BMS-986263 in patients with advanced hepatic fibrosis: 36-week results from a randomized, placebo-controlled phase 2 trial.

BACKGROUND AND AIMS: Hepatic fibrosis secondary to HCV infection can lead to cirrhosis and hepatic decompensation. Sustained virologic response (SVR) is possible with direct-acting antiviral drug regimens; however, patients with advanced fibrosis have an increased risk for HCC. Heat shock protein 47 (HSP47), a key collagen chaperone, has been implicated in fibrosis development. We evaluated the efficacy and safety of BMS-986263, a lipid nanoparticle delivering small interfering RNA designed to degrade HSP47 mRNA, for the treatment of advanced fibrosis. APPROACH AND RESULTS: NCT03420768 was a Phase 2, randomized (1:1:2), placebo-controlled trial conducted at a hepatology clinic in the United States. Patients with HCV-SVR (for ≥ 1 year) and advanced fibrosis received once-weekly i.v. infusions of placebo or BMS-986263 (45 or 90 mg) for 12 weeks. The primary endpoint was ≥ 1 METAVIR stage improvement at Week 12; key secondary endpoints included Ishak score improvement, pharmacokinetics, fibrosis biomarkers, and safety. All 61 patients completed treatment, and 2/15 (13%, placebo), 3/18 (17%, 45 mg), and 6/28 (21%, 90 mg) had METAVIR improvements of ≥ 1 stage at Week 12. Five patients in the 90-mg arm had Ishak improvements by ≥ 2 stages. BMS-986263 plasma concentrations increased in a generally dose-proportional fashion between BMS-986263 doses, with no notable accumulation with weekly dosing. All adverse events (AEs) were mild or moderate in intensity; most treatment-related AEs were infusion-related reactions in the BMS-986263 arms. At baseline, collagen levels were low, indicating low levels of fibrogenesis in these patients. CONCLUSIONS: In patients with HCV-SVR, BMS-986263 administration was generally well tolerated through Week 36 and resulted in METAVIR and Ishak score improvements. Further evaluation of BMS-986263 in patients with active fibrogenesis is warranted.

Sofosbuvir with peginterferon-ribavirin for 12 weeks in previously treated patients with hepatitis C genotype 2 or 3 and cirrhosis.

UNLABELLED: Sofosbuvir (SOF) in combination with ribavirin (RBV) for 12 or 24 weeks is the current standard of care for patients infected with hepatitis C virus (HCV) genotypes 2 and 3, respectively. However, in clinical trials treatment-experienced patients, particularly those with cirrhosis, had suboptimal sustained virological response (SVR) rates. We assessed the efficacy and safety of sofosbuvir plus peginterferon and ribavirin (SOF+Peg-IFN+RBV) administered for 12 weeks to treatment-experienced patients with HCV genotypes 2 and 3, with and without cirrhosis. We enrolled 47 patients in this open-label, nonrandomized, uncontrolled phase 2 study. The primary endpoint was the proportion of patients with SVR at 12 weeks after cessation of study treatment (SVR12). The overall rate of SVR12 was 89% (95% confidence interval [CI]: 77-97). Rates of SVR12 were higher in patients with genotype 2 than in those with genotype 3, 96% (95% CI: 78-100) and 83% (95% CI: 62-95), respectively. Rates of SVR12 were similar in patients with and without cirrhosis: for genotype 2, 93% of patients with cirrhosis and 100% of patients without cirrhosis achieved SVR12, and for genotype 3, the SVR12 rate was 83% in patients both with and without cirrhosis. One patient discontinued study treatment because of an adverse event and four patients experienced serious adverse events. The most common adverse events were influenza-like illness, fatigue, anemia, and neutropenia. CONCLUSION: In treatment-experienced patients with HCV genotypes 2 and 3, 12-week administration of SOF+Peg-IFN+RBV provided high SVR rates, irrespective of cirrhosis status. No safety concerns were identified.

Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Pegylated interferon (peginterferon) alfa 2a or 2b plus ribavirin regimens were the standard of care in patients with hepatitis C virus (HCV) infection, but the sustained virological response can be suboptimum in patients with HCV genotype 1 infection. The efficacy, safety, and tolerability of the combination of simeprevir, a one-pill, once-daily, oral HCV NS3/4A protease inhibitor versus placebo, plus peginterferon alfa 2a or 2b plus ribavirin was assessed in treatment-naive patients with HCV genotype 1 infection. METHODS: In the QUEST-2, phase 3 study, done at 76 sites in 14 countries (Europe, and North and South Americas), patients with confirmed chronic HCV genotype 1 infection and no history of HCV treatment were randomly assigned with a computer-generated allocation sequence in a ratio of 2:1 and stratified by HCV genotype 1 subtype and host IL28B genotype to receive simeprevir (150 mg once daily, orally), peginterferon alfa 2a (180 µg once weekly, subcutaneous injection) or 2b (according to bodyweight; 50 µg, 80 µg, 100 µg, 120 µg, or 150 µg once weekly, subcutaneous injection), plus ribavirin (1000-1200 mg/day or 800-1400 mg/day, orally; simeprevir group) or placebo (once daily, orally), peginterferon alfa 2a or 2b, plus ribavirin (placebo group) for 12 weeks, followed by just peginterferon alfa 2a or 2b plus ribavirin. Total treatment duration was 24 weeks or 48 weeks (simeprevir group) based on criteria for response-guided therapy (ie, HCV RNA <25 IU/mL undetectable or detectable at week 4 and undetectable week 12) or 48 weeks (placebo). Patients, study personnel, and the sponsor were masked to treatment assignment. The primary efficacy endpoint was sustained virological response at 12 weeks after the planned end of treatment (SVR12). Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01290679. Results from the primary (SVR12, week 60) analysis are presented. FINDINGS: 209 (81%) of 257 patients in the simeprevir group and 67 (50%) of 134 in the placebo group had SVR12 (adjusted difference 32·2%, 95% CI 23·3-41·2; p<0·0001). The incidences of adverse events were similar in the simeprevir and placebo groups at 12 weeks (246 [96%] vs 130 [97%]) and for the entire treatment (249 [97%] vs 132 [99%]), irrespective of the peginterferon alfa used. The most common adverse events were headache, fatigue, pyrexia, and influenza-like illness at 12 weeks (95 [37%) vs 45 [34%], 89 [35%] vs 52 [39%], 78 [30%] vs 48 [36%], and 66 [26%] vs 34 [25%], respectively) and for the entire treatment (100 [39%] vs 49 [37%], 94 [37%] vs 56 [42%], 79 [31%] vs 53 [40%], and 66 [26%] vs 35 [26%], respectively). Rash and photosensitivity frequencies were higher in the simeprevir group than in the placebo group (61 [24%] vs 15 [11%] and ten [4%] vs one [<1%], respectively). There was no difference in the prevalence of anaemia between the simeprevir and placebo groups (35 [14%] vs 21 [16%], respectively, at 12 weeks, and 53 [21%] vs 37 [28%], respectively, during the entire treatment). INTERPRETATION: Addition of simeprevir to either peginterferon alfa 2a or peginterferon alfa 2b plus ribavirin improved SVR in treatment-naive patients with HCV genotype 1 infection, without worsening the known adverse events associated with peginterferon alfa plus ribavirin. FUNDING: Janssen Infectious Diseases-Diagnostics.

Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV infection and cirrhosis, allowing for effective antiviral therapy.

BACKGROUND & AIMS: Thrombocytopenia is common among patients with hepatitis C virus (HCV) infection and advanced fibrosis or cirrhosis, limiting initiation and dose of peginterferon-alfa (PEG) and ribavirin (RBV) therapy. The phase 3 randomized, controlled studies, Eltrombopag to Initiate and Maintain Interferon Antiviral Treatment to Benefit Subjects with Hepatitis C-Related Liver Disease (ENABLE)-1 and ENABLE-2, investigated the ability of eltrombopag to increase the number of platelets in patients, thereby allowing them to receive initiation or maintenance therapy with PEG and RBV. METHODS: Patients with HCV infection and thrombocytopenia (platelet count <75,000/µL) who participated in ENABLE-1 (n = 715) or ENABLE-2 (n = 805), from approximately 150 centers in 23 countries, received open-label eltrombopag (25-100 mg/day) for 9 weeks or fewer. Patients whose platelet counts reached the predefined minimal threshold for the initiation of PEG and RBV therapy (95% from ENABLE-1 and 94% from ENABLE-2) entered the antiviral treatment phase, and were assigned randomly (2:1) to groups that received eltrombopag or placebo along with antiviral therapy (24 or 48 weeks, depending on HCV genotype). The primary end point was sustained virologic response (SVR) 24 weeks after completion of antiviral therapy. RESULTS: More patients who received eltrombopag than placebo achieved SVRs (ENABLE-1: eltrombopag, 23%; placebo, 14%; P = .0064; ENABLE-2: eltrombopag, 19%; placebo, 13%; P = .0202). PEG was administered at higher doses, with fewer dose reductions, in the eltrombopag groups of each study compared with the placebo groups. More patients who received eltrombopag than placebo maintained platelet counts of 50,000/µL or higher throughout antiviral treatment (ENABLE-1, 69% vs 15%; ENABLE-2, 81% vs 23%). Adverse events were similar between groups, with the exception of hepatic decompensation (both studies: eltrombopag, 10%; placebo, 5%) and thromboembolic events, which were more common in the eltrombopag group of ENABLE-2. CONCLUSIONS: Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV and advanced fibrosis and cirrhosis, allowing otherwise ineligible or marginal patients to begin and maintain antiviral therapy, leading to significantly increased rates of SVR. Clinical trial no: NCT00516321, NCT00529568.

Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial.

BACKGROUND & AIMS: Simeprevir (TMC435) is an oral NS3/4 protease inhibitor in phase III trials for chronic hepatitis C virus (HCV) infection. We performed a phase IIb, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of the combination of simeprevir, peginterferon-α2a (PegIFN), and ribavirin (RBV) in patients with HCV genotype-1 infection previously treated with PegIFN and RBV. METHODS: We analyzed data from patients who did not respond (null response), had a partial response, or relapsed after treatment with PegIFN and RBV, randomly assigned to receive simeprevir (100 or 150 mg, once daily) for 12, 24, or 48 weeks plus PegIFN and RBV for 48 weeks (n = 396), or placebo plus PegIFN and RBV for 48 weeks (n = 66). All patients were followed for 24 weeks after planned end of treatment; the primary end point was the proportion of patients with sustained virologic response (SVR; undetectable HCV RNA) at that time point. RESULTS: Overall, rates of SVR at 24 weeks were significantly higher in the groups given simeprevir than those given placebo (61%-80% vs 23%; P < .001), regardless of prior response to PegIFN and RBV (simeprevir vs placebo: prior null response, 38%-59% vs 19%; prior partial response, 48%-86% vs 9%; prior relapse, 77%-89% vs 37%). All groups had comparable numbers of adverse events; these led to discontinuation of simeprevir or placebo and/or PegIFN and RBV in 8.8% of patients given simeprevir and 4.5% of those given placebo. CONCLUSIONS: In treatment-experienced patients, 12, 24, or 48 weeks simeprevir (100 mg or 150 mg once daily) in combination with 48 weeks PegIFN and RBV significantly increased rates of SVR at 24 weeks compared with patients given placebo, PegIFN, and RBV and was generally well tolerated. ClinicalTrials.gov number: NCT00980330.

Infections during peginterferon/ribavirin therapy are associated with the magnitude of decline in absolute lymphocyte count: results of the IDEAL study.

BACKGROUND: Myelosuppression due to pegylated interferon (peg-IFN) is common during treatment for hepatitis C virus. The relationship between infection risk and decreases in leukocyte lines, however, is not well established. The objective of this analysis was to determine the incidence of and risk factors for infections during peg-IFN/ribavirin (RBV) therapy. METHODS: A total of 3070 treatment-naive, chronic hepatitis C genotype 1-infected patients were treated for up to 48 weeks with peg-IFN alfa-2b 1.5 µg/kg/week or 1 µg/kg/week, or peg-IFN alfa-2a 180 µg/week plus RBV. On-treatment leukocyte counts were obtained every 2-6 weeks. Dose reduction was required for a neutrophil count <0.75 × 10(9) cells/L, and treatment discontinuation was required for a neutrophil count <0.5 × 10(9) cells/L. Granulocyte colony-stimulating factor was prohibited. Data on infections were captured at each study visit and categorized according to MedDRA version 13.0. RESULTS: A total of 581 (19%) patients experienced moderate, severe, or life-threatening infections as assessed by the investigator; 648 (21%) patients had at least 1 neutrophil count <0.75 × 10(9) cells/L, but only 242 (8%) sustained an infection and had a neutrophil count <0.75 × 10(9) cells/L at any time while on treatment. Twelve patients had severe or life-threatening infection and grade 3/4 neutropenia, but only 4 had temporally related infections. In a multivariate logistic regression model, nadir lymphocyte count, history of depression, and female sex, but not nadir neutrophil count, were associated with moderate, severe, or life-threatening infection. CONCLUSIONS: Nadir lymphocyte count, not nadir neutrophil count, was independently associated with moderate, severe, or life-threatening infections in the IDEAL study. Clinicians should be aware of their patients' absolute lymphocyte counts during peg-IFN/RBV therapy; peg-IFN dose reductions may be a consideration in patients with significant lymphocytopenia (<0.5 × 10(9) cells/L).

Safety and efficacy of boceprevir/peginterferon/ribavirin for HCV G1 compensated cirrhotics: meta-analysis of 5 trials.

