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-log(10) 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-log(10) decline in HCV-RNA after lead-in and 76% of those with >= 1-log(10) 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. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.

BACKGROUND:Resistance to direct-acting antivirals represents a new challenge in the treatment of chronic hepatitis C.METHODS:SPRINT-1 was a randomized study of treatment-naive patients with genotype (G) 1 hepatitis C infection (n=595) that evaluated the safety and efficacy of boceprevir (BOC) when added to pegylated interferon-α2b plus ribavirin (PR). Plasma samples collected at protocol-specified visits were analysed by population sequencing for detection of BOC-associated resistance-associated variants (RAVs).RESULTS:A total of 17/24 (71%) patients randomized to BOC with baseline RAVs achieved sustained virological response (SVR). V55A/I (n=14), Q41H (n=11) and T54S (n=9) were the most frequently detected polymorphisms at baseline. Seven non-SVR patients with baseline RAVs had V55A (relapse, n=3; breakthrough, n=1; and non-response, n=1) and/or R155K (non-response, n=2). In total, 63/144 (44%) patients with sequenced post-baseline samples (2 SVR, 61 non-SVR) had detectable RAVs after BOC treatment (G1a: R155K [39/49; 80%], V36M [37/49; 76%] and T54S [24/49; 49%]; G1b: T54S [3/11; 27%], T54A [4/11; 35%], A156S [2/11; 18%] and V170A [2/11; 18%]). RAV frequency varied according to the virological response: 90%, 67%, 27% and 37% of breakthrough, incomplete virological response, relapse and non-responder patients, respectively, had post-baseline RAVs present. Similar RAVs were identified in both the PR lead-in and no-lead-in arms and the frequency of post-baseline RAVs was highest in the low-dose ribavirin arm.CONCLUSIONS:SVR rates were not compromised among patients with RAVs at baseline; however, a lower starting mg/kg dose of ribavirin was associated with a higher frequency of post-baseline RAVs.

Background & AimsTriple 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.MethodsSPRINT-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.ResultsOnly 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.ConclusionsThe 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.

Background 82 Aims: Interferon-alfa (IFN)-related cytopenias are common and may be dose-limiting. We performed a genome wide association study on a well-characterized genotype 1 HCV cohort to identify genetic determinants of peginterferon-alpha, (pegIFN)-related thrombocytopenia, neutropenia, and leukopenia.Methods: 1604/3070 patients in the IDEAL study consented to genetic testing. Trial inclusion criteria included a platelet (PI) count >= 80 x 10(9)/L and an absolute neutrophil count (ANC) >= 1500/mm(3). Samples were genotyped using the Illumina Human610-quad BeadChip. The primary analyses focused on the genetic determinants of quantitative change in cell counts (PI, ANC, lymphocytes, monocytes, eosinophils, and basophils) at week 4 in patients >80% adherent to therapy (n = 1294).Results: 6 SNPs on chromosome 20 were positively associated with PI reduction (top SNP rs965469, p = 10(-10)). These tag SNPs are in high linkage disequilibrium with 2 functional variants in the ITPA gene, rs1127354 and rs7270101, that cause ITPase deficiency and protect against ribavirin (RBV)-induced hemolytic anemia (HA). rs1127354 and rs7270101 showed strong independent associations with PI reduction (p = showed strong independent associations with PI reduction (p = 10(-12), p = 10(-7)) and entirely explained the genome-wide significant associations. We believe this is an example of an indirect genetic association due to a reactive thrombocytosis to RBV-induced anemia: Hb decline was inversely correlated with PI reduction (r = -0.28, p = 10(-17)) and Hb change largely attenuated the association between the ITPA variants and PI reduction in regression models. No common genetic variants were associated with pegIFN-induced neutropenia or leucopenia.Conclusions: Two ITPA variants were associated with thrombocytopenia; this was largely explained by a thrombocytotic response to RBV-induced HA attenuating IFN-related thrombocytopenia. No genetic determinants of pegIFN-induced neutropenia were identified. (C) 2011 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.

