The interferon-free regimen of ABT-450 with ritonavir (ABT-450/r), ombitasvir, and dasabuvir with or without ribavirin has shown efficacy in inducing a sustained virologic response in a phase 2 study ...involving patients with hepatitis C virus (HCV) genotype 1 infection. We conducted two phase 3 trials to examine the efficacy and safety of this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis.
We randomly assigned 419 patients with HCV genotype 1b infection (PEARL-III study) and 305 patients with genotype 1a infection (PEARL-IV study) to 12 weeks of ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and ribavirin administered according to body weight or to matching placebo for ribavirin. The primary efficacy end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter) 12 weeks after the end of treatment.
The study regimen resulted in high rates of sustained virologic response among patients with HCV genotype 1b infection (99.5% with ribavirin and 99.0% without ribavirin) and among those with genotype 1a infection (97.0% and 90.2%, respectively). Of patients with genotype 1b infection, 1 had virologic failure, and 2 did not have data available at post-treatment week 12. Among patients with genotype 1a infection, the rate of virologic failure was higher in the ribavirin-free group than in the ribavirin group (7.8% vs. 2.0%). In both studies, decreases in the hemoglobin level were significantly more common in patients receiving ribavirin. Two patients (0.3%) discontinued the study drugs owing to adverse events. The most common adverse events were fatigue, headache, and nausea.
Twelve weeks of treatment with ABT-450/r-ombitasvir and dasabuvir without ribavirin was associated with high rates of sustained virologic response among previously untreated patients with HCV genotype 1 infection. Rates of virologic failure were higher without ribavirin than with ribavirin among patients with genotype 1a infection but not among those with genotype 1b infection. (Funded by AbbVie; PEARL-III and PEARL-IV ClinicalTrials.gov numbers, NCT01767116 and NCT01833533.).
Summary 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.
The lifestyle causes of metabolic disorders in patients with hypothyroidism should be investigated. We aimed to assess the lifestyle and quality of life of women diagnosed with hypothyroidism and ...search for the presence of differences between the lifestyle and quality of life of women with and without diagnosed lipid metabolism disorders. This study included 311 women. To assess the differences between the groups with and without metabolic disorders, a non-parametric Mann–Whitney U test was performed. Of the products that were potentially beneficial for health, statistically significant differences in the average frequency of consumption were observed for legume seeds (p = 0.014), and of the products potentially unbeneficial for health, the frequencies of consumption of fried dishes (p = 0.016) and fast-food products (p = 0.001) were significant. Only 11.9% rated their free-time physical activity as high. The quality of life was significantly different between the groups. The lifestyle was moderately appropriate. Compared with women with lipid metabolism disorders, women without them exhibited a higher frequency of correct dietary behaviors regarding the consumption of products with a potentially beneficial effect and sleeping duration. Women without lipid metabolism disorders had a better quality of life. Women with hypothyroidism should be educated about the beneficial aspects of the regular consumption of vegetables, fruits, legumes, and fish and sleeping for the optimal amount of time.
Interconnections between hypothyroidism and metabolic disturbances manifesting in the liver and body composition have not yet been comprehensively analyzed in the context of lifestyle. This study ...aimed to assess the selected lifestyle factors and quality of life in the context of the development of NAFL (non-alcoholic fatty liver) in women diagnosed with hypothyroidism. This study included 134 women categorized into three groups: with hypothyroidism and NAFL, with only hypothyroidism, and with only NAFL. We compared the groups concerning the KomPAN and WHOQOL-BREF questionnaires, anthropometric measurements, body composition parameters, and the stage of liver steatosis. The individuals with NAFL most frequently consumed lard, fried dishes, processed meats, red meat, sweets, and sweetened beverages. The individuals with hypothyroidism without coexisting NAFL exhibited the highest satisfaction with health. The NAFL group had the highest average body fat percentage. Selected lifestyle aspects influenced the development of NAFL in women diagnosed with hypothyroidism. Women's overall quality of life did not vary depending on the coexisting medical conditions. Preventive programs should promote the following: the regular consumption of meals, the appropriate energy supply, physical activity, mental health support, and striving for proper body composition parameters.
