Safety, pharmacokinetics and pharmacodynamics of obeticholic acid in subjects with fibrosis or cirrhosis from NASH.

BACKGROUND & AIMS: Fibrosis stage is a strong predictor of nonalcoholic steatohepatitis (NASH) outcomes. Two blinded studies evaluated the pharmacokinetics, pharmacodynamics and safety of obeticholic acid (OCA) in subjects with staged NASH fibrosis or cirrhosis. METHODS: Study 747-117 randomized 51 subjects with NASH (fibrosis stages F1-F4) to daily placebo, OCA 10 or OCA 25 mg (1:2:2) for 85 days. Study 747-118 randomized 24 subjects with NASH cirrhosis (F4; Child-Pugh [CP]-A) and normal liver control subjects matched for similar body weight to daily OCA 10 or OCA 25 mg (1:1) for 28 days. Individual and combined study data were analysed. RESULTS: No severe or serious adverse events (AEs) or AEs leading to discontinuation or death occurred. Pruritus was the most frequent AE. Plasma OCA exposure (dose-normalized area under the curve) increased with fibrosis stage but was a relatively poor predictor of hepatic OCA exposure (primary site of action), which remained constant across fibrosis stages F1-F3 and increased 1.8-fold compared with F1 in subjects with cirrhosis due to NASH. Both cohorts showed robust changes in farnesoid X receptor activation markers with OCA treatment and marked decreases in alanine transaminase, aspartate transaminase and gamma-glutamyltransferase. CONCLUSIONS: Despite higher drug exposures in subjects with NASH cirrhosis, short-term daily treatment with OCA 10 or 25 mg was generally safe and well tolerated in subjects with NASH fibrosis or NASH CP-A cirrhosis. Both cohorts experienced improvements in nonhistologic pharmacodynamic markers consistent with previously conducted OCA phase 2 and phase 3 studies in NASH fibrosis.

Pivoting to telemedicine in a single-day multidisciplinary liver tumor clinic during COVID-19: the Texas Liver Tumor Center experience.

Cancer guidelines recommend that all patients with hepatocellular carcinoma (HCC) have an evaluation by a multidisciplinary team to assess liver health, stage the cancer, and discuss treatment and palliative care options. Coronavirus disease 2019 (COVID-19) had a catastrophic impact on patients with cancer resulting in increased disease burden due to late diagnosis and treatment delays. Late diagnosis has highlighted the need for the early intervention of palliative care for patients with HCC. Conversion to telemedicine has been essential to caring for patients with all stages of cancer without added delays. Texas Liver Tumor Center (TLTC) offers patients with liver cancer at any stage a single-day multidisciplinary evaluation with tumor board review facilitating the early integration of treatment and palliative care services. National Comprehensive Cancer Network (NCCN) guidelines support increasing and improving access to palliative care. TLTC allows for the early integration of palliative care within a 1-day clinic model with an incorporated tumor board. This unique model of patient care decreases the burden of separate patient visits, may expedite the time from diagnosis to first treatment, facilitates the early intervention of palliative care specialists, and allows for optimal screening for clinical trials. In this review, we will provide an overview of the current multidisciplinary models of care for HCC and describe the successful pivot of TLTC from a fully in-person single-day multidisciplinary clinic with a multidisciplinary tumor board (MDTB) to a fully virtual experience, thereby maintaining access to this unique clinical model of patient care during the COVID-19 pandemic. The ability to pivot from in-person clinical visits to completely virtual visits increases patient access to care and enables more physicians to participate. Areas for future study include the impact on patient experience, clinical outcomes, and cost-effectiveness of this high-resource model.

High sustained virologic response rates, regardless of race or socioeconomic class, in patients treated with chronic hepatitis C in community practice using a specialized pharmacy team.

