Prior Partial Responders Research Articles

Patient Disease Trajectories in Rheumatoid Arthritis Patients Treated with Baricitinib 4-mg in FourPhase 3 Clinical Studies.

We sought to identify and compare treatment response groups based on individual patient responses (rather than group mean response) over time on the Clinical Disease Activity Index (CDAI) for rheumatoid arthritis (RA), in patients treated with baricitinib 4-mg in 4phase 3studies. Trajectory subgroups were identified within each study using growth mixture modeling. Following grouping, baseline characteristics and disease measures were summarized and compared. In each study, three response trajectories were identified. In the three studies of patients naïve to biological disease-modifying anti-rheumatic drugs (bDMARDs) patients had, on average, high disease activity, as measured by CDAI. In these studies, a group of rapid responders (65-71% of patients) had the lowest baseline CDAI scores and achieved mean CDAI ≤ 10 by week 16. Gradual responders (10-17%) had higher baseline CDAI, but generally achieved low disease activity (CDAI ≤ 10) by week 24. A group of partial responders (18-22%) had higher baseline CDAI and did not achieve mean CDAI ≤ 10. In bDMARD-experienced patients, the subgroups were rapid responders, who achieved mean CDAI ≤ 10 (42% of patients); partial responders, with mean CDAI decrease of ~ 15 points from baseline (42% of patients); and limited responders (15% of patients). Changes in modified total sharp score (mTSS; assessed only in biologic-naïve patients) were below the smallest detectable difference at 24/52weeks for > 90% of patients in each group, excepting partial responders in RA-BEGIN (≥ 75% no detectable change). In patients receiving baricitinib 4-mg, lower baseline CDAI was generally associated with rapid response, while higher baseline CDAI scores were generally seen for patients who either reached treatment targets more gradually, or who had a partial or limited response. Maintenance of response was observed with continued baricitinib treatment in all response groups and generally included maintenance of mTSS.

Telaprevir combination therapy in patients infected with hepatitis C virus genotype 4

Background: The sustained virological response (SVR) rate for genotype 4 (G4) HCV-infected patients after pegylated interferon (PegIFN) and ribavirin (RBV) treatment is approximately 60%. We aimed to investigate the efficacy and safety of telaprevir (TVR) in combination with PegIFN and RBV in patients infected with G4 HCV who were previously treated with PegIFN/RBV and failed to achieve SVR. Material and Methods: The study included 10 patients: two prior relapsers, two prior partial responders, and six prior null responders to PegIFN/RBV treatment. The patients were given TVR/PegIFN/RBV for 12 weeks, followed by a 12-36 weeks PegIFN/RBV treatment. Rapid virological response (RVR), early virological response (EVR), extended rapid virological response (eRVR), SVR, and side effects of therapy were evaluated. Results: The mean age of the patients was 48.90±12.52 years and seven were female. All of HCV isolates were typed as 4d. Interleukin (IL) 28B genotype was found CT in seven patients and two patients had cirrhosis. Treatment was stopped within four weeks because of the side effects in two patients. Three of the remaining eight patients (37.5%) achived HVR, RVR, and eHVR. SVR was obtained in two of these patients, but one patient relapsed. SVR rates were 25% in all patients. Conclusion: TVR combination therapy had limited antiviral activity in this patient population. Further investigation of TVR combination therapy in patients with HCV G4 infection is warranted.

Retreatment of Chronic Hepatitis C Infection with Telaprevir: Preliminary Results in Turkey.

