bms-790052 and Liver-Neoplasms

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

During the first years of the use of direct acting Hepatitis C antiviral drugs (DAAS), several studies reported a possible correlation between this new era of treatment and an increased risk of Hepatocellular carcinoma (HCC). Its development could possibly be favored by the changes in the immunological milieu and the different cellular behavior after eradication of HCV infection with them. For this reason, this study aimed to address the immunological effect of DAAS.. Prospective paired -sample design, carried out on 90 naïve chronically infected HCV patients before and after receiving a combination therapy of sofosbuvir; at a dose of 400 mg once daily and daclatasvir; at a dose of 60 mg once daily for 12 weeks and follow up for one year. immunological tests including: total T cell count, T helper cell count, T cytotoxic cell count and natural killer cell count in peripheral blood through (CD3, CD3/CD4, CD3/CD8 and CD56 respectively) by Fluorochrome monoclonal antibodies labelled with specific dyes through Multiparameter, FACSCanto ™ II flow cytometer (Becton Dickinson, USA).. Concerning the immunological changes, total T cells (CD3+), Natural killer cells showed non-significant decrease at end of therapy while significant decrease in T helper cells (CD3+CD4+) T cytotoxic cells (CD3+CD8+) compared to pre-treatment value. Long follow up revealed 26.6% developed focal HCC, in more addition, multivariate analysis show CD4/CD8 ratio could be predictor as well as sex for early development of HCC after combined DAAS therapy.. HCV treatment by DAAS produces significant decrease in T helper, T cytotoxic cells in CHC patients at the end of therapy. 26.6% developed focal HCC with independent CD4/CD8 predictor for burden malignancy. Further large extended population study is needed for clarify this concern.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; CD8-Positive T-Lymphocytes; Egypt; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Neoplasms; Prospective Studies; Sofosbuvir

We prospectively investigated the changes of liver stiffness (LS) and the occurrence of hepatocellular carcinoma (HCC) after hepatitis C virus (HCV) eradication using direct antiviral agents (DAA) over three years. LS measurement using transient elastography and serum fibrosis surrogate markers before treatment and at 48, 96, 144 weeks after starting direct-acting antivirals (DAA) according to the protocol were evaluated. Patients were also compared with historical cohort treated with pegylated interferon (peg-IFN). Sustained viral response (SVR) was observed in 95.8%. LS value in the patients achieving SVR significantly decreased over time (19.4 ± 12.9 kPa [baseline], 13.9 ± 9.1 kPa [48 weeks], 11.7 ± 8.2 kPa [96 weeks], 10.09 ± 6.23 [144 weeks], all p < 0.001). With matched analysis, the decrease in LS value was significantly larger in DAA group than peg-IFN group at both 48 weeks (29% vs. 9%) and 96 weeks (39% vs. 17%). The incidence of HCC was not significantly different between DAA and peg-IFN groups (5.5% vs. 5.4%) at 144 weeks. HCV eradication with DAA can lead to improvement of liver stiffness over time. The regression of fibrosis was greater in the group with DAA than peg-IFN.Clinical trials registration: ClinicalTrials.gov (NCT02865369).

Topics: Administration, Oral; Aged; Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Drug Therapy, Combination; Elasticity Imaging Techniques; Female; Hepatitis C, Chronic; Humans; Imidazoles; Incidence; Interferons; Isoquinolines; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Prospective Studies; Pyrrolidines; Retrospective Studies; Ribavirin; Seoul; Sulfonamides; Sustained Virologic Response; Time Factors; Treatment Outcome; Valine

Many successful anti-viral and anti-cancer drugs are nucleoside analogs, which disrupt RNA and/or DNA synthesis. Here, we present liver-specific prodrugs of the chemotherapy drug gemcitabine (2',2'-difluorodeoxycytidine) for the treatment of hepatitis C virus (HCV) infection and hepatocellular carcinoma. The prodrugs were synthesized by introducing aromatic functional moieties to the cytosine 4-NH

Topics: Antineoplastic Agents; Antiviral Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cell Survival; Deoxycytidine; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Gemcitabine; Hepacivirus; Hepatitis C; Humans; Liver Neoplasms; Microbial Sensitivity Tests; Molecular Structure; Prodrugs; Structure-Activity Relationship; Virus Replication

This study aimed to assess the correlation between the genotyping of interleukin-10 (IL-10 polymorphism rs 1800871) and the incidence hepatocellular carcinoma (HCC) among patients with hepatitis C virus (HCV) treated with direct acting antivirals (DAAs).. For 200 patients with HCV infection who completed DAA treatment and followed up for 1 year, IL-10 polymorphism SNP(-819) rs 1800871 analysis was conducted via real time polymerase chain reaction. During the follow-up period, 100 patients who developed HCC were selected and compared with 100 patients who did not develop any complications.. The studied patients were divided into two groups according to the incidence of complications after completion of DAA treatments. During the follow-up, 100 patients with HCV infection who developed HCC were selected and compared with 100 patients with HCV infection who did not develop any complications (positive control group). For the HCC group (n = 100), the mean age was 58.1 ± 6.4 years, with 92.7% being male and 7.3% being female; 91% had cirrhosis, 10% had lymphadenitis, 75% had splenomegaly, and 17% had ascites. In the positive control group (n = 100), mean age was 46.3 ± 9.4 years, with 68% being male and 32% being female; 20% had cirrhosis, 12% had splenomegaly, and 4.2% had ascites. The results demonstrated that sofosbuvir (SOF) + daclatasvir + ribavirin regimen was the most prevalent drug treatment for patients with HCC (72%), while SOF + Simeprevir was the most safe treatment for HCV infection among patients with HCC (2%). CT genotype was the most common genotype in the HCC group (56%), among different drug regimen (67.8%). T allele was the most prevalent in HCC group (61%), while the C allele was the least prevalent (39%).. IL-10 genotyping may help in selecting the safest and most accurate drug regimen according to the safest genotype response relationship and follow-up of genotype resistance.

