Telaprevir impairs renal function and increases blood ribavirin concentration during telaprevir/pegylated interferon/ribavirin therapy for chronic hepatitis C.

We aimed to examine the relationship between renal dysfunction and anaemia that may develop during combination therapy involving pegylated interferon, ribavirin and telaprevir (PEG-IFN/RBV/TVR) for the treatment of chronic hepatitis C. Sixty-eight patients with genotype 1b high viral loads were treated with PEG-IFN/RBV/TVR. Peg-IFN and RBV doses were administered according to body weight. TVR was prescribed at 2250 mg/day for 44 patients and at 1500 mg/day for 24 patients who had low haemoglobin level (<12 g/dL). When anaemia had developed, the RBV dose was decreased. The serum TVR concentration at day 8 was measured, and the serum RBV concentration was measured serially. The estimated glomerular filtration rate (eGFR) was estimated to assess renal function. At week 1, serum TVR concentration was not correlated with a decrease in eGFR; however, the TVR dose, on a weight basis (mg/kg), and eGFR were correlated (r = 0.2691; P = 0.0265). Moreover, there was a negative correlation between eGFR and RBV serum concentration (r = −0.3694; P = 0.0025), and the serum RBV concentration and decrease in the haemoglobin were significantly correlated from week 1 to week 8. In triple therapy, the TVR dose per weight is correlated with a decline in renal function. Thus, the serum concentration of RBV increases, with a concomitant decrease in haemoglobin. It is important to adjust the doses of TVR and RBV to avoid excessive serum RBV levels and the development of severe anaemia, to achieve a good clinical effect.

Helicobacter pylori infection in two areas in Japan with different risks for gastric cancer.

BACKGROUND: We evaluated the relationship between Helicobacter pylori and various factors associated with gastric cancer in two areas in Japan with different risks for mortality due to gastric cancer. METHODS: A total of 250 sera from Niigata and 209 from Okinawa were used. H. pylori antibody and CagA antibody were measured by antigen-specific ELISAs. Serum gastrin and pepsinogen levels were determined by RIA. RESULTS: Although there was no significant difference in H. pylori prevalence among the persons in Niigata (50%) and Okinawa (42%), CagA prevalence in these populations was significantly different, at 41% and 26%, respectively (OR = 1.98, 95%CI: 1.33-2.95, P < 0.01). Serum gastrin levels in Niigata were significantly lower than those in Okinawa in H. pylori-negative persons (P < 0.01). The serum pepsinogen I/II ratio in Niigata was significantly lower than that in Okinawa in H. pylori positive persons (P < 0.01), whereas there was no significant difference in H. pylori-negative persons. Among those positive for H. pylori, serum pepsinogen I/II ratio in Niigata was significantly lower than that in Okinawa in CagA-negative persons (P < 0.01), whereas no significant difference was observed in CagA-positive persons. CONCLUSIONS: These results suggest that the difference in the mortality ratio of gastric cancer between Niigata and Okinawa is mainly associated with the difference between areas in the prevalence of cagA-positive strains rather than that of H. pylori itself.

Efficacy of triple therapy with rabeprazole for Helicobacter pylori infection and CYP2C19 genetic polymorphism.

BACKGROUND: Rabeprazole is a new, potent, proton pump inhibitor. The metabolism of rabeprazole is less dependent on CYP2C19 genetic polymorphism. METHODS: A total of 102 Helicobacter pylori-positive patients with gastric ulcer were randomly allocated to three groups: rabeprazole 10 mg (RAC10), rabeprazole 20 mg (RAC20) or rabeprazole 40 mg (RAC40) plus amoxicillin 750 mg and clarithromycin 200 mg twice daily for 7 days. CYP2C19 genotype was determined by the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: All-patients-treated-based eradication rates in patients treated with RAC10, RAC20 and RAC40 were 83%, 77% and 90%, respectively, and per protocol-based eradication rates were 83%, 80% and 90%, respectively. The eradication rates in the three groups were not significantly different. There was also no significant difference between the all-patients-treated-based eradication rate in CYP2C19 extensive metabolizers and that in poor metabolizers (86% vs. 77%). Adverse events were 12% in extensive metabolizers and 23% in poor metabolizers, and the difference in these incidence rates was also not statistically significant. CONCLUSIONS: Triple therapy with 10 mg of rabeprazole combined with amoxicillin/clarithromycin is effective for Japanese patients with H. pylori infection, and the H. pylori eradication rate is not affected by CYP2C19 genetic polymorphism.