(1) Background: Treatment of hepatitis C virus (HCV) infections with direct-acting antivirals (DAA) has demonstrated high efficacy and an excellent safety profile. The cured patients showed a ...sustained virological response and improved liver function, but also a continued risk of hepatocellular carcinoma (HCC) during the 2–3 years of follow-up after treatment; (2) Methods: A total of 192 patients out of 209 of the primary AMBER study were analyzed five years after treatment with ombitasvir/paritaprevir/ritonavir with or without dasabuvir and with or without ribavirin. Results: We confirmed that HCV clearance after DAA treatment is stable regardless of baseline liver fibrosis. We found that sustained virologic response is associated with a gradual but significant reduction in liver stiffness over 5 years. Liver function improved during the first 2 years of follow-up and remained stable thereafter. The risk of death due to HCC as well as death due to HCV persists through 5 years of follow-up after successful DAA treatment. However, in non-cirrhotic patients, it appears to clear up 3 years after treatment; (3) Conclusions: Monitoring for more than 5 years after curing HCV infection is necessary to assess the long-term risk of possible development of HCC, especially in patients with cirrhosis of the liver.
Direct-acting antivirals (DAA) regimens have provided hope for eliminating hepatitis C virus (HCV) infection. Patients following ineffective therapy with DAA, especially those previously treated with ...inhibitors of non-structural protein 5A (NS5A), remain a challenge. The study aimed to assess the effectiveness of DAA pangenotypic options in patients after failure of NS5A containing genotype-specific regimens. The analysis included 120 patients selected from the EpiTer-2 database with data on 15675 HCV-infected individuals treated with IFN-free therapies from 1 July 2015 to 30 June 2022 at 22 Polish hepatology centres. The majority of them were infected with genotype (GT) 1b (85.8%) and one-third was diagnosed with fibrosis F4. Among the rescue pangenotypic regimens, the most commonly used was the sofosbuvir/velpatasvir (SOF/VEL) ± ribavirin (RBV) combination. The sustained virologic response, which was a measure of treatment effectiveness, was achieved by 102 patients, resulting in cure rate of 90.3% in the per protocol analysis. All 11 non-responders were infected with GT1b, 7 were diagnosed with cirrhosis, and 9 were treated with SOF/VEL±RBV. We demonstrated the high effectiveness of the pangenotypic rescue options in patients after genotype specific NS5A-containing regimens failures, identifying cirrhosis as a negative prognostic factor of treatment effectiveness.
Chronic hepatitis C (CHC) is an ongoing epidemiological problem. The hepatitis C virus (HCV) may infect brain tissue, worsening mental health outcomes. The new era of highly effective oral ...Direct-Acting Agents (DAA) has brought a chance to eradicate the infection by 2030, however, screening campaigns are urgently needed as the majority of the infected are still undiagnosed. The aim of this study was to assess the prevalence of anxiety and depression among HCV patients, and the correlation with health-related quality of life (HRQoL) in the real-world setting, before and after DAA treatment. Data on anxiety, depression, and HRQoL, were collected by using self-reported questionnaires in a single center in Poland. The study group involved 90 respondents, 50% female, with a mean age of 43.8 years. HCV eradication decreased anxiety prevalence from 30.4% to 19.1% and depression from 35.2% to 18.2%. Significant improvement in 3 out of 4 of the WHOQOL-BREF (TheWorld Health Organization Quality of Life-BREF) domains and 8 out of 10 of the HQLQv.2 domains was obtained. Anxiety diminished the somatic domain scores by 3.5 (p < 0.0001), psychological by 2.3 (p = 0.0062), social by 1.75 (p = 0.0008), and environmental by 2.68 points (p = 0.0029). Depression diminished the somatic domain scores by 3.79 (p < 0.001), psychological by 2.23 (p < 0.001), social by 1.84 (p < 0.001), and environmental by 2.42 points (p = 0.004). In the Hepatitis Quality of Life Questionnaire version 2 (HQLQ v.2), the presence of depression and/or anxiety-impaired mental health, physical health, well-being, and vitality. These results indicate the need for an active search for HCV-infective people, especially among patients in psychiatric and psychological care.
The combination of three direct‐acting antiviral agents (AL‐335, odalasvir, and simeprevir: JNJ‐4178 regimen) for 6 or 8 weeks demonstrated good efficacy and safety in a phase IIa study in chronic ...hepatitis C virus (HCV) genotype (GT)‐1‐infected patients without cirrhosis and has now been evaluated in a larger phase IIb study, OMEGA‐1. This multicenter, randomized, open‐label study (NCT02765490) enrolled treatment‐naïve and interferon (±ribavirin) treatment‐experienced patients with HCV GT1, 2, 4, 5, or 6 infection. Patients with HCV GT3 infection and/or liver cirrhosis were excluded. Patients received AL‐335 800 mg, odalasvir 25 mg, and simeprevir 75 mg once daily for 6 or 8 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). In total, 365 patients (GT1a, 29.3%; GT1b, 42.5%; GT2, 12.3%; GT4, 14.2%; GT5, 1.4%; GT6, 0%) were randomized to receive 6 weeks (n = 183) or 8 weeks (n = 182) of treatment. SVR12 rates after 6 weeks (98.9%) or 8 weeks (97.8%) of treatment were noninferior to a historical control (98%). Viral relapse occurred in 5 patients (1.4%; 4 with HCV GT2c; 1 with GT1a). With the exception of 4 patients in the 8‐week group, including 3 patients with missing data at the SVR24 timepoint, all patients who achieved SVR12 also achieved SVR24. One GT1a‐infected patient experienced late viral relapse after achieving SVR18. Most adverse events (AEs) were mild with no treatment‐related serious AEs. All randomized patients completed treatment. Conclusion: In HCV‐infected patients, 6 and 8 weeks of treatment with JNJ‐4178 resulted in SVR12 rates of 98.9% and 97.8%, respectively, and was well tolerated.