Approved direct-acting antiviral (DAA) regimens against hepatitis C virus (HCV) can cure nearly all patients; however, socioeconomic disparities may impact access and outcome. This study assesses socioeconomic factors, differences in insurance coverage and the drug prior authorization process in HCV-infected patients managed in community practices partnered with a dedicated pharmacy team with expertise in liver disease. This Institutional Review Board-approved, ongoing study captures data on a cohort of 2480 patients from community practices. Patients had chronic hepatitis C and were treated with DAA regimens selected by their physician. The HCV Health Outcomes Centers Network provides comprehensive patient management including a dedicated pharmacy support team with expertise in the prior authorization process. In this cohort, 60.1% were male, 49% were Hispanic Whites (HW), 37% were Non-Hispanic Whites (NHW), and 14% were Black/African American (BAA). Eighty-seven percent of patients were treatment-naïve, 74% were infected with genotype 1 virus and 63% had advanced fibrosis/cirrhosis (F3/F4 = 68.2% HW, 65.6% BAA, 55.4% NHW). Forty percent of patients were on disability with the highest percentage in the BAA group and less than one-third were employed full time, regardless of race/ethnicity. Medicare covered 42% of BAA patients versus 32% of HW and NHW. The vast majority of HW (80%) and BAA (75%) had a median income below the median income of Texas residents. Additionally, 75% of HW and 71% of BAA had median income below the poverty level in Texas. Despite the above socioeconomic factors, 92% of all prior authorizations were approved upon first submission and patients received DAAs an average of 17 days from prescription. DAA therapy resulted in cure in 95.3% of patients (sustained virologic response = 94.8% HW, 94.0% BAA, 96.5% NHW). Despite having more advanced diseases and more negative socioeconomic factors, >94% of HW and BAA patients were cured. Continued patient education and communication with the healthcare team can lead to high adherence and > 94% HCV cure rates regardless of race/ethnicity or underlying socioeconomic factors in the community setting.

Durability of sustained virological response to glecaprevir/pibrentasvir and resistance development: A long-term follow-up study.

BACKGROUND AND AIMS: This study aimed to determine durability of sustained virologic response (SVR) in hepatitis C virus-infected participants treated with glecaprevir- and/or pibrentasvir-containing regimens. METHODS: M13-576, a rollover study, evaluated the durability of SVR in a follow-up period of approximately 3 years after hepatitis C virus genotype 1-6-infected participants received a glecaprevir- and/or pibrentasvir-containing regimen in previous phase 2/3 clinical trials. The primary efficacy endpoint was the percentage of participants maintaining SVR and the percentage of participants experiencing relapse or reinfections. Resistance-associated substitutions and safety outcomes related to liver progression were also assessed. RESULTS: Of 384 participants enroled, 377 participants were included in the as-observed population and 287 participants completed the study. In prior studies, 99.7% (376/377) of participants achieved SVR12; of those, an observed 99.5% (374/376) and 100% (286/286) completing the study, maintained SVR. After non-responder imputation of missing data, 286/376 participants (76%) maintained SVR. The participant previously not achieving SVR was a treatment-experienced male with compensated cirrhosis who had NS3 and NS5A substitutions at enrolment, which remained detectable for 12 months. Of the two participants not maintaining SVR, one was re-infected and one experienced late relapse at post-treatment week 60. Five participants (all with a fibrosis stage ≥F3) had hepatocellular carcinoma. No events were deemed related to glecaprevir/pibrentasvir. CONCLUSIONS: Glecaprevir/pibrentasvir demonstrated long-term durability of efficacy after SVR12 was achieved. Hepatic-related decompensation events were not seen. Owing to low incidence of virologic failure, conclusions were not drawn on persistence of resistance-associated substitutions.

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.

The Current Management of Hepatorenal Syndrome-Acute Kidney Injury in the United States and the Potential of Terlipressin.

Acute kidney injury (AKI) in the setting of cirrhosis (hepatorenal syndrome [HRS]-AKI) is a severe and often fatal complication of end-stage liver disease. The goals of treatment are to reverse renal failure and prolong survival in patients who are critically ill. However, interventions have limited efficacy, and mortality rates remain high. In the United States, the mainstay of pharmacologic therapy consists of the off-label use of vasoconstrictive agents in combination with plasma expanders, a strategy that produces modest effects. Liver transplantation is the ultimate solution but is only an option in a minority of patients because contraindications to transplantation are common and organ availability is limited. Renal replacement therapy is a temporary option but is known to confer an extremely poor short-term prognosis in patients with HRS-AKI and at best serves as a bridge to liver transplantation for the minority of patients who are transplantation candidates. The high mortality rate associated with HRS-AKI in the United States is a reflection of the suboptimal standard of care. Improved therapeutic options to treat HRS-AKI are sought. Terlipressin is a drug approved in Europe for treatment of HRS-AKI and supported by recommendations for first-line therapy by some liver societies and experts around the world. This review article will discuss the substantial unmet medical need associated with HRS-AKI and the potential benefits if terlipressin was approved in the United States.