The use of pegylated interferon alpha and ribavirin (PegIFN/RBV) for the retreatment of chronic hepatitis C virus (HCV) infection without a sustained virological response (SVR) prior to PegIFN/RBV treatment has resulted in low success rates. To investigate the efficacy and safety of telaprevir (TVR) in combination with PegIFN/RBV in patients infected with HCV genotypes 1 and 4 who were previously treated with PegIFN/RBV and failed to achieve SVR. Multi-center, retrospective, cross-sectional study. The study included 111 patients: 80 prior relapsers, 25 prior null responders, and six prior partial responders to PegIFN/RBV treatment. The patients were given TVR/PegIFN/RBV for 12 weeks, followed by a 12-week PegIFN/RBV treatment; virological response results were assessed at weeks 4, 12, and 24. Treatment was discontinued in patients with HCV RNA >1000 IU/mL at week 4 or with negative RNA results at week 4 but >1000 IU/mL at week 12. Rapid virological response (RVR), early virological response (EVR), extended rapid virological response (eRVR), and virological response at 24th week of treatment were evaluated. The side effects of combination therapy and the rates of treatment discontinuation were investigated. The mean age of the patients was 56.02±9.96 years and 45.9% were male. Ninety-one percent of the patients were infected with viral genotype 1, 69.6% with the interleukin (IL) 28B genotype CT and 20.2% were cirrhotic. The RVR rate was 86.3% in prior relapsers, 56% in prior null responders, and 50% in prior partial responders (p=0.002). EVR rates in those groups were 91.3%, 56%, and 83.3%, respectively (p<0.001). eRVR rates were 83.8% in prior relapsers, 48% in prior null responders, and 50% in prior partial responders (<0.001). The virological response at the 24th week of treatment was found to be the highest in prior relapsers (88.8%); it was 56% in prior null responders and 66.7% in prior partial responders (p<0.001). Common side effects were fatigue, headache, anorexia, malaise, anemia, pruritus, dry skin, rash, dyspepsia, nausea, pyrexia, stomachache, and anorectal discomfort. All treatments were discontinued due to side effects in 9.9% of patients. High virological response rates were obtained with TVR/PegIFN/RBV treatment. Although side effects were frequently observed, the discontinuation rate of combination therapy was low.

Direct costs of first-generation protease inhibitors for the treatment of genotype 1 chronic hepatitis C viral infection.

To evaluate the cost-effectiveness of Hepatitis C therapy, robust real-world data are needed to understand the costs and benefits of treatment alternatives. The objective of this study was to evaluate the true direct cost of treatment in an unselected sequential population of patients treated at a tertiary care centre for hepatitis C virus genotype 1. A total of 200 consecutive patients were treated with interferon, ribavirin and a first-generation direct-acting antiviral agent (DAA) between 2011 and 2013. A total of 41% had cirrhosis, 31% were prior relapsers, and 41% were prior partial or null responders. Costs used were wholesale acquisition cost prices for medications, average hospital costs per day for each diagnosis code based on US inpatient hospital charges. All costs were adjusted to 2013 dollars. Sustained virologic response (SVR) was achieved in 97 patients (48.5%). A total of 14% experienced relapse, 19% breakthrough or nonresponse, and 18.5% discontinued secondary to side effects. Twenty per cent of patients had at least one hospitalization attributable to a complication of therapy. Thirty-seven per cent of patients required erythropoietin-stimulating agents, 16% received filgastrim, and 15% needed a red blood cell transfusion. The mean overall cost of treatment was $83,851 per patient. The cost per SVR was $172,889; $266,670 for patients with cirrhosis. The costs per SVR after treatment with first-generation DAAs are dependent on the stage of disease and therapy side effects. These real-world costs significantly exceed those described in prior cost-effectiveness assessments and should be used instead for future studies.

Daclatasvir and asunaprevir plus peginterferon alfa and ribavirin in HCV genotype 1 or 4 non-responders

Improved therapies for peginterferon/ribavirin null or partial responders are needed. This study evaluated daclatasvir (NS5A inhibitor) and asunaprevir (NS3 protease inhibitor) plus peginterferon alfa-2a and ribavirin in this patient population. This open-label, phase 3 study (HALLMARK-QUAD; NCT01573351) treated patients with chronic hepatitis C virus (HCV) genotype 1 (n=354) or 4 (n=44) infection who had a prior null or partial response to peginterferon/ribavirin. Patients received daclatasvir 60 mg once-daily plus asunaprevir 100mg twice-daily, with weekly peginterferon alfa-2a and weight-based ribavirin for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12 (SVR12) among genotype 1-infected patients. Daclatasvir plus asunaprevir and peginterferon/ribavirin demonstrated SVR12 rates of 93% (95% CI 90-96) in prior non-responders infected with HCV genotype 1. SVR12 rates among genotype 4-infected patients were 98% (95% CI 93-100); one patient had a missing post-treatment week-12 HCV-RNA measurement, but achieved an SVR at post-treatment week 24, yielding a 100% SVR rate in genotype 4 patients. Prior peginterferon/ribavirin response, sex, age, IL28B genotype, or cirrhosis status did not influence SVR12 rates. Serious adverse events occurred in 6% of patients; 5% discontinued treatment due to an adverse event. Grade 3/4 laboratory abnormalities included neutropenia (22%), lymphopenia (16%), anemia (6%), thrombocytopenia (4%), and ALT/AST elevations (3% each). Daclatasvir plus asunaprevir and peginterferon/ribavirin demonstrated high rates of SVR12 in genotype 1- or 4-infected prior null or partial responders. The combination was well tolerated and no additional safety and tolerability concerns were observed compared with peginterferon/ribavirin regimens.