Successful allogeneic bone marrow transplantation from an HBV-positive donor into an HBV-positive recipient using lamivudine.

A 21-year-old woman with severe aplastic anemia underwent allogeneic bone marrow transplantation from an HLA-identical sibling donor. The patient also had chronic hepatitis B and the donor was an HBV carrier. To decrease HBV and improve hepatic dysfunction before BMT, the patient had received lamivudine for 6 months. After marrow transfusion, administration of lamivudine was continued to inhibit replication of donor-derived HBV. The patient showed hematological engraftment on day 13 without any serious liver dysfunction. Eight months after BMT, she is now alive and well without chronic liver GVHD or reactivation of hepatitis B. HBV-DNA was not detected in the patient's serum. Administration of lamivudine to a BMT recipient with chronic hepatitis B may be a safe and promising way to prevent fatal liver dysfunction in the setting of allogeneic BMT, even in the event of BMT from an HBV-positive donor.

Lamivudine treatment for reverse seroconversion of hepatitis B 4 years after allogeneic bone marrow transplantation.

Reverse seroconversion of hepatitis B virus (HBV) after allogeneic BMT is rare. We present a case of HBV reactivation late after allogeneic BMT which responded well to lamivudine therapy. A 35-year-old woman with CML received an allogeneic BMT. Before BMT, the patient had immunity to HBV, with serum antibodies against hepatitis B surface antigen (HBsAb), and the donor was completely negative for HBV. Four years after BMT, acute hepatitis occurred with a detectable level of HBV-DNA. Lamivudine rapidly reduced transaminase and bilirubin levels, and serum HBV-DNA decreased to negative. Retrospective analysis revealed that there had been a gradual decrease in serum HBsAb titers after BMT. Administration of lamivudine immediately after HBV replication may be more effective than vaccination of hepatitis B surface antigen-negative donors before BMT.

Combined hepatocellular carcinoma and cholangiocarcinoma growing into the common bile duct.

We report a patient with combined hepatocellular carcinoma and cholangiocarcinoma (HCC-CC) growing into the common bile duct (CBD) and showing obstructive jaundice within 2 years of the onset of the disease. The patient was a 59-year-old Japanese man in whom, at the age of 57 years. a hepatic tumor was discovered by diagnostic imaging during follow-up of hepatitis B surface antigen (HBsAg)-positive liver cirrhosis. The tumor was diagnosed as HCC. Epirubicin was injected twice, intraarterially. The patient then received oral etoposide therapy for the next 14 months. The treatment was initially effective, but approximately 2 years after the hepatic tumor was discovered, local recurrence of the tumor and a tumor thrombus in the CBD were discovered. Although he was treated with percutaneous transhepatic biliary drainage (PTBD), to reduce obstructive jaundice, the jaundice was irreversible and he died of severe hepatic failure. The autopsy findings confirmed that the hepatic tumor was HCC-CC, in which the HCC and CC components expressed alpha-fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19-9), respectively, which accurately reflected the disease process. The underlying mechanism of the growth of HCC-CC into the CBD may differ from the underlying mechanism of the development of icteric-type HCC.

Ten minute 13C-urea breath test for the diagnosis of Helicobacter pylori infection.

