Therapeutic drug monitoring of telaprevir in chronic hepatitis C patients receiving telaprevir-based triple therapy is useful for predicting virological response.

OBJECTIVES: This prospective, pharmacokinetic study was done to investigate the impact of telaprevir plasma trough concentration (Ctrough) in the early stage of treatment on the response to telaprevir-based triple therapy for chronic hepatitis C patients. METHODS: Participants were 70 chronic hepatitis C patients infected with genotype 1. All patients received 12 week triple therapy that included telaprevir (2250 mg/day), pegylated interferon-α2b (pegylated-IFNα2b) (60-150 µg/week) and ribavirin (600-1000 mg/day) followed by a 12 week dual therapy that included pegylated-IFNα2b and ribavirin. Plasma telaprevir Ctrough was determined by a validated assay using HPLC at days 3, 7 and 14. The study was registered as a clinical trial on the University Hospital Medical Information Network (ID 000009656). RESULTS: The rates of undetectable hepatitis C virus RNA at week 4 [rapid virological response (RVR)] and at 24 weeks after therapy [sustained virological response (SVR)] were 71.4% and 82.9%, respectively. Of the patients with RVR, 90% achieved SVR. The mean telaprevir Ctrough levels at days 3, 7 and 14 of SVR patients (2.748, 2.733 and 2.999 µg/mL, respectively) were significantly higher than those of non-SVR patients (1.616, 1.788 and 2.314 µg/mL, respectively) (all P < 0.05). Multiple logistic regression analysis of possible predictors of SVR extracted higher telaprevir Ctrough at day 3 (OR 1.012 by 0.001 µg/mL, P < 0.0001) and interleukin 28B (rs8099917) TT allele (OR 6.16 versus non-TT alleles, P < 0.0001). CONCLUSIONS: Therapeutic drug monitoring of telaprevir in the early stage of treatment is useful in clinical practice for predicting the virological response of patients receiving telaprevir-based triple therapy.

Longitudinal assessment of liver stiffness by transient elastography for chronic hepatitis B patients treated with nucleoside analog.

AIM: To evaluate the association between liver stiffness measured by transient elastography (FibroScan) and the efficacy of long-term nucleoside analog (NA) treatment for patients with chronic hepatitis B. METHODS: Study 1: Forty-four chronic HBV patients had liver stiffness measured by FibroScan and underwent liver biopsy. Study 2: Group A: 22 patients started NA treatment at entry and FibroScan was done annually for 3 years. Group B: 23 patients started NA treatment prior to pretreatment FibroScan measurement, and FibroScan was done for from 3 to 5 years after the start of NA treatment. RESULTS: Study 1: The FibroScan values were significantly correlated with fibrosis stage (r = 0.672, P < 0.0001). Optimal cutoff of FibroScan values were 6.1 kPa for ≥ F1, 6.3 kPa for ≥ F2, 8.9 kPa for ≥ F3 and 12.0 kPa for F4. Study 2: For Group A, the baseline median FibroScan value was 8.2 kPa. FibroScan values significantly decreased annually for 3 years after the start of NA treatment (6.4 kPa, 5.8 kPa and 5.3 kPa at years 1, 2 and 3, respectively). For Group B, the FibroScan values did not significantly improve over the 3 years after the start of NA treatment. CONCLUSIONS: Liver stiffness, measured by transient elastography, of chronic hepatitis B patients treated with NA showed a rapid decline in the first 3 years followed by a more steady transition for from 3 to 5 years irrespective of long term virological effect.

Long-term effects of lamivudine treatment in Japanese chronic hepatitis B patients.