Efficacy and safety of simeprevir with PegIFN/ribavirin in naïve or experienced patients infected with chronic HCV genotype 4

Simeprevir (SMV) is a once-daily (QD), oral hepatitis C virus (HCV) NS3/4A protease inhibitor approved for treatment of genotype (GT) 1 and GT4 infection. This Phase III, open-label, single-arm study (RESTORE; NCT01567735) evaluated efficacy/safety of SMV with peginterferon-α-2a/ribavirin (PR) in patients with chronic HCV GT4 infection. 107 patients were included. Treatment-naïve (n=35) and prior relapse patients (n=22) received SMV 150mg QD+PR (12 weeks), followed by PR alone (12 or 36 weeks, response-guided [HCV RNA <25IU/ml detectable/undetectable at week 4 and <25IU/ml undetectable at week 12]). Prior non-responders (partial, n=10; null, n=40) received SMV/PR (12 weeks), followed by PR for 36 weeks. The primary endpoint was sustained virologic response 12 weeks after end of treatment (SVR12). Median age: 49.0years; 28.0% Black/African; 7.5% IL28B CC; 28.8% METAVIR F4. Overall, 65.4% (70/107) of patients achieved SVR12 (82.9% [29/35] treatment-naïve; 86.4% [19/22] prior relapsers; 60.0% [6/10] prior partial responders; 40.0% [16/40] prior null responders). In treatment-naïve and prior relapser patients fulfilling response-guided criteria for 24 weeks of treatment (88.6% [31/35] and 90.9% [20/22]), SVR12 rates were high: 93.5% [29/31] and 95.0% [19/20], respectively. Overall on-treatment failure and relapse rates were 23.4% (25/107) and 14.6% (12/82), respectively. Adverse events (AEs) were mainly grade 1/2; serious AEs were infrequent (4.7%) and considered unrelated to SMV. Efficacy and safety of SMV 150mg QD for 12 weeks with PR in treatment-naïve or -experienced patients with chronic HCV GT4 infection were in line with previous reports for HCV GT1 infection.

Low-density lipoprotein and other predictors of response with telaprevir-based therapy in treatment-experienced HCV genotype 1 patients: REALIZE study.

Predictors of response to treatment with peginterferon plus ribavirin are well established. In these post-hoc analyses of the REALIZE study, we sought to identify predictors of response for telaprevir-based triple therapy. Patients from the REALIZE study with baseline data for all predictors evaluated (including baseline disease characteristics and demographics, prior treatment response and baseline laboratory assessments) were included in the post-hoc analyses (n = 465). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes. Sustained viral response (SVR) rates were 86% in prior relapsers, 63% in prior partial responders and 32% in prior null-responders. In the final multivariate analysis, baseline factors predicting SVR were prior response to treatment [Odds ratio (OR) = 2.80; 95% confidence interval (CI), 2.13-3.69], low-density lipoprotein (LDL) (≥2.6 mmol/L) (OR = 2.11; 95% CI, 1.52-2.93), HCV genotype (OR = 0.58; 95% CI, 0.36-0.93), and maximum alanine amino transferase and aspartate amino transferase (OR = 0.62; 95% CI, 0.40-0.97). Prior response to peginterferon plus ribavirin treatment and LDL levels are the main independent predictive markers of response with telaprevir-based triple therapy.