We investigated the utility of a 10-min 13C-urea breath test (13C-UBT) using 100mg of 13C-urea; this is a simple and rapid method for the detection of Helicobacter pylori infection. One hundred and fifty-one patients in whom the identification of H. pylori was established by rapid urease test, culture, and histology of six biopsy specimens underwent 254 13C-UBT examinations before and/or after eradication treatment. In the 133 patients who did not receive eradication treatment, the calculated sensitivity of the 10-min 13C-UBT was 99.4% and specificity 100% when the cut-off point was set at 3.5/1000, using a mass spectrometer. In the 121 patients who received eradication treatment, this cut-off point gave a sensitivity of 86.7%, a specificity of 99.1%, and a positive predictive value of 92.9%, with a negative predictive value of 98.1%. There were no significant differences between the diagnosis of H. pylori infection at 1 month and more than 3 months after the endpoint of eradication treatment. The 10-min 13C-UBT is suitable for the diagnosis of H. pylori infection before and after eradication treatment.

[Extramedullary plasmacytoma forming a mass in the epidural space of the spinal cord: report of a case].

Plasmacytoma often forms an intramedullary mass in the vertebrae with absorption of trabecula and cortex of the bone. However, occasionally, it forms a mass in the extramedullary space of the vertebrae. The authors report such a rare case with plasmacytoma which formed a mass in the thoracic epidural space without evidence of involvement of the adjacent vertebra. On May 22, 1985, a 80-year-old man was admitted to our clinic with chief complaints of gait disturbance and hypesthesia below the umbilical level. Difficulty of walking developed approximately four months prior to admission with gradual aggravation and hypesthesia added thereafter. Neurological examinations at admission showed paraparesis with positive Babinski's and Chaddock's reflexes, hypesthesia and disturbances of vibration and position senses below the 9th thoracic nerve level. Myelography and CT scan using metrizamide indicated a presence of epidural mass at the 8th to 9th thoracic vertebrae. There was no abnormal bony change in the spine on plain X-ray and CT scan. On May 30, 1985, total removal of epidural tumor was performed by removing the laminae from the 7th to 10th vertebrae. Histological examinations including immunological stainings showed a plasmacytoma which produced monoclonal immunoglobulin of IgG-lambda type. Radiation therapy was not carried out. The serum protein fraction, immunoglobulin, immunoelectrophoresis, Bence-Jones protein and CSF immunoglobulin examined after operation, supported a histological diagnosis of plasmacytoma. Also, slight proliferation of plasma cells was noted in the bone marrow and peripheral blood.(ABSTRACT TRUNCATED AT 250 WORDS)

[Hepatitis C].

Hepatitis C virus (HCV) is a major cause of post transfusion non-A, non-B hepatitis. The virus contains a positive-strand RNA genome comprised of approximately 9,400 nucleotides. HCV E2/NS1 is probably an envelope glycoprotein (E2). The E2 hypervariable domain appears to contain isolate-specific antibody-binding linear epitopes. Recently, comparative sequence analysis of all the complete and partial HCV sequences published to date indicates that known genotypes of HCV can be classified into six basic groups. We report here that the prevalence of HCV-I, HCV-II, and a mixed form are 77.2%, 11.4%, and 11.4%, respectively. Patients with anti-HCV and HCV-RNA positive chronic active hepatitis received 6MU of interferon-alpha or beta everyday for two weeks followed by 6MU thrice a week for 14 weeks. Complete response to interferon treatment was defined as an ALT level normalized within six months after the end of treatment and maintained within the normal limit for an additional six months. Complete response was found in 42.9% of patients treated for 16 weeks. In a six month follow-up of the complete responders, clearance of viremia was observed in 90.3% at the end of interferon treatment and in 71.0% six months after the end of interferon treatment.

[Classification of hepatitis C virus into two major groups in serologic activity: correlation with response to interferon].

Genotypes of HCV have been reported to be one of the predictors of response to IFN therapy in patients with chronic hepatitis C. HCV genotypes were determined enzyme-linked immunoblot assay based on group I and II specific recombinant peptides of the NS-4 region (amino acid No. 1676-1670). We examined the correlation between HCV groups and response to IFN in patients with chronic hepatitis C. Among the 84 patients with chronic hepatitis C who underwent IFN treatment, 16 of 51 (31.4%) patients with group I and 12 of 23 (52.2%) patients with group II showed complete sustained response. These results suggest that HCV group assay may improve the ability to predict IFN treatment outcomes.

