Rapidly growing hepatocellular carcinoma recurrence during direct-acting antiviral treatment for chronic hepatitis C.

We herein report the case of a woman in her 80s with a recurrent hepatocellular carcinoma (HCC) tumor that rapidly increased in size during direct-acting antiviral (DAA) treatment. She suffered from HCC at her initial visit to our department and underwent hepatectomy. Thereafter, she underwent DAA treatment for chronic hepatitis C; however, her alpha-fetoprotein (AFP) level rapidly increased, and a liver tumor of > 1 cm in diameter was observed that had not been seen immediately before DAA treatment. She underwent hepatectomy again and moderate to poorly differentiated HCC was diagnosed. The patient's AFP level showed a rapid increase immediately after the start of DAA treatment; however, the increase ceased after the first month, and the influence from the surrounding environment of the tumor was considered to be temporary.

[Hypoxemia due to pulmonary tumor microembolisms from a hepatocellular carcinoma: a case report].

We report a case of pulmonary tumor embolism due to hepatocellular carcinoma (HCC). A woman in her 60s was treated with sorafenib 800 mg daily for HCC with lymph node metastasis. Approximately 50 days after taking sorafenib, she experienced dyspnea and was admitted to the hospital on account of hypoxia. Although her oxygen saturation levels deteriorated, we could find no obvious cause for the hypoxia; despite artificial respiration and oxygenation, she died of respiratory failure on the fourth day of admission. Tissue samples revealed that the HCC cells had infiltrated her lung arterioles; therefore, we concluded that multiple tumor microembolisms from the HCC to the lungs had caused death via respiratory failure. Cases of hypoxia caused by multiple invisible embolisms from HCCs are rarely reported. We believe that infiltration into the lymphatic system may have been related to the development of pulmonary tumor microembolisms.

Weight loss during telaprevir-based triple therapy due to telaprevir-induced appetite loss.

OBJECTIVE: The sustained virological response (SVR) rate has improved to >70% for patients with hepatitis C virus genotype 1 treated with the triple therapy of telaprevir (TVR), pegylated interferon (PEG-IFN)-α, and ribavirin (RBV). However, this therapy has various adverse effects, although there have been no reports of it decreasing body weight. METHODS: A total of 175 patients with chronic hepatitis C received one of three IFN-based regimens (35 received the PEG-IFN/RBV/TVR (PRT) regimen, 70 received the PEG-IFN/RBV (PR) regimen, and 70 received the IFN-ß/RBV (FR) regimen) and body weight was followed for 12 weeks. RESUTS: Decreases in body weight up to week 12 were significantly greater in the PRT group than in the PR or FR groups (p<0.001). The proportion of patients who experienced weight loss ≥5.0 kg by week 12 in the PRT group was significantly higher than in the PR or FR groups (p<0.001) regardless of baseline ghrelin level. The question 18 score (appetite) of the Beck Depression Inventory-II at week 12 was significantly higher in the PRT group than in the PR or FR groups (p<0.001). A multivariate analysis revealed PRT, the ghrelin level before treatment (<7.0 fmol/mL), and the question 18 score in week 12 (2 or 3) to be independent factors associated with a decrease in body weight ≥5.0 kg from week 0 to week 12. CONCLUSION: PEG-IFN/RBV/TVR therapy yielded high SVR rates, but it was associated with a decreased body weight due to TVR-induced appetite loss.

Interferon-beta plus ribavirin therapy can be safely and effectively administered to elderly patients with chronic hepatitis C.

AIM: This study aims to evaluate the efficacy and safety of interferon-beta plus ribavirin therapy in older Japanese patients. PATIENTS AND METHODS: This study enrolled 132 older patients (age, ≥65 years) with chronic hepatitis C who received 24-48 weeks of interferon-beta plus ribavirin (FR; n = 66) or pegylated interferon-alpha plus ribavirin (PR; n = 66) therapy. RESULTS: Patients with the ITPA genotype (CA/AA) in the PR group had significantly greater decreases in hemoglobin levels than those in the FR group at or after week 8. The proportions of patients with a dose reduction of interferon-beta and ribavirin in the FR group were significantly lower than those in the PR group. A significantly higher proportion of patients completed treatment in the FR group than in the PR group. The sustained virological response (intention-to-treat analysis) rate of naïve patients with genotype 1 was 29% (6 of 21) in the PR group and 29% (6 of 21) in the FR group. The sustained virological response (intention-to-treat) rate of those with genotype 2 was 67% (12 of 18) in the PR group and 72% (13 of 18) in the FR group. CONCLUSION: Interferon-beta plus ribavirin therapy was safe in elderly patients, with lower proportions of patients with a dose reduction of interferon-beta or ribavirin and treatment discontinuation. In treatment-naïve patients, the sustained virological response rate was similar between interferon-beta plus ribavirin therapy and pegylated interferon-alpha plus ribavirin therapy, regardless of whether the patients had hepatitis C virus genotype 1 or 2.