Randomized study of danoprevir/ritonavir-based therapy for HCV genotype 1 patients with prior partial or null responses to peginterferon/ribavirin

Chronic hepatitis C treatment for prior non-responders to peginterferon (PegIFN)/ribavirin remains suboptimal. The MATTERHORN study evaluated regimens containing ritonavir-boosted danoprevir (danoprevir/r) in prior PegIFN alfa/ribavirin non-responders. Prior partial responders (N=152) were randomized to 24 weeks of twice-daily danoprevir/r 100/100mg, mericitabine 1000 mg and ribavirin 1000/1200 mg (IFN-free); danoprevir/r plus PegIFN alfa-2a/ribavirin (triple); or danoprevir/r, mericitabine and PegIFN alfa-2a/ribavirin (Quad). Prior null responders (N=229) were randomized to 24 weeks of IFN-free therapy, or quad alone (Quad 24) or quad plus 24-weeks of PegIFN alfa-2a/ribavirin (Quad 48). The primary endpoint was sustained virological response (HCV RNA <25 IU/ml) 24 weeks after end-of-treatment (SVR24). Due to high relapse rates, genotype (G) 1a patients in IFN-free arms were offered additional PegIFN alfa-2a/ribavirin. Among prior partial responders, SVR24 rates were 46.2%, 51.0%, and 86.0%, in the IFN-free, Triple and Quad arms, respectively; among prior null responders, SVR24 rates were 45.5%, 80.5%, and 83.8% respectively. Relapse rates were lower and SVR24 rates higher in G1b-infected than G1a-infected patients. SVR24 rates in G1a and G1b patients randomized to Quad were 75.0% and 96.2%, respectively, in the partial Quad arm, and 68.1% and 100%, respectively, in the null Quad 24 arm. Treatment failure was associated with resistance to danoprevir, but not to mericitabine, and was more common in G1a infected patients. Treatment was well-tolerated. Danoprevir/r, mericitabine plus PegIFN alfa-2a/ribavirin was well-tolerated and produced high overall SVR24 rates in prior partial and null responders to PegIFN alfa/ribavirin. In contrast, IFN-free regimens were associated with unacceptably high relapse rates.

Non-invasive fibrosis assessment predicts sustained virological response to telaprevir with pegylated interferon and ribavirin for chronic hepatitis C.

Liver fibrosis remains one of the most important predictors of sustained virological response (SVR) in this era of direct-acting antiviral treatment of chronic hepatitis C. We compare non-invasive fibrosis assessment with liver biopsy (METAVIR) in terms of their ability to predict SVR by telaprevir (TVR)-based triple therapy. This prospective study consisted of 108 patients with chronic HCV genotype 1 infection who received TVR in combination with pegylated interferon (PEG-IFN)-α2b and ribavirin (RBV). Non-invasive fibrosis data included transient elastography (FibroScan), FIB-4 index and aspartate aminotransferase to platelet ratio index (APRI). SVR was achieved by 84.3% of the patients by intention-to-treat analysis. In contrast to the high SVR rates for treatment-naive patients (87.1%, 27 of 31) and patients who previously relapsed (97.9%, 46 of 47), the SVR rate of prior partial/null responders was significantly lower (60.0%, 18 of 30). The impact of fibrosis on SVR was greater for prior partial/null responders, and fibrosis data, including both METAVIR score and non-invasive fibrosis assessments, were useful for predicting SVR. The METAVIR score (area under the receiver operating characteristic curve [AUROC] 0.91, cutoff ≤F2), FibroScan values (AUROC 0.99, cutoff ≤10.0 kPa), FIB-4 index (AUROC 0.91, cutoff ≤3.5) and APRI (AUROC 0.91, cutoff ≤0.80) were shown to have equal, excellent predictive power. An alternative to METAVIR score by liver biopsy, non-invasive fibrosis assessments are useful options for predicting SVR by prior partial or null responders in TVR-based triple therapy.

Influence of low-density lipoprotein cholesterol on virological response to telaprevir-based triple therapy for chronic HCV genotype 1b infection

Elevated serum low-density lipoprotein cholesterol (LDL-C) level has been associated with sustained virological response (SVR) by chronic hepatitis C patients treated with pegylated-interferon (PEG-IFN) α and ribavirin (RBV). The aim of this study was to investigate the relation between the baseline LDL-C level and the treatment outcome from telaprevir (TVR)-based triple therapy. This prospective, multicenter study consisted of 241 treatment-experienced patients infected with HCV genotype 1b. All received 12weeks of TVR in combination with 24weeks of PEG-IFNα2b and RBV. The SVR rate was 81.3% (196 of 241) by intention-to-treat analysis. Higher LDL-C level was strongly associated with SVR (P=1.3×10−8). The area under the receiver operating characteristic curve for predicting SVR was 0.78 and the cutoff value for the LDL-C level at baseline was 95mg/dL. In multivariable logistic regression analysis of predictors of SVR, LDL-C ⩾95mg/dL (odds ratio [OR] 3.60, P=0.0238), α-fetoprotein ⩽5.0ng/mL (OR 5.06, P=0.0060), prior relapse to PEG-IFNα and RBV (OR 5.71, P=0.0008), and rapid virological response (HCV RNA undetectable at week 4) (OR 5.52, P=0.0010) were extracted as independent predictors of SVR. For prior partial and null responders, the SVR rates of the groups with LDL-C ⩾95mg/dL were significantly higher than those of the <95mg/dL groups with IL28B TG/GG and pretreatment platelet count <150×109/L (both P<0.05). The baseline LDL-C level exerted a potent influence on the SVR of treatment-experienced patients treated with TVR-based triple therapy, especially for prior partial and null responders to PEG-IFNα and RBV.

