the end of therapy. They may also be a relapser, defined as undetectable HCV-RNA levels throughout duration of therapy and at the end of treatment (EOT; also known as end-of-treatment response, ETR), but then HCV-RNA levels become detectable on ceasing therapy. It is important to identify the type of patient nonresponse because those who relapse are more likely to have a greater chance of SVR with the new hepatitis C agents than null responders.8 The various definitions of virologic response to hepatitis C treatment are summarized in Table 2.5,9-11
STANDARD OF CARE: DRUGS USED IN THE PAST
The first agents approved for the treatment of chronic hepatitis C were interferon alfa-2b (IFN α-2b) in 1991, interferon alfa-2a (IFN α-2a) in 1996, and interferon alfacon-1 in 1997. At the first National Institutes of Health (NIH) Consensus Development Conference in 1997, the meeting focused on the management of hepatitis C. The general approach to treating patients infected with HCV was to administer IFN 3 times weekly for 24 to 48 weeks. SVR rates ranged between 5% and 9% for genotype 1 and approximately 30% for genotype 2 and genotype 3.6 A significant treatment breakthrough occurred in 1998 when ribavirin, a synthetic guanosine analogue, was approved and combined with IFN. SVR was observed in about 30% for genotype 1 and 60% for genotype 2 and genotype 3 when both drugs were administered concurrently.12 Notably ribavirin is only effective in reducing and normalizing serum alanine aminotransferase concentrations and has no effect on HCV-RNA levels when given without IFN.13,14
Additional research further revolutionized the treatment of hepatitis C when the concept of pegylation was introduced.15 Pegylated interferon (PegIFN) is IFN that is covalently attached to an inert water-soluble molecule, polyethelene glycol, which prolongs the IFN half-life. IFN has a half-life of only a few hours, whereas the half-life with PegIFN is several days, allowing for once-weekly dosing and improved pharmacokinetic profiles.15 FDA-approved PegIFNs include PegIFN alfa-2b in 2001 and PegIFN alfa-2a in 2002. The SVR rate with either formulation when given as monotherapy ranges between 25% and 40% for 48 weeks of treatment, rates similar to combination therapy with unmodified IFN and ribavirin. Several trials of ribavirin with PegIFN have demonstrated significant increases in genotype nonspecific SVR of approximately 55%.5,6,16 When results were stratified according to genotype, SVR was about 40% to 50% in patients with genotype 1 and 75% to 85% in patients with genotype 2 or genotype 3.5,6 Therefore, obtaining a genotype prior to initiating treatment is important as it can dictate the duration of therapy and predict the likelihood of SVR.
Comparative efficacy of the Peg-IFN agents has been investigated in both prospective and retrospective randomized and non-randomized trials.17-20 The largest of these was the IDEAL trial (Individualized Dosing Efficacy vs Flat Dosing to Assess Optimal Pegylated Interferon Therapy), which screened 4,469 genotype 1 patients from 118 sites.17 Subjects were randomized to 1 of 3 treatment arms: PegIFN alfa-2a 180 µg weekly plus ribavirin 1,000 mg to 1,200 mg daily; a standard dose of PegIFN alfa-2b 1.5 µg/kg weekly combined with weight-based ribavirin 800 mg to 1,400 mg daily; and a low dose of PegIFN alfa-2b 1 µg/kg weekly combined with weight-based ribavirin 800 mg to 1,400 mg daily. The ribavirin dose was based on approved prescribing information per package insert specific to the PegIFN product. The trial included 3,070 genotype 1 naïve patients who were treated for 48 weeks if they had achieved EVR or undetectable HCV-RNA levels by week 24 with a primary end point of SVR. The SVR rates were similar among treatment arms, at 40.9%, 39.8%, and 38%, respectively.17 The relapse rate was higher in the PegIFN alfa-2a arm, at 31.5%, versus 23.5% and 20%, respectively, in the others.
The IDEAL trial ironically has some flaws. It was not blinded, which allowed bias to play a role in the results, but more importantly the initial ribavirin dose and dosage reductions schedule between the PegIFN agents were different. Guidelines were subsequently developed by the second NIH Consensus Development Conference in 2002, in conjunction with the American Association for the Study of Liver Diseases and the American Gastroenterology Association. These guidelines recommend the combination of PegIFN and ribavirin, in the absence of contraindications, as standard of care for the treatment of hepatitis C.5,6,16
Relapsers or nonresponders to PegIFN and ribavirin.
