Safety and efficacy of faldaprevir with pegylated interferon alfa-2a and ribavirin in Japanese patients with chronic genotype-1 hepatitis C infection.

BACKGROUND & AIMS: Faldaprevir (BI 201335) is a potent once-daily (QD) NS3/4A protease inhibitor for the treatment of patients with genotype-1 (GT-1) hepatitis C virus (HCV). The aim of this study was to evaluate the safety, pharmacokinetics and efficacy of faldaprevir plus pegylated interferon alfa-2a (PegIFN) and ribavirin (RBV) in Japanese patients infected with chronic GT-1 HCV. METHODS: Part 1 of this phase II study was a randomized, double-blind, placebo-controlled, dose-ascending study. Treatment-naïve patients received faldaprevir 120 or 240 mg QD, or placebo, plus PegIFN/RBV for 4 weeks, then PegIFN/RBV alone for 44 weeks. In Part 2 (open label), treatment-experienced patients received faldaprevir 240 mg QD plus PegIFN/RBV for 4 weeks, then PegIFN/RBV alone for 44 weeks. Efficacy was assessed using sustained virological response (SVR) 24 weeks after treatment completion. The pharmacokinetics, safety and tolerability of faldaprevir were also assessed. RESULTS: SVR was achieved by 4/6 (67%) treatment-naïve patients treated with faldaprevir 120 mg QD, 5/6 (83%) patients treated with faldaprevir 240 mg QD and 2/4 (50%) patients who received placebo. Of the treatment-experienced patients, 3/6 (50%) achieved SVR. Faldaprevir was well tolerated. There was one serious adverse event, which was not considered to be treatment related. Rash and hyperbilirubinaemia were more frequently reported with faldaprevir than with placebo in treatment-naïve patients, but no cases were severe or serious and none led to discontinuation. Steady-state plasma concentrations of faldaprevir were reached within 7 days of QD dosing. CONCLUSIONS: Faldaprevir with PegIFN/RBV was efficacious and well tolerated, supporting further evaluation of this combination in Japanese patients.

[A case of Crohn's disease concomitant with IgA nephropathy].

A 34-year-old woman with underlying IgA nephropathy was admitted to our hospital with chief complaints of abdominal pain and pyrexia. Computed tomography showed increased mural thickness of the ileum and increased mesenteric fat density. Colonoscopic findings revealed a longitudinal ulcer in the terminal ileum and irregularly shaped ulcers and a longitudinal ulcer scar in the descending colon. Histopathological analysis of biopsy specimens from the ileum and descending colon showed non-caseating epithelioid cell granuloma. On the basis of these findings, the condition of the patient was diagnosed as ileocolonic Crohn's disease, and the patient received parenteral nutrition, followed by elemental diet. The patient was responsive to nutrition therapy, and the amount of uric protein decreased as her Crohn's disease activity index decreased. In conclusion, we assume that the Crohn's disease activity correlated with that of IgA nephropathy.

Comparison of therapeutic effects between radiofrequency ablation and percutaneous microwave coagulation therapy for small hepatocellular carcinomas.

BACKGROUND: Although thermal ablation therapies have gained fairly wide acceptance as an effective treatment for small hepatocellular carcinoma (HCC), there have been only a few clinical studies comparing the response to radiofrequency ablation (RFA) and percutaneous microwave coagulation therapy (PMCT). We evaluated the therapeutic efficacy and safety of these two procedures for the treatment of small HCC measuring < or = 2 cm in diameter. METHODS: Thirty-four patients who had 37 nodules were treated by RFA and were compared with 49 patients (56 nodules) who underwent PMCT. Treatment was repeated until complete tumor necrosis was confirmed by contrast computed tomography (CT) scanning. The therapeutic efficacy and complications were retrospectively compared between the two procedures. RESULTS: (i) There were significantly fewer treatment sessions (P < 0.001) in the RFA group than in the PMCT group, but the necrotic area was significantly larger (P < 0.001) in the former group. (ii) The local recurrence rate was significantly lower (P = 0.031) after RFA than after PMCT, although the ectopic recurrence rate showed no significant difference. (iii) The cumulative survival rate was significantly higher (P = 0.018) after RFA than after PMCT. (iv) The incidence of pain and fever after treatment was significantly higher in the PMCT group. Bile duct injury, pleural effusion, and ascites were also significantly more common in the PMCT group. CONCLUSIONS: RFA is more useful than PMCT for the treatment of small HCC because it is minimally invasive and achieves a low local recurrence rate, high survival rate, and extensive necrosis after only a few treatment sessions.