Impact of IL28B polymorphisms on 24‐week telaprevir‐based combination therapy for Asian chronic hepatitis C patients with hepatitis C virus genotype 1b

The aim of this study was to clarify which or how factors could influence the probability of sustained virological response (SVR) in 24-week telaprevir-based triple combination therapy for East Asian chronic hepatitis C patients infected with hepatitis C virus genotype 1b. Of 140 patients who were enrolled in this study, 137 received 12-week telaprevir combined with 24-week pegylated interferon alpha-2b plus ribavirin and were subjected to the analysis. Factors associated with SVR were analyzed by multiple logistic regression analysis. Of the 137 patients, 112 (82%) achieved SVR. Of 87 patients with IL28B single nucleotide polymorphism rs8099917 genotype TT, 84 (97%) achieved SVR. By contrast, 28 of 50 (56%) patients with the genotype TG/GG had SVR (P = 3.29 × 10(-9) ). Fifty-three of 60 (88%) naïve patients and 50 of 54 (93%) prior relapsers achieved SVR. Nine of 13 (69%) prior partial responders and none of 10 (0%) prior null responders achieved SVR. Multivariable analysis identified four independent factors that were significantly associated with SVR: IL28B SNP rs8099917 genotype (P = 6.90 × 10(-5) ), pre-existence of cirrhosis (P = 3.99 × 10(-3) ), prior treatment response (P = 0.0126), and rapid virological response (P = 0.0239). The IL28B single nucleotide polymorphism still remained informative as a predictor of SVR to 24-week telaprevir-based triple combination therapy for East Asian patients infected with hepatitis C virus genotype 1b.

Similar Effectiveness of Boceprevir and Telaprevir Treatment Regimens for Hepatitis C Virus Infection on the Basis of a Nationwide Study of Veterans

We investigated the real-world effectiveness of triple therapy regimens against hepatitis C virus (HCV) and compared rates of sustained virologic response (SVR) between telaprevir-based and boceprevir-based regimens in a population-based study. We analyzed data on all patients in the Veterans Administration healthcare system who were infected with HCV genotype 1 and began treatment with pegylated interferon, ribavirin, and either boceprevir (n = 3696, 83%) or telaprevir (n = 759, 17%) from June 2011 to February 2013. Patients treated with telaprevir were more likely to have baseline characteristics associated with not achieving SVR than patients treated with boceprevir. Fewer than half of patients eligible for short-duration regimens (28 weeks for boceprevir, 24 weeks for telaprevir) successfully completed treatment (37% for boceprevir, 27.5% for telaprevir); ∼25% discontinued early, and the remaining patients were treated for longer durations. Of the patients who were supposed to complete 48-week regimens, only 35% of boceprevir-treated and 34% of telaprevir-treated patients completed >44 weeks. The rate of SVR was 51.5% overall, 42.7% among patients with cirrhosis, 56.8% among treatment-naive patients, 64.2% among prior relapsers, 31.7% among prior partial responders, and 29.8% among prior null responders. There were no significant differences in rate of SVR between patients given boceprevir or telaprevir in the entire population or among subgroups. The most important predictors of failure to achieve SVR were IL28B genotype, high viral load, black race, diabetes, high aspartate aminotransferase to platelet ratio index or FIB-4 scores, low platelet counts, or low levels of low-density lipoprotein cholesterol. Erythropoietin use was not associated with SVR. In a nationwide analysis of veterans with HCV genotype 1 infection, rates of SVR were similar for those treated with boceprevir vs telaprevir. However, rates of treatment completion and SVR in real clinical practice were substantially lower than those in clinical trials.