BACKGROUND & AIMS: HCV-infected cirrhotics may urgently need therapy but are often under-represented in clinical trials resulting in limited data to guide their management. We performed a meta-analysis of well-compensated cirrhotic patients from five Phase 3 trials. METHODS: Patients received P/R (peginterferon/ribavirin; 4 weeks) followed by BOC (boceprevir)/P/R or P/R for 24, 32, or 44 weeks. Sustained virologic response (SVR) rates were calculated by Metavir score. Multivariate logistic regression (MLR) models identified baseline and on-treatment predictors of SVR. Safety was evaluated by adverse-event (AE) reporting and laboratory monitoring. RESULTS: Pooled meta-estimates for SVR rates (95% confidence interval) in 212 F4 (cirrhotic) patients were 55% (43, 66) with BOC/P/R vs.17% (0, 41) with P/R. MLR identified 4 predictors of SVR in F3/F4 patients: undetectable HCV-RNA at treatment week (TW) 8; ⩾ 1 log10 decline in HCV-RNA from baseline at TW4; male; and baseline HCV-RNA ⩽ 800,000 IU/ml. SVR rate was 89% (65/73) in F4 patients who were HCV-RNA undetectable at TW8. No F3 (0/5) or F4 (0/17) patients with <3 log10 decline and detectable HCV-RNA at TW8 achieved SVR. Anemia and diarrhea occurred more frequently in cirrhotic than non-cirrhotic patients. Serious AEs, discontinuations due to an AE, interventions to manage anemia, infections, and thrombocytopenia occurred more frequently in cirrhotics with BOC/P/R than P/R. Potential hepatic decompensation and/or sepsis were identified in 2 P/R and 3 BOC/P/R recipients. CONCLUSIONS: BOC/P/R appears to have a generally favorable benefit-risk profile in compensated cirrhotic patients. SVR rates were particularly high in cirrhotic patients with undetectable HCV-RNA at TW8.

Boceprevir for chronic HCV genotype 1 infection in patients with prior treatment failure to peginterferon/ribavirin, including prior null response.

BACKGROUND & AIMS: Boceprevir with peginterferon/ribavirin (BOC/PR) leads to significantly higher sustained virological response (SVR) rates in patients with chronic hepatitis C and partial response or relapse after prior treatment with peginterferon/ribavirin. We studied the efficacy of BOC/PR in patients with prior treatment failure, including those with a null response (<2-log10 decline in HCV RNA), to peginterferon/ribavirin. METHODS: Patients in the control arms of boceprevir Phase 2/3 studies who did not achieve SVR were re-treated with BOC/PR for up to 44 weeks. Patients enrolling >2 weeks after end-of-treatment in the prior study received PR for 4 weeks before adding boceprevir. RESULTS: Of 168 patients enrolled, four discontinued from the PR lead-in and 164 received BOC/PR. Baseline viral load was >800,000 IU/ml in 77% of patients; 62% had HCV genotype 1a, and 10% were cirrhotic. In the ITT analysis (all 168 patients), SVR was achieved in 20 (38%) of 52 patients with prior null response, 57 (67%) of 85 with prior partial response, and 27 (93%) of 29 with prior relapse. In the mITT analysis (164 BOC/PR-treated patients), SVR rates were 41% (20/49), 67% (57/85), and 96% (27/28), respectively. SVR was achieved by 48% of patients with <1-log10 decline in HCV-RNA after lead-in and 76% of those with ⩾ 1-log10 decline or undetectable HCV-RNA after lead-in. The most common adverse events were anemia (49%), fatigue (48%), and dysgeusia (35%); 8% of patients discontinued due to adverse events. CONCLUSIONS: Re-treatment with BOC/PR improved SVR rates in all patient subgroups, including those with prior null response.

Boceprevir for untreated chronic HCV genotype 1 infection.

BACKGROUND: Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies. METHODS: We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately. RESULTS: A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively. CONCLUSIONS: The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.).

Boceprevir for previously treated chronic HCV genotype 1 infection.

BACKGROUND: In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment. METHODS: To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. RESULTS: A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log(10) IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41 to 46% of boceprevir-treated patients and 21% of controls. CONCLUSIONS: The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon-ribavirin alone. (Funded by Schering-Plough [now Merck]; HCV RESPOND-2 ClinicalTrials.gov number, NCT00708500.).

Response-guided telaprevir combination treatment for hepatitis C virus infection.

BACKGROUND: Patients with chronic infection with hepatitis C virus (HCV) genotype 1 often need 48 weeks of peginterferon-ribavirin treatment for a sustained virologic response. We designed a noninferiority trial (noninferiority margin, -10.5%) to compare rates of sustained virologic response among patients receiving two treatment durations. METHODS: We enrolled patients with chronic infection with HCV genotype 1 who had not previously received treatment. All patients received telaprevir at a dose of 750 mg every 8 hours, peginterferon alfa-2a at a dose of 180 µg per week, and ribavirin at a dose of 1000 to 1200 mg per day, for 12 weeks (T12PR12), followed by peginterferon-ribavirin. Patients who had an extended rapid virologic response (undetectable HCV RNA levels at weeks 4 and 12) were randomly assigned after week 20 to receive the dual therapy for 4 more weeks (T12PR24) or 28 more weeks (T12PR48). Patients without an extended rapid virologic response were assigned to T12PR48. RESULTS: Of the 540 patients, a total of 352 (65%) had an extended rapid virologic response. The overall rate of sustained virologic response was 72%. Among the 322 patients with an extended rapid virologic response who were randomly assigned to a study group, 149 (92%) in the T12PR24 group and 140 (88%) in the T12PR48 group had a sustained virologic response (absolute difference, 4 percentage points; 95% confidence interval, -2 to 11), establishing noninferiority. Adverse events included rash (in 37% of patients, severe in 5%) and anemia (in 39%, severe in 6%). Discontinuation of all the study drugs was based on adverse events in 18% of patients overall, as well as in 1% of patients (all of whom were randomly assigned) in the T12PR24 group and 12% of the patients randomly assigned to the T12PR48 group (P<0.001). CONCLUSIONS: In this study, among patients with chronic HCV infection who had not received treatment previously, a regimen of peginterferon-ribavirin for 24 weeks, with telaprevir for the first 12 weeks, was noninferior to the same regimen for 48 weeks in patients with undetectable HCV RNA at weeks 4 and 12, with an extended rapid virologic response achieved in nearly two thirds of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ILLUMINATE ClinicalTrials.gov number, NCT00758043.).