Topics: Adult; Aged; Antiviral Agents; Ascites; Carbamates; Carcinoma, Hepatocellular; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Interleukin-10; Liver Cirrhosis; Liver Neoplasms; Lymphadenitis; Male; Middle Aged; Polymorphism, Single Nucleotide; Pyrrolidines; Ribavirin; Simeprevir; Sofosbuvir; Splenomegaly; Valine

Chronic hepatitis C (CHC) is a major cause of cirrhosis, hepatocellular carcinoma (HCC), and mortality. Eliminating hepatitis C virus (HCV) can greatly improve long-term outcomes. Several direct-acting antiviral agents (DAAs), including sofosbuvir (SOF) plus different NS5A inhibitors, as well as non-SOF-based DAAs, including glecaprevir/pibrentasvir (GLE/PIB), have been approved for treating CHC genotype-2 (GT-2) patients in Taiwan. However, there is limited real-world effectiveness data regarding these different regimens. Thus, we aimed to evaluate the real-world efficacy in CHC GT-2 patients who underwent these DAA regimens. We retrospectively enrolled CHC GT-2 patients who were treated with SOF-based DAAs or GLE/PIB at a single medical center. A total of 704 enrolled patients were treated with either SOF + ribavirin (RBV), SOF/daclatasvir (DCV) ± RBV, SOF/ledipasvir (LDV) ± RBV, SOF/velpatasvir (VEL) ± RBV, or with GLE/PIB. The overall sustained virological response (SVR) rate was 97.9%. The SVR rate was significantly lower in the SOF + RBV group (95.6%) than in the non-SOF + RBV (98.9%) group, especially compared to the SOF/DCV (100%) and GLE/PIB groups (99.5%). Among patients treated with SOF + RBV, cirrhotic patients had significantly lower SVR rates than noncirrhotic patients (89.4% vs 98.2%). Multivariate analysis showed that patients with a younger age, hepatitis B virus coinfection, baseline cirrhosis, or those who received SOF + RBV were less likely to achieve SVR. In conclusion, for CHC GT-2 patients, SOF in combination with DCV, LDV, or VEL, as well as GLE/PIB, achieved similar high efficacies, regardless of cirrhosis, treatment experience, or chronic kidney disease status. Therefore, the use of DAA therapy to eradicate HCV should not be delayed in these populations.

Topics: Age Factors; Aged; Antiviral Agents; Benzimidazoles; Carbamates; Carcinoma, Hepatocellular; Drug Combinations; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Pyrrolidines; Quinoxalines; Retrospective Studies; Ribavirin; Sofosbuvir; Sulfonamides; Taiwan; Treatment Outcome; Valine

Liver malignant tumors (LMTs) represent a serious adverse drug event associated with drug-induced liver injury. Increases in endocrine-disrupting chemicals (EDCs) have attracted attention in recent years, due to their liver function-inhibiting abilities. Exposure to EDCs can induce nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, which are major etiologies of LMTs, through interaction with nuclear receptors (NR) and stress response pathways (SRs). Therefore, exposure to potential EDC drugs could be associated with drug-induced LMTs. However, the drug classes associated with LMTs and the molecular initiating events (MIEs) that are specific to these drugs are not well understood. In this study, using the Food and Drug Administration Adverse Event Reporting System, we detected LMT-inducing drug signals based on adjusted odds ratios. Furthermore, based on the hypothesis that drug-induced LMTs are triggered by NR and SR modulation of potential EDCs, we used the quantitative structure-activity relationship platform for toxicity prediction to identify potential MIEs that are specific to LMT-inducing drug classes. Events related to cell proliferation and apoptosis, DNA damage, and lipid accumulation were identified as potential MIEs, and their relevance to LMTs was supported by the literature. The findings of this study may contribute to drug development and research, as well as regulatory decision making.

