abt-450 and Liver-Neoplasms

Chronic hepatitis C (CHC) constitutes a major health concern. Hepatitis C virus eradication by antiviral treatment can markedly reduce the risk of developing cirrhosis, hepatocellular carcinoma and liver-related death. A plethora of new direct antiviral agents have been developed and are being explored in clinical trials. One of the newest members of this family is the NS3/4A protease inhibitor ABT-450. The multi-targeted approach combining ritonavir-enhanced ABT-450 with ombitasvir and dasabuvir has been evaluated for the treatment of CHC Gt1 in treatment-naïve and treatment-experienced adults. In this article, we sought to discuss the current knowledge on ABT-450-containing regimens, with special emphasis on treatment-experienced CHC Gt1 patients. This new combination was found to be potent, safe and well tolerated. Future Phase III trials with larger sample size in patients with decompensated cirrhosis, non-Gt1, end-stage renal disease and liver transplant recipients are eagerly awaited.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cyclopropanes; Drug Interactions; Drug Resistance, Viral; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Liver Neoplasms; Macrocyclic Compounds; Proline; Protease Inhibitors; Randomized Controlled Trials as Topic; Ribavirin; Ritonavir; RNA, Viral; Sulfonamides; Uracil; Valine

Chronic hepatitis C, without treatment, can cause liver cirrhosis, liver failure and liver cancer. The availability of new oral direct acting antivirals, such as the protease inhibitors simeprevir, asunaprevir and paritaprevir, the NS5A inhibitors daclatasvir, ledipasvir, and ombitasvir, the polymerase inhibitors Sofosbuvir and dasabuvir have resulted an enormous progress in the treatment of chronic hepatitis C, leading to >90% sustained viral response rates. Even the hard-to-treat or previously treatment ineligible patients can be cured with the combination of these drugs. Furthermore the treatment duration is much shorter, and the side effects are minimal. Today, treatment of all hepatitis C virus infected patients is recommended, and the best choices are the interferon-free options. Eradication of hepatitis C virus has become realistic, however, appropriate screening programs are mandatory to achieve this goal.

Topics: 2-Naphthylamine; Administration, Oral; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Clinical Trials as Topic; Cyclopropanes; Drug Therapy, Combination; Fluorenes; Hepacivirus; Hepatitis C, Chronic; Heterocyclic Compounds, 3-Ring; Humans; Imidazoles; Interferons; Isoquinolines; Lactams, Macrocyclic; Liver Neoplasms; Macrocyclic Compounds; Nucleic Acid Synthesis Inhibitors; Proline; Protease Inhibitors; Pyrrolidines; Simeprevir; Sofosbuvir; Sulfonamides; Uracil; Uridine Monophosphate; Valine; Viral Load; Viral Nonstructural Proteins; Virus Replication

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.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carcinoma, Hepatocellular; Cyclopropanes; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Humans; Lactams, Macrocyclic; Liver Neoplasms; Proline; Ribavirin; Ritonavir; Sulfonamides; Sustained Virologic Response; Uracil; Valine

Recent studies have suggested a higher recurrence rate of hepatocellular carcinoma (HCC) in patients with a history of HCC and hepatitis C virus (HCV)-associated cirrhosis treated with direct-acting antiviral (DAA) agents.. We conducted a prospective analysis of 24 patients with HCV-associated cirrhosis and treated HCC who received ombitasvir/paritaprevir/ritonavir+dasabuvir+ribavirin for 12 weeks. Prior therapies for HCC included resection (9/24 patients), radiofrequency ablation (RFA) (7/24) and trans-arterial chemoembolization (TACE) (8/24). All patients were eligible for treatment if they had no HCC recurrence 6 months after their last procedure. A control group was defined. All patients were followed every 6 months, with dynamic computed tomography and/or magnetic resonance imaging.. DAA therapy significantly reduced the recurrence rate of HCC and improved survival without recurrence in patients with treated HCV-associated HCC.