Radiofrequency ablation versus percutaneous microwave coagulation therapy for small hepatocellular carcinomas: a retrospective comparative study.

BACKGROUND/AIMS: Although local ablation procedures are useful in eradication treatment for small hepatocellular carcinoma (HCC), there have only been a few clinical studies comparing the response to radiofrequency ablation (RFA) and percutaneous microwave coagulation therapy (PMCT). We evaluated the clinical effect and safety of these two procedures for the treatment of small HCCs measuring 2cm or less in diameter. METHODOLOGY: Twenty-four patients with HCC who were treated by RFA and were compared with 39 patients with HCC who underwent PMCT. These procedures were repeated until complete tumor necrosis was achieved. The therapeutic and adverse effects were retrospectively compared between the two procedures. RESULTS: (1) There were significantly fewer treatment sessions (P < 0.001) in the RFA group than the PMCT group, and the necrotic area was significantly larger (P < 0.001) in the former group. (2) The local recurrence rate was significantly lower (P = 0.012) after RFA than after PMCT, even though the ectopic recurrence rate showed no significant difference. 3) The cumulative survival rate was significantly higher (P = 0.028) in the RFA group. (4) The incidence of pain and fever after treatment was significantly higher after PMCT than after RFA. Bile duct injury and pleural effusion were also more frequent in the PMCT group. CONCLUSIONS: RFA is more useful than PMCT in the treatment of small HCCs because it is minimally invasive and achieves a low local recurrence rate, high survival rate, and extensive necrosis after only a few treatment sessions.

[Hepatocellular carcinoma occurring after 11 year-long sustained viral response to interferon therapy for chronic hepatitis C].

The patient was a 61-year-old man with chronic hepatitis C who achieved a sustained virological response to interferon therapy in 1993. As a result, the status of his liver improved pathologically from F2A2 to F1A1. Eleven years later, however, a tumor measuring 15 mm in diameter in segment 6 of the liver was indicated by CT. A well-differentiated hepatocellular carcinoma was detected by a fine needle biopsy. The lesion was treated by transcatheter arterial chemoembolization combined with radiofrequency ablation. Even if patients with chronic hepatitis C have achieved a sustained virological response to interferon therapy, patients with risk factors for the development of hepatocellular carcinoma, such as being a male of advanced age and with progressive fibrosis of the liver, should receive careful long-term follow-up.

[Pyogenic liver abscess complicated by gastric fistula and bacterial meningitis].

A 77-year-old woman was admitted suffering from fever and headache. On laboratory examination, bacterial meningitis and sepsis due to Klebsiella pneumoniae were diagnosed. In addition, a hepatic cystic lesion measuring 13 cm in diameter in the left lobe was indicated on diagnostic imaging. After treatment with antibiotics, her signs of infection improved and the hepatic lesion decreased in size. After discharge, however, the cystic liver mass increased and a gastric fistula developed. Hepatic and gastric resections were performed because of the possibility of biliary cystadenocarcinoma and gastric invasion. Pathologically, a pyogenic liver abscess complicated by gastric fistula was diagnosed.

Thermal ablation therapy for hepatocellular carcinoma: comparison between radiofrequency ablation and percutaneous microwave coagulation therapy.

BACKGROUND/AIMS: To evaluate the initial therapeutic effect and safety of radiofrequency ablation (RFA) and percutaneous microwave coagulation therapy (PMCT) for the treatment of small hepatocellular carcinomas (HCCs). METHODOLOGY: Forty-eight patients with HCC were treated by RFA and 70 patients with HCC were treated by PMCT. These procedures were repeated until complete tumor necrosis was confirmed by contrast CT scanning. The therapeutic and adverse effects were compared between the two procedures. RESULTS: 1) The number of treatment sessions was significantly lower in RFA patients, and the necrotic area was significantly larger. 2) The local recurrence rate was significantly lower after RFA than after PMCT, while the ectopic recurrence rate showed no significant difference between the two procedures. 3) The survival rate was significantly higher after RFA compared with PMCT. 4) The incidence of pain and fever after treatment was significantly higher in PMCT patients. Occurrence of bile duct injury, pleural effusion and ascites were also significantly more common in PMCT patients. CONCLUSIONS: RFA is more useful for the treatment of small HCCs compared with PMCT because it is minimally invasive and achieves a low local recurrence rate, a high survival rate, and extensive necrosis after only a few treatment sessions.