Topics: Adverse Drug Reaction Reporting Systems; Carbamates; Chemical and Drug Induced Liver Injury; Databases, Factual; Forecasting; Humans; Imidazoles; Isoquinolines; Liver Neoplasms; Protease Inhibitors; Pyrrolidines; Receptors, Calcitriol; Receptors, Estrogen; Sulfonamides; United States; United States Food and Drug Administration; Valine

There are conflicting data regarding the risk of hepatocellular carcinoma (HCC) after direct-acting antiviral agent (DAA) treatment. Risk of HCC in HCV genotype-3 infected persons after DAA therapy is not well known.. We prospectively studied HCV infected persons initiated on a DAA regimen between October 2014 and March 2017 at two centers in Pakistan. All persons were free of HCC at study initiation. HCC was confirmed based on characteristic CT scan findings. Patients were followed for 12 months after the completion of therapy.. A total of 662 persons initiated treatment. Median age (IQR) was 50 (41, 57) years and 48.8% were male. At baseline, 49.4% were cirrhotic, 91% were genotype 3 and 91.9% attained SVR. Treatment regimens used were: Sofosbuvir (SOF)/ribavirin (RBV)/pegylated interferon (PEG-IFN), 25.2%; SOF/RBV, 62.4%; SOF/RBV/daclatasavir (DCV), 10.6%; SOF/DCV, 2.0%. Incident HCC was detected in 42 patients (12.8%) in the 12-month period after treatment completion and was exclusively observed in those with cirrhosis. In multivariable Cox regression analysis, SVR was associated with a reduction in HCC risk (HR, 95% CI: 0.35, 0.14,0.85). In Kaplan-Meier plots by treatment regimen, those treated with SOF/RBV, SOF/RBV/DCV, or SOF/DCV regimens had a shorter HCC-free survival compared with those treated with a SOF/RBV/PEG-IFN regimen.. In a predominantly genotype 3 cohort, incident HCC occurred frequently and early after treatment completion, and exclusively in those with pre-treatment cirrhosis. SVR reduced the risk of HCC. Treating HCV infected persons before development of cirrhosis may reduce risk of HCC.

Topics: Adult; Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Interferons; Kaplan-Meier Estimate; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Pakistan; Polyethylene Glycols; Proportional Hazards Models; Prospective Studies; Pyrrolidines; Ribavirin; Sofosbuvir; Sustained Virologic Response; Time Factors; Tomography, X-Ray Computed; Valine

Combination therapy of interferon and ribavirin has traditionally been used to eradicate hepatitis C virus. The sustained virologic response achieved with interferon-related therapy is persistent, and late relapses after achieving sustained virologic response at 24 weeks using this therapy are reportedly rare (< 1%). In 2014, interferon-free therapy with direct-acting antivirals was developed, and the rate of sustained virologic response was improved. However, the persistence thereof remains uncertain, and the appropriate follow-up period for hepatitis C virus-positive patients is under discussion.. A 74-year-old Japanese man who had hepatitis C virus-related hepatocellular carcinoma and was successfully treated with radiofrequency ablation four times underwent direct-acting antiviral therapy with daclatasvir and asunaprevir; sustained virologic response at 24 weeks was confirmed. However, although he had no high risk factors for reinfection, hepatitis C virus ribonucleic acid was detected again 6 months after achieving sustained virologic response at 24 weeks. Moreover, he developed active hepatitis with an increased viral load. Five months after development of hepatitis, recurrent hepatocellular carcinoma emerged in segment II, where we had performed radiofrequency ablation 17 months previously. The recurrent hepatocellular carcinoma enlarged quite rapidly and induced multiple peritoneal disseminations and lung metastases. He died 3 months after the abrupt recurrence. A sarcomatous change in the hepatocellular carcinoma was identified during the autopsy.. Although sustained virologic response at 24 weeks has generally been regarded to denote complete eradication of hepatitis C virus, we present a patient in whom hepatitis C virus recurred 6 months after achieving sustained virologic response at 24 weeks with direct-acting antiviral therapy. In addition, a sarcomatous change in hepatocellular carcinoma emerged 5 months after active hepatitis developed due to late hepatitis C virus relapse in this case. The sarcomatous change in hepatocellular carcinoma is generally thought to be related to anticancer therapies, such as radiofrequency ablation. However, in this case, late viral relapse and active hepatitis in addition to the previous radiofrequency ablation could have been the trigger. There may be a need for follow-up of hepatitis C virus ribonucleic acid beyond sustained virologic response at 24 weeks with direct-acting antiviral therapy, owing to the possibility of late viral relapse and tumorigenesis.

Topics: Aged; Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Fatal Outcome; Hepacivirus; Hepatitis C; Humans; Imidazoles; Isoquinolines; Liver Neoplasms; Male; Neoplasm Recurrence, Local; Pyrrolidines; Radiofrequency Ablation; Recurrence; Sulfonamides; Valine; Viral Load

Direct-acting antivirals (DAAs) against hepatitis C virus (HCV) exert high anti-HCV activity and are expected to show anti-inflammatory effects associated with HCV elimination. Furthermore, hepatocellular carcinoma (HCC) is known to dedifferentiate from hypovascular tumors, such as dysplastic nodules or well-differentiated HCC, to hypervascular tumors. We therefore explored whether or not DAAs can suppress the growth and hypervascularization of hypovascular tumors.. We enrolled 481 patients with HCV genotype 1 infection who were treated with Daclatasvir and Asunaprevir therapy. Of these, 29 patients had 33 hypovascular tumors, which were confirmed by contrast-enhanced MRI or CT before therapy. We prospectively analyzed the cumulative incidence of HCC, i.e. the growth or hypervascularization of hypovascular tumors, and compared the HCC development rates between patients with hypovascular tumors and those without any tumors.. The mean size of the hypovascular tumors was 11.3 mm. Twenty seven of 29 patients who achieved an SVR had 31 nodules, 19 of 31 nodules (61.3%) showed tumor growth or hypervascularization, and 12 (38.7%) nodules showed no change or improvement. The cumulative incidence rates of tumor growth or hypervascularization were 19.4% at 1 year, 36.0% at 2 years, 56.6% at 3 years, and 65.3% at 4 years. Among the patients who achieved a sustained virologic response, the cumulative HCC development rates of patients with hypovascular tumors was significantly higher than in those without any tumors. A Cox proportional hazard analysis showed that a history of HCC therapy, the presence of a hypovascular tumor, and AFP >4.6 ng/mL at the end of treatment were independent risk factors for HCC development.. Hypovascular tumors developed into HCC at a high rate despite the elimination of HCV by DAAs. As patients with hypovascular tumors were shown to have a high risk of HCC development, they should undergo strict HCC surveillance.

