Real-World Virological Efficacy and Safety of Ledipasvir and Sofosbuvir in Patients with Chronic Hepatitis C Virus Genotype 2 Infection: A Multicenter Study.

INTRODUCTION: The real-world virological efficacy and safety of interferon-free direct-acting antiviral (DAA) therapy with ledipasvir (LDV) plus sofosbuvir (SOF) were assessed in patients who were chronically infected with hepatitis C virus (HCV) genotype 2. METHODS: A total of 126 patients with chronic hepatitis C due to HCV genotype 2 infection who were treated with the LDV/SOF regimen were enrolled. The sustained virological response (SVR) rate and safety were analyzed. SVR was assessed in the intention-to-treat (ITT) population as well as in the modified intention-to-treat (mITT) population, which excluded patients with non-virological failure, including those who dropped out before the SVR assessment. RESULTS: The overall SVR rates of the ITT and mITT populations were 87.3% (95% confidence interval [CI] 80.2-92.6) (110/126) and 97.3% (95% CI 92.4-99.4) (110/113), respectively. In the mITT population, the percentages of patients with undetectable HCV RNA at 4, 8, and 12 weeks after the start of therapy were 92.9% (95% CI 86.5-96.9) (105/113), 99.1% (95% CI 95.2-100.0) (112/113), and 100.0% (95% CI 97.4-100.0) (113/113), respectively. Subgroup analyses of the mITT population showed no significant differences in SVR rates according to age, sex, HCV genotype (subtype), history of interferon-based therapy, baseline FIB-4 index, or baseline estimated glomerular filtration rate. In all subpopulations, the SVR rates were > 90%. There were no severe adverse events associated with the treatment. CONCLUSION: The LDV/SOF regimen showed high virological efficacy and acceptable safety in patients with HCV genotype 2 infection. TRIAL REGISTRATION: UMIN registration no. 000038604.

[Cirrhotic cardiomyopathy-associated acute cardiac failure in a patient with decompensated alcoholic cirrhosis with massive hepatic hydrothorax].

Cirrhotic cardiomyopathy (CCM) is a chronic cardiac dysfunction in patients with cirrhosis and is characterized by altered diastolic relaxation, blunted contractile response to stress, and electrophysiological abnormalities;however, causes of CCM are unknown. Moreover, reduced cardiac afterload due to cirrhosis-related vasodilatation often masks cardiac insufficiency, whereas rapid hemodynamic overload reveals the presence of cirrhotic cardiomyopathy. Herein, we present the case of previously unrecognized cirrhotic cardiomyopathy that became overt with the development of severe acute cardiac failure. The rapidly worsening hepatic hydrothorax increased cardiac preload and intrathoracic pressure, which impaired cardiac filling. Furthermore, cardiac contractile function might have been worsened by hypoxia due to passive atelectasis and concomitant anemia.

Real-world efficacy of elbasvir and grazoprevir for hepatitis C virus (genotype 1): A nationwide, multicenter study by the Japanese Red Cross Hospital Liver Study Group.

AIM: The present study aimed to determine the real-world efficacy and safety of the non-structural protein (NS)5A inhibitor elbasvir (EBR) combined with the NS3/4A protease inhibitor grazoprevir (GZR) in patients with hepatitis C virus (HCV) genotype 1 (GT1) infection. METHODS: This study retrospectively evaluated the rate of sustained virologic response at 12 weeks post-treatment (SVR12) and the safety of EBR/GZR treatment in 159 men and 194 women with a median age of 72 years, and it assessed factors associated with the SVR12 rate. The attending physicians were responsible for selecting candidate patients for EBR/GZR in this retrospective study. RESULTS: Treatment outcomes for EBR/GZR were good in direct-acting antiviral (DAA)-naïve patients, of whom 99.4% achieved SVR. Of 353 patients, 10 (2.9%) had treatment failure. Of these patients, eight previously underwent DAA therapy, and the remaining two had NS5A-L31/Y93 double mutation. The SVR rate was 50% (8/16 patients) in patients who previously underwent DAA therapy, and 18.2% (2/11 patients) in patients with NS5A-L31/Y93 double mutation. On multivariate logistic regression analysis, NS5A-Y31/Y93 double mutation (odds ratio 356.3; 95% confidence interval, 23.91-16 940; P < 0.0001) was identified as an independent predictor of treatment failure. No serious adverse events were observed with EBR/GZR therapy. CONCLUSIONS: The SVR rate of EBR/GZR would have been 100% in patients without either a history of DAA therapy or double mutation. This combination of drugs could be safely given and is, thus, considered a highly useful first-line treatment for DAA-naïve patients with HCV.