Carbon dioxide-enhanced sonographically guided radiofrequency ablation combined with transcatheter arterial chemoembolization for sonographically undetectable hepatocellular carcinoma.

A 73-year-old man was diagnosed as having hepatitis C virus-related liver cirrhosis 11 years ago. Two years ago, he developed hepatocellular carcinoma in segment 6 of the right lobe and received radiofrequency ablation. This time, he was admitted to our hospital with a local recurrence in segment 6 of the liver. Standard sonography could not visualize the lesion clearly. However, carbon dioxide-enhanced sonogram clearly showed the whole lesion, so a needle electrode could be inserted precisely, allowing safe and accurate radiofrequency ablation. By combining radiofrequency ablation with transcatheter arterial chemoembolization, complete tumor necrosis was achieved without the need to perform additional ablation. In conclusion, carbon dioxide-enhanced sonographically guided radiofrequency ablation combined with transcatheter arterial chemoembolization is useful for complete cure of localized tumors, such as recurrent hepatocellular carcinoma, which cannot be detected clearly by conventional sonography.

Spontaneous regression of focal nodular hyperplasia of the liver.

Focal nodular hyperplasia (FNH) of the liver is a rare benign lesion that probably reflects a local hyperplastic response of hepatocytes to a vascular abnormality. Currently, the natural history of the disease remains largely unknown. We present a patient with FNH of the liver who was followed up for 4 years. A 22-year-old woman with a 3-year history of oral contraceptive use was referred to our hospital in September 1996 for further examination of a liver tumor. A diagnosis of FNH was made using various imaging methods, such as ultrasonography, enhanced computed tomography (CT) scanning, MR imaging, and hepatic angiography, as well as fine-needle biopsy. A decrease in the size of the lesion was observed by enhanced CT scanning during the 4-year observation period. In this patient, oral contraceptive use and its discontinuation may have influenced the natural history of FNH. The present case suggests that an accurate diagnosis is of the utmost importance, and a patient with FNH should be managed conservatively rather than by resection, because FNH has the potential for spontaneous regression with the discontinuation of oral contraceptives.

CT-guided percutaneous ethanol injection therapy for ultrasonically invisible hepatocellular carcinoma.

We report the case of a 75-year-old woman with hepatitis C virus-related cirrhosis and recurrent hepatocellular carcinoma located just beneath the diaphragm. Computed tomography-guided percutaneous ethanol injection therapy was performed, because images of the tumor were hard to obtain on ultrasonography. The angle and depth of needle insertion were determined by using the geometric relationship between the target lesion and the skin insertion site on computed tomography scans. A 22-gauge needle was inserted through the right 6th intercostal space under local anesthesia. Computed tomography scanning was repeated to verify the needle position. After entry of the needle into the target lesion was confirmed, 10 mL of absolute ethanol was injected. This procedure caused transient mild pain, but there were no serious adverse effects such as pneumothorax or hemothorax. Three months after treatment, the lesion was not enhanced on dynamic computed tomography scanning, suggesting complete tumor ablation. At present, the patient is doing well. In conclusion, computed tomography-guided percutaneous ethanol injection therapy was safe and accurately achieved the desired tumoricidal effect in a patient with ultrasonically invisible hepatocellular carcinoma.

Combined intraarterial 5-fluorouracil and intramuscular interferon-alpha therapy for advanced hepatocellular carcinoma.

We report the case of a 66-year-old man with hepatic cirrhosis and multiple hypervascular tumors in both lobes of the liver as well as tumor thrombi in the portal vein. After unresectable hepatocellular carcinoma was diagnosed, transcatheter arterial embolization was considered to be difficult, because he had major portal vein thrombosis. Conventional ultrasonically-guided local treatments, such as percutaneous ethanol injection therapy and radiofrequency ablation, were also of no value because the tumors were huge and multiple. Ultimately, he was treated with a combination of intraarterial 5-fluorouracil and intramuscular interferon-alpha. After treatment, the multiple tumors became non-enhancing on contrast computed tomography scans and showed a marked decrease in size. There were no serious adverse effects (such as myelosuppression or hepatotoxicity) during treatment or follow-up and the patient is doing well at present. In conclusion, a combination of intraarterial 5-fluorouracil with intramuscular interferon-alpha appears to be useful for the management of advanced hepatocellular carcinoma, especially in patients for whom more aggressive treatment is not acceptable.