Interferon- α -Induced Changes to Natural Killer Cells Are Associated with the Treatment Outcomes in Patients with HCV Infections.

Aim. We analyzed the pretreatment natural killer (NK) cell functions with the aim of predicting the sustained virological response (SVR) or the interleukin (IL) 28B polymorphism that is strongly associated with the treatment response. Methods. The peripheral NK cells from chronic hepatitis patients with HCV genotype 1 and high virus titers were activated using a Toll-like receptor (TLR) 4 ligand and IFN- α . The cell surface markers were evaluated using a flow cytometric analysis, and IFN- γ production was evaluated using an enzyme-linked immunosorbent assay (ELISA). The genotyping of the polymorphisms in the IL28B gene region (rs8099917) on chromosome 19 was performed on the DNA collected from each patient. Results. The production of IFN- γ was significantly higher in the SVR patients compared with the no-response (NR) patients, whereas the cell surface markers were similar between the SVR and the NR patients. There were no significant differences found in the IL28B genotype distribution associated with the production of IFN- γ . Conclusion. Differences in the NK cell functions were observed between the SVR patients and the NR patients, suggesting that NK cells play a potential role in the treatment response independent of the IL28B genotype.

[A case of double liver cancer: hepatocellular carcinoma and combined hepatocellular and mucinous cholangiocarcinoma].

We report a case of double liver cancer in an elderly woman with chronic hepatitis C. The patient was diagnosed with two liver tumors when she was in her 70s, and she underwent hepatectomy for the same. Histopathological examination determined that the two tumors were distinct. One was a well-to-moderately differentiated hepatocellular carcinoma (HCC) and the other was a combined hepatocellular carcinoma and mucinous cholangiocarcinoma (ChC). The HCC component was positive for cytokeratin 19, and it infiltrated into the portal vein and artery and the gall bladder. The ChC component was positive for hepatocyte paraffin 1 (HepPar1) staining and infiltrated into the bile duct. There has been no cancer recurrence at 6 months after surgery. Double cancer of the liver with these histological types is extremely rare and interesting, given the origin and differentiation of liver cancer.

Estimation of two real-time RT-PCR assays for quantitation of hepatitis C virus RNA during PEG-IFN plus ribavirin therapy by HCV genotypes and IL28B genotype.

Hepatitis C virus (HCV) RNA values measured with two real-time PCR methods (Cobas Ampliprep/Cobas TaqMan, CAP/CTM, and the Abbott real-time PCR test, ART) vary among patients with genotype 1. We investigated HCV RNA values measured by two real-time PCR assays during pegylated interferon plus ribavirin (PEG-IFN/RBV) therapy. We evaluated 185 cases of chronic hepatitis C patients, among which 97 patients received the PEG-IFN/RBV therapy. HCV RNA values of CAP/CTM for genotype 1 were significantly higher than those of ART (p < 0.05) The difference in HCV RNA values (CAP/CTM minus ART) of genotype 1 was significantly higher than those in genotype 2 (p < 0.0001). The positive rate (>0) of the difference of HCV RNA values in genotype 1 was 100 % (55/55), which was significantly higher than the 78.6 % (33/42) of genotype 2 (p < 0.001). There was no difference between TT and TG/GG genotype groups in terms of difference of HCV RNA values (CAP/CTM minus ART). After PEG-IFN/RBV therapy was administered, reduction of HCV measurements was observed from day 1 for both assays regardless of genotype. The HCV value of CAP/CTM during PEG-IFN/RBV therapy was consistently higher than the value of ART, although the difference in these two values gradually became smaller during the course of therapy, and eventually no significant difference was observed near the detection level. No correlation was observed between the sustained virological response (SVR) rate and the difference between the CAP/CTM HCV values and the ART HCV value before treatment.

Increase in platelet count based on inosine triphosphatase genotype during interferon beta plus ribavirin combination therapy.