Topics: Aged; alpha-Fetoproteins; Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Incidence; Isoquinolines; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Proportional Hazards Models; Pyrrolidines; Risk Factors; Sulfonamides; Sustained Virologic Response; Valine

Though direct-acting antiviral agents (DAAs) therapy is associated with a high cure rate of hepatitis C virus infection, a potential risk of serious adverse events (SAEs) exists. The aim of this study was to determine the incidence and predictors of morbidity and mortality related to DAAs therapy.. This prospective study was conducted on a real word cohort of 1562 treatment naïve chronic hepatitis C (CHC) Egyptian patients, who received 12-weeks therapy with sofosbuvir (SOF) plus daclatasvir (DCV) ± ribavirin (RBV). The incidence and predictors of SAEs and mortality during treatment course and over the following 12 weeks were recorded.. The mean age of study participants was 51.38 ± 9.70 years (55.22%, males). Liver cirrhosis was defined in 72.4% of participants. SAEs were recorded in 120 participants (7.68%), including hepatic decompensation, gastrointestinal bleeding, anemia and hepatocellular carcinoma. Nine patients (0.58%) died and 69 patients (4.42%) discontinued therapy due to SAEs. Severity of cirrhosis was the significant predictor of morbidities and mortality. Hepatic decompensation was predicted by baseline serum albumin [cutoff value: 3.00 g/dL, area under the receiver operating characteristic curve (AUROC): 0.953] and serum bilirubin (cutoff value: 1.75 mg/dL, AUROC: 0.940).. The risk of morbidity and mortality related to SOF/DCV ± RBV therapy in CHC patients is small and is significantly linked to advanced cirrhosis.

Topics: Antiviral Agents; Carbamates; Child; Drug Therapy, Combination; Egypt; Female; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Imidazoles; Liver Neoplasms; Male; Morbidity; Prospective Studies; Pyrrolidines; Ribavirin; Sofosbuvir; Treatment Outcome; Valine

Data are sparse on treatment of chronic hepatitis C virus (HCV) in cancer patients. We evaluated the efficacy and safety of sofosbuvir-based therapy (SOFBT) in cancer patients.. Patients treated with SOFBT at our center during 2014-2017 were included in a prospective observational study. Efficacy [sustained virologic response at 12 weeks after the end of treatment (SVR12)], cancer-related outcomes and adverse events (AEs) were assessed.. We included 153 patients. Most were men (109; 71%), white (92; 60%), non-cirrhotic (105; 69%), and with HCV genotype 1 (110; 72%). The most common cancers were hepatocellular carcinoma (HCC) (27; 18%) and multiple myeloma (14; 9%). The overall SVR12 rate was 91% (128/141). SVR12 was 100% in patients treated with ledipasvir/sofosbuvir for 8 weeks. Of the 32 patients initially excluded from cancer clinical trials because of HCV, 27 (84%) were granted cancer therapy access after starting SOFBT. Six patients with indolent non-Hodgkin's lymphoma (NHL) received SOFBT without cancer treatment. Two achieved complete remission, one had partial remission, and two had stable cancer. Within 6 months after SOFBT, 5% (6/121) of patients in remission or with stable cancer, had progression or recurrence (two with HCC and one each with esophageal cancer, cholangiocarcinoma, NHL, and tonsillar cancer). No de novo HCCs occurred. AEs were most commonly grade 1-2 (90%).. SOFBT in HCV-infected cancer patients is effective and safe, may permit access to investigational cancer therapy expanding treatment options, may induce remission of NHL, and may be used for 8 weeks.

Topics: Aged; Antiviral Agents; Benzimidazoles; Breast Neoplasms; Carbamates; Carcinoma, Hepatocellular; Drug Therapy, Combination; Female; Fluorenes; Head and Neck Neoplasms; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Interferons; Liver Neoplasms; Lymphoma, Non-Hodgkin; Male; Middle Aged; Multiple Myeloma; Neoplasms; Polyethylene Glycols; Prospective Studies; Pyrrolidines; Ribavirin; Simeprevir; Sofosbuvir; Sustained Virologic Response; Valine