Hepatocellular Carcinoma in a Patient with Hereditary Hemorrhagic Telangiectasia.

A 76-year-old woman with hereditary hemorrhagic telangiectasia (HHT) showed elevated serum hepatobiliary enzyme levels, and abdominal imaging studies revealed a hepatic tumor. Her serum alpha-fetoprotein level was 759.5 ng/mL. A pathological examination after hepatectomy confirmed a diagnosis of hepatocellular carcinoma (HCC). An examination of the surrounding liver revealed dilated vessels and thickened endothelial cells without inflammations. HHT patients without other risk factors (like this patient) reportedly have a lower incidence of common cancers, including HCC, in comparison to the unaffected population. One intriguing hypothesis that might explain the hepatocarcinogenesis in this situation is the ischemic liver cirrhosis theory, which suggests that chronic ischemia may cause parenchymal strain and promote inappropriate hepatocyte proliferation.

Infectious Hepatic Cyst: An Underestimated Complication.

Objective An infectious hepatic cyst (IHC) is a hepatic cyst complicated with secondary infection and is generally assumed to be rare. However, we have experienced no small number of patients with IHC in recent clinical practice. We therefore examined the incidence and clinical characteristics of IHC. Methods The medical records of patients with IHC who were hospitalized at our institution between January 2012 and December 2016 were retrospectively reviewed. Their demographic factors, biochemical, bacteriological, imaging, and treatment results were explored and compared with those of patients with pyogenic liver abscess (PLA). Patients Twelve patients with IHC and 39 with PLA were identified. Results The IHCs were significantly larger in diameters than the PLAs, and patients with IHCs tended to be older and more often women than those with PLAs. IHCs showed characteristic imaging features, including heterogeneous contents with occasional fluid-debris levels, a thickened cystic wall with rim enhancement, perilesional edema and hyperaemia. Patients with IHCs had a significantly shorter hospital stay than those with PLAs. Conclusion Physicians should note that IHCs are not rare. A careful imaging evaluation can suggest an IHC, and the timely aspiration of the content can lead to an accurate diagnosis. The cystic wall may keep the infectious material confined within the IHC, resulting in the observed good treatment outcome with catheter drainage.

Efficacy of daclatasvir plus asunaprevir in patients with hepatitis C virus infection undergoing and not undergoing hemodialysis.

AIM: To evaluate the virologic responses and clinical course of daclatasvir plus asunaprevir treatment in non-hemodialysis (non-HD) and hemodialysis (HD) patients infected with genotype 1 hepatitis C virus (HCV). METHODS: A total of 1113 non-HD patients and 67 HD patients were assessed. To evaluate pretreatment factors contributing to sustained virological response at 12 weeks (SVR12), univariate and multivariate analyses were carried out. To adjust for differences in patient background, propensity score matching was undertaken. RESULTS: The overall SVR12 rates were 91.6% in non-HD patients and 95.5% in HD patients. Compared with non-HD patients, HD patients were younger, were more likely to be male, were less likely to have received interferon-based pretreatment, had a lower viral load, and had lower levels of alanine transaminase, hemoglobin, and α-fetoprotein. Multivariate analysis revealed that viral load, α-fetoprotein, L31 substitution negative, and Y93 substitution negative were independent predictive factors for SVR12 in non-HD patients. The proportion of patients with undetectable HCV-RNA during the initial 4 weeks was significantly higher in HD patients than in non-HD patients. The SVR12 rate was clearly higher in HD patients than in non-HD patients, although the difference was not statistically significant. After propensity score matching to adjust for viral load, α-fetoprotein, L31 substitution, and Y93 substitution, these trends disappeared. CONCLUSIONS: For treatment of HCV genotype 1 infection, daclatasvir plus asunaprevir is useful not only in non-HD patients but also in HD patients. Viral load, α-fetoprotein levels, L31 substitution, and Y93 substitution influence treatment course and outcome.