Efficacy and safety of glecaprevir/pibrentasvir in patients with HCV genotype 5/6: An integrated analysis of phase 2/3 studies.

BACKGROUND & AIMS: Hepatitis C virus (HCV) has high genetic diversity with six major genotypes (GT) GT1-6 and global distribution. HCV GT5 and 6 are rare with < 10 million people infected worldwide. Data on direct-acting antiviral use in these rare HCV genotypes are limited. The study aimed to evaluate the efficacy and safety of glecaprevir/pibrentasvir (G/P) in a pooled analysis of phase 2/3 trials in HCV GT5 or 6-infected patients without cirrhosis or with compensated cirrhosis. METHODS: Patients with chronic HCV GT5 or 6 infection received oral G/P (300 mg/120 mg) once daily for 8 or 12 weeks. The primary efficacy endpoint was sustained virological response at post-treatment week 12 (SVR12) in the intention-to-treat population. RESULTS: One hundred eighty-one patients were evaluated; 56 with HCV GT5 and 125 with HCV GT6. The majority were treatment-naïve (88%) and non-cirrhotic (85%). Overall SVR12 rate with 8- or 12-week G/P treatment was 98% (178/181). Eight-week treatment with G/P yielded SVR12 rates of 95% (21/22) in HCV GT5- and 99% (69/70) in HCV GT6-infected non-cirrhotic patients. Eight- and 12-week treatment of patients with compensated cirrhosis achieved SVR12 rates of 100% (10/10) and 94% (17/18) respectively. The G/P regimen was well-tolerated; 3% (6/181) Grade 3 or higher adverse events, and no serious adverse events were attributed to G/P or led to study drug discontinuation. CONCLUSIONS: This integrated dataset demonstrates a high SVR12 rate following 8-week G/P treatment in patients with HCV GT5 (96%) or GT6 (99%) infection without cirrhosis or with compensated cirrhosis.

Simeprevir, daclatasvir, and sofosbuvir for hepatitis C virus-infected patients: Long-term follow-up results from the open-label, Phase II IMPACT study.

BACKGROUND AND AIMS: Direct-acting antiviral agents (DAAs) for hepatitis C virus (HCV) infection have resulted in high rates of sustained virologic response (SVR) following 8 to 24 weeks of treatment. However, difficult-to-cure/cirrhotic patients typically require a longer treatment duration and less is known regarding the long-term durability of SVR or effect on liver disease progression; to assess this, the IMPACT study followed patients for a 3-year period after end of treatment. METHODS: The Phase II, open-label, nonrandomized IMPACT study assessed the efficacy, safety, and pharmacokinetics of the combination of three DAAs (simeprevir, sofosbuvir, and daclatasvir) in HCV genotype 1/4-infected, treatment-naïve/-experienced cirrhotic patients with portal hypertension or decompensated liver disease. Patients from a single site in the United States were assigned to one of two groups by Child-Pugh (CP) score: CP A, CP score less than 7 and evidence of portal hypertension; CP B, CP score of 7 to 9. All patients received simeprevir 150 mg, daclatasvir 60 mg, and sofosbuvir 400 mg once-daily for 12 weeks between September 2014 and August 2015. All 40 patients included in the study (male, 63%; median age, 58.5 years) achieved SVR 12 and 24 weeks after end of treatment, and the combination was well tolerated. RESULTS: All patients who reached the 3-year follow-up timepoint maintained SVR (CP A, 15/15; CP B, 18/18). CP scores and Model for End-stage Liver Disease scores remained relatively stable, and mean FibroScan and FibroTest scores declined. No new safety signals were identified. CONCLUSIONS: In the IMPACT study, virologic response to simeprevir, sofosbuvir, and daclatasvir was durable over 3 years (http://ClinicalTrials.gov number: NCT02262728).