Effects of ribavirin dose reduction vs erythropoietin for boceprevir-related anemia in patients with chronic hepatitis C virus genotype 1 infection--a randomized trial.

BACKGROUND & AIMS: Treatment of hepatitis C virus (HCV) infection with boceprevir, peginterferon, and ribavirin can lead to anemia, which has been managed by reducing ribavirin dose and/or erythropoietin therapy. We assessed the effects of these anemia management strategies on rates of sustained virologic response (SVR) and safety. METHODS: Patients (n = 687) received 4 weeks of peginterferon and ribavirin followed by 24 or 44 weeks of boceprevir (800 mg, 3 times each day) plus peginterferon and ribavirin. Patients who became anemic (levels of hemoglobin approximately ≤10 g/dL) during the study treatment period (n = 500) were assigned to groups that were managed by ribavirin dosage reduction (n = 249) or erythropoietin therapy (n = 251). RESULTS: Rates of SVR were comparable between patients whose anemia was managed by ribavirin dosage reduction (71.5%) vs erythropoietin therapy (70.9%), regardless of the timing of the first intervention to manage anemia or the magnitude of ribavirin dosage reduction. There was a threshold for the effect on rate of SVR: patients who received <50% of the total milligrams of ribavirin assigned by the protocol had a significantly lower rate of SVR (P < .0001) than those who received ≥50%. Among patients who did not develop anemia, the rate of SVR was 40.1%. Eleven thromboembolic adverse events were reported in 9 of 295 patients who received erythropoietin, compared with 1 of 392 patients who did not receive erythropoietin. CONCLUSIONS: Reduction of ribavirin dosage can be the primary approach for management of anemia in patients receiving peginterferon, ribavirin, and boceprevir for HCV infection. Reduction in ribavirin dosage throughout the course of triple therapy does not affect rates of SVR. However, it is important that the patient receives at least 50% of the total amount (milligrams) of ribavirin assigned by response-guided therapy. ClinicalTrials.gov number, NCT01023035.

Anemia during treatment with peginterferon Alfa-2b/ribavirin and boceprevir: Analysis from the serine protease inhibitor therapy 2 (SPRINT-2) trial.

UNLABELLED: Boceprevir (BOC) added to peginterferon alfa-2b (PegIFN) and ribavirin (RBV) significantly increases sustained virologic response (SVR) rates over PegIFN/RBV alone in previously untreated adults with chronic hepatitis C genotype 1. We evaluate the relationship of incident anemia with triple therapy. A total of 1,097 patients received a 4-week lead-in of PegIFN/RBV followed by: (1) placebo plus PegIFN/RBV for 44 weeks (PR48); (2) BOC plus PegIFN/RBV using response-guided therapy (BOC/RGT); and (3) BOC plus PegIFN/RBV for 44 weeks (BOC/PR48). The management of anemia (hemoglobin [Hb]<10 g/dL) included RBV dose reduction and/or erythropoietin (EPO) use. A total of 1,080 patients had ≥1 Hb measurement during treatment. The incidence of anemia was 50% in the BOC arms combined (363/726) and 31% in the PR48 arm (108/354, P<0.001). Among BOC recipients, lower baseline Hb and creatinine clearance were associated with incident anemia. In the BOC-containing arms, anemia was managed by the site investigators as follows: EPO without RBV dose reduction, 38%; RBV dose reduction without EPO, 8%; EPO with RBV dose reduction, 40%; and neither RBV dose reduction nor EPO, 14%. SVR rates were not significantly affected by management strategy (70%-74%), and overall patients with anemia had higher rates of SVR than those who did not develop anemia (58%). Serious and life-threatening adverse events (AEs) and discontinuations due to AEs among BOC-treated patients did not differ by EPO use. CONCLUSION: With BOC/PR therapy, SVR rates in patients with incident anemia were higher than nonanemic patients and did not vary significantly according to the investigator-selected approach for anemia management. Prospective studies are needed to confirm this observation.

Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naïve genotype 1 hepatitis C: the randomized PILLAR study.

UNLABELLED: The phase IIb, double-blind, placebo-controlled PILLAR trial investigated the efficacy and safety of two different simeprevir (SMV) doses administered once-daily (QD) with pegylated interferon (Peg-IFN)-α-2a and ribavirin (RBV) in treatment-naïve patients with HCV genotype 1 infection. Patients were randomized to one of five treatments: SMV (75 or 150 mg QD) for 12 or 24 weeks or placebo, plus Peg-IFN and RBV. Patients in the SMV arms stopped all treatment at week 24 if response-guided therapy (RGT) criteria were met; patients not meeting RGT continued with Peg-IFN and RBV until week 48, as did patients in the placebo control group. Sustained virologic response (SVR) rates measured 24 weeks after the planned end of treatment (SVR24) were 74.7%-86.1% in the SMV groups versus 64.9% in the control group (P < 0.05 for all comparisons [SMV versus placebo], except SMV 75 mg for 24 weeks). Rapid virologic response (HCV RNA <25 IU/mL undetectable at week 4) was achieved by 68.0%-75.6% of SMV-treated and 5.2% of placebo control patients. According to RGT criteria, 79.2%-86.1% of SMV-treated patients completed treatment by week 24; 85.2%-95.6% of these subsequently achieved SVR24. The adverse event profile was generally similar across the SMV and placebo control groups, with the exception of mild reversible hyperbilirubinemia, without serum aminotransferase abnormalities, associated with higher doses of SMV. CONCLUSION: SMV QD in combination with Peg-IFN and RBV significantly improves SVR rates, compared with Peg-IFN and RBV alone, and allows the majority of patients to shorten their therapy duration to 24 weeks.

Overall safety profile of boceprevir plus peginterferon alfa-2b and ribavirin in patients with chronic hepatitis C genotype 1: a combined analysis of 3 phase 2/3 clinical trials.

BACKGROUND & AIMS: Triple therapy with peginterferon/ribavirin (PR) plus an NS3 protease inhibitor has emerged as the standard-of-care for patients with chronic hepatitis C genotype-1. We provide a detailed safety analysis comparing PR to boceprevir plus PR (BOC/PR) across three phase 2/3 studies. METHODS: SPRINT-1 was an open-label phase 2 study in 595 treatment-naive patients. In the two phase 3 studies, 1500 patients (1097 treatment-naive, SPRINT-2; 403 treatment-failure, RESPOND-2) were randomized to receive PR alone, or one of two regimens where BOC was added to PR after a 4-wk PR lead-in. In this analysis, the respective BOC/PR and PR arms were combined for all three trials. The benefit of shortened duration of treatment using response-guided therapy (RGT) was also explored in the SPRINT-2 trial. RESULTS: Only two adverse events, anaemia and dysgeusia, occurred 20% more often with the BOC-containing regimens compared with PR. Nausea, diarrhoea and neutropenia were the only other common events with an incidence of at least 5% greater when BOC was added to the PR backbone. The proportions of patients reporting serious adverse events (AE), life-threatening AEs, and study drug discontinuation because of an AE were similar in the PR and BOC/PR arms. In treatment-naive patients, RGT generally did not result in a lower frequency of common AEs; however, RGT led to decreased exposure to all 3 study drugs and to a decrease in the mean duration of several clinically relevant AEs such as anaemia, neutropenia, fatigue and depression, as well as earlier normalization of haemoglobin and neutrophil counts. CONCLUSIONS: The safety profile of BOC combination therapy largely reflects the known profile of peginterferon and ribavirin, with incremental haematolgical effects and dysgeusia. Shorter treatment duration with RGT significantly reduced the duration of AEs.

Boceprevir plus peginterferon α-2b/ribavirin in chronic hepatitis C genotype 1: impact of baseline viral load on sustained virologic response.

BACKGROUND: Baseline viral load is a predictor of treatment outcome in patients with hepatitis C virus (HCV) infection receiving peginterferon and ribavirin. The impact of baseline viral load on sustained virologic response (SVR) after boceprevir-based therapy is unknown. METHODS: This retrospective analysis included patients with chronic HCV genotype 1 infection who were previously untreated or were previous treatment failures. Virologic response was assessed according to baseline viral load (≤1 million IU/mL, >1 to ≤5 million IU/mL, >5 to ≤10 million IU/mL, and >10 million IU/mL). RESULTS: SVR was higher in patients receiving boceprevir plus peginterferon and ribavirin than in those receiving peginterferon and ribavirin alone, regardless of baseline viral load. Patients with a baseline viral load ≤1 million IU/mL had the highest SVR (boceprevir plus peginterferon and ribavirin, 78% to 83%; peginterferon and ribavirin, 33% to 63%). Among patients with baseline viral load >1 million IU/mL, SVR rates were 57% to 68% in patients receiving boceprevir plus peginterferon and ribavirin, and 11% to 41% in patients receiving peginterferon and ribavirin. Relapse was higher in patients receiving peginterferon and ribavirin (previously untreated, 12% to 40%; previous treatment failures, 17% to 67%) than in those receiving boceprevir plus peginterferon and ribavirin (previously untreated, 3% to 12%; previous treatment failure, 9% to 16%), irrespective of baseline viral load. CONCLUSIONS: The efficacy of boceprevir plus peginterferon and ribavirin was unaffected by baseline viral loads >1 million IU/mL, whereas viral burden >1 million IU/mL was associated with lower SVR with peginterferon and ribavirin. Relapse rates were lower with boceprevir plus peginterferon and ribavirin than with peginterferon and ribavirin, and were unaffected by baseline viral load.