Black Americans are disproportionally infected with hepatitis C virus (HCV) and are less likely than whites to respond to treatment with peginterferon (PEG-IFN) plus ribavirin (RBV). The impact of race on HCV treatment eligibility is unknown. We therefore performed a retrospective analysis of a phase 3B multicenter clinical trial conducted at 118 United States community and academic medical centers to evaluate the rates of and reasons for HCV treatment ineligibility according to self-reported race. In all, 4,469 patients were screened, of whom 1,038 (23.2%) were treatment ineligible. Although blacks represented 19% of treated patients, they were more likely not to be treated due to ineligibility and/or failure to complete required evaluations (40.2%) than were nonblack patients (28.5%; P < 0.001). After the exclusion of persons not treated due to undetectable HCV RNA or nongenotype 1 infection, blacks were 65% less likely than nonblacks to be eligible for treatment (28.1% > 17.0%; relative risk, 1.65; 95% confidence interval, 1.46-1.87; P < 0.001). Blacks were more likely to be ineligible due to neutropenia (14% versus 3%, P < 0.001), anemia (7% versus 4%, P = 0.02), elevated glucose (8% versus 3%, P < 0.001), and elevated creatinine (5% versus 1%, P < 0.001). Conclusion: Largely due to a higher prevalence of neutropenia and uncontrolled medical conditions, blacks were significantly less likely to be eligible for HCV treatment. Increased access to treatment may be facilitated by less conservative neutrophil requirements and more effective care for chronic diseases, namely, diabetes and renal insufficiency. (HEPATOLOGY 2011;54:70-78)

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.).

PRESENTATIONSand randomized (1:1:1) to receive placebo (A); GS-9450, 10 mg QD (B); or GS-9450, 40 mg QD (C) for 24 weeks.The primary outcome was pre-specified histologic response (≥2-point decrease in Knodell necroinflammation score with no worsening in fibrosis score) between study groups from pre-treatment and Week 24 liver biopsies.Results: 307 subjects were randomized and treated [n = 103 (A), 101 (B), and 103 (C)].70% were male, 81% were Caucasian, mean age was 53, mean baseline (BL) ALT was 107 IU/mL, mean BL HAI and fibrosis scores were 8.0 and 2.8, and 9% were cirrhotic.Median ALT in GS-9450 groups improved at Week 4, with normalization in 46%, and was maintained through Week 20 in a majority.Adverse events led to treatment discontinuation in 1.9% (A), 5.0% (B) and 4.9% (C) of patients.During treatment, Grade 3 or 4 treatment emergent (TE) ALT elevations occurred in 6.8% (A), 5.0% (B), and 7.8% (C) of subjects.Notably, three subjects receiving GS-9450 developed marked simultaneous marked simultaneous ALT (7, 8, 28 × BL) and bilirubin (4.3, 6.8, 11.0 mg/dL) elevation by Week 8-12, and two others developed marked marked ALT elevation alone (11, 18 ×BL), resulting in study termination by the sponsor for possible drug-induced livery injury (DILI).Two placebo recipients also developed simultaneous elevation of ALT (2, 3 ×BL) and bilirubin (1.9, 3.3 mg/dL).50% of study subjects received study medication through Week 20, and 87 paired liver biopsies were obtained.Histologic improvement by pre-defined criteria occurred in 10/27 (37%), 5/28 (18%) and 5/32 (16%) of Group A, B, and C subjects, respectively.Conclusions: GS-9450 induced ALT improvement in patients with chronic HCV infection previously failing PEG/RBV, but was associated with presumptive DILI.The histology data do not support the concept of therapeutic caspase inhibition in chronic HCV infection.