Excellent efficacy and safety profile of second-generation DAA combinations improved treatment of chronic hepatitis C (HCV) as well as in HCV recurrence after orthotopic liver transplantation (OLT). The need of ribavirin addition is under debate as anaemia and decreased renal function are prevalent in transplant cohorts. The aim of this study was thus to assess safety and long-term efficacy of RBV-free DAA combinations in HCV-recurrent patients after OLT.. A total of 62 OLT recipients (male: 50%/81%; age: 60.7 ± 8.5 years [mean ± SD]; GT - 1: 48, GT - 3: 9, GT - 4: 5; cirrhosis: 34%/55% [7%/21% decompensated], fibrosing cholestatic hepatitis: 1%/2%) received RBV-free treatment with second-generation DAA combinations: sofosbuvir (SOF)/daclatasvir (DCV): 42%/68%, SOF/simeprevir (SMV): 10%/16%, SOF/ledipasvir (LDV): 6%/10% and PrOD: 4%/7%.. Data of at least 96 weeks of FUP after treatment cessation (mean: 120; up to 167 weeks) were analysed. All patients showed on-treatment response. By intention-to-treat (ITT) analysis, SVR12 was 97% (60/62, GT-1a: 11/11 [100%]; 1b: 33/34 [97%]; 1g: 1/1 [100%]; subtype not specified: 2/2 [100%]; GT3a: 9/9 [100%]; GT4: 4/5 [80%]) compared to SVR96 of 89% (55/62). No late relapses occurred. In total, 16 severe adverse events occurred, including two newly diagnosed carcinoma (lung cancer, hepatocellular carcinoma). Six patients died; one at treatment week 24 (HCV-RNA undetectable) and five during treatment-free FUP and after achieving SVR (SVR4: N = 1, SVR12: N = 3, after SVR96: N = 1 respectively). Reasons for death were: multi-organ failure (N = 4), impaired graft function (N = 1) and unknown (N = 1).. RBV-free DAA combinations for the treatment of HCV recurrence after OLT are highly efficacious and well tolerated. Our long-term data show that viral eradication is durable but not necessarily translated into beneficial long-term clinical outcome.

Topics: Aged; Antiviral Agents; Austria; Benzimidazoles; Carbamates; Carcinoma, Hepatocellular; Drug Therapy, Combination; Female; Fluorenes; Follow-Up Studies; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Pyrrolidines; Recurrence; Ribavirin; Simeprevir; Sofosbuvir; Sustained Virologic Response; Valine

The efficacy of direct-acting anti-viral (DAA) therapy in patients with a history of hepatocellular carcinoma (HCC) is unknown.. We prospectively evaluated whether previously treated HCC affects DAA efficacy in a large real-life cohort of cirrhotic patients.. From January to December 2015 all consecutive HCV mono-infected patients with cirrhosis and/or history of HCC attending 10 Italian tertiary liver centres were enrolled. Baseline characteristics and response to therapy were recorded. 1927 patients were enrolled (mean age: 62.1 ± 10.9 years; 1.205 males). Genotype 1 was the most frequent (67.9%) followed by genotypes 3 (12.4%), 2 (11.2%) and 4 (8.6%). 88.4% and 10.9% of cases were classified Child A and B, respectively, and 14 (<1%) cases were classified Child C. Ascites and hepatic encephalopathy occurred in 10.7% and 3.2% of patients, respectively. Varices were detected in 39.3% of patients. Suboptimal and optimal treatment was prescribed: 15.9% of patients received sofosbuvir/simeprevir, 33.4% sofosbuvir/ledipasvir, 20.2% a Viekirax + Exviera regimen, 15.7% sofosbuvir/ribavirin, 9.9% sofosbuvir/daclatasvir and 3.4% Viekirax; 1.3% of patients received an interferon-based regimen.. The sustained virologic response (SVR) rate at intention-to-treat analysis was 95.1%. It differed significantly across Child classes, that is, 96.3%, 86.1% and 71.4% Child A, B and C, respectively (P < 0.0001) and across genotypes (P = 0.002). The SVR rate did not differ between patients with (95.0%) and those without previous HCC (95.1%). At multivariable analysis, SVR was significantly associated with HCV genotype, Child class.. This large real-life study proves that the efficacy of DAA in cirrhotic patients is not impaired by successfully treated HCC.

Topics: Aged; Antiviral Agents; Benzimidazoles; Carbamates; Carcinoma, Hepatocellular; Cohort Studies; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepacivirus; Hepatic Encephalopathy; Hepatitis C, Chronic; Humans; Imidazoles; Interferons; Italy; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Prospective Studies; Pyrrolidines; Ribavirin; Simeprevir; Sofosbuvir; Sustained Virologic Response; Uridine Monophosphate; Valine

Treatment of hepatitis C virus (HCV) after successfully treated hepatocellular carcinoma (HCC) becomes possible with the introduction of direct-acting antivirals because of their favorable efficacy, safety, and short period of treatment. Few data are available on the results of treatment using different direct-acting antiviral regimens in successfully treated HCC and a lot of debate about its role in tumor recurrence.. Sixty-two HCV-related HCC patients were enrolled in the study after successfully treated HCC; the studied population included either Child-Pugh 'A' or 'B7'. The patients were subcategorized to receive one of the following regimens: group 1: sofosbuvir (SOF)+ribavirin (RBV) for 24 weeks, group 2: SOF+simeprevir for 12 weeks, group 3: SOF+daclatasvir for 24 weeks, and group 4: SOF+daclatasvir+RBV for 12 weeks. The overall median follow-up period is 12 months after treatment initiation.. All treatment regimens were tolerable for all patients, with no reported major adverse events during treatment. The overall sustained virologic response rate was 64.5%, with the highest result in group 4 and the lowest result in group 1; 87.5 and 26.7%, respectively. HCC recurrence was observed in 42% of patients; 80.7% of these patients developed recurrence within 6 months of treatment initiation.. Treatment of HCV in successfully treated HCC is feasible, with the best results achieved using multiple direct-acting antivirals and RBV; a high rate of HCC recurrence was observed, especially within the first 6 months of treatment initiation (ClinicalTrials.gov no: NCT02771405).