Efficacy and safety of boceprevir plus peginterferon-ribavirin in patients with HCV G1 infection and advanced fibrosis/cirrhosis.

BACKGROUND & AIMS: We assessed the safety and efficacy of boceprevir (BOC) plus peginterferon-ribavirin (PR) in patients with HCV-G1 infection and advanced fibrosis/cirrhosis (Metavir F3/F4). METHODS: In two randomized controlled studies of previously untreated and previous treatment failures, patients received a 4-week lead-in of PR followed by PR plus placebo for 44 weeks (PR48); PR plus BOC using response guided therapy (BOC/RGT); or PR plus BOC for 44 weeks (BOC/PR48). RESULTS: The trials enrolled 178 patients with F3/4. HCV RNA levels at week 4 and 8 were highly predictive of response. No patient with F3/4 in the PR48 arm with a <1 log(10) decline in HCV RNA at week 4 achieved SVR, whereas those randomized to BOC/RGT or BOC/PR48 had SVR rates of 11-33% (F3) and 10-14% (F4). In these latter groups, patients with high baseline viral load (>2 × 10(6)IU/ml) had an overall SVR rate of 6% (2/33). For patients with a ≥1 log(10) decline at week 4, SVR rates in the BOC/PR48 arm of SPRINT-2 and RESPOND-2, respectively, were 77% and 87% vs. 18% and 50% for PR48; SVR rates in early responders (undetectable HCV RNA at week 8) were 90-93% in the BOC/PR48 arm. Neutropenia and thrombocytopenia were more common in cirrhotics than non-cirrhotics. CONCLUSIONS: BOC improves SVR rates in patients with F3/4, and longer treatment duration provides the most benefit. With triple therapy, SVR rates are modest in F4 patients with a <1 log(10) decline at week 4, thus the 4-week PR lead-in aids in the assessment of early futility.

Factors that predict response of patients with hepatitis C virus infection to boceprevir.

BACKGROUND & AIMS: Little is known about factors associated with a sustained virologic response (SVR) among patients with hepatitis C virus (HCV) infection to treatment with protease inhibitors. METHODS: Previously untreated patients (from the Serine Protease Inhibitor Therapy 2 [SPRINT-2] trial) and those who did not respond to prior therapy (from the Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2 [RESPOND-2] trial) received either a combination of peginterferon and ribavirin for 48 weeks or boceprevir, peginterferon, and ribavirin (triple therapy) after 4 weeks of peginterferon and ribavirin (total treatment duration, 28-48 wk). A good response to interferon was defined as a ≥ 1 log(10) decrease in HCV RNA at week 4; a poor response was defined as a <1 log(10) decrease. We used multivariate regression analyses to identify baseline factors of the host (including the polymorphism interleukin [IL]-28B rs12979860) associated with response. The polymorphism IL-28B rs8099917 also was assessed. RESULTS: In the SPRINT-2 trial, factors that predicted a SVR to triple therapy included low viral load (odds ratio [OR], 11.6), IL-28B genotype (rs 12979860 CC vs TT and CT; ORs, 2.6 and 2.1, respectively), absence of cirrhosis (OR, 4.3), HCV subtype 1b (OR, 2.0), and non-black race (OR, 2.0). In the RESPOND-2 trial, the only factor significantly associated with a SVR was previous relapse, compared with previous nonresponse (OR, 2.6). Most patients with rs12979860 CC who received triple therapy had undetectable levels of HCV RNA by week 8 (76%-89%), and were eligible for shortened therapy. In both studies, IL-28B rs12979860 CC was associated more strongly with a good response to interferon than other baseline factors; however, a ≥ 1 log(10) decrease in HCV-RNA level at week 4 was associated more strongly with SVR than IL-28B rs12979860. Combining the rs8099917 and rs12979860 genotypes does not increase the association with SVR. CONCLUSIONS: The CC polymorphism at IL-28B rs12979860 is associated with response to triple therapy and can identify candidates for shorter treatment durations. A ≥ 1 log(10) decrease in HCV RNA at week 4 of therapy is the strongest predictor of a SVR, regardless of polymorphisms in IL-28B.