Daclatasvir Combined with Peginterferon Alfa-2A and Ribavirin in Japanese Patients Infected with Hepatitis C Genotype 1

New direct-acting antiviral agents are currently being developed to treat chronic HCV. The efficacy and safety of daclatasvir combined with peginterferon alfa-2a (alfa-2a) and ribavirin were assessed in a randomized, double-blind Phase IIa study of Japanese patients with chronic HCV genotype-1 infection. Japanese patients who were treatment-naive (n=25) or prior null (n=12) or partial (n=5) responders received once-daily daclatasvir 10 mg or 60 mg or placebo in combination with alfa-2a and ribavirin. Daclatasvir recipients with a protocol-defined response (HCV RNA<15 IU/ml at week 4 and undetectable at week 12) were treated for 24 weeks; placebo recipients and patients without a protocol-defined response were treated for 48 weeks. Sustained virological response at 24 weeks post-treatment (SVR24) was achieved by 89% and 100% of treatment-naive patients receiving daclatasvir 10 mg and 60 mg, respectively, versus 75% in placebo recipients. Virological failure was more frequent in prior non-responder patients, with 50% and 78% achieving SVR24 in daclatasvir 10 mg and 60 mg groups, respectively. Adverse events occurred with similar frequency among treatment groups and were consistent with the adverse event profile of alfa-2a/ribavirin alone. The most commonly reported adverse events included pyrexia, alopecia, anaemia, lymphopenia, neutropenia, pruritus and diarrhoea. Three patients discontinued treatment due to anaemia. Daclatasvir combined with alfa-2a/ribavirin in treatment-naive patients showed greater efficacy than alfa-2a/ribavirin alone and was generally well tolerated. The 60-mg dose of daclatasvir achieved the highest rates of SVR24 in both treatment-naive and non-responder populations and will be evaluated in a Phase III clinical trial.

A Randomized Trial of Daclatasvir with Peginterferon Alfa-2B and Ribavirin for HCV Genotype 1 Infection

Daclatasvir-containing regimens have the potential to address limitations of current regimens combining peginterferon alfa and ribavirin with first-generation protease inhibitors for treatment of chronic HCV genotype 1 infection. In this randomized, double-blind study, 27 Japanese treatment-naive patients received once-daily daclatasvir 10 mg or 60 mg or placebo, each combined with peginterferon alfa-2b/ribavirin; 18 prior null (n=9) or partial (n=9) responders received the same daclatasvir-containing regimens without a placebo arm. Daclatasvir recipients with protocol-defined response (HCV RNA<15 IU/ml at week 4, undetectable at week 12) were treated for 24 weeks; those without protocol-defined response and placebo recipients continued treatment to week 48. Sustained virological response 24 weeks post-treatment (SVR24) was achieved by 66.7%, 90.0% and 62.5% of treatment-naive patients in the daclatasvir 10 mg, 60 mg and placebo groups, respectively. Prior non-responders had more frequent virological failure; 22.2% and 33.3% of daclatasvir 10 mg and 60 mg recipients, respectively, achieved SVR24. Adverse events were similar across groups and were typical of peginterferon alfa-2b/ribavirin. Pyrexia, headache, alopecia, decreased appetite and malaise were the most common adverse events; two daclatasvir recipients discontinued due to adverse events. Daclatasvir 60 mg combined with peginterferon alfa-2b and ribavirin achieved a high rate of SVR24 in treatment-naive patients with HCV genotype 1 infection, with tolerability similar to that of peginterferon alfa-2b/ribavirin alone. However, regimens with greater antiviral potency are needed for prior non-responders.

Faldaprevir combined with peginterferon alfa-2a and ribavirin in chronic hepatitis C virus genotype-1 patients with prior nonresponse: SILEN-C2 trial