Topics: Aged; Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Drug Therapy, Combination; Egypt; Female; Hepatitis C; Humans; Imidazoles; Incidence; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Prospective Studies; Pyrrolidines; Ribavirin; Risk Factors; Simeprevir; Sofosbuvir; Sustained Virologic Response; Time Factors; Treatment Outcome; Valine

Recently, two conflicting articles about recurrence of hepatocellular carcinoma (HCC) after direct acting antivirals (DAA) against hepatitis C virus (HCV) were published. We investigated the relationship between DAA and HCC recurrence. Eligible patients were (1) history of HCC and treated curatively with interventions, and (2) interferon-free DAA therapy was initiated after eradication of HCC. We analyzed contributing factor for HCC recurrence. Ten out of 23 participants (43%) encountered recurrence of HCC. Age, sex, diabetes mellitus, fibrosis score, chemistry, and alpha-fetoprotein did not differ between patients with recurrence and patients without recurrence. The patients with recurrence had significantly higher values of antibody to hepatitis B core antigen (anti-HBc) than the patients without recurrence, 6.06±3.75 vs. 0.91±2.43 (p=0.0019). The relative risk of HCC recurrence comparing anti-HBc positive to negative was 5.2 (95% confidence interval 1.40 to 19.32). Odds ratio was 22.0 (95% confidence interval 2.5 to 191.1). We conclude that anti-HBc positivity was a strong contributing factor for HCC recurrence after DAA therapy.

Topics: Aged; Aged, 80 and over; Antibodies, Viral; Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Drug Therapy, Combination; Female; Hepatitis B Core Antigens; Hepatitis C, Chronic; Humans; Imidazoles; Liver Neoplasms; Male; Neoplasm Recurrence, Local; Pyrrolidines; Retrospective Studies; Ribavirin; Risk Factors; Sofosbuvir; Valine

Topics: Aged, 80 and over; Antiviral Agents; Carbamates; Fatal Outcome; Female; Hemangioendothelioma, Epithelioid; Hepatitis C; Humans; Imidazoles; Liver Neoplasms; Palliative Care; Pyrrolidines; Valine

The risk of hepatocellular carcinoma (HCC) development is reduced following viral elimination by interferon therapy in chronic hepatitis C patients. However, the risk in patients treated with interferon-free direct-acting antivirals (DAAs) is unknown. We evaluated chronic hepatitis C patients who achieved viral eradication by pegylated-interferon plus ribavirin (PEG-IFN/RBV, n = 244) or daclatasvir plus asunaprevir (DCV/ASV, n = 154) therapy. None of the patients had prior history of HCC or antiviral therapy. The median observation period after the end of treatment for the PEG-IFN/RBV and DCV/ASV groups were 96 (range 10-196) and 23 (range 4-78) months, respectively. During the observation period, HCC developed in 13 (5.3%) and 7 (4.5%) patients in the PEG-IFN/RBV and DCV/ASV groups, respectively. The cumulative HCC development rate after 1-, 3- and 5-years (0.4%, 3% and 5% for the PEG-IFN/RBV group and 0.6%, 9% and 9% for the DAA group, respectively) were similar between the two groups. Propensity score matching analysis also showed no significant difference in HCC development rates between the two groups. Serum AFP levels decreased to similar levels between PEG-IFN/RBV and DCV/ASV groups following the achievement of viral eradication. The risk for HCC development following viral eradication by IFN-free DAA therapy may be similar to that in IFN-based therapy.

Topics: Adult; Aged; Aged, 80 and over; Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Drug Therapy, Combination; Hepatitis C, Chronic; Humans; Imidazoles; Incidence; Interferon-alpha; Isoquinolines; Kaplan-Meier Estimate; Liver Neoplasms; Middle Aged; Proportional Hazards Models; Pyrrolidines; Ribavirin; Risk Factors; Sulfonamides; Treatment Outcome; Valine; Viral Load; Young Adult

Interferon-based antiviral therapies against hepatitis C virus (HCV) infection have been shown to reduce the incidence of hepatocellular carcinoma (HCC) in patients with sustained viral response (SVR). Recently, direct-acting antivirals (DAAs) have been proven to be much more effective in achieving SVR than interferon-based therapies. However, whether DAAs can efficiently prevent the occurrence of HCC after SVR remains controversial. To clarify this issue, we analyzed the clinical features of patients in whom HCC developed after achievement of SVR with DAAs for chronic HCV infection.. Among patients who achieved SVR with daclatasvir and asunaprevir (n = 100), HCC developed in 17 patients (HCC group; n = 17) and did not develop in 83 patients (non-HCC group; n = 83) during a mean observation period of 15 months. A multivariate Cox proportional hazards analysis identified past history of HCC and male sex as significant risk factors for the emergence of HCC after DAAs. Sixteen cases with HCC after DAAs were in the very early or early stage (16/17, 94.1%), and one case was in the advanced stage (1/17, 5.9%) with portal venous tumor thrombus. Radiofrequency ablation and/or transarterial chemoembolization were performed in most cases as curative therapy (16/17, 94.1%). Key Messages: SVR by DAAs did not completely prevent the occurrence of HCC. However, even if HCC did develop after SVR, curative anticancer therapy was applicable in most cases.