In the past, treatment options for patients with HCV genotype 1 disease who relapsed or had not attained a virologic response were limited. Several treatment strategies have been evaluated including: retreatment using the other PegIFN agent, treating with a prolonged duration of therapy up to 72 weeks, increased PegIFN and/or ribavirin doses, and utilizing adjunctive agents in cases of dosage reductions or adverse effects to maintain full doses of HCV medications throughout retreatment.21-23 In an international multicenter trial patients who were nonresponders to PegIFN alfa-2b were retreated.21 Subjects were enrolled into 1 of 4 treatment arms: high-dose PegIFN alfa-2a 360 µg weekly for 12 weeks, followed by 180 µg weekly for a total of 72 weeks; high-dose PegIFN alfa-2a 360 µg weekly for 12 weeks, followed by 180 µg weekly for a total of 48 weeks; standard-dose PegIFN alfa-2a 180 µg weekly for 72 weeks; and standard-dose PegIFN alfa-2a 180 µg weekly for 48 weeks.21 All subjects received ribavirin at a dose of 1,000 mg if they weighed less than 75 kg and 1,200 mg if they weighed 75 kg or more.
The study included 950 patients who were randomly assigned into 1 of the study arms and allowed adjunctive agents for laboratory abnormalities with the primary end point being SVR. SVR rates were low, yet prolonging treatment duration to 72 weeks increased SVR rates compared to those at 48 weeks of therapy (16%, 7%, 14%, and 9%, respectively).21 In another prospective, international, open-label trial, PegIFN alfa-2b at a dose of 1.5 µg/kg weekly with weight-based ribavirin dosing, per package insert, was evaluated for 48 weeks.23 A total of 2,312 subjects labeled as nonresponders or relapsers were enrolled. The overall SVR rate was 22%. Relapsers were more likely to demonstrate SVR than nonresponders who were previously treated with PegIFN, at 33% vs 6%, respectively. Subjects who were initially treated with unmodified IFN had a more favorable overall chance of SVR than those who were treated with PegIFN, at 25% vs 17%, respectively. This trial reconfirmed along with others that low HCV-RNA levels, non-black race, favorable genotype, minimal fibrosis, and achieving EVR are predictive factors for the likelihood of attaining SVR.5,6,21,23-25 In addition to these factors, higher ribavirin doses greater than 13 mg/kg daily have been shown to increase RVR and SVR rates in patients with HCV genotype 1.26,27
Adverse effects.
Various side effects have been associated with PegIFN and ribavirin. The rate of discontinuing therapy due to an adverse event ranged from 10% to 14% in the registration trials.5 Dose modifications as a result of side effects ranged from 20% to 30%.25 The most common side effect is mild-to-severe flu-like symptoms. These usually occur about 6 to 8 hours after the first dose of PegIFN has been administered. Symptoms may be minimized by administering antipyretics such as acetaminophen or nonsteroidal anti-inflammatory agents prior to the injection. With each additional weekly PegIFN dose, the flu-like symptoms eventually dissipate due to a tachyphylaxis reaction and are rarely the cause of treatment discontinuation.28,29
Neuropsychiatric adverse effects are frequently experienced during the course of therapy in patients with or without a history of psychiatric disorders. Incidence ranges between 20% and 60%.28,29 Patients may develop depression, irritability, anxiousness, and in severe cases, suicidal ideation. Selective serotonin reuptake inhibitors, mood stabilizers, or anxiolytics are often used as adjunctive therapy to manage these psychiatric conditions.25,28-30
Approximately 20% of patients experience hematologic abnormalities while on HCV therapy.6 PegIFN induces neutropenia and thrombocytopenia, whereas a mixed and more pronounced hemolytic anemia is a direct result of ribavirin. These laboratory changes may be significant enough to warrant dosage adjustment and even discontinuing therapy. This practice is discouraged because the response to viral clearance and SVR may decrease significantly. Adjunctive therapies including erythropoietin for anemia and granulocyte colony-stimulating factor (G-CSF) for neutropenia, although somewhat controversial, are commonly used in clinical practice to manage these hematologic adverse effects.28,29 Table 3 provides a summary of adverse effects associated with PegIFN and ribavirin.5,28,29
STANDARD OF CARE: DRUGS USED IN THE FUTURE
Treatment results for hepatitis C genotype 1 disease with PegIFN and ribavirin are suboptimal. In the last several decades, significant research has allowed many patients, about 50% with genotype 1 and about 80% with genotype 2 or genotype 3, to be virologically cured by attaining SVR.6 The remaining nonresponders to the standard-of-care regimen are left with no other treatment option to cure their infection. If treatment is considered, it is recommended that a hepatitis C genotype be secured prior to initiating therapy. With continued efforts to gain more knowledge of the HCV life cycle and its viral structure, the first generation of drugs known as specifically targeted antiviral therapy for hepatitis C (STAT-C) or direct-acting antivirals (DAAs) have emerged to improve SVR cure rates and reduce the treatment duration of therapy. FDA-approved DAA drugs for HCV genotype 1 disease are the protease inhibitors boceprevir and telaprevir.