Accuracy of Noninvasive Fibrosis Scores to Detect Advanced Fibrosis in Patients With Type-2 Diabetes With Biopsy-proven Nonalcoholic Fatty Liver Disease.

BACKGROUND: Recent guidelines have recommended screening for nonalcoholic fatty liver disease (NAFLD) and case finding of advanced disease with fibrosis in patients with type-2 diabetes (T2D). The aim of this study is to assess the accuracy of commonly used noninvasive scores to predict the presence of advanced fibrosis (AF) in a large cohort of diabetics in real-life settings. PATIENTS AND METHODS: Using International Classification of Diseases, Ninth Revision (ICD-9) codes, all patients with the diagnosis of T2D who had a liver biopsy for suspected NAFLD between January 2000 and December 2015, were identified and analyzed. Patients with secondary causes of hepatic steatosis were excluded. AST/ALT ratio, aspartate aminotransferase to platelet ratio index (APRI), fibrosis-4 (FIB-4) index, and Nonalcoholic fatty liver disease Fibrosis Score (NFS) were calculated to predict advanced disease. Sensitivity, specificity, and area under the receiver operator curve were calculated and compared with liver biopsies to predict the overall accuracy of each score. RESULTS: A total of 1319 patients with T2D underwent liver biopsy for suspected NAFLD. After exclusions, 1,157 subjects were included in the final analysis. Our cohort consisted of 64.6% females and 88.4% were whites. Overall, 85% of the population was overweight or obese (body mass index>25 kg/m). Liver biopsy showed 31.7% with AF [Nonalcoholic Steatohepatitis Clinical Research Network (NASH-CRN) stage 3 to 4]. In comparison to liver biopsy, for the diagnosis of AF, AST/ALT>1.4, APRI>1.5, FIB-4>2.67, and NFS>0.676 had reasonable specificities of 84.2%, 97.4%, 69.9%, and 93% but poor sensitivities of 27.4%, 16.5%, 6.7%, and 44.1%, respectively. Even at lower cutoff values of AST/ALT≥1, APRI≥1, and FIB-4≥1.45 sensitivities remained low at 60.7%, 27.9%, and 72.6%, respectively, except for NFS ≥-1.455 with sensitivity of 94.6%, but at this cutoff, its specificity decreased to 16.9%. The area under the receiver operator curve to detect AF was 0.62, 0.74, 0.77, and 0.72, respectively. CONCLUSIONS: In this large cohort of adult patients with T2D and NAFLD, commonly used fibrosis scores had reasonable specificity, but poor sensitivity for detecting AF in diabetics. The development of reliable biomarkers for NAFLD/NASH in diabetics is urgently needed.

Avatrombopag, an Alternate Treatment Option to Reduce Platelet Transfusions in Patients with Thrombocytopenia and Chronic Liver Disease-Integrated Analyses of 2 Phase 3 Studies.

AIMS: Thrombocytopenia complicates the management of patients with chronic liver disease (CLD) undergoing invasive procedures with a bleeding risk. Until recently, prophylactic platelet transfusion was the only treatment option, but has significant safety and efficacy limitations. Phase 3 data demonstrated the superiority of avatrombopag to placebo in reducing platelet transfusions for bleeding, supporting its recent approval. METHODS: Integrated analyses of pooled data (N = 435) from two randomized, double-blind, placebo-controlled, phase 3 studies assessed the original efficacy endpoints. Additional analyses included subgroup analyses, alternate Baseline platelet count definitions, and another efficacy endpoint. RESULTS: Avatrombopag was superior to placebo in increasing patients not requiring a platelet transfusion or rescue procedure, those achieving a platelet count ≥50 × 109/L on Procedure Day, and the change in platelet counts from Baseline. The avatrombopag treatment effect was consistently positive across clinically important disease and Baseline clinical characteristic subgroups, and using alternate Baseline platelet count cohort definitions. Similarly, more avatrombopag-treated patients achieved ≥50 × 109/L platelets with an increase of ≥20 × 109/L from Baseline. The incidence and severity of adverse events were similar between avatrombopag and placebo. Further, safety data demonstrated a low risk for thromboembolic events and hepatotoxicity. CONCLUSION: These integrated analyses confirmed the superiority of avatrombopag to placebo in reducing platelet transfusions or rescue procedures for bleeding in patients with thrombocytopenia and CLD scheduled to undergo an invasive procedure, and its tolerable safety profile. Importantly, these data warrant reconsideration of clinical decision making regarding the need to treat thrombocytopenia in patients with CLD. This trial was registered with NCT01972529 and NCT01976104.