Topics: Adult; Aged; Aged, 80 and over; alpha-Fetoproteins; Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Isoquinolines; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Neoplasm Recurrence, Local; Proportional Hazards Models; Pyrrolidines; Risk Factors; Sulfonamides; Sustained Virologic Response; Tomography, X-Ray Computed; Valine

Wisteria floribunda agglutinin positive (WFA. This study included 119 patients with chronic hepatitis C (CHC). Of these patients, 97 were treated with IFN-based therapy and 22 were treated with daclatasvir and asunaprevir. Serum M2BPGi values were measured prior to, at the end of, and at 24 weeks after the completion of treatment. As subanalysis, serum total M2BP levels were measured in patients treated with pegylated-interferon and ribavirin.. In patients treated with IFN-based therapy, M2BPGi levels were elevated at the end of treatment but decreased afterwards. In contrast, M2BPGi levels in patients treated with IFN-free therapy decreased immediately after starting the treatment without transient elevation. Though pre-treatment M2BPGi levels significantly correlated with fibrosis in both patients with a sustained virological response (SVR) and non-SVR, post-treatment M2BPGi levels decreased regardless of the degree of fibrosis in patients with SVR. In multivariate analysis, non-SVR and HCC development were independent factors associated with M2BPGi level ≥2.2. In patients treated with pegylated-interferon and ribavirin, total M2BP levels were positively correlated with fibrosis and HCC development.. Real-time monitoring of the serum M2BPGi level after antiviral therapy for CHC patients could be a helpful screening tool for assessing the risk of HCC. M2BP and its glycan structure could be associated together with hepatocarcinogenesis.

Topics: Antigens, Neoplasm; Antiviral Agents; Biomarkers, Tumor; Carbamates; Carcinoma, Hepatocellular; Carrier Proteins; Early Diagnosis; Female; Glycoproteins; Hepatitis C, Chronic; Humans; Imidazoles; Interferon-alpha; Isoquinolines; Liver Cirrhosis; Liver Neoplasms; Male; Membrane Glycoproteins; Plant Lectins; Pyrrolidines; Sulfonamides; Valine

Predictive factors for hepatocarcinogenesis following eradication of hepatitis C virus (HCV) RNA by antiviral therapy with direct-acting antivirals are unknown. Especially the impact of treatment with or without interferon on hepatocarcinogenesis is not clear.. A total of 958 patients with HCV genotype 1-related chronic liver disease and a sustained virological response defined as negative HCV RNA 24 weeks after cessation of antiviral therapy with direct-acting antivirals (triple therapy of NS3/4A protease inhibitor/peginterferon/ribavirin or all-oral combination therapy with NS3/4A protease inhibitor plus NS5A inhibitor) were included in a retrospective study. None of the patients had hepatocellular carcinoma before and during antiviral therapy.. In all, 14 patients developed hepatocellular carcinoma during follow-up, and the development rate per 1,000 person-years was 7.35. The cumulative hepatocarcinogenesis rates were 4.2 and 4.2% at the end of 5 and 7 years, respectively. Multivariate analysis identified fibrosis 4 (FIB4) index (≥2.7) and body mass index (≥23.0) as determinants of hepatocarcinogenesis, but they did not identify the treatment regimen. In patients with a FIB4 index ≥2.7, the hepatocarcinogenesis rates with the interferon regimen were not different from those for the regimen without interferon, regardless of gender.. Liver fibrosis and body mass index, but not treatment regimen, are important predictors of hepatocarcinogenesis following eradication of HCV RNA by direct-acting antivirals.

Topics: Adult; Aged; Aged, 80 and over; Antiviral Agents; Body Mass Index; Carbamates; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Interferon Type I; Isoquinolines; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Oligopeptides; Pyrrolidines; Ribavirin; Risk Factors; RNA, Viral; Sulfonamides; Sustained Virologic Response; Valine; Young Adult

We report a case of sustained remission of a liver transplant patient infected with hepatitis C virus (HCV) genotype 1 undergoing hemodialysis treatment. Oral treatment regimen of the HCV infection consists of a combination of sofosbuvir 400 mg after each hemodialysis session and daclatasvir 60 mg daily, for a period of 3 months. Laboratory testing indicate that the combination regimen was well-tolerated with no sign of drug-drug interaction. Confirmation of these clinical observations in large clinical studies may help improve morbidity and decrease mortality outcome in patients infected with HCV and undergoing hemodialysis treatment.