Increasing incidence of elderly-onset autoimmune hepatitis.

AIM: Autoimmune hepatitis (AIH) commonly shows bimodal distribution of onset age: at young adulthood and at 50-60 years-of-age. However, in recent times, the incidence of elderly-onset AIH seems to be increasing. This study aimed to investigate whether the incidence of elderly-onset AIH is increasing, and whether these patients show any clinical features different from those observed in younger patients. METHODS: Data about patients with newly diagnosed AIH visiting the Japanese Red Cross Society Himeji Hospital, Himeji, Hyogo, Japan, were retrospectively collected for the period ranging from January 2010 to May 2016. A total of 71 patients (56 women and 15 men, age 18-88 years) were included in this study. Patients were divided into two cohorts: elderly (≥70 years; n = 28) and adult cohort (15-69 years; n = 43). Demographic and clinical characteristics, biochemical and serological markers, radiological and histological findings, and therapeutic courses were evaluated. RESULTS: The median age of the patients was 65 years, the most frequent range being the 70s (37%), followed by the 60s (25%). The elderly cohort had significantly higher levels of serum immunoglobulin G and antinuclear antibody, lesser hepatitis activity scores, and lesser chance of developing other autoimmune diseases. They tended to have higher C-reactive protein levels and lower serum alanine aminotransferase levels. All patients achieved clinical remission after treatment. CONCLUSIONS: This study clearly showed an increase in the incidence of elderly-onset AIH. These patients had some unique characteristics, showing that the development of elderly-onset AIH is influenced by age-associated immune dysfunction called immunosenescence. Geriatr Gerontol Int 2017; 17: 1722-1728.

Complex Pattern of Resistance-Associated Substitutions of Hepatitis C Virus after Daclatasvir/Asunaprevir Treatment Failure.

BACKGROUNDS & AIMS: We aimed to clarify the characteristics of resistance-associated substitutions (RASs) after treatment failure with NS5A inhibitor, daclatasvir (DCV) in combination with NS3/4A inhibitor, asunaprevir (ASV), in patients with chronic hepatitis C virus genotype 1b infection. METHODS: This is a nationwide multicenter study conducted by the Japanese Red Cross Liver Study Group. The sera were obtained from 68 patients with virological failure after 24 weeks of DCV/ASV treatment. RASs in NS5A and NS3 were determined by population sequencing. RESULTS: The frequency of signature RASs at position D168 of NS3 was 68%, and at positions L31 and Y93 of NS5A was 79 and 76%, respectively. The frequency of dual signature RASs in NS5A (L31-RAS and Y93-RAS) was 63%. RASs at L28, R30, P32, Q54, P58, and A92 in addition to dual signature RAS were detected in 5, 5, 1, 22, 2, and 0 patients, respectively. In total, triple, quadruple, and quintuple RASs in combination with dual signature RAS were detected in 35, 10, and 1.5% patients, respectively. These RASs were detected in patients without baseline RASs or who prematurely discontinued therapy. Co-existence of D168 RAS in NS3 and L31 and/or Y93 RAS in NS5A was observed in 62% of patients. CONCLUSION: Treatment-emergent RASs after failure with DCV/ASV combination therapy are highly complex in more than 50% of the patients. The identification of complex RAS patterns, which may indicate high levels of resistance to NS5A inhibitors, highlights the need for RAS sequencing when considering re-treatment with regimens including NS5A inhibitors.