Boceprevir.
Boceprevir is a linear peptidomimetic ketoamide serine NS3/4A protease inhibitor that inhibits viral HCV replication.31 This oral drug, approved by FDA on May 13, 2011, is indicated for HCV genotype 1 infection in the adult patient with compensated liver disease (including cirrhosis), naïve patients, or previously treated patients who failed IFN/PegIFN and ribavirin therapy. Boceprevir is not recommended as monotherapy because there is a high likelihood that drug-resistant mutations may develop. Thus, it must be utilized with PegIFN and ribavirin.31,32
The efficacy of boceprevir triple therapy was investigated in untreated HCV patients in the SPRINT-2 (Serine Protease Inhibitor Therapy 2) trial.31 Those who were previously treated and had no response or relapsed were evaluated in the RESPOND-2 (Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2) trial.33 In these phase 3, open-label trials, patients were treated with boceprevir 800 mg 3 times daily, PegIFN alfa 2b 1.5 µg/kg weekly, and weight-based ribavirin 600 mg to 1,400 mg in 2 divided doses daily.
All patients naïve to HCV therapy in the SPRINT-2 study received a 4-week lead-in treatment period of PegIFN and ribavirin and were randomly assigned into 1 of 3 study arms. Group 1 was the placebo arm in which subjects received PegIFN/ribavirin from weeks 5 to 48, as well as placebo 3 times daily beginning at week 5. Group 2 was the RGT arm in which subjects received boceprevir/PegIFN/ribavirin from weeks 5 to 28. If HCV RNA was undetectable at weeks 8 to 24, therapy was stopped at week 28. If the HCV-RNA level was detectable from weeks 8 to 23, PegIFN/ribavirin was administered from weeks 28 to 48. Group 3 was the triple arm in which subjects received boceprevir/PegIFN/ribavirin from weeks 5 to 48.31 A lead-in phase with PegIFN and ribavirin for 4 weeks before boceprevir was added to the treatment regimen because in the phase 2 SPRINT-1 trial subjects were less likely to develop viral resistance and viral breakthrough when compared to subjects who did not receive the lead-in phase.34
SVR rates were higher in the boceprevir arms and in subjects who were non-blacks in groups 1, 2, and 3 when compared to the black cohort: 40%, 67%, 68% vs 23%, 42%, and 53%, respectively.31 All treatment cohorts achieving RVR by week 4 had higher overall SVR rates, at 97%, 89%, and 90%, respectively. In a subgroup analysis, subjects with hemoglobin levels lower than 10 g/dL had higher SVR rates than those who had hemoglobin levels above this threshold, ie, 60%, 72%, and 79% vs 33%, 64%, and 59%, respectively.31 Of note, in the SPRINT-1 trial, subjects receiving low-dose ribavirin 400 mg to 1,000 mg daily had a lower SVR rate than those receiving ribavirin 800 mg to 1,400 mg daily.34
Patients who had previously been treated with PegIFN and ribavirin and who did not achieve SVR were eligible for the phase 3 RESPOND-2 trial.33 The study design included a lead-in phase with PegIFN and ribavirin for 4 weeks with identical treatment arms as in the SPRINT-2 trial for group 1 and group 3. For the RGT group 2, however, boceprevir/PegIFN/ribavirin was given from weeks 5 to 36 and treatment stopped at week 36 if HCV-RNA levels were undetectable at weeks 8 and 12. If HCV RNA was detectable at week 8 and undetectable at week 12, PegIFN/ribavirin was administered from weeks 37 to 48. A futility rule defined as having detectable HCV-RNA level at week 12 would result in discontinuing all study medications.