Topics: 2-Naphthylamine; Aged; Anilides; Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Cyclopropanes; Hepatectomy; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Liver Neoplasms; Macrocyclic Compounds; Middle Aged; Neoplasm Recurrence, Local; Proline; Prospective Studies; Radiofrequency Ablation; Ribavirin; Ritonavir; Sulfonamides; Treatment Outcome; Uracil; Valine

We followed for 2 years patients treated with direct-acting agents (DAA) to assess long-term durability of virologic response, improvement of liver function, reduction in liver stiffness (LS) and risk of hepatocellular carcinoma (HCC). The study included patients from 16 hepatologic centres involved in the AMBER, investigator-initiated study on treatment of chronic hepatitis C patients within a programme preceding EU registration of ombitasvir/paritaprevir/ritonavir±dasabuvir±ribavirin. A total of 204 patients among 209 from the primary study were enrolled, 200 with available testing at 2-year follow-up (2yFU) with undetectable HCV RNA (198 responders and 2 nonresponders retreated). During 2yFU, 4 patients died, 17 had hepatic decompensation and 3 needed liver transplantation. De novo hepatocellular carcinoma was diagnosed in 4 and its recurrence in 3 patients. Significant decreases in bilirubin, MELD, Child-Pugh scores and liver stiffness, and increases in albumin level were observed during 2yFU. Strengths of the study were a fixed period of post-treatment follow-up, prospective character of the study and high proportion of available patients from the primary study. The major weaknesses were lack of a comparative arm and relatively insufficient number of patients for subsets analysis. In conclusion, 2-year follow-up confirmed durability of virologic response after treatment of HCV infection with ombitasvir/paritaprevir/ritonavir±dasabuvir±ribavirin. It was accompanied by significant improvement of major measures of hepatic function and reduction of hepatic stiffness. Successful therapy did not prevent hepatic decompensation, HCC or death in cirrhotics that support the need for longer than 2-year monitoring for possible disease progression.

Topics: 2-Naphthylamine; Adult; Aged; Anilides; Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Cyclopropanes; Drug Therapy, Combination; Female; Follow-Up Studies; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver; Liver Cirrhosis; Liver Neoplasms; Macrocyclic Compounds; Male; Middle Aged; Poland; Proline; Ribavirin; Ritonavir; Sulfonamides; Treatment Outcome; Uracil; Valine; Viral Load

No studies have evaluated the use of sorafenib with the direct-acting antiviral ombitasvir/paritaprevir/ritonavir and dasabuvir (OBV/PTV/r+DSV).. Three hepatitis C virus genotype 1b-infected patients with well-preserved liver function were included in this prospective case series. The patients were taking sorafenib for advanced hepatocellular carcinoma and received OBV/PTV/r+DSV for 12 weeks. One patient discontinued sorafenib while concomitant treatment due to grade 2 fatigue and muscular pain. The other two patients reported only grade 1 adverse effects. Sustained virologic response at 24 weeks was achieved, and no tumour recurrences were found.. The concurrent use of OBV/PTV/r+DSV with sorafenib was considered safe and effective.

Topics: 2-Naphthylamine; Aged; Anilides; Antineoplastic Agents; Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Neoplasms; Macrocyclic Compounds; Male; Middle Aged; Proline; Prospective Studies; Ritonavir; Sorafenib; Sulfonamides; Treatment Outcome; Uracil; Valine

We are presenting the case study of the patient diagnosed at the age of 37 with liver cirrhosis due to genotype 1b hepatitis C virus infection. At the age of 46, he was diagnosed with hepatocellular carcinoma with subsequent resection of the tumour in May 2015. In December 2015, the treatment was started with ombitasvir, paritaprevir/ritonavir and dasabuvir (3D) with ribavirin (RBV) 1000 mg per day. After 24 days of this treatment, the patient received a deceased donor liver transplantation, followed by 18-day interruption of 3D therapy. Due to the anaemia, RBV dose was reduced to 600 mg per day for the rest of the treatment. At the 11th week of 3D+RBV treatment, there was another 8-day long discontinuation of therapy due to the postoperative wound infection. In total, the patient received 24 weeks of 3D+RBV treatment, achieving sustained virological response at week 24 post-treatment.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Cyclopropanes; Drug Therapy, Combination; Hepatitis C; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Uracil; Valine