Synergistic anti-tumor effects of zoledronic acid and radiotherapy against metastatic hepatocellular carcinoma.

A 72-year-old man with advanced hepatocellular carcinoma and decompensated hepatitis C virus-related cirrhosis suffered from a metastatic femoral fracture. After undergoing radiotherapy, he was only treated with supportive care, except for the administration of zoledronic acid (ZA). Thereafter, the initially elevated serum α-fetoprotein and des-gamma carboxyprothrombin levels declined to within the normal ranges. Hepatic and metastatic adrenal tumors, distant from the radiation field, exhibited a surprising regression. ZA is known to inhibit the activity of osteoclasts, bone-residential macrophages, and has been reported to have a direct anti-tumor effect. ZA may adjust the immunological milieu in tumor microenvironments by inhibiting the tumor-associated macrophages. Because radiotherapy can enhance the presentation of tumor-associated antigens, ZA and radiotherapy may exert synergistic anti-tumor effects.

Indices of initial hepatitis C virus RNA reduction rate to predict efficacy of interferon-beta followed by peginterferon plus ribavirin for genotype 1b high viral load.

AIM: Initial hepatitis C virus (HCV) RNA reduction was investigated as a potential index for sustained virological response (SVR) in the treatment of interferon (IFN)-ß followed by peginterferon plus ribavirin (PEG IFN/RBV). METHODS: The treatment course was retrospectively analyzed in 64 genotype 1b patients with a HCV RNA level of 5.0 logIU/mL or higher. IFN-ß was administrated twice a day for 2 weeks followed by 24 or 48 weeks of PEG IFN/RBV. The serum HCV RNA level was measured by real-time polymerase chain reaction before administration and at 1, 2 and 4 weeks of therapy. RESULTS: By the duration of PEG IFN administration, the SVR rates were 11% (2/18, <19 weeks), 64% (23/36, 20-24 weeks) and 40% (4/10, 25-72 weeks) (P = 0.0011, χ(2) -test). The SVR rate was high in patients in whom the HCV RNA level had decreased by 2.5 logIU/mL or greater at 1 week of IFN-ß (29/55 [53%] vs 0/9 [0%], P = 0.0029, χ(2) -test). Among these patients, the SVR rate was even higher in those with continuous reduction in the first 2 weeks after the switch to PEG IFN/RBV (27/45 [60%] vs 2/10 [20%], P = 0.0048). Age below 65 years, no previous IFN course and good initial HCV RNA reduction were significantly associated with SVR on multivariate analysis, and the SVR rate was 95% (18/19) among these patients. CONCLUSION: The 2.5 logIU/mL reduction in HCV RNA at 1 week of IFN-ß and the continuous reduction just after the switch to PEG IFN/RBV are important SVR-predictive indices.

Hepatitis C virus relapse was suppressed by long-term self-injection of low-dose interferon in patients with chronic hepatitis C after pegylated interferon plus ribavirin treatment.

AIM: The recommended treatment for chronic hepatitis C is a combination of pegylated interferon (PEG IFN) plus ribavirin (RBV). However, the sustained virological response (SVR) rate of PEG IFN-RBV therapy was approximately 50% in patients with genotype 1b and a high viral load. Thus, we compared the efficiencies and side-effects of PEG IFN-RBV and self-injected low-dose natural (n) IFN-α in patients with hepatitis C virus (HCV). METHODS: A prospective, multicenter, open-label study was conducted in 12 Japanese institutions. A total of 129 patients with chronic hepatitis C and no detectable HCV after 24-72 weeks of PEG IFN-RBV treatment were assigned to the control (n = 82) or treated (n = 47) group. Treated patients received 3 million units of nIFN-α 2-3 times/week over 96 weeks. The groups were compared regarding treatment efficiency and side-effects. RESULTS: Significant treatment success regarding virus negativation rates was found, with 89% and 73% for the treated and control groups, respectively (P = 0.039). In contrast, there was no difference in relapse rate between the groups 24 weeks after the 96-week nIFN-α treatment (P = 0.349). However, when early viral responders and late viral responders (LVR) were separated, LVR patients responded significantly to the treatment with 90% sustained virological response, compared to 53% for the control group (P = 0.044). The side-effects of nIFN-α were less than that of PEG IFN-RBV treatment. CONCLUSION: Self-injected nIFN-α has larger benefits than prolonged PEG IFN-RBV for chronic hepatitis C patients with high viral loads of genotype 1b who fail to achieve early viral response during initial combination treatment.