AIM: To analyze the association between the emergence of tyrosine-methionine-asparatate-asparatate (YMDD) mutants (reverse transcription; rtM204I/V) and deterioration of liver function during long-term lamivudine treatment of Japanese patients with chronic hepatitis B virus (HBV) infection. METHODS: The data of 61 consecutive Japanese patients with chronic hepatitis B who underwent continuous lamivudine treatment for more than 24 mo and had a virological response were analyzed. Analysis of YMDD mutants was done by real-time polymerase chain reaction with LightCycler probe hybridization assay for up to 90 mo (mean, 50.8 mo; range, 24-90 mo). RESULTS: A mixed mutant-type (YMDD + tyrosine-isoleucine-asparatate-asparatate: YIDD or tyrosine-valine-asparatate-asparatate: YVDD) or a mutant-type (YIDD or YVDD) were found in 57.4% of 61 patients at 1 year, 78.7% of 61 patients at 2 years, 79.6% of 49 patients at 3 years, 70.5% of 34 patients at 4 years, 68.4% of 19 patients at 5 years, 57.1% of 14 patients at 6 years, and 33.3% of 6 patients at 7 years. Of the 61 patients, 56 (92%) had mixed mutant- or a mutant-type. Only 5 (8%) had no mutants at each observation point. Virological breakthrough was found in 26 (46.4%) of 56 patients with YMDD mutants, 20 of whom had a hepatitis flare-up: the remaining 30 (53.6%) had neither a virological breakthrough nor a flare-up. All 20 patients who developed a hepatitis flare-up had a biochemical and virological response after adefovir was added to the lamivudine treatment. CONCLUSION: Our results suggest that it is possible to continue lamivudine treatment, even after the emergence of YMDD mutants, up to the time that the patients develop a hepatitis flare-up.

Risk factors for and the prevalence of peripheral arterial disease and its relationship to carotid atherosclerosis: the Kyushu and Okinawa Population Study (KOPS).

AIM: Peripheral arterial disease (PAD) is associated with cerebrovascular disease, ischemic heart disease, and other cardiovascular disease. We investigated the prevalence of and factors related to PAD to clarify the relationship between PAD and carotid atherosclerosis in a cross-sectional population-based study. METHODS: The study included 2,402 (900 males and 1,502 females; mean+/-SD=64.9+/-10.9 years) of 3,862 residents of two Japanese rural areas who reported for a free health examination in 2005 or 2006. An ankle brachial index value < or =0.9 was considered to be PAD. The carotid artery intima-media thickness (CA-IMT) was measured by carotid ultrasound. RESULTS: The prevalence of PAD was 1.71% (n=41) of all participants. The risk factors independently associated with a significantly higher risk of PAD, identified by multivariate analysis, are as follows: For males, age, dyslipidemia, and CA-IMT, and for females, age, waist circumference, and dyslipidemia. CONCLUSION: The prevalence of PAD in Japan was confirmed to be lower than that of similar studies performed in other countries. PAD was strongly correlated with age and dyslipidemia in both sexes, carotid atherosclerosis in males, and abdominal fat in females.

Efficacy and safety of ezetimibe for Japanese patients with dyslipidaemia: The ESSENTIAL Study.

BACKGROUND: There are insufficient data available on the efficacy and safety of lipid-lowering therapy for patients with dyslipidaemia complicated by multiple metabolic abnormalities. OBJECTIVE: This study aimed to examine the efficacy and safety of ezetimibe 10 mg/day administered to Japanese patients with dyslipidaemia. METHODS: This was a prospective study carried out at Kyushu University Hospital, Fukuoka, Japan. In one group, ezetimibe 10 mg/day alone was given to 33 patients for 12 weeks. In the other two groups, ezetimibe was given with an HMG-CoA reductase inhibitor (statin) to 13 patients for 12 weeks: pravastatin 10 mg/day (n = 7) or rosuvastatin 2.5 mg/day (n = 6). The main outcome measure was the effect of ezetimibe on low-density lipoprotein cholesterol (LDL-C) and other lipid levels from baseline to 12 weeks. RESULTS: After 12 weeks of treatment, all groups showed marked reductions in mean +/- SD LDL-C level (from 155.4 +/- 22.0 mg/dL at baseline to 118.0 +/- 28.1 mg/dL, i.e. -37.4 mg/dL; p < 0.001). The mean reduction in LDL-C level with ezetimibe monotherapy was significantly greater in patients with impaired LDL-C metabolism, glucose metabolism or hypertension than in those without such abnormalities (-21.0% vs -8.4%, p < 0.01; -22.7% vs -9.5%, p < 0.05; and -22.5% vs -5.