Percutaneous microwave coagulation therapy for superficial hepatocellular carcinoma on the surface of the liver.

BACKGROUND/AIMS: This study was performed to evaluate the efficacy and safety of percutaneous microwave coagulation therapy for superficial hepatocellular carcinoma located on the surface of the liver. METHODOLOGY: Among 58 cirrhosis patients with 71 hepatocellular carcinomas measuring < or = 20 mm in greatest dimension, 18 patients had a solitary superficial lesion located on the liver surface (superficial hepatocellular carcinoma group) and the other 40 patients had 53 lesions that were not in contact with the liver surface (non-superficial hepatocellular carcinoma group). All patients were treated by percutaneous microwave coagulation therapy alone and the response was assessed by using contrast-enhanced CT. The survival, tumor recurrence, and adverse effects were compared between the superficial and non-superficial hepatocellular carcinoma groups. RESULTS: The 4-year survival rates of the superficial hepatocellular carcinoma group (64.2%) and the non-superficial hepatocellular carcinoma group (58.9%) were not significantly different, and neither were the 4-year local recurrence rates (27.1% vs. 29.8%). Although there was a significantly higher incidence of severe pain during microwave irradiation in the superficial hepatocellular carcinoma group (23/47) when compared with the non-superficial hepatocellular carcinoma group (25/148), there were no differences between them in the incidence of fever or the changes in liver function after treatment. There were no serious adverse effects, such as hemorrhage or tumor cell seeding, in either group. CONCLUSIONS: Percutaneous microwave coagulation therapy can be performed safely, even in patients with superficial hepatocellular carcinoma and cirrhosis, so this method is effective for treating hepatic neoplasms regardless of the tumor location.

[A case of infliximab-related liver damage -case report and literature review].

A 50-year-old woman was admitted to our hospital with complaints of loss of vision, diarrhea and arthralgia. She was given a diagnosis of Behçet disease and given infliximab (IFX) to halt the progression of acute vision loss. Liver damage was detected after the fourth IFX dose. We assumed that this was a drug-induced condition caused by salazosulfapyridine (SASP). However, the liver damage worsened, and the condition did not improve even after discontinuing SASP. Thus, therapy to enhance hepatic function was initiated. Histological analysis of liver biopsy specimens showed centrilobular spotty necrosis and periportal hepatitis. We diagnosed autoimmune hepatitis rather than drug-induced liver damage. Because of liver function deterioration, we initiated steroid treatment and rapid improvement was observed. Therefore, liver function should be carefully monitored during IFX administration for patients with genetic predispositions to autoimmune hepatitis, such as human leukocyte antigen-DR4.

Peginterferon alpha-2a (40 KD) plus ribavirin for the treatment of chronic hepatitis C in Japanese patients.

BACKGROUND: The efficacy and safety of peginterferon alpha-2a (40 KD) (peg-IFNalpha-2a) plus ribavirin has not been reported for Japanese patients with chronic hepatitis C. The aim of this study was to evaluate this combination in treatment-naïve patients and in non-responders or relapsers to interferon monotherapy. METHODS: Overall, 201 treatment-naïve patients with hepatitis C virus (HCV) genotype-1b were randomly assigned to 180 microg peg-IFNalpha-2a once-weekly plus ribavirin 600-1000 mg/day or peg-IFNalpha-2a plus placebo for 48 weeks. Additionally, peg-IFNalpha-2a plus ribavirin was administered for 48 weeks to 100 non-responders or relapsers (85% genotype-1) to previous interferon monotherapy. RESULTS: A sustained virological response (SVR) was attained among significantly more treatment-naïve patients receiving combination therapy than monotherapy (61% vs 26%, P < 0.001). For patients with high baseline HCV RNA, the SVR rate was 59% with peg-IFNalpha-2a plus ribavirin versus 24% with peg-IFNalpha-2a monotherapy. Among non-responders or relapsers to previous interferon monotherapy, 54% attained an SVR. Adverse events were generally mild, and discontinuations rates due to adverse events or laboratory abnormalities were low. CONCLUSION: In Japanese patients, peg-IFNalpha-2a plus ribavirin provided significant improvement in SVR rates compared with peg-IFNalpha-2a alone in treatment-naïve patients, and was effective as re-treatment for non-responders or relapsers to previous treatment with interferon monotherapy.