Long-term safety and efficacy results in hepatitis C virus genotype 1-infected patients receiving ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin in the TOPAZ-I and TOPAZ-II trials.

The 3-DAA regimen consisting of ombitasvir/paritaprevir/ritonavir plus dasabuvir (OBV/PTV/r + DSV) ± ribavirin (RBV) has shown high sustained virologic response rates (~95%) in phase 3 clinical trials including >2300 HCV genotype 1-infected patients. Real-world evidence studies have confirmed the effectiveness of OBV/PTV/r ± DSV ± RBV in patients with chronic HCV genotype 1 infection and are consistent with clinical trial results. TOPAZ-I and TOPAZ-II are ongoing phase 3b trials, assessing safety, efficacy and long-term progression of liver disease and clinical outcomes for up to 5 years post-treatment in patients treated with OBV/PTV/r + DSV ± RBV. High rates of sustained virologic response (SVR) were achieved regardless of presence or absence of cirrhosis.In this report, we assessed the long-term progression of liver disease and incidence of clinical outcomes up to 3 years of post-treatment follow-up in patients with chronic HCV GT1 infection who were treated with (OBV/PTV/r + DSV) ± RBV in the TOPAZ-I and TOPAZ-II studies. Improvements were observed in liver disease markers including FIB-4, METAVIR and Child-Pugh scores as well as platelet counts. Clinical outcomes related to long-term progression of liver disease such as liver decompensation were infrequent (<1%). Hepatocellular carcinoma (HCC) occurred in 1.4% of cirrhotic patients.

The burden associated with thrombocytopenia and platelet transfusions among patients with chronic liver disease.

Background: Thrombocytopenia (TCP), a common complication of chronic liver disease (CLD), can cause uncontrolled bleeding during procedures. As such, CLD patients with TCP and platelet counts <50,000/µL often receive prophylactic platelet transfusions before invasive procedures. However, platelet transfusions are associated with clinical complications, which may result in increased healthcare utilization and costs.Objective: This retrospective database analysis describes the clinical and economic burden in CLD patients with TCP, CLD patients without TCP, and CLD patients with TCP who receive platelet transfusions.Methods: Adult CLD patients with or without TCP were identified in the IBM MarketScan Commercial Claims and Medicare Supplemental data from 1 January 2012 to 31 December 2015. CLD patients with or without TCP were propensity-score matched (1:1) for the analysis of annual healthcare utilization and costs. Platelet transfusions among CLD patients with TCP were identified using procedure codes.Results: Of the 601,626 patients with CLD, 8,292 (1.4%) patients with TCP were matched to patients without TCP. Among CLD patients with TCP, 981 (11.8%) patients received ≥1 platelet transfusions and met inclusion/exclusion criteria. Compared to patients without TCP, CLD patients with TCP had more complications, including higher prevalence of neutropenia (11.4% vs 2.9%) and bleeding events (21.4% vs 10.9%), greater resource utilization including greater average hospital admissions (1.2 vs 0.7, p < .01), greater average ER visits (2.1 vs 1.3, p < .01), higher average outpatient office visits (20.1 vs 18.4, p < .01), and higher average healthcare costs including total costs (p < .01), inpatient costs (p < .01), ER visit costs (p < .01), and outpatient office visit costs (p < .01). The mean annual total costs in CLD and TCP patients with platelet transfusions were $206,396.Conclusions: CLD patients with TCP, and particularly those who received platelet transfusions, experienced significantly greater clinical and economic burden compared to CLD patients without TCP. Safer and more cost-effective treatments to increase platelets are necessary.