BACKGROUND AND AIM: The inosine triphosphatase (ITPA) genotype is associated with ribavirin-induced anemia and pegylated interferon α (PEG IFN-α)-induced platelet reduction during PEG IFN-α plus ribavirin combination therapy. Natural IFN-ß plus ribavirin therapy is associated with increases in platelet counts during treatment. We investigated decreases in platelet counts according to ITPA genotype during natural IFN-ß/ribavirin therapy to determine if patients with low platelet counts were eligible for this combination therapy. METHODS: A total of 187 patients with chronic hepatitis C received PEG IFN-α/ribavirin or natural IFN-ß/ribavirin therapy. Decreases in platelet counts based on ITPA genotype were investigated during treatment through 24 weeks. RESULTS: Platelet counts decreased during week 1 of PEG IFN-α/ribavirin therapy, but increased during week 2, after which platelet counts decreased gradually. Platelet counts decreased until week 4 of natural IFN-ß/ribavirin therapy, after which platelet counts increased. Platelet counts after week 8 were higher relative to pretreatment platelet counts. Patients with the ITPA-CC genotype showed a smaller decrease in platelet counts during natural IFN-ß/ribavirin therapy than those with the ITPA-CA/AA genotype; platelet counts after week 8 of this therapy were higher than pretreatment platelet counts, regardless of pretreatment platelet counts. Multivariate logistic regression analyses showed that natural INF-ß/ribavirin therapy was the only significant independent predictor for an increase in platelets through week 8. CONCLUSION: Natural IFN-ß/ribavirin therapy is safe for patients with the ITPA-CC genotype, even if their pretreatment platelet counts are low.

Occurrence of clinical depression during combination therapy with pegylated interferon alpha or natural human interferon beta plus ribavirin.

AIM: The onset of depression symptoms during pegylated interferon α plus ribavirin (PEG-IFN/RBV) combination therapy has led to treatment discontinuation in some cases. In the present study, we conducted a questionnaire survey during treatment to determine whether natural human interferon ß plus ribavirin (IFNß/RBV) therapy is associated with a lower incidence of depression symptom onset compared with PEG-IFN/RBV therapy. METHODS: Seventy-seven patients with chronic hepatitis C received PEG-IFN/RBV (PR) or IFNß/RBV (FR) therapy. A questionnaire survey was administered at the start of treatment, and at 4 and 12 weeks, using the Beck Depression Inventory II (BDI-II) and the Pittsburgh Sleep Quality Index (PSQI). RESULTS: BDI-II scores in the PR group increased at 4 and 12 weeks, but remained unchanged in the FR group. At 12 weeks, the mean BDI-II score and incidence of abnormalities with a BDI-II score of ≥14 were significantly lower in the FR group than in the PR group. BDI-II scores during IFNß/RBV therapy in 11 patients currently using antidepressants remained unchanged up to 12 weeks. None of these 11 patients required addition or dose increases of antidepressants, and there was no evidence of worsened depression symptoms. Nine PR patients had BDI-II scores of ≥14 and PSQI scores of ≥11 at 12 weeks. CONCLUSIONS: IFNß/RBV therapy was associated with a lower incidence of depression symptom onset during treatment. In patients already diagnosed with depression, there was no evidence that IFNß/RBV therapy caused any worsening of symptoms, indicating that IFNß/RBV therapy is safe for patients with depression.

Effective prediction of outcome of combination therapy with pegylated interferon alpha 2b plus ribavirin in Japanese patients with genotype-1 chronic hepatitis C using early viral kinetics and new indices.

BACKGROUND: The rates of sustained virologic response (SVR) and relapse with pegylated interferon alpha 2b (peginterferon) plus ribavirin in patients with genotype-1 chronic hepatitis C (CHC) are approximately 50 and 30%, respectively. We investigated whether SVR and transient response (TR) can be differentiated during treatment using new indices calculated from early viral kinetics and the timing of when hepatitis C virus (HCV)-RNA becomes undetectable. METHODS: Peginterferon alpha 2b (1.5 microg/kg per week) plus weight-based ribavirin (600-1,000 mg/day) were administered to 141 patients with genotype-1 CHC for 48 weeks. The HCV-RNA loads were measured at baseline, 24 h, week 1, and week 2. The rebound index (RI, viral load at week 1 divided by viral load at 24 h) and the second rebound index (RI-2nd, viral load at week 2 divided by viral load at 24 h) were calculated. RESULTS: With SVR, the viral load was reduced at 24 h, did not rise during week 1 (RI < or = 1.0), and was significantly reduced at week 2 (P < 0.05). Viral loads with TR and non-response increased at week 1. The SVR rate was 90% with RI < or = 1.0, 96% with rapid viral responders, and 93% with RI-2nd < 0.7 and week 8 early viral responders. The SVR rate with these 3 groups was 90% and administration for 48 weeks was recommended. With other groups, the SVR rate was 23% and the TR rate was 77%. Administration for 72 weeks was therefore recommended. CONCLUSIONS: We distinguished SVR from TR during treatment using two indices (RI and RI-2nd) and the timing of HCV-RNA negativity.