CO2-enhanced sonographically guided radiofrequency ablation and transcatheter arterial chemoembolization for small hepatocellular carcinoma poorly defined on conventional sonography.

We report a case of hepatocellular carcinoma located just below the right hemidiaphragm that was diagnosed as having hepatitis C virus-related cirrhosis 12 years ago. Although the lesion was not clear on conventional sonography, it was clearly defined on CO(2)-enhanced sonography, allowing safe and accurate radiofrequency ablation. By combining radiofrequency ablation with transcatheter arterial chemoembolization, extensive cauterization and complete tumor necrosis were obtained with only 1 session of treatment. The patient had no serious adverse effects and has shown no recurrence during 35 months of follow-up.

Use of intra-arterial carbon-dioxide-enhanced ultrasonography for guidance of radiofrequency ablation and transcatheter arterial chemoembolization in hepatocellular carcinoma.

A 73-year-old man with hepatitis-C-related cirrhosis and an elevated alpha-fetoprotein level and tumor in segment 3 of his liver was referred for interventional radiologic treatment. He was not a candidate for surgical resection due to impaired liver function and his personal preferences. On conventional ultrasonography no lesion could be detected, but the tumor was clearly depicted by intra-arterial carbon-dioxide-enhanced ultrasonography. Radiofrequency ablation was performed safely and accurately under the guidance of carbon-dioxide-enhanced ultrasonography. By concomitant performance of transcatheter arterial chemoembolization with radiofrequency ablation, extensive necrosis was obtained and adequate tumor volume reduction achieved with only one treatment session.

Improved prognosis of cirrhosis patients with esophageal varices and thrombocytopenia treated by endoscopic variceal ligation plus partial splenic embolization.

The aim of this study was to assess the efficacy of the combination of endoscopic variceal ligation (EVL) and partial splenic embolization (PSE) compared with EVL alone in cirrhosis patients with thrombocytopenia. In a prospective study, 84 cirrhosis patients with esophageal varices and thrombocytopenia (platelet count < 50,000/mm(3)) underwent EVL plus PSE (N = 42) or EVL alone (N = 42). Primary end points assessed during the follow-up period included the recurrence of varices, progression to variceal bleeding, and death. Comparison between combined treatment and variceal ligation alone by multivariate analysis showed a hazard ratio of 0.44 for the recurrence of varices (P = 0.02), 0.19 for progression to variceal bleeding (P = 0.01), and 0.31 for death (P = 0.04). These results suggest that the combination of EVL plus PSE can prevent the recurrence of varices, progression to variceal bleeding, and death in cirrhosis patients with esophageal varices and thrombocytopenia.

Carbon dioxide-enhanced sonographically guided radiofrequency ablation plus transcatheter arterial chemoembolization for hepatocellular carcinoma.

A 78-year-old man had a history of blood transfusion and hepatitis C virus-related liver cirrhosis. He was admitted to the authors' hospital with a hepatocellular carcinoma just below the right hemidiaphragm. Although the lesion was not well visualized with standard sonography, it was clearly defined by performance of sonography with intraarterial injection of carbon dioxide, allowing safe and accurate radiofrequency ablation. To increase the extent of tumor ablation, transcatheter arterial chemoembolization was performed immediately before radiofrequency ablation. By concomitant application of these two techniques, complete tumor necrosis was achieved without the need to perform additional ablation.

Autoantibody in a patient with chronic hepatitis C virus infection showing complete remission after interferon therapy.

A 42-year-old woman was admitted to Kinashi Ohbayashi Hospital for liver dysfunction. She presented with hepatitis C viral infection accompanied by autoimmune hepatitis-like serological manifestations, such as antinuclear antibody (ANA), antismooth muscle cell antibody and especially anti-ribonucleoprotein (RNP) antibody and anti-SSB antibody. After interferon therapy, hepatitis C virus was not detected and ANA, anti-RNP antibody and anti-SSB antibody disappeared. To our knowledge, this is the first reported hepatitis C patient showing anti-RNP antibody and anti-SSB antibody, having complete remission after interferon therapy.