Clinical trials evaluating second-generation direct-acting antiviral agents (DAAs) have shown excellent rates of sustained virologic response (SVR) and good safety profiles in patients with chronic hepatitis C virus (HCV) genotype 1 infection. We aimed to investigate the effectiveness and safety of two oral DAA combination regimens, ombitasvir/paritaprevir/ritonavir plus dasabuvir (OMV/PTV/r+DSV) and ledipasvir/sofosbuvir (LDV/SOF), in a real-world clinical practice.. Data from HCV genotype 1 patients treated with either OMV/PTV/r+DSV±ribavirin (RBV) (n=1567) or LDV/SOF±RBV (n=1758) in 35 centers across Spain between April 1, 2015 and February 28, 2016 were recorded in a large national database. Demographic, clinical and virological data were analyzed. Details of serious adverse events (SAEs) were recorded.. The two cohorts were not matched with respect to baseline characteristics and could not be compared directly. The SVR12 rate was 96.8% with OMV/PTVr/DSV±RBV and 95.8% with LDV/SOF±RBV. No significant differences were observed in SVR according to HCV subgenotype (p=0.321 [OMV/PTV/r+DSV±RBV] and p=0.174 [LDV/SOF]) or degree of fibrosis (c0.548 [OMV/PTV/r/DSV±RBV] and p=0.085 [LDV/SOF]). Only baseline albumin level was significantly associated with failure to achieve SVR (p<0.05) on multivariate analysis. Rates of SAEs and SAE-associated treatment discontinuation were 5.4% and 1.7%, in the OMV/PTV/r+DSV subcohort and 5.5% and 1.5% in the LDV/SOF subcohort, respectively. Hepatocellular carcinoma (HCC) recurred in 30% of patients with a complete response to therapy for previous HCC. Incident HCC was reported in 0.93%.. In this large cohort of patients managed in the real-world setting in Spain, OMV/PTV/r+DSV and LDV/SOF achieved high rates of SVR12, comparable to those observed in randomized controlled trials, with similarly good safety profiles.. In clinical trials, second-generation direct-acting antiviral agents (DAAs) have been shown to cure over 90% of patients chronically infected with the genotype 1 hepatitis C virus and have been better tolerated than previous treatment regimens. However, patients enrolled in clinical trials do not reflect the real patient population encountered in routine practice. The current study, which includes almost 4,000 patients, demonstrates comparable rates of cure with two increasingly used DAA combinations as those observed in the clinical trial environment, confirming that clinical trial findings with DAAs translate into the real-world setting, where patient populations are more diverse and complex.

Topics: 2-Naphthylamine; Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Carcinoma, Hepatocellular; Cohort Studies; Cyclopropanes; Drug Therapy, Combination; Female; Fluorenes; Genotype; Glomerular Filtration Rate; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Neoplasms; Macrocyclic Compounds; Male; Middle Aged; Neoplasm Recurrence, Local; Proline; Retrospective Studies; Ribavirin; Ritonavir; Sofosbuvir; Spain; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Uracil; Uridine Monophosphate; Valine; Young Adult

We observed a sustained viral response (SVR) of ombitasvir/paritaprevir/ritonavir, dasabuvir and ribavirin therapy, for 12 wk, in two cases with compensated liver cirrhosis and fully destroyed early hepatocellular carcinoma (HCC). Patients were infected with hepatitis C virus (HCV) genotype 1b and were previous null responders/relapsers to interferon-alpha/ribavirin (IFN/RBV). There was a rapid suppression of HCV RNA to undetectable levels within the first two treatment weeks. SVR was achieved even after marked reduction of the RBV dose. The treatment was well tolerated. Both subjects experienced worsening of liver disease during therapy, in different patterns: severe, transient, predominantly direct hyperbilirubinemia without cytolysis (case 1) or progressive increase of aminotransferases (grade 4) without severe hyperbilirubinemia (case 2). Adverse events spontaneously resolved. The patients remained in a good clinical condition without hepatic decompensation. There was no re-occurrence of HCC. This is the first report for treatment of HCV cirrhosis after complete HCC destruction.

Topics: 2-Naphthylamine; Aged; Anilides; Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Liver Function Tests; Liver Neoplasms; Macrocyclic Compounds; Male; Proline; Ribavirin; Ritonavir; RNA, Viral; Sulfonamides; Treatment Outcome; Uracil; Valine; Viral Load