Topics: Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Drug Therapy, Combination; Hepatitis C; Humans; Imidazoles; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Pyrrolidines; Renal Dialysis; Renal Insufficiency, Chronic; Risk Factors; Sofosbuvir; Treatment Outcome; Valine

The efficacy of the all-oral administration of daclatasvir and asunaprevir for 24 weeks was compared with that of telaprevir for 12 weeks plus pegylated interferon and ribavirin (PEG-IFN/RBV) for 24 weeks, and that of simeprevir for 12 weeks plus PEG-IFN/RBV for 24 weeks, with a focus on the prevention of occurrence and recurrence of hepatocellular carcinoma (HCC). The levels of alanine aminotransferase (ALT) and α-fetoprotein (AFP) as suppressive markers of HCC were also measured.. Patients received daclatasvir and asunaprevir (n = 17), simeprevir plus PEG-IFN/RBV (n = 15) and telaprevir plus PEG-IFN/RBV (n = 25). Sustained virological response (SVR) and the mean change in the level of serum ALT, AFP and platelet (PLT) count were compared among the three groups.. No difference in SVR was observed in patients given daclatasvir with asunaprevir (SVR4), telaprevir plus PEG-IFN/RBV or simeprevir plus PEG-IFN/RBV (SVR24). Also, no significant difference was observed in the mean change of serum ALT, AFP or PLT count among the three groups.. The preventive effect of the IFN-free, all-oral regimen of daclatasvir and asunaprevir was observed with a focus on the occurrence and recurrence of HCC, as was IFN-based treatment with telaprevir or simeprevir plus PEG-IFN/RBV.

Topics: Adult; Aged; Aged, 80 and over; alpha-Fetoproteins; Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Drug Therapy, Combination; Female; Follow-Up Studies; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Interferon alpha-2; Interferon-alpha; Isoquinolines; Japan; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Oligopeptides; Polyethylene Glycols; Polymerase Chain Reaction; Prognosis; Pyrrolidines; Recombinant Proteins; Ribavirin; RNA, Viral; Simeprevir; Sulfonamides; Valine; Viral Load

This Letter describes the discovery of a number of functionalized bisimidazoles bearing a cyclohexylphenyl, piperidylphenyl, or bicyclo[2,2,2]octylphenyl motif as HCV NS5A inhibitors. Compounds 2c, 4b and 6 have demonstrated low single-digit nM potency in gt-1a replicon and double-digit pM potency in gt-1b replicon, respectively. Moreover, both 4b and 6 have, respectively, exhibited good oral bioavailability in rats with a favorable liver/plasma ratio of the drug concentration.

Topics: Animals; Antiviral Agents; Carcinoma, Hepatocellular; Drug Discovery; Drug Evaluation, Preclinical; Hepacivirus; Hepatitis C; Humans; Hydrocarbons, Acyclic; Imidazoles; Liver Neoplasms; Male; Models, Molecular; Molecular Structure; Rats; Rats, Sprague-Dawley; Replicon; Structure-Activity Relationship; Tumor Cells, Cultured; Viral Nonstructural Proteins; Virus Replication

Hepatitis C virus (HCV) therapy will benefit from the preclinical evaluation of direct-acting antiviral (DAA) agents in infectious culture systems that test the effects on different virus genotypes. We developed HCV recombinants comprising the 5' untranslated region-NS5A (5-5A) from genotypes 1-6 and 2a(JFH1) NS5B-3' untranslated region, and tested the effects of NS3 protease and NS5A inhibitors on these recombinants.. The HCV 5-5A recombinants with previously identified mutations in the NS3-helicase (F1464L), NS4A (A1672S), and NS5B (D2979G) were adapted and improved, by incorporating additional recovered mutations that increased their propagation in Huh7.5 cells. Concentration-response profiles were determined for each DAA agent in replicate infected Huh7.5 cells.. Developed efficient 1a(H77), 1a(TN), 3a(S52), 4a(ED43), 5a(SA13), and 6a(HK6a) 5-5A recombinants did not require mutations after viral passage in the NS3 protease or NS5A domain-I regions targeted by the drugs. They were inhibited in a concentration-dependent manner by the NS3 protease inhibitors telaprevir, boceprevir, asunaprevir, simeprevir, vaniprevir, faldaprevir, and MK-5172 and by the NS5A inhibitor daclatasvir. The 1a(TN) 5-5A and JFH1-independent full-length viruses had similar levels of sensitivity to the DAA agents, validating the 5-5A recombinants as surrogates for full-length viruses in DAA testing. Compared with the 1a(TN) full-length virus, the 3a(S52) 5-5A recombinant was highly resistant to all protease inhibitors, and the 4a(ED43) recombinant was highly resistant to telaprevir and boceprevir, but most sensitive to other protease inhibitors. Compared with other protease inhibitors, MK-5172 had exceptional potency against all HCV genotypes. The NS5A inhibitor daclatasvir had the highest potency observed, but with genotype-dependent activity.. The mutations F1464L, A1672S, and D2979G permitted the development of efficient HCV recombinants comprising genotype-specific 5' untranslated region-NS5A (5-5A), which include the natural NS3 protease and NS5A domain-I drug targets. The robust replication of adapted 5-5A recombinants allowed for direct comparison of NS3 protease and NS5A inhibitors against HCV strains of genotypes 1-6.

Topics: Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Carrier Proteins; Cell Line, Tumor; Genotype; Hepacivirus; Humans; Imidazoles; Intracellular Signaling Peptides and Proteins; Liver; Liver Neoplasms; Mutation; Oligopeptides; Proline; Protease Inhibitors; Pyrrolidines; Valine; Viral Nonstructural Proteins