A total of 403 patients with HCV genotype 1 disease were enrolled into group 1, 2, or 3 and were analyzed based on the subjects' response to previous therapy (relapser vs nonresponder).33 The overall SVR rates were significantly higher in the boceprevir arms, at 59% in group 2 and 66% in group 3, than in the placebo arm, at 21% in group 1 (P<.001). Relapsers were more likely to demonstrate higher SVR than those who were nonresponders, at 29%, 69%, and 75% vs 7%, 40%, and 52%, respectively. In this trial, subjects who achieved RVR, had no cirrhosis, and had a low baseline viral load of 800,000 IU/mL or less were strong predictors of SVR.33
Resistance-associated amino acid variants (RAVs) were observed in the SPRINT-2 and RESPOND-2 trials. The frequency of RAVs in non-SVR patients in these trials was greater in those with genotype 1a, at 55%, compared to those with genotype 1b, at 47%. The most common resistant variants associated with genotype 1a included V36M and R155K, whereas RAVs associated with genotype 1b included T54A, T54S, V170A, and A156S.35
Overall, more adverse effects were experienced in the boceprevir treatment arms. The most common adverse effects included anemia and dysgeusia (taste alterations). Anemia was reported in 49% of those in the boceprevir treatment arms and 29% of those in the placebo arm in the SPRINT-2 trial.31 Similar results were observed in the RESPOND-2 trial where the incidence of anemia was approximately 45% in the boceprevir groups and 20% for those who received placebo.33 In the boceprevir trials, dosage reductions and discontinued therapy rates were higher in the boceprevir arms than in those receiving only PegIFN and ribavirin. Additionally, the use of erythropoietin was approximately 41% to 46% in those treated with boceprevir compared with 21% to 24% in controls.31,33 Serious and life-threatening infections were reported and documented in the SPRINT-2 and RESPOND-2 trials. Grade 3 neutropenia (absolute neutrophil count [ANC] 0.5 x 109 /L - <0.75 x 109 /L) was observed more often in the boceprevir treatment groups at approximately 23% when compared to 13% in the control groups.31,33 Grade 4 neutropenia (ANC <0.5 x 109 /L) occurred in 7% of subjects receiving triple therapy and 4% with standard of care. Three patients treated with boceprevir/PegIFN/ribavirin developed severe, life-threatening infections. Complete blood counts with differential must be obtained at baseline and at a minimum of every 4 weeks or more frequently as clinically necessary to monitor for anemia and neutropenia. Dysgeusia was reported more commonly in the groups receiving boceprevir than in controls.31,33 Dermatologic symptoms including rash and dry skin were experienced more often with boceprevir than placebo in the RESPOND-2 trial.33
Telaprevir.
Telaprevir is an orally administered reversible, selective, peptidomimetic NS3/4A serine protease inhibitor. This drug, approved by FDA on May 23, 2011, is indicated for HCV genotype 1 disease in adult patients with compensated liver disease (including cirrhosis), who are treatment-naïve or who have been previously treated with IFN-based treatment and are null responders, partial responders, or relapsers. Telaprevir is not recommended as monotherapy because of the high likelihood that drug-resistant mutations may develop. Thus it must be combined with PegIFN and ribavirin.32 Telaprevir has been evaluated in phase 3 trials in treatment-naïve patients (ADVANCE and ILLUMINATE) and treatment-experienced patients who failed PegIFN and ribavirin (REALIZE).36-38 In all 3 studies, patients received telaprevir 750 mg every 8 hours combined with PegIFN alfa-2a 180 µg weekly with ribavirin 1,000 mg to 1,200 mg in 2 divided daily doses in a variety of dosing regimens.36-38
In the ADVANCE international, randomized trial, 3 treatment arms were assessed for efficacy and safety with RGT in treatment-naïve patients.36 In arm 1 telaprevir/PegIFN/ribavirin was administered for 8 weeks, and in arm 2 telaprevir/PegIFN/ribavirin was administered for 12 weeks. In both telaprevir arms, if extended (e)RVR was achieved, that is, undetectable HCV RNA at weeks 4 and 12, PegIFN/ribavirin would be administered up to 24 weeks. If eRVR was not attained, PegIFN/ribavirin would be administered up to 48 weeks. The 2 cohorts were compared with arm 3, the control group, which received placebo/PegIFN/ribavirin for 48 weeks. A total of 1,088 patients were assigned to 1 of the treatment arms. The overall SVR rate was significantly higher among those receiving telaprevir for 8 weeks, at 69%, or 12 weeks, at 75%, vs 44% in the placebo group (P<.001). Additionally, all study arms achieving eRVR were more likely to attain SVR, at 83%, 89%, and 97%, respectively, than those who did not attain eRVR, at 50%, 54%, and 39%, respectively.36