Boceprevir with peginterferon alfa-2a-ribavirin is effective for previously treated chronic hepatitis C genotype 1 infection.

BACKGROUND & AIMS: The addition of boceprevir to therapy with peginterferon alfa-2b and ribavirin results in significantly higher rates of sustained virologic response (SVR) in previously treated patients with chronic hepatitis C virus (HCV) genotype-1 infection, compared with peginterferon alfa-2b and ribavirin alone. We assessed SVR with boceprevir plus peginterferon alfa-2a-ribavirin (PEG2a/R) in patients with identical study entry criteria. METHODS: In a double-blind, placebo-controlled trial, 201 patients with HCV genotype-1 who had relapsed or not responded to previous therapy were assigned to groups (1:2) and given a 4-week lead-in phase of PEG2a/R, followed by placebo plus PEG2a/R for 44 weeks (PEG2a/R) or boceprevir plus PEG2a/R for 44 weeks (BOC/PEG2a/R). The primary end point was SVR 24 weeks after therapy ended. RESULTS: The addition of boceprevir after 4 weeks of lead-in therapy with PEG2a/R significantly increased the rate of SVR from 21% in the PEG2a/R group to 64% in the BOC/PEG2a/R group (P < .0001). Among patients with poor response to interferon therapy (<1-log(10) decline in HCV RNA at week 4), 39% in the BOC/PEG2a/R group had SVRs, compared with none of the patients in the PEG2a/R group. Among patients with good response to interferon (≥1-log(10) decline), 71% in the BOC/PEG2a/R group had SVRs, compared with 25% in the PEG2a/R group. A ≥1-log(10) decline in HCV RNA at treatment week 4 was the strongest independent predictor of SVR, exceeding that of IL-28B genotype. Among 8 patients who began the study with HCV amino acid variants associated with boceprevir resistance, 3 (38%) achieved SVRs. Fifty percent of patients in the BOC/PEG2a/R group developed anemia (hemoglobin <10.0 g/dL), compared with 27% in the PEG2a/R group; 43% vs 21%, respectively, developed neutropenia (neutrophil count <750/mm(3)). CONCLUSIONS: The addition of boceprevir after 4 weeks of lead-in therapy with PEG2a/R caused significantly higher rates of SVR in previously treated patients with chronic HCV genotype-1 infection, compared with patients given only PEG2a/R. ClinicalTrials.gov Identifier: NCT00845065.

Refinement of stopping rules during treatment of hepatitis C genotype 1 infection with boceprevir and peginterferon/ribavirin.

UNLABELLED: In comparison with peginterferon/ribavirin alone, boceprevir with peginterferon/ribavirin significantly improves sustained virological response (SVR) rates in patients with chronic hepatitis C virus (HCV) genotype 1 infections, but treatment failure remains a significant problem. Using phase 3 trial databases, we sought to develop stopping rules for patients destined to fail boceprevir-based combination therapy in order to minimize drug toxicity, resistance, and costs in the face of ultimate futility. Exploratory post hoc analyses using data from the Serine Protease Inhibitor Therapy 2 (SPRINT-2) study (treatment-naive patients) and the Retreatment With HCV Serine Protease Inhibitor Boceprevir and Pegintron/Rebetol 2 (RESPOND-2) study (treatment-experienced patients) were undertaken to determine whether protocol-specified stopping rules (detectable HCV RNA at week 24 for SPRINT-2 and at week 12 for RESPOND-2) could be refined and harmonized. In SPRINT-2, a week 12 rule with an HCV RNA cutoff of ≥ 100 IU/mL would have discontinued therapy in 65 of 195 failures (sensitivity = 33%) without sacrificing a single SVR among 475 successes (specificity = 100%). Viral variants emerged after week 12 in 36 of the 49 evaluable patients (73%) who would have discontinued at week 12 using a ≥ 100 IU/mL stopping rule. In RESPOND-2, five of six patients with week 12 HCV RNA levels between the lower limit of detection (9.3 IU/mL) and the lower limit of quantification (25 IU/mL) who continued therapy despite the protocol-stipulated futility rule achieved SVR; one additional patient with a week 12 HCV RNA level of 148 IU/mL also continued therapy, had undetectable HCV RNA at week 16, and attained SVR. CONCLUSION: Although a stopping rule of detectable HCV RNA at week 12 would have forfeited some SVR cases, week 12 HCV RNA levels ≥ 100 IU/mL almost universally predicted a failure to achieve SVR in both treatment-naive and treatment-experienced patients. In boceprevir recipients, the combination of 2 stopping rules-an HCV RNA level ≥ 100 IU/mL at week 12 and detectable HCV RNA at week 24--maximized the early discontinuation of futile therapy and minimized premature treatment discontinuation.