BACKGROUND & AIMS: We recently identified a polymorphism upstream of interleukin (IL)-28B to be associated with a 2-fold difference in sustained virologic response (SVR) rates to pegylated interferon-alfa and ribavirin therapy in a large cohort of treatment-naive, adherent patients with chronic hepatitis C virus genotype 1 (HCV-1) infection. We sought to confirm the polymorphism's clinical relevance by intention-to-treat analysis evaluating on-treatment virologic response and SVR. METHODS: HCV-1 patients were genotyped as CC, CT, or TT at the polymorphic site, rs12979860. Viral kinetics and rates of rapid virologic response (RVR, week 4), complete early virologic response (week 12), and SVR were compared by IL-28B type in 3 self-reported ethnic groups: Caucasians (n = 1171), African Americans (n = 300), and Hispanics (n = 116). RESULTS: In Caucasians, the CC IL-28B type was associated with improved early viral kinetics and greater likelihood of RVR (28% vs 5% and 5%; P < .0001), complete early virologic response (87% vs 38% and 28%; P < .0001), and SVR (69% vs 33% and 27%; P < .0001) compared with CT and TT. A similar association occurred within African Americans and Hispanics. In a multivariable regression model, CC IL-28B type was the strongest pretreatment predictor of SVR (odds ratio, 5.2; 95% confidence interval, 4.1-6.7). RVR was a strong predictor of SVR regardless of IL-28B type. In non-RVR patients, the CC IL-28B type was associated with a higher rate of SVR (Caucasians, 66% vs 31% and 24%; P < .0001). CONCLUSIONS: In treatment-naive HCV-1 patients treated with pegylated interferon and ribavirin, a polymorphism upstream of IL-28B is associated with increased on-treatment and sustained virologic response and effectively predicts treatment outcome.

Background: In SPRINT-2, BOC added to P/R given for 44 wks or as RGT after a 4-wk lead-in (LI) treatment period with P/R significantly improved the sustained virologic response (SVR) in treatment-naive G1 patients compared to standard of care. We examined whether RGT based on the HCV RNA response during Wks 8-24 for a total duration of 28 or 48 wks (but including only 24 wks of BOC from Wks 4 to Wk 28 regardless of the Wk 8-24 HCV RNA response) produced similar results to the 4-wk LI & then BOC/P/R for 44 wks. Methods: SPRINT-2 compared a LI treatment period with P/R, followed by (1) P/R plus placebo for 44 wks (48P/R); (2) RGT: BOC/P/R for 24 wks, with an additional 20 wks of P/R alone only if HCV RNA was detected during Wks 8-24 (LI+24BOC/P/R+/-20P/R); or (3) BOC/P/R for 44 wks (LI+44BOC/P/R). Study therapy was stopped for futility in patients with detectable HCV RNA at Wk 24. The primary efficacy endpoint was the SVR in all randomized patients treated with ≥1 dose of any study medication. Non-black (Cohort 1) & black (Cohort 2) patients were enrolled & analyzed separately per protocol. Results: In Cohort 1, the overall SVR (95%CI) was similar for RGT (66.8%) & LI+44BOC/P/R (68.5%), with a Δ=1.7% (-5.6%, 9.0%). For the 47% of subjects in RGT arm who achieved persistently undetectable HCV RNA during Wks 8-24, the SVR was 97% after LI+24/BOC/P/R & similar to the 96% SVR for the corresponding patients receiving LI+44BOC/P/R (Table). 31% of patients in the RGT arm discontinued treatment by 28 weeks (mostly due to the 24-wk futility rule or adverse events) & were not assigned a treatment duration. For the 22% of patients in the RGT arm with detectable HCV RNA during Wks 8-24 who received >28 wks of therapy, the SVR was 74% after LI+24BOC/P/R+20P/R & matched the 74% SVR for the corresponding patients given LI+44BOC/P/R. Generally comparable results were seen in the much smaller Cohort 2. Conclusions: RGT with LI+24BOC/P/R+/-20P/R based upon on-treatment HCV RNA response produced SVR similar to LI+44BOC/P/R. Non-black patients achieving undetectable HCV RNA on LI+BOC/P/R from Wk 8 through Wk 24 can have their treatment duration shortened from 48 wks to 28 wks. a 14 of the 15 patients were originally reported to have low detectable HCV-RNA level(s) between weeks 8-24 and assigned 48-week treatment duration, although two repeat tests on the detectable sample confirmed undetectable HCV-RNA. b Undetectable week 8 HCV-RNA 1 day outside week 8 visit window.