Immunocompetent adults with certain medical and behavioral factors are at increased risk of pneumococcal disease. In some countries, sequential vaccination with 13-valent pneumococcal conjugate ...vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for at-risk adults. This subgroup analysis from a phase 3 study evaluated the safety, tolerability, and immunogenicity of sequential administration of either V114 (a 15-valent PCV containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F) or PCV13, followed 6 months later by PPSV23, in immunocompetent adults 18-49 years of age with pre-defined risk factors for pneumococcal disease. Safety and immunogenicity post-vaccination were analyzed by type and baseline number of risk factors for pneumococcal disease (1 and ≥2 risk factors). This analysis included 1,131 participants randomized 3:1 to receive either V114 or PCV13, followed by PPSV23. The majority (73.1%) of participants had at least one risk factor. Safety and tolerability profiles of V114 and PCV13 were similar across risk factor groups. V114 administered either alone or sequentially with PPSV23 6 months later was immunogenic for all 15 serotypes, including those not contained in PCV13, regardless of the number of baseline risk factors. V114 has the potential to broaden serotype coverage for at-risk adults.
The safety, tolerability, and efficacy of the non-bile acid farnesoid X receptor agonist tropifexor were evaluated in a phase II, double-blind, placebo-controlled study as potential second-line ...therapy for patients with primary biliary cholangitis (PBC) with an inadequate ursodeoxycholic acid response.
Patients were randomised (2:1) to receive tropifexor (30, 60, 90, or 150 μg) or matched placebo orally once daily for 28 days, with follow-up on Days 56 and 84. Primary endpoints were safety and tolerability of tropifexor and reduction in levels of γ-glutamyl transferase (GGT) and other liver biomarkers. Other objectives included patient-reported outcome measures using the PBC-40 quality-of-life (QoL) and visual analogue scale scores and tropifexor pharmacokinetics.
Of 61 enrolled patients, 11, 9, 12, and 8 received 30-, 60-, 90-, and 150-μg tropifexor, respectively, and 21 received placebo; 3 patients discontinued treatment because of adverse events (AEs) in the 150-μg tropifexor group. Pruritus was the most frequent AE in the study (52.5% tropifexor vs. 28.6% placebo), with most events of mild to moderate severity. Decreases seen in LDL-, HDL-, and total-cholesterol levels at 60-, 90-, and 150 μg doses stabilised after treatment discontinuation. By Day 28, tropifexor caused 26–72% reduction in GGT from baseline at 30- to 150-μg doses (p <0.001 at 60-, 90-, and 150-μg tropifexor vs. placebo). Day 28 QoL scores were comparable between the placebo and tropifexor groups. A dose-dependent increase in plasma tropifexor concentration was observed, with 5- to 5.55-fold increases in AUC0-8h and Cmax between 30- and 150-μg doses.
Tropifexor showed improvement in cholestatic markers relative to placebo, predictable pharmacokinetics, and an acceptable safety–tolerability profile, thereby supporting its potential further clinical development for PBC.
The bile acid ursodeoxycholic acid (UDCA) is the standard-of-care therapy for primary biliary cholangitis (PBC), but approximately 40% of patients have an inadequate response to this therapy. Tropifexor is a highly potent non-bile acid agonist of the farnesoid X receptor that is under clinical development for various chronic liver diseases. In the current study, in patients with an inadequate response to UDCA, tropifexor was found to be safe and well tolerated, with improved levels of markers of bile duct injury at very low (microgram) doses. Itch of mild to moderate severity was observed in all groups including placebo but was more frequent at the highest tropifexor dose.
This study is registered at ClinicalTrials.gov (NCT02516605).
Display omitted
•Phase II study on the farnesoid X receptor agonist, tropifexor, in patients with primary biliary cholangitis.•Itch of mild to moderate severity was the most frequent adverse event.•Markers of bile duct injury were reduced with tropifexor after 4 weeks of therapy.•Higher tropifexor exposure was observed in patients with PBC than that in healthy volunteers.
PDF