Faldaprevir (BI 201335) is a potent, hepatitis C virus (HCV) NS3/4A protease inhibitor. In all, 290 noncirrhotic HCV genotype (GT)-1 patients with prior null (<1 log10 viral load [VL] drop at any time on treatment) or partial response (≥1 log10 VL drop but never undetectable on treatment) were randomized 2:1:1 to receive 48 weeks of peginterferon alfa-2a and ribavirin (PegIFN/RBV) in combination with faldaprevir 240 mg once daily (QD) with 3 days PegIFN/RBV lead-in (LI), 240 mg QD without LI, or 240 mg twice daily (BID) with LI. Patients in the 240 mg QD/LI group achieving maintained rapid virologic response (mRVR; VL <25 IU/mL [Roche TaqMan] at week 4 and undetectable at weeks 8 to 20) were rerandomized to cease all treatment at week 24 or continue PegIFN/RBV up to week 48. Sustained virologic response (SVR) rates were 32%, 50%, and 42% in prior partial responders, and 21%, 35%, and 29% in prior null responders in the faldaprevir 240 mg QD/LI, 240 mg QD, and 240 mg BID/LI groups, respectively. In the 240 mg QD/LI group, a significantly higher proportion of mRVR patients rerandomized to 48 weeks' treatment achieved SVR compared with those assigned to 24 weeks treatment (72% versus 43%; P = 0.035). Rates of gastrointestinal disorders, jaundice, dry skin, and photosensitivity were increased at 240 mg BID compared with the 240 mg QD dose. Faldaprevir discontinuations owing to adverse events occurred in 6%, 4%, and 23% of patients in the 240 mg QD/LI, 240 mg QD, and 240 mg BID/LI groups, respectively. Faldaprevir 240 mg QD with PegIFN/RBV was safe and tolerable and produced substantial SVR rates in prior null and partial responders. The 240 mg QD dose is currently undergoing phase 3 evaluation.

Early Virologic Responses and Hematologic Safety of Direct-Acting Antiviral Therapies in Veterans With Chronic Hepatitis C

There are limited data on the early effectiveness of direct-acting antiviral (DAA) therapies for patients with hepatitis C virus (HCV) infection in routine medical practice. We aimed to evaluate real-world experience with DAA-based regimens. By using the Veterans Affairs' Clinical Case Registry, we conducted a prospective observational intent-to-treat analysis of veterans infected with HCV genotype 1 who began treatment with pegylated interferon, ribavirin, and boceprevir (BOC, n = 661) or telaprevir (TVR, n = 198) before January 2012. We determined rates of virologic response at treatment weeks 4, 8, 12, and 24; futility; early discontinuation; and adverse hematologic events. About one third of patients discontinued treatment by week 24 (30% BOC, 34% TVR). A higher percentage of treatment-naive, noncirrhotic patients receiving BOC had undetectable levels of virus at week 24 than patients receiving TVR (74% vs 60%; P = .03). There were no significant differences in rates of early response within subgroups of cirrhotic patients, prior relapsers, prior partial responders, or prior null responders. By week 24, treatment was determined to be futile for 14% of patients receiving BOC and 17% of those receiving TVR. No differences were observed in overall rates of anemia (50% BOC, 49% TVR) or thrombocytopenia (16% BOC, 18% TVR); higher rates of neutropenia were observed in BOC-treated patients (34% BOC, 21% TVR; P = .008). HCV-infected veterans treated in routine medical practice with DAA-based regimens (BOC or TVR) had rates of early response comparable with those reported in clinical trials. However, they had higher rates of futility and early discontinuation than clinical trial participants. Further studies are needed to determine rates of sustained viral response.

Boceprevir dosing for late responders and null responders: The role of bridging data between treatment-naïve and -experienced subjects

Boceprevir dosing for late responders and null responders: The role of bridging data between treatment-naïve and -experienced subjects

Characterization of telaprevir treatment outcomes and resistance in patients with prior treatment failure: Results from the REALIZE trial

In the Phase 3 REALIZE study, 662 genotype 1 hepatitis C virus (HCV)-infected patients with prior peginterferon/ribavirin treatment failure (including relapsers, partial, and null responders) were randomized to 12 weeks of telaprevir given immediately (T12/PR48) or following 4 weeks of peginterferon/ribavirin (lead-in T12/PR48), or 12 weeks of placebo (PR48), combined with a total of 48 weeks of peginterferon alfa-2a/ribavirin. Sustained virologic response (SVR) rates were 64% (T12/PR48), 66% (lead-in T12/PR48), and 17% (PR48). This analysis aimed to characterize treatment outcomes and viral variants emerging in telaprevir-treated patients not achieving SVR. HCV NS3·4A population sequencing was performed at baseline, during treatment, and follow-up. Telaprevir-resistant variants were classified into lower-level (3- to 25-fold 50% inhibitory concentration [IC(50) ] increase: V36A/M, T54A/S, R155I/K/M/T, and A156S) and higher-level (>25-fold IC(50) increase: V36M+R155K and A156T/V) resistance. Resistant variants were uncommon at baseline. Overall, 18% (52%, 19%, and 1% of prior null and partial responders and relapsers, respectively) of telaprevir-treated patients had on-treatment virologic failure, with no significant difference with or without a lead-in. Virologic failure during the telaprevir-treatment phase was predominantly associated with higher-level resistance; virologic failure during the peginterferon/ribavirin-treatment phase was associated with higher- or lower-level, or wildtype variants, depending on genotype. Relapse occurred in 9% of patients completing assigned treatment and was generally associated with lower-level resistant variants or wildtype. Resistant variants were no longer detectable by study end (median follow-up of 11 months) in 58% of non-SVR patients. In REALIZE, variants emerging in non-SVR, telaprevir-treated patients were similar irrespective of the use of a lead-in and were consistent with those previously reported. In most patients, resistant variants became undetectable over time.