Efficacy of low dose long-term interferon monotherapy in aged patients with chronic hepatitis C genotype 1 and its relation to alpha-fetoprotein: A pilot study.

AIM: The objective of this study was to examine the efficacy and safety of low dose long-term interferon (IFN) therapy in aged patients with chronic hepatitis C genotype 1. METHODS: The IFN therapy was performed in Shin-Kokura Hospital on 44 patients aged 60 or older with chronic hepatitis C. All patients had high viral loads of genotype 1. Three million units of natural IFN-alpha was administered intramuscularly or intrasubcutaneously, three times a week for three years. A control group of 44 subjects not treated with IFN, matched for age, gender and hepatic histology, was formed. RESULTS: Two of the 44 patients showed a sustained virological response. Alanine aminotransferase was below the upper limit of normal in 59% (23/39) of the patients and alpha-fetoprotein was less than 40 ng/mL in 97% (38/39) on the completion of treatment. Sustained biochemical response was observed in 53% (19/36) of the patients. In the liver cirrhosis group, serum albumin values and platelet counts increased in 38% (6/16) and 33% (6/18) of patients, respectively. Hepatocellular carcinoma (HCC) appeared in three patients by 13 months after the start of treatment, but no cases were reported thereafter. The cumulative non-carcinogenesis rate of HCC in the liver cirrhosis group was significantly higher in the IFN treatment group compared to the control group (log-rank test, P = 0.046). CONCLUSION: Low dose long-term interferon monotherapy to prevent carcinogenesis of HCC was considered useful in aged patients for whom peg-interferon and ribavirin combination therapy is difficult.

Efficacy of prolonged treatment following combination with ribavirin and interferon for chronic hepatitis type C: A pilot study.

The aim of the present study was to assess the efficacy of the prolonged interferon monotherapy following combination treatment. Seventy-six patients were enrolled. Of these, 7 were withdrawn while undergoing treatment with interferon combined with ribavirin, and 12 remained positive for HCV-RNA at the completion of the combination treatment. We studied 57 Japanese patients with chronic hepatitis C due to genotype 1b HCV of a high viral load. These patients tested negative for HCV-RNA at the completion of the combination treatment for 24 weeks. After the combination treatment, 29 patients of the prolonged treatment group successively received interferon-alpha monotherapy for 24 weeks, while 28 patients in the combination treatment alone group received no medication. The rate of a sustained virologic response (SVR) was higher in the prolonged treatment group (41%, 12/29) than in the combination treatment alone group (25%, 7/28), but not significantly. Patients who became HCV-RNA negative by 4 weeks after the start of the combination treatment showed an SVR rate of 86%. The prolonged treatment resulted in SVR in all five patients who newly became HCV-RNA negative at 12 weeks. In conclusion, the prolonged treatment was effective for patients who newly became HCV-RNA negative at 12 weeks.

Factors contributing to ribavirin-induced anemia.

BACKGROUND AND AIM: Interferon and ribavirin combination therapy for chronic hepatitis C produces hemolytic anemia. This study was conducted to identify the factors contributing to ribavirin-induced anemia. METHODS: Eighty-eight patients with chronic hepatitis C who received interferon-alpha-2b at a dose of 6 MU administered intramuscularly for 24 weeks in combination with ribavirin administered orally at a dose of 600 mg or 800 mg participated in the study. A hemoglobin concentration of <10 g/dL was defined as ribavirin-induced anemia. RESULTS: Ribavirin-induced anemia occurred in 18 (20.5%) patients during treatment. A 2 g/dL decrease in hemoglobin concentrations in patients with anemia was observed at week 2 after the start of treatment. The hemoglobin concentration in patients with > or =2 g/dL decrease at week 2 was observed to be significantly lower even after week 2 than in patients with <2 g/dL decrease (P < 0.01). A significant relationship was observed between the rate of reduction of hemoglobin concentrations at week 2 and the severity of anemia (P < 0.01). Such factors as sex (female), age (> or =60 years old), and the ribavirin dose by body weight (12 mg/kg or more) were significant by univariate analysis. CONCLUSIONS: Careful administration is necessary in patients > or =60 years old, in female patients, and in patients receiving a ribavirin dose of 12 mg/kg or more. Patients who experience a fall in hemoglobin concentrations of 2 g/dL or more at week 2 after the start of treatment should be monitored with particular care.