Telaprevir 750 mg every 8 hours for 12 weeks was evaluated in an open-label study in the ILLUMINATE trial to assess 24 vs 48 weeks of total therapy for subjects with HCV genotype 1 disease who achieved eRVR.37 If HCV-RNA levels were undetectable at week 4 and 12, at week 20 subjects were randomly assigned to continue with PegIFN/ribavirin for an additional 24 weeks or 48 weeks. If eRVR was not attained, Peg-IFN/ribavirin would be administered up to 48 weeks. All patients who did not have a less than 2 log10 IU/mL drop from baseline at week 12 or detectable HCV-RNA levels at week 24 discontinued all drug therapies. Of the 540 subjects enrolled, 389 (72%) had undetectable HCV-RNA levels at week 4 and achieved RVR and 352 (65%) attained eRVR with an overall SVR rate of 72%. Subjects who were eRVR positive and were randomly assigned to the 24-week cohort had a 92% SVR rate compared to 88% for those who received 48 weeks of a telaprevir-based regimen.37
Patients with HCV genotype 1 disease treated with PegIFN and ribavirin who did not achieve SVR were enrolled into the REALIZE trial.38 This study included relapsers with HCV RNA undetectable during treatment and EOT that became detectable once therapy was stopped; nonresponders categorized as partial responders, with HCV-RNA levels decreased by 2 log10 IU/mL but that failed to reach undetectable levels by week 24; and null responders, with HCV RNA levels that failed to decrease by 2 log10 IU/mL by week 12 of therapy. The 3 study arms included the no lead-in phase of telaprevir/PegIFN/ribavirin for 12 weeks followed by PegIFN/ribavirin for 36 weeks; a lead-in phase with PegIFN/ribavirin for 4 weeks then telaprevir/PegIFN/ribavirin for 12 weeks followed by PegIFN/ribavirin for 32 weeks; and control with placebo/PegIFN/ribavirin for 12 weeks followed by PegIFN/ribavirin for 36 weeks. All patients were treated for a total of 48 weeks. SVR was assessed 24 weeks after therapy was ceased. Of the 662 subjects treated, relapsers demonstrated higher SVR rates (83%, 88%, 24%) than nonresponders (41%, 41%, 9%) for treatment arms 1, 2, and 3, respectively. As expected, partial responders (59%, 54%, 15%) were more likely to achieve SVR than were null responders (29%, 33%, 5%), respectively. In this trial, no difference was observed in SVR rates if subjects were treated with or without a lead-in phase of PegIFN/ribavirin.38
Telaprevir was assessed in a phase 2a study evaluating patients infected with HCV genotype 2 and genotype 3 disease.39 Patients were randomly assigned into 1 of 3 treatment arms: telaprevir 750 mg every 8 hours for 2 weeks, then PegIFN 180 µg weekly and ribavirin 400 mg twice daily for 22 weeks; telaprevir 750 mg every 8 hours and PegIFN 180 µg weekly and ribavirin 400 mg twice daily for 2 weeks, then only PegIFN and ribavirin administered from day 15 to complete 24 weeks of therapy; and placebo, PegIFN 180 µg weekly, and ribavirin 400 mg twice daily for 24 weeks. This small trial evaluated 49 patients stratified according to genotypes. SVR rates among the genotype 2 group were highest in those receiving all 3 agents at day 1 of therapy, 5/5 (100%) compared to 5/9 (55.6%) when telaprevir was given as monotherapy for the first 2 weeks, which was lower than the control arm of 8/9 (88.9%). For genotype 3 patients, SVR rates were comparable across all 3 cohorts but were highest for the triple therapy arm at 6/9 (66.7%), compared with those receiving monotherapy at 4/8 (50%) or placebo at 4/9 (44.4%).39
Telaprevir monotherapy is highly discouraged because resistance may develop within days or weeks.32,40 The emergence of viral variants of amino acid substitutions observed occurring in low levels are with V36M/A, T54A, and R155K/T and in high levels with A156V/T and 36/155.41 In an interim report, the EXTEND trial was a 3-year follow-up study evaluating patients who were enrolled in several phase 2 and 3 studies. The primary objective of this study was to determine the durability of response in patients who achieved SVR and to analyze HCV variant changes for those who did not achieve SVR.42 Subjects who did achieve SVR (n=123) were followed for a median of 22 months (range, 5-35 months) and those who did not (n=79) were followed for a median of 25 months (range, 7-35 months). The results included 202 subjects who demonstrated SVR of whom all but 1 relapsed at week 44. At the time of this interim analysis, the durability of response to telaprevir/PegIFN/ribavirin is 99%. The study also reported 89% who were followed no longer had resistant variants detected.42 Given these results, would one re-treat with telaprevir (or another protease inhibitor) at a later date with higher doses or combined with other agents targeting other parts of the HCV life cycle? This question remains to be answered.