Mesenteric panniculitis presenting as liver dysfunction.

Mesenteric panniculitis is a non-specific inflammatory disorder affecting adipose tissues of the mesentery. Mesenteric adipose tissues contain macrophages and other inflammatory cells, which may secrete tumor necrosis factor α, interleukin (IL)-1, and IL-6. These cytokines collect into the portal vein and thereby flow into the liver, possibly influencing hepatic function. Mesenteric panniculitis often occurs with inflammatory reactions such as fever and elevated erythrocyte sedimentation rates. Systemic inflammatory disorders can evoke acute cholestatic liver involvement, which is mediated by proinflammatory cytokines. However, no reports have focused on the association between mesenteric panniculitis and liver involvement. We report a rare case of mesenteric panniculitis presenting as liver dysfunction. Immunohistochemical staining of the liver demonstrated a marked decrease in expression of canalicular transport systems. These findings indicated cholestatic liver dysfunction associated with mesenteric panniculitis.

Twenty four-week peginterferon plus ribavirin after interferon-ß induction for genotype 1b chronic hepatitis C.

AIM: To investigate the possibility of shortening the duration of peginterferon (Peg-IFN) plus ribavirin (RBV) combination therapy by incorporating interferon-ß (IFN-ß) induction therapy. METHODS: A one treatment arm, cohort prospective study was conducted on seventy one patients. The patients were Japanese adults with genotype 1b chronic hepatitis C, HCV-RNA levels of ≥ 5.0 Log IU/mL or 100 KIU/mL, and platelet counts of ≥ 90 000/µL. The treatment regimen consisted of a 2 wk course of twice-daily administration of IFN-ß followed by 24 wk Peg-IFN plus RBV combination therapy. We prolonged the duration of the Peg-IFN plus RBV therapy to 48 wk if the patient requested it. RESULTS: The patients, including 44% males, were characterized by an median age of 63 years (range: 32-78 years), an median platelet count of 13.9 (range: 9.1-30.6) × 10(4)/µL, 62% IFN-naïve, and median HCV-RNA of 6.1 (range: 5.1-7.2) Log IU/mL. The sustained virologic response (SVR) rates were 34% (Peg-IFN: 1-24 wk, n = 61, 95% confidence interval (CI): 24%-47%) and 55% (Peg-IFN: 20-24 wk, n = 31, 95% CI: 38%-71%, P < 0.001; vs Peg-IFN: 1-19 wk). The SVR rate when the administration was discontinued early was 13% (Peg-IFN: 1-19 wk, n = 30, 95% CI: 5%-30%), and that when the administration was prolonged was 50% (Peg-IFN: 25-48 wk, n = 10, 95% CI: 24%-76%, P < 0.05; vs Peg-IFN: 1-19 wk). In the patients who received 20-24 wk of Peg-IFN plus RBV, only the higher platelet count (≥ 130 000/µL) was significantly correlated with the SVR (odds ratio: 11.680, 95% CI: 2.3064-79.474, P = 0.0024). In 45% (14/31) of the patients with a higher platelet count (≥ 130 000/µL) before therapy, the HCV-RNA level decreased to below 3.3 Log IU/mL at the completion of IFN-ß, and their SVR rate was 93% (13/14) after 20-24 wk administration of Peg-IFN plus RBV. CONCLUSION: These results suggest the possibilities of shortening the duration of Peg-IFN plus RBV combination therapy by actively reducing HCV-RNA levels using the IFN-ß induction regimen.