This study compared the cost-effectiveness of direct-acting antiviral therapies currently recommended for treating genotypes (GT) 1 and 4 chronic hepatitis C (CHC) patients in the US.. A cost-effectiveness analysis of treatments for CHC from a US payer's perspective over a lifelong time horizon was performed. A Markov model based on the natural history of CHC was used for a population that included treatment-naïve and -experienced patients. Treatment alternatives considered for GT1 included ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin (3D ± R), sofosbuvir + ledipasvir (SOF/LDV), sofosbuvir + simeprevir (SOF + SMV), simeprevir + pegylated interferon/ribavirin (SMV + PR) and no treatment (NT). For GT4 treatments, ombitasvir/paritaprevir/ritonavir + ribavirin (2D + R), SOF/LDV and NT were compared. Transition probabilities, utilities and costs were obtained from published literature. Outcomes included rates of compensated cirrhosis (CC), decompensated cirrhosis (DCC), hepatocellular carcinoma (HCC) and liver-related death (LrD), total costs, life-years and quality-adjusted life-years (QALYs). Costs and QALYs were used to calculate incremental cost-effectiveness ratios.. In GT1 patients, 3D ± R and SOF-containing regimens have similar long-term outcomes; 3D ± R had the lowest lifetime risks of all liver disease outcomes: CC = 30.2%, DCC = 5.0 %, HCC = 6.8%, LT = 1.9% and LrD = 9.2%. In GT1 patients, 3D ± R had the lowest cost and the highest QALYs. As a result, 3D ± R dominated these treatment options. In GT4 patients, 2D + R had lower rates of liver morbidity and mortality, lower cost and more QALYs than SOF/LDV and NT.. While the results are based on input values, which were obtained from a variety of heterogeneous sources-including clinical trials, the findings were robust across a plausible range of input values, as demonstrated in probabilistic sensitivity analyses.. Among currently recommended treatments for GT1 and GT4 in the US, 3D ± R (for GT1) and 2D + R (for GT4) have a favorable cost-effectiveness profile.

Topics: 2-Naphthylamine; Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Carcinoma, Hepatocellular; Cost-Benefit Analysis; Cyclopropanes; Drug Therapy, Combination; Female; Fibrosis; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Neoplasms; Macrocyclic Compounds; Male; Markov Chains; Middle Aged; Models, Econometric; Proline; Quality-Adjusted Life Years; Ribavirin; Simeprevir; Sofosbuvir; Sulfonamides; Uracil; Valine

New treatments for chronic hepatitis C virus (HCV) are highly effective in patients coinfected with human immunodeficiency virus (HIV). This study estimated the cost-effectiveness of treatments for genotype 1 (GT1) HCV in HIV-coinfected patients.. A Markov model based on HCV natural history was used. The base-case analysis included both treatment-naïve and -experienced patients. Alternatives were ombitasvir/paritaprevir/ritonavir, dasabuvir with or without ribavirin (3D ± R) for 12 or 24 weeks, sofosbuvir plus peginterferon and R (SOF + PR) for 12 weeks, SOF + R for 24 weeks, and no treatment (NT). A subgroup analysis restricted to treatment-naïve, non-cirrhotic patients compared 3D ± R for 12 weeks to SOF plus ledipasvir (LDV) for 12 weeks and NT. Transition probabilities, utilities, and costs were obtained from the published literature. Outcomes were measured over a lifetime horizon and included rates of compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma and liver-related death, total costs, life-years, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER).. In the base-case, SOF + R was dominated by both SOF + PR and 3D ± R. Compared to SOF + PR, 3D ± R had an ICER of $45,581. The lifetime rates of liver morbidity and mortality were lower among those treated with 3D ± R compared to SOF + PR, SOF + R, or NT. In the subgroup analysis, 3D ± R was cost-effective compared to NT at a threshold of $50,000 per QALY (ICER $27,496). SOF/LDV had an ICER of $104,489 per QALY gained compared to 3D ± R.. In the GT1 HCV population coinfected with HIV, 3D ± R was cost-effective compared to NT, SOF + R, and SOF + PR. In the treatment-naïve sub-population, 3D ± R was cost-effective compared to NT and SOF/LDV.

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Carcinoma, Hepatocellular; Cost-Benefit Analysis; Cyclopropanes; Disease Progression; Drug Therapy, Combination; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; HIV Infections; Humans; Interferon-alpha; Lactams, Macrocyclic; Liver Cirrhosis; Liver Neoplasms; Macrocyclic Compounds; Markov Chains; Middle Aged; Polyethylene Glycols; Proline; Quality-Adjusted Life Years; Recombinant Proteins; Ribavirin; Ritonavir; Sofosbuvir; Sulfonamides; United States; Uracil; Valine