[Interstitial pneumonia induced by interferon therapy in type C hepatitis].

Interstitial pneumonia is known as one of the serious side effect of drugs. Recently, many investigators have reported that interstitial pneumonia (IP) which occurred during interferon (IFN) therapy for type C chronic hepatitis, and its appearance rate is considered to be more than 0.2% of patients who receive IFN. Though the mechanisms of IP during IFN therapy remains to be elucidated, one of the possible explanations is that excessive focal immune response in the lung derived from IFN might leads to the inflammation. For safe treatment, we must recognize that IFN induces IP during IFN therapy and give attention to its occurrence.

[Clinical studies on the detection of hepatitis C virus genome in the serum and the liver].

Hepatitis C virus (HCV) is the major cause of non-A, non-B hepatitis worldwide. Since the HCV viral genome was molecularly cloned and antibody detection systems were established, a considerable amount of information on HCV has been accumulated. In the present study, I have examined the sera and liver tissues of the patients of type C chronic liver disease using molecular biological methods and tried to correlate the data obtained with the clinical, pathological and therapeutic outcomes. A reverse transcription-polymerase chain reaction (RT-PCR) method using radiolabeled nucleotides provided constant results in genome amplification, and could be shown to be a reliable method for quantifying the levels of HCV genome. The amount of HCV RNA in the serum tended to increase as a function of the duration of the disease and the progression of histopathologic changes of the liver. In addition, the serum HCV RNA titers correlated well with those of liver tissues, which showed that the amount of circulating HCV genome reflected the intrahepatic amount of HCV. HCV, a positive-stranded RNA virus, is likely to make a negative strand during viral replication. In studies to detect the positive and negative strands of HCV RNA separately using strand specific primers, the existence of both strands in the liver was demonstrated, confirming viral replication in the liver. The ratio of negative to positive strands ranged from 0.03% to 30%, being 3.7% in chronic persistent hepatitis, 4.8-6.0% in chronic aggressive hepatitis and 6.7% in liver cirrhosis. The viral factors influencing the interferon (IFN) response were also examined. Individuals who had low titers of HCV genome tended to respond well to IFN. Moreover, IFN was more effective for patients with HCV type III than for those with HCV type II. Thus, IFN response was shown to depend both on virus titers and genotypes. However, mean levels of HCV RNA were almost the same between the patients with HCV type II and those with HCV type III before the treatment, there were significant differences in the disappearance of HCV and the effects of IFN therapy. It is suggested that the susceptibility to IFN is different for each genotype. Hokkaido J Med Sci 69 (6), 1382-1398, 1994.

Significance of 2',5'-oligoadenylate synthetase activity and HCV genotype in IFN therapy for type C chronic hepatitis.

Although the mechanisms of elimination of HCV by IFN have not been fully elucidated, the 2-5A system was reported to be one of the mechanisms of the anti-viral effect of IFN. Therefore, the relationship between HCV genotype, induction of 2-5AS and clinical effect was investigated. As for the anti-viral effect during IFN therapy, in type III or IV, most patients lost HCV-RNA regardless of serum 2-5AS induction even in high HCV-RNA concentration cases. In contrast, in type II, the negativity rate of HCV-RNA became high along with an increase of serum 2-5AS activity, but in patients with high HCV-RNA concentration, HCV-RNA was persistently positive. As for the long term clinical effect of IFN therapy judged 6 months after completion of IFN therapy, HCV genotypes were closely related to the effect; that is, the patients with type III or type IV HCV genotype showed a higher complete response rate compared with the patients with type II HCV genotype. However, the relationship between the long term clinical effects and induction of serum 2-5AS during IFN therapy was obscure. These results suggest that induction of 2-5AS is closely related to the anti-viral effect during IFN administration, but the viral factors appeared to be related to long term clinical effects after cessation of IFN therapy.