Background: The objective of this retrospective analysis was to investigate the correlation between HCV viral load declines at treatment weeks (TW) 4 and 12 in patients from the IDEAL trial in order to delineate a week 4 null response definition. Methods: 3070 treatment-naive, HCV genotype 1 infected patients were treated for up to 48 weeks with ribavirin 800-1400mg/day plus PEG2b 1.5 or 1 mcg/kg/week, or PEG2a 180mcg/ week plus ribavirin 1000-1200mg/day. Simple linear regression was used to assess the relationship between TW4 and TW12 log viral decline, and Pearson’s correlation coefficient (r) was computed. Concordance in subjects who had data at both TWs 4 and 12 was assessed using a definition for null response of <1 log decline at TW4 vs <2 log at TW12. Testing for IL28B was performed in 1604 patients. Results: There is a high positive correlation between HCV viral load decline at TWs 4 and 12 for patients receiving standard of care therapy: PEG2b 1.5/R (r=0.76), PEG2a/R (r=0.73), or PEG2b 1.0/R (r=0.78) (p<0.001 for each). Null response defined as a <2 log decline at TW12 corresponds to ~0.7-1.1 log decline at TW4 for PEG2b 1.5/R. Concordance of null or ‘non-null’ response defined by both TW4 and TW12 definitions was high for each of the treatment arms (Table) and for all 3 arms combined 89% (2459/2777) regardless of IL28b genotype, CC 98% (466/474) and CT/TT 83% (785/943). Nearly all patients who met the TW4 or TW12 definition for null response had the less favorable CT or TT allele. Conclusions: TW4 viral load decline of <1 log approximates to that of <2 logs at TW12 and is an earlier predictor of null response. The TW4 definition of null response may have increased utility in aiding early treatment decisions.

BACKGROUND & AIMS:Hepatitis C virus (HCV) treatment is frequently complicated by anemia from ribavirin (RBV)-related hemolysis and peginterferon-alfa (PEG-IFN)-related bone marrow suppression. We investigated the relationships among treatment outcomes, anemia, and their management with RBV dose reduction and/or erythropoiesis-stimulating agents (ESAs). METHODS:We analyzed data from a trial conducted at 118 United States academic and community centers in treatment-naïve patients with HCV genotype 1. Patients were treated for as many as 48 weeks with 1 of 3 PEG-IFN/RBV regimens. ESAs were permitted for anemic patients (hemoglobin [Hb] <10 g/dL) after RBV dose reduction. Sustained virologic responses (SVR) were assessed based on decreases in Hb, anemia, and ESA use. RESULTS:While patients received treatment, 3023 had their Hb levels measured at least once. An SVR was associated with the magnitude of Hb decrease: >3 g/dL, 43.7%; ≤3 g/dL, 29.9% (P < .001). Anemia occurred in 865 patients (28.6%); 449 of these (51.9%) used ESAs. In patients with early-onset anemia (≤ 8 weeks of treatment), ESAs were associated with higher SVR rate (45.0% vs 25.9%; P < .001) and reduced discontinuation of treatment because of adverse events (12.6% vs 30.1%, P < .001). ESAs did not affect SVR or discontinuation rates among patients with late-stage anemia. CONCLUSIONS:Among HCV genotype 1-infected patients treated with PEG-IFN/RBV, anemia was associated with higher rates of SVR. The effect of ESAs varied by time to anemia; patients with early-onset anemia had higher rates of SVR with ESA use, whereas no effect was observed in those with late-onset anemia. Prospective trials are needed to assess the role of ESAs in HCV treatment.