Nintedanib and immunomodulatory therapies in progressive fibrosing interstitial lung diseases.

BACKGROUND: In the INBUILD trial in patients with chronic fibrosing interstitial lung diseases (ILDs) and a progressive phenotype, nintedanib reduced the rate of ILD progression with adverse events that were manageable for most patients. We investigated the potential impact of immunomodulatory therapies on the efficacy and safety of nintedanib. METHODS: Subjects with fibrosing ILDs other than idiopathic pulmonary fibrosis, who had shown progression of ILD within the prior 24 months despite management in clinical practice, were randomized to receive nintedanib or placebo. Certain immunomodulatory therapies were restricted for the first 6 months. We analyzed post-hoc the rate of decline in forced vital capacity (FVC) over 52 weeks in subgroups by glucocorticoid use at baseline and in analyses excluding subjects or FVC measurements taken after initiation of restricted immunomodulatory or antifibrotic therapies. RESULTS: Of 663 subjects, 361 (54.4%) were taking glucocorticoids at baseline (353 at a dose of ≤ 20 mg/day). In the placebo group, the adjusted rate of decline in FVC (mL/year) over 52 weeks was numerically greater in subjects taking than not taking glucocorticoids at baseline (- 206.4 [SE 20.2] vs - 165.8 [21.9]). The difference between the nintedanib and placebo groups was 133.3 (95% CI 76.6, 190.0) mL/year in subjects taking glucocorticoids at baseline and 76.1 (15.0, 137.2) mL/year in subjects who were not (interaction P = 0.18). The effect of nintedanib on reducing the rate of FVC decline in analyses excluding subjects or measurements taken after initiation of restricted immunomodulatory or antifibrotic therapies was similar to the primary analysis. The adverse event profile of nintedanib was similar between subjects who did and did not use prohibited or restricted therapies at baseline or during treatment with trial drug. CONCLUSIONS: In patients with progressive fibrosing ILDs, the effect of nintedanib on reducing FVC decline was not influenced by the use of immunomodulatory therapies. Nintedanib can be used in combination with immunomodulatory therapies in patients with progressive fibrosing ILDs. Trial registration ClinicalTrials.gov, NCT02999178. Registered 21 December 2016, https://clinicaltrials.gov/ct2/show/NCT02999178.

A tool for selecting patients with a high probability of sustained virological response to peginterferon alfa-2a (40kD)/ribavirin.

BACKGROUND & AIMS: Pretreatment identification of patients likely to achieve a sustained virological response (SVR) with peginterferon alfa-2a/ribavirin would be useful for individualizing treatment choices. The aim of this analysis was to devise a simple scoring system to identify patients with high probability of achieving an SVR with peginterferon alfa-2a/ribavirin. METHODS: Using data from 2109 Caucasian treatment-naive hepatitis C virus (HCV) genotype 1 mono-infected patients from the PROPHESYS cohorts, the relationship between favourable baseline characteristics and SVR was explored using generalized additive model analysis, and a scoring system was devised to predict SVR. RESULTS: Points were assigned for: age (years) (≤35: 2; >35, ≤45: 1; >45: 0); body mass index (kg/m(2)) (≤20: 2; >20, ≤22: 1; >22: 0); HCV RNA (IU/ml) (≤100,000: 3; >100,000-400,000: 2; >400,000-800,000: 1; >800,000: 0); platelets (>150 ×10(9)/l: 1; ≤150 ×10(9)/l: 0); alanine aminotransferase [×upper limit of normal (ULN)] (>3: 1; ≤3: 0); serum aspartate aminotransferase (×ULN) (≤1: 1; >1: 0). 1029, 698 and 382 patients had scores of 0-2, 3-4 and ≥5, respectively, among whom SVR rates were 35.0, 54.9 and 76.7%. SVR in patients with scores ≥5 and undetectable HCV RNA by week 4 was 86.7%. The score was tested against two databases of patients who received peginterferon alfa-2a/ribavirin in other clinical trials; similar high SVR rates in patients with scores ≥5 were reported. CONCLUSIONS: The scoring system can reliably identify treatment-naive HCV genotype 1 mono-infected Caucasian patients who have a high probability of achieving an SVR with peginterferon alfa-2a/ribavirin and will be particularly useful where protease inhibitors are not readily available.

In routine clinical practice, few physicians use early viral kinetics to guide HCV dual therapy treatment decisions.