Similar to patients who were treated with boceprevir, patients treated with telaprevir were more likely to develop adverse effects compared to those who received only PegIFN and ribavirin. The most common side effects included fatigue, pruritus, rash, anemia, nausea, and diarrhea.36-38 A unique adverse effect was anorectal disorders, including hemorrhoids, anorectal discomfort, and anal pruritus, which was reported more with telaprevir/PegIFN/ribavirin (29%) than PegIFN/ribavirin (7%).36,38 On reviewing and pooling the phase 3 trials for analysis, rash and/or pruritus was observed in about 70% of the subjects treated with telaprevir and in about 45% of those treated with PegIFN/ribavirin. Grade 3 anemia, fatigue, or rash occurred more with telaprevir (5.5%, 2%, 2%) than with PegIFN/ribavirin (0.6%, 0.4%, 0.2%), respectively.36-38 Permanent treatment discontinuation was more common in telaprevir-treated subjects, with about 5% caused by anemia and rash versus less than 1% for controls.36-38
The mechanism of developing rash is still being investigated as it was first reported during the phase 2 trials.43,44 Rashes were more likely to be observed in those treated with 12 weeks of telaprevir versus 8 weeks of telaprevir. One case reported a 57-year-old woman who was previously treated with PegIFN and ribavirin for 48 weeks and later relapsed and was randomly assigned into the PROVE 2 trial.44,45 She had been on telaprevir for 6 weeks when she developed a generalized maculopapular exanthema rash that was pruritic in nature. She developed flu-like symptoms with a temperature of 101.8° F and elevated liver function tests. Additionally she had an elevated eosinophilia count and skin biopsy, supporting a drug allergy. An oral corticosteroid, 1 mg/kg daily, was required to resolve her symptoms as topical agents were not effective. Once all HCV therapy was discontinued, the patient's symptoms resolved within 1 month. Unfortunately the patient did relapse, and no rechallenge with telaprevir was considered.45 In addition to DRESS (drug rash with eosinophilia and systemic symptoms), Stevens-Johnson syndrome has also been reported.46 Therefore patients should be hospitalized, carefully monitored for dermatologic symptoms, and topical corticosteroids initiated. Systemic corticosteroids may be used, however, with caution and not in the presence of telaprevir because of drug interactions whereby plasma concentrations may be significantly increased. PegIFN and ribavirin may be continued based on clinical judgment.45
Mean hemoglobin levels are expected to decrease about 0.5 to 1.5 g/dL more in those receiving telaprevir than in those not receiving it.47,48 The incidence of hemoglobin levels less than 10 g/dL occurred in 37% and required ribavirin dosage reductions in 24% for the telaprevir group compared to 15% and 10%, respectively, with PegIFN/ribavirin. Unlike the boceprevir trials in which erythropoietin was allowed, it was not in trials of telaprevir per protocols. Discontinuing all treatment in the telaprevir group (4.2%) or control group (0.4%) secondary to anemia was rare.47,48
CURRENT TREATMENT GUIDELINES
The treatment recommendations for the management of hepatitis C infections in the United States are being updated and should be available in late 2011. The European Association for the Study of the Liver recently released 2011 HCV treatment guidelines, but these include only approved therapies at that time.49
Update Noted by HCV New Drugs ; Sept 26 2011
An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases
Hepatitis C genotype 1 disease.