Characterization of patients with both alcoholic and nonalcoholic fatty liver disease in a large United States cohort.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome (MetS) and is characterized by steatosis in the absence of significant alcohol consumption. However, MetS and significant alcohol intake coexist in certain individuals which may lead to the development of BAFLD. AIM: To assess the clinical characteristics of patients with both alcoholic and NAFLD (BAFLD) in a large cohort in the United States. METHODS: Adults from the National Health and Nutrition Examination Survey between 2003-2014 were included. NAFLD was diagnosed based on elevated alanine aminotransferase (ALT) and being overweight or obese in the absence of other liver diseases. BAFLD patients met the criteria for NAFLD but also had either MetS or type 2 diabetes and consumed excessive amounts of alcohol. Univariable and multivariable analysis were performed to assess differences between NAFLD and BAFLD and to compare severity based on a validated fibrosis score (FIB4 index). RESULTS: The prevalence of NAFLD was at 25.9% (95%CI; 25.1-26.8) and that of BAFLD was 0.84% (0.67, 1.02) which corresponds to an estimated 1.24 million Americans affected by BAFLD. Compared to NAFLD, patients with BAFLD were more likely to be male, smokers, have higher ALT, aspartate aminotransferase, triglycerides, and lower platelets; P < 0.01 for all. More importantly, after adjusting for MetS components, BAFLD patients were significantly more likely to have advanced fibrosis [adjusted OR (95%CI) based on FIB4 index > 2.67 was 3.2 (1.4, 7.0), P = 0.004]. CONCLUSION: A significant percentage of the American general population is afflicted by BAFLD and these patients tend to have more advanced liver fibrosis.

Real-world observational experience with direct-acting antivirals for hepatitis C: baseline resistance, efficacy, and need for long-term surveillance.

The aim of this study was to obtain real-world, US, observational data on the effect of baseline resistance-associated substitutions (RASs) on achieving sustained virologic response (SVR) in hepatitis C (HCV) patients treated with direct-acting antiviral (DAA) regimens; the need for long-term follow-up in post-SVR patients.It is uncertain if the presence of RASs limits efficacy to DAAs. Once SVR is achieved, society guidelines recommend long-term surveillance for hepatocellular carcinoma in certain patients. Real-world data are limited on these topics.Adult patients treated with DAAs at community hepatitis clinics between January 2015 and April 2017 were included in this study. Baseline resistance testing was performed before treatment. Per guidelines, post-SVR long-term monitoring was required in patients with F3 to F4 fibrosis before treatment or with elevated ALT levels (>19 U/L females; >30 U/L males).A total of 875 chronic, mostly GT1a (60%) HCV patients were treated with an approved DAA regimen. Average baseline AST and ALT were 75 and 67 U/L, respectively, and 47% had F3 to F4 fibrosis at baseline. SVR was achieved in 863 (98.6%) patients despite a high presence of baseline RASs (61%). Long-term monitoring was required post-SVR in 539 patients (62%).In a real-life, US cohort of HCV-infected patients, nearly all patients achieved SVR with available DAA regimens regardless of baseline RASs. Approximately two-thirds of these patients required long-term follow-up, despite viral eradication.

Ombitasvir/paritaprevir/ritonavir + dasabuvir +/- ribavirin in real world hepatitis C patients.

BACKGROUND: The hepatitis C virus (HCV) NS5A inhibitor ABT-267 (ombitasvir, OBV), the HCV NS4/4A protease inhibitor ABT-450 (paritaprevir, PTV), the CYP3A inhibitor ritonavir (r) and the non-nucleoside NS5B polymerase inhibitor ABT-333 (dasabuvir, DSV) (OBV/PTV/r + DSV) with or without ribavirin (RBV) is a direct-acting antiviral regimen approved in the United States and other major countries for the treatment of HCV in genotype 1 (GT1) infected patients. Patients with HCV who are considered "hard-to-cure" have generally been excluded from registration trials due to rigorous study inclusion criteria, presence of comorbidities and previous treatment failures. AIM: To investigate the efficacy of this regimen in HCV G1-infected patients historically excluded from clinical trials. METHODS: Patients were ≥ 18 years old and chronically infected with HCV GT1 (GT1a, GT1b or GT1a/1b). Patients were treatment-naïve or previously failed a regimen including pegylated interferon/RBV +/- telaprevir, boceprevir, or simeprevir. One hundred patients were treated with the study drug regimen, which was administered for 12 or 24 wk +/- RBV according to GT1 subtype and presence/absence of cirrhosis. Patients were evaluated every 4 wk from treatment day 1 and at 4 and 12 wk after end-of-treatment. RESULTS: Many of the patients studied had comorbidities (44.2% hypertensive, 33.7% obese, 20.2% cirrhotic) and 16% previously failed HCV treatment. Ninety-six patients completed study follow-up and 99% achieved 12-wk sustained virologic response. The majority (88.4%) of patients had undetectable HCV RNA by week 4. The most common adverse events were fatigue (12%), headache (10%), insomnia (9%) and diarrhea (8%); none led to treatment discontinuation. Physical and mental patient reported outcomes scores significantly improved after treatment. Almost all (98%) patients were treatment compliant. CONCLUSION: In an all-comers HCV GT1 population, 12 or 24-wk of OBV/PTV/r + DSV +/- RBV is highly effective and tolerable and results in better mental and physical health following treatment.