BACKGROUND & AIMS: PROPHESYS is a large, multinational, non-interventional prospective cohort study of chronic hepatitis C patients treated with peginterferon alfa/ribavirin. This subanalysis assesses rates of premature treatment discontinuation stratified by on-treatment virological response (VR). METHODS: This PROPHESYS subanalysis is restricted to treatment-naive, hepatitis C virus (HCV) genotype (G)1/2/3 mono-infected patients who received peginterferon alfa-2a (40KD)/ribavirin with intended treatment duration of 48 (G1) or 24 weeks (G2/3). Early virological responses were classified into four mutually exclusive categories [rapid VR (RVR), complete early VR (cEVR), partial EVR (pEVR), no RVR/EVR], using standard criteria. RESULTS: The likelihood for shortening treatment owing to good efficacy was highest among patients with an RVR and HCV RNA≤400 000 IU/ml (G1 10.0%; G2/3 5.8%) whereas for poor efficacy, it was highest in G1 non-RVR/EVR patients with HCV RNA>400 000 IU/ml (56.6%). Factors significantly associated with early treatment discontinuation as a result of good efficacy in G1 patients included RVR vs. no RVR/EVR and, at baseline, lower HCV RNA, lower FIB-4 score, HCV infection via injection drug use. For G2/3 patients, factors included lower baseline HCV RNA and G2 vs. G3 infection. Most patients started with the recommended peginterferon alfa-2a dose, but a high proportion received a higher-than-recommended ribavirin dose. CONCLUSIONS: Despite international guidelines, few physicians used early viral kinetics to abbreviate treatment. Therefore, relatively few patients with an RVR and low baseline HCV RNA abbreviated treatment. In addition, there were deviations in ribavirin starting doses, suggesting that physicians tailor treatment according to local guidelines or previous experience.

Treatment Outcomes and Predictors of Response in Treatment-Naive HCV Patients Treated with Peginterferon Alfa/Ribavirin in Real-World Italian Clinics: Sub-Analysis from the PROPHESYS Cohort.

BACKGROUND/AIMS: Within Europe, Italy has the highest incidence of HCV. PROPHESYS was a large, non-interventional, multinational cohort study of patients treated with peginterferon alfa-2a or -2b/ribavirin for CHC; 22.4% of patients were from Italian centers. This sub-analysis evaluates real-life practice and treatment outcomes in Italy. METHODOLOGY: The PROPHESYS 2 cohort included 1604 HCV mono-infected, treatment-naive patients. All patients were prescribed peginterferon alfa/ribavirin at the discretion of the treating physician according to country-specific requirements. RESULTS: The majority of G1-3 patients were White/Caucasian and 48.4% had HCV G1 infection. Overall, SVR24 rates of 44.9%, 81.4% and 69.1% were achieved in G1-, 2- and 3-infected patients. In G1 patients, SVR24 rates declined with increasing FIB-4 score; this trend was not observed for G2/3-infected patients. Virologic response by Week 2 and 4 was highly predictive of SVR24 (G1: 91.7%, 84.8%; G2: 91.1%, 89.7%; G3: 92.9%, 86.7%, respectively). Absence of virologic response by Week 12 had the highest negative predictive value across genotypes. CONCLUSIONS: In Italian patients, a virologic response by Week 2 or 4 was highly predictive of SVR24 across genotypes. These data demonstrate the importance of monitoring on-treatment response to help guide treatment decisions. FIB-4 score correlated well with SVR24 in G1 patients.

High sustained virologic response rates in rapid virologic response patients in the large real-world PROPHESYS cohort confirm results from randomized clinical trials.

UNLABELLED: The ability to predict which patients are most likely to achieve a sustained virologic response (SVR) with peginterferon/ribavirin would be useful in optimizing treatment for hepatitis C virus (HCV). The objective of this large international noninterventional cohort study was to investigate the predictive value (PV) of a virologic response (VR) by weeks 2, 4, and 12 of treatment on SVR. Treatment-naive HCV monoinfected patients (N = 7,163) age ≥ 18 years were prescribed peginterferon/ribavirin at the discretion of the treating physician according to country-specific requirements in accordance with the local label. The main outcome measure was the PV of a VR (HCV RNA <50 IU/mL) by weeks 2, 4, and 12 of treatment for SVR24 (HCV RNA <50 IU/mL after 24 weeks of untreated follow-up) by HCV genotype. The overall SVR24 rate was 49.4% (3,541/7,163; 95% confidence interval [CI]: 48.3-50.6%). SVR24 rates in patients with an HCV RNA titer <50 IU/mL by weeks 2, 4, and 12, respectively, were 66.2% (95% CI: 60.4-71.7%), 68.4% (95% CI: 65.7-71.0%), and 60.3% (95% CI: 58.5-62.1%) among genotype 1 patients; 82.0% (95% CI: 76.8-86.5%), 76.3% (95% CI: 73.3-79.1%), and 74.2% (95% CI: 71.3-76.9%) among genotype 2 patients; 67.3% (95% CI: 61.1-73.1%), 67.3% (95% CI: 64.2-70.3%), and 63.8% (95% CI: 61.0-66.6%) among genotype 3 patients; and 59.4% (95% CI: 40.6-76.3%), 63.3% (95% CI: 54.3-71.6%), and 54.3% (95% CI: 47.5-60.9%) among genotype 4 patients. The absence of a VR by week 12 had the highest negative PV across all genotypes. CONCLUSION: A VR by week 2 or 4 had the highest positive PV for SVR24 and differed according to HCV genotype.