A new era has begun for patients infected with hepatitis C because the 2 DAAs have been approved.46,50 These now become a part of the hepatitis C genotype 1 disease treatment armamentarium. For this group of patients, a DAA with PegIFN and ribavirin should be considered because the SVR response rates are significantly higher, ranging between 60% and 75% compared to between 40% and 50% with standard of care (Table 4).51 Each DAA has its own specific dosing regimen and treatment duration is based on RGT. This approach individualizes the drug regimen based on the patient's on-treatment virologic response at specific time points during the course of HCV therapy. It is believed RGT may shorten the duration of treatment, lessen the potential of developing adverse effects, prevent the development of resistance, and decrease drug costs. Additionally, duration of therapy is determined by the patient's treatment status (naïve to treatment, treatment experienced [relapser, partial responder, null responder]) and the presence or absence of cirrhosis. Monotherapy with boceprevir or telaprevir must be avoided, and these agents must be administered with PegIFN and ribavirin. Dosing recommendations for PegIFN and ribavirin are based on the manufacturers' package inserts and are listed in Table 5.52,53
Table 5 Dosing recommendation for pegylated interferon and ribavirin for patients with HCV
Table 6 Boceprevir response-guided therapy guideline dosing regimen and duration of therapy
Boceprevir 200 mg capsule is dosed at 800 mg (4 capsules) 3 times a day every 7 to 9 hours with food and must be coadministered with PegIFN and ribavirin.50 Initially all patients receive a lead-in 4-week therapy of PegIFN and ribavirin before boceprevir 800 mg 3 times daily is added to the regimen at week 5. RGT will determine duration of therapy based on the patient's viral load at treatment weeks 8, 12, and 24 and treatment status (Table 6).50 For example, if the patient is treatment naïve with no cirrhosis and has an undetectable HCV-RNA level at week 8, the patient would complete the therapy with boceprevir and PegIFN and ribavirin at week 28. All patients receiving boceprevir and demonstrating detectable HCV-RNA levels greater than 100 IU/mL at week 12 or confirmed detectable HCV-RNA level at week 24 must discontinue all hepatitis C medications.
Table 7 Telaprevir response-guided therapy guideline dosing regimen and duration of therapy
Telaprevir 375-mg oral tablet is dosed at 750 mg 3 times a day every 7 to 9 hours with food having content of at least 20 g of fat and must be coadministered with PegIFN and ribavirin.46 The meal must be ingested within 30 minutes prior to each telaprevir dose. The meal should be high-fat to increase systemic exposure by 330% compared to a low-fat meal for which the systemic exposure would only be about 117%.46 All patients receive 12 weeks of telaprevir if they demonstrate an undetectable HCV-RNA level at week 4 (Table 7).46 Futility rules for telaprevir must be followed because patients failing to achieve RVR or EVR have a higher chance of developing DAA resistance.46
In addition to monitoring for HCV-RNA levels for efficacy, hematologic and clinical chemistry laboratories must be obtained at baseline and at weeks 2, 4, 8, and 12, or as clinically necessary to detect anemia, neutropenia, thrombocytopenia, and any other abnormalities. To prevent treatment failures, dosage reduction or interruptions must not occur with boceprevir and telaprevir. If dosage reductions are required for anemia, the ribavirin dose should be reduced or erythropoietin added. The use of erythropoietin has become controversial because some studies have shown an increase in SVR with ribavirin dosage reductions versus other trials that have shown no difference in SVR rates with erythropoietin usage.5,28,54 Erythropoietin therapy is not free of adverse effects because its use has been associated with an increased risk of tumor progression, thrombosis, and cardiovascular events.55 If erythropoietin or darbepoetin is chosen to manage the anemia, there may be some benefit if used during the first 8 weeks of HCV therapy.28
PegIFN-induced neutropenia occurs in about 25% of patients undergoing treatment for hepatitis C.5,28 The clinical manifestation of developing severe infections by having low ANC remains to be determined, but appears to be rare.5 As mentioned earlier, however, patients treated with boceprevir were more likely to develop severe and life-threatening infections compared to those receiving only PegIFN and ribavirin as reported and documented in the SPRINT-2 trial.31 According to the PegIFN package inserts, dosage reductions of PegIFN are recommended when ANC levels are less than 0.75 x 109 /L and to discontinue therapy when levels are less than 0.5 x 109 /L.52,53 The use of growth factors such as G-CSF have been commonly used in clinical practice, but more studies are needed before its use may be recommended.5,28,49