Efficacy and safety of ombitasvir/paritaprevir/ritonavir and dasabuvir with low-dose ribavirin in patients with chronic hepatitis C virus genotype 1a infection without cirrhosis.

Patients infected with hepatitis C virus (HCV) treated with interferon-free direct-acting antivirals may still require ribavirin. However, ribavirin is associated with adverse events that can limit its use. This open-label, multicentre, Phase 3 study evaluated the safety and efficacy of ombitasvir/paritaprevir/ritonavir + dasabuvir (OBV/PTV/r + DSV) with low-dose ribavirin for 12 weeks in genotype 1a-infected patients without cirrhosis. The primary efficacy endpoint was sustained virologic response at post-treatment Week 12 (SVR12). The primary safety endpoint was haemoglobin <10 g/dL during treatment and decreased from baseline. Overall, 105 patients enrolled. The SVR12 rate was 89.5% (n/N = 94/105; 95% CI, 83.7-95.4). The study did not achieve noninferiority versus the historic SVR12 rate for OBV/PTV/r + DSV plus weight-based ribavirin. Five patients experienced virologic failure, four discontinued, and two had missing SVR12 data. Excluding nonvirologic failures, the SVR12 rate was 94.9% (n/N = 94/99). One patient met the primary safety endpoint. OBV/PTV/r + DSV plus low-dose ribavirin offers an alternative option for patients in whom full-dose ribavirin may compromise tolerability, although noninferiority to the weight-based ribavirin regimen was not met.

Elbasvir/Grazoprevir in People With Hepatitis C Genotype 1 Infection and Child-Pugh Class B Cirrhosis: The C-SALT Study.

INTRODUCTION: Treatment options are limited for people infected with hepatitis C virus (HCV) with decompensated liver disease. The C-SALT study assessed elbasvir (EBR) plus grazoprevir (GZR) in individuals with HCV genotype 1 infection and Child-Pugh class B (CP-B) cirrhosis. METHODS: In this 12-week, phase 2, nonrandomized, open-label study (NCT02115321; Protocol MK-5172-059), participants with CP-B cirrhosis received EBR 50 mg plus GZR 50 mg once daily, and a control group of noncirrhotic participants received EBR 50 mg plus GZR 100 mg once daily. The primary endpoint was sustained virologic response 12 weeks after the end of therapy. RESULTS: Sustained virologic response at 12 weeks after the end of therapy was achieved by 27/30 (90.0%) CP-B participants and 10/10 (100.0%) noncirrhotic participants. Two participants relapsed, and one died during follow-up after having undetectable HCV RNA at the end of treatment. Most CP-B participants had stable or improved model for end-stage liver disease and Child-Pugh scores at follow-up week 12 compared with baseline. There was no significant difference in drug exposure between groups, despite the differing GZR dose. Adverse events occurring in >10% of participants were fatigue (CP-B: 30.0%; noncirrhotic: 30.0%), arthralgia (16.7%; 20.0%), nausea (10.0%; 20.0%), and headache (10.0%; 50.0%). No serious treatment-related adverse events or hepatic events of clinical interest occurred. CONCLUSIONS: EBR 50 mg plus GZR 50 mg once daily for 12 weeks was highly effective and well tolerated in a traditionally hard-to-treat population. TRANSLATIONAL IMPACT: Although EBR plus reduced-dose GZR is not available for people with CP-B cirrhosis, these results complement phase 2/3 trial data and real-world experience with EBR/GZR.