Short-term interferon-alfa therapy for acute hepatitis C: a randomized controlled trial.

Acute hepatitis C often progresses to chronic infection. We undertook a randomized controlled trial to determine whether short-term therapy with interferon (IFN) during acute hepatitis C is effective in preventing the development of chronic hepatitis. Thirty patients with acute hepatitis C were randomized into 1 of 2 treatment groups. IFN therapy was initiated 8 weeks after the onset of acute hepatitis in the early-intervention group and after 1 year of observation in the late-intervention group. Short-term therapy consisted of natural IFN-alfa (6 million units) administered on consecutive days for a period of 4 weeks. Any signs of recrudescence of disease were immediately followed by interval IFN therapy (3 times weekly for 20 weeks). In the early-intervention group, short-term therapy was associated with a sustained virological response in 13 of 15 patients (87%). Follow-up treatment was associated with a sustained virological response in both of the remaining 2 patients (100%). The sustained virological response rate was significantly higher in the early-intervention group (87%, 13 of 15 patients after short-term therapy alone, and 100%, 15 of 15 patients after short-term with or without follow-up therapy) than in the late-intervention group (40%, 6 of 15 patients after short-term therapy alone, and 53%, 8 of 15 patients after short-term therapy with or without follow-up therapy, P =.021 and P =.006, respectively). In conclusion, short-term (4 weeks) IFN treatment of patients with acute hepatitis C may be associated with satisfactory results, if initiated at an early stage of the disease.

Pilot study of prolonged interferon-alpha retreatment in chronic hepatitis C patients with genotype 1b.

OBJECTIVES: To investigate the efficacy of prolonged IFN retreatment for 3 years in chronic hepatitis C patients with high viral load and IFN treatment-resistant genotype 1b. PATIENTS AND METHODS: The study was conducted in 12 patients, not HCV RNA-negative after completion of the initial treatment. Retreatment consisted of administration of 6 million international units (MIU) of natural interferon-alpha, two or three times a week for 3 years. RESULTS: One patient was withdrawn for personal reasons. All other 11 patients completed treatment without any serious adverse reactions and were followed for 3 years. Of the patients, 4 (36%) showed a sustained virological response, 5 (45%) showed a biochemical response, and 2 (18%) relapsed after retreatment. All patients with a sustained response had a transient response to initial therapy. Patients showing a sustained response tested negative for HCV RNA within the first 6 months of retreatment. CONCLUSIONS: After prolonged IFN retreatment, a significant number of patients showed a sustained response for the first time and long-term improvement in ALT level.

Promiscuous T cells selected by Escherichia coli: OGDC-E2 in primary biliary cirrhosis.

The etiology of primary biliary cirrhosis (PBC) remains enigmatic. One theory that has attracted attention proposes that PBC is induced via molecular mimicry with Escherichia coli. If molecular mimicry is responsible for the immunogenic response in PBC, then T cell clones specific for E. coli antigens should stimulate and be cross-reactive with peptides specific for the human immunodominant autoepitopes. To address this issue, we developed T cell clones specific for E. coli OGDC-E2 peptide. Importantly, we demonstrate the presence of T cell clones specific for E. coli OGDC-E2 that react promiscuously with the human mitochondrial equivalents. Indeed, there was a significant increase in the liver derived T cell precursor frequency of such reactivity and such liver clones were only found in patients with PBC. In conclusion, these data suggest that PBC is a multi-hit disease involving a genetic predisposition, a mucosal response, and activation of promiscuous T cells; such activation may occur either directly from bacterial antigens, or indirectly through chemically-modified bacterial antigens. Dissection of the mechanisms involved will lead not only to understanding the immunogenetic basis of PBC, but likely its pathogenic etiology.