Other adverse effects in patients treated with boceprevir or telaprevir that should be monitored include rash, pruritus, anorectal discomfort or pain, and dysgeusia. Additionally, PegIFN and ribavirin have their own side-effect profiles; patients should be monitored for psychiatric disturbances (eg, irritability, depression, anxiety, suicidal ideation), endocrine abnormalities (thyroid abnormalities or diabetes mellitus), and hypertriglyceridemia among other untoward effects during the course of HCV therapy (Table 3).5,28,29
Contraindications associated with boceprevir and telaprevir include women and men who want to have a child.46,50 Because the DAAs are coadministered with PegIFN and ribavirin, and ribavirin is known to cause birth defects on the exposed fetus, 2 forms of effective birth control must be used during and 6 months post therapy to prevent any pregnancies. Concomitant administration of DAAs with drugs metabolized through the CYP3A pathway is also contraindicated.46,50 Boceprevir and telaprevir are potent CYP3A4 inhibitors. Therefore, serum/plasma concentrations of concomitantly administered drugs may be elevated, prolonging their therapeutic and adverse effects. In an open-label, healthy volunteer study, subjects were given oral cyclosporine or tacrolimus, drugs known to be CYP-3A4 inhibitors, with telaprevir.56 The coadministration of cyclosporine resulted in a 4.6-fold increase in the area under the curve (AUC) and prolonged half-life by 4 fold. The effect with tacrolimus was much more pronounced with the AUC increased by about 70 fold and half-life by 5 fold.56 Plasma concentrations may also be elevated for drugs that are substrates for p-glycoprotein because in vitro studies have found DAAs to be potential inhibitors. Extreme caution must be taken when coadministering drugs that are potent CYP3A inducers or inhibitors with DAAs.46,50
Hepatitis C non-genotype 1 disease.
PegIFN and ribavirin will continue to be the standard of care for patients with hepatitis C non-genotype 1 disease.5 Patients with genotype 2 and genotype 3 achieve SVR rates averaging 80% to 90% with 24 weeks of therapy. DAAs, in particular telaprevir, have comparable responses when studied against PegIFN and ribavirin.39 Because DAAs have their own adverse-effect profile along with an increased risk of developing drug resistance and comparable SVR rates with standard of care, DAAs are not recommended at this time for non-genotype 1 disease until more studies are conducted.57
PegIFN doses are listed in Table 5. Ribavirin should be administered with PegIFN if there are no contraindications. Per package inserts, ribavirin is dosed at 400 mg twice daily if the patient has HCV genotype 2 or genotype 3 disease.52,53 Certain factors may lead to a decreased SVR, however, including insulin resistance, presence of bridging fibrosis or cirrhosis, metabolic syndrome, and weight more than 85 kg. In most cases, these patients have a body mass index greater than 25. Thus, to achieve a greater chance of virologic clearance, higher than recommended ribavirin doses of 15 mg/kg may be considered.5,49 Although guideline recommendations may be forthcoming, it would be reasonable to treat genotype 2 and genotype 3 patients for 24 weeks.5 Utilizing the RGT approach by securing HCV-RNA levels at week 4 and 12 may be considered to determine if therapy needs to be extended beyond 24 weeks. If at week 12, HCV-RNA levels are still detectable and have not decreased by 2 log10 IU/mL compared to baseline, then all medications should be discontinued.5,49 Adverse effects, warnings, and contraindications associated with PegIFN and ribavirin remain the same as discussed for patients with HCV genotype 1 disease in Table 3.
CONCLUSION
Hepatitis C is a disease affecting millions worldwide. It is an exciting time for patients and healthcare providers as a new generation of drugs predicting more effective drug treatments are now available. The newly approved DAAs will improve SVR rates with shorter duration of therapies. However, these will present another set of problems—more diverse side effects and the potential of developing resistance. The DAAs to be used in combination with PegIFN and ribavirin are now only approved and recommended for HCV genotype 1 disease. Treatment duration should be based on an RGT approach to individualize drug therapy to maximize cure rates, minimize resistance, and decrease incidence of adverse effects. Until further studies are conducted, DAAs should not be used in post-transplant patients with recurrent HCV infection, those coinfected with HIV, and children. Additionally, caution must be exercised to review the patient's medications profile to prevent significant and potentially life-threatening drug interactions. The traditional standard of care, PegIFN with ribavirin, remains for HCV genotype 2 and genotype 3 disease. The treatment of HCV will continue to evolve as additional agents are discovered and clinical studies are conducted.
Dr Chan is clinical assistant professor, Department of Pharmacy Practice, College of Pharmacy and Department of Medicine, Sections of Digestive Diseases and Nutrition and Hepatology, University of Illinois at Chicago, Ill.
Disclosure Information:
The author reports no financial disclosures as related to products discussed in this article.
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