Safety and Pharmacokinetics of Glecaprevir/Pibrentasvir in Adults With Chronic Genotype 1-6 Hepatitis C Virus Infections and Compensated Liver Disease.

BACKGROUND: Untreated, chronic hepatitis C virus (HCV) infection may lead to progressive liver damage, which can be mitigated by successful treatment. This integrated analysis reports the safety, efficacy, and pharmacokinetics (PK) of the ribavirin-free, direct-acting, antiviral, fixed-dose combination of glecaprevir/pibrentasvir (G/P) in patients with chronic HCV genotype 1-6 infections and compensated liver disease, including patients with chronic kidney disease stages 4 or 5 (CKD 4/5). METHODS: Data from 9 Phase II and III clinical trials, assessing the efficacy and safety of G/P treatment for 8-16 weeks, were included. The presence of cirrhosis was determined at screening using a liver biopsy, transient elastography, or serum biomarkers. The objectives were to evaluate safety, the rate of sustained virologic response at post-treatment week 12 (SVR12), and steady-state PK by cirrhosis status. RESULTS: Among 2369 patients, 308 (13%) were Child-Pugh Class A, including 20 with CKD 4/5. Overall, <1% of patients experienced an adverse event (AE) that led to G/P discontinuation or G/P-related serious AEs (SAEs). The most common AEs were headache and fatigue, occurring at similar frequencies with and without cirrhosis. SAEs were more common in patients with CKD 4/5, but all were unrelated to G/P. There were no cases of drug-induced liver injury or clinically relevant hepatic decompensation. SVR12 rates were 96.4% (297/308) with compensated cirrhosis and 97.5% (2010/2061) without cirrhosis. PK analysis demonstrated a 2.2-fold increase in glecaprevir exposure, but not pibrentasvir exposure, in patients with compensated cirrhosis. CONCLUSIONS: G/P was safe and efficacious in patients with compensated liver disease, including those with CKD 4/5. CLINICAL TRIALS REGISTRATION: NCT02243280, NCT02243293, NCT02604017, NCT02640482, NCT02640157, NCT02636595, NCT02642432, NCT02651194, and NCT02446717.

Ombitasvir/paritaprevir/ritonavir and dasabuvir with or without sofosbuvir for patients with hepatitis C virus genotype 1 infection who failed a prior course of direct-acting antiviral therapy.

INTRODUCTION: Despite high efficacy of current direct-acting antiviral agents (DAAs) in treating chronic hepatitis C virus (HCV) infection, a small portion of patients fail treatment. QUARTZ-I was a phase 2, open-label, multicenter, two-part study that assessed the safety and efficacy of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) with dasabuvir (DSV) with or without the addition of sofosbuvir (SOF) and/or ribavirin (RBV) in DAA treatment-experienced adults with chronic HCV GT1 infection. MATERIALS AND METHODS: Genotype 1 HCV-infected patients with or without compensated cirrhosis had prior treatment failure to any DAA (part 1) or ledipasvir/SOF (part 2). Patients received OBV/PTV/r + DSV ± SOF with or without RBV for 12 or 24 weeks. The primary endpoint of this study is the percentage of patients achieving sustained virologic response at post-treatment week 12 (SVR12). RESULTS: In part 1 of the study, 95.5% (21/22) of patients achieved SVR12, and in part 2, the SVR12 rate was 85.7% (6/7). Most adverse events (AEs) were mild and moderate in severity. Two serious AEs occurred and were assessed as not being related to study drug, of which one resulted in study drug discontinuation. Two patients experienced grade 3 elevations of serum alanine aminotransferase, and no other grade ≥3 laboratory abnormalities were observed. CONCLUSION: The multi-targeted regimen of OBV/PTV/r + DSV ± SOF with or without RBV was effective in the treatment of patients who failed previous DAA regimens including NS3/4A protease and NS5A and NS5B polymerase inhibitors. These results provide a promising outcome for patients that traditionally had limited treatment options.