Sustained virologic response rates with telaprevir by response after 4 weeks of lead-in therapy in patients with prior treatment failure

For hepatitis C virus (HCV)-infected patients who have not responded to previous PegIFN/ribavirin treatment, it is unclear whether subsequent direct-acting antiviral therapy outcomes are better predicted by prior treatment response or by on-treatment response to a PegIFN/ribavirin lead-in. In REALIZE, treatment-experienced patients randomized to the lead-in telaprevir arm received 4 weeks of PegIFN-α-2a (180 μg/week) and ribavirin (1000-1200 mg/day), then 12 weeks of telaprevir (750 mg every 8h) plus PegIFN-α-2a/ribavirin, followed by 32 weeks of PegIFN-α-2a/ribavirin. This subanalysis only included patients in the lead-in telaprevir arm with available week 4 on-treatment response data (n=240). After 4weeks of PegIFN/ribavirin, 90% of relapsers, 60% of partial responders, and 41% of null responders in the lead-in telaprevir arm had ⩾1 log(10) HCV RNA reduction. Sustained virologic response (SVR) rates for telaprevir-treated patients with ≥1 versus <1 log(10) HCV RNA reduction after the PegIFN/ribavirin lead-in were 94% versus 62% in relapsers, 59% versus 56% in partial responders and 54% versus 15% in null responders. In prior relapsers and partial responders there is no apparent benefit of assessing response after a PegIFN/ribavirin lead-in with the aim of guiding telaprevir-based treatment. For patients known to be prior null responders, on-treatment response after a 4-week PegIFN/ribavirin lead-in may provide clinically useful prognostic information. However, withholding telaprevir-containing therapy in uncategorised treatment-experienced patient populations (i.e., that could include prior relapsers or partial responders), using response after a PegIFN/ribavirin lead-in could potentially exclude some patients with a high chance of SVR.

Interferon Responsiveness Does Not Change in Treatment-Experienced Hepatitis C Subjects: Implications for Drug Development and Clinical Decisions

The purpose of this research was to compare interferon (IFN) responsiveness in treatment-naive and pegylated interferon α-ribavirin (P/R)-experienced subjects and to understand the implications of comparability in IFN responsiveness across treatment courses on drug development and clinical decision making. Data from 3750 subjects treated with P/R in 8 trials were reviewed. The change in hepatitis C virus (HCV) RNA at week 4 in response to P/R was compared according to end-of-study (EOS) status (responder, relapser, partial and null responder) for treatment-naive subjects and the previous P/R response status (known as prior relapsers, prior partial responders, and prior null responders at the baseline) for P/R-experienced subjects. In subjects receiving a first course of P/R treatment (treatment-naive subjects), HCV RNA change after 4 weeks of P/R was correlated with EOS status on a P/R regimen. Importantly, for the first time, we have quantitatively demonstrated that IFN responsiveness in P/R-experienced subjects administered a second course of P/R treatment was similar to the IFN responsiveness in the treatment-naive subjects with corresponding EOS status. We contend that P/R-experienced subjects are represented within treatment-naive subjects. There are 2 important implications of this finding: (1) from a drug development perspective, a successful direct antiviral plus P/R therapy (IFN-based triple therapy) trial in P/R-experienced subjects may serve as supportive evidence in treatment-naive subjects; and (2) from a clinical decision perspective, previous P/R exposure should not alter new treatment decisions involving IFN-based triple therapy, as the IFN responsiveness to a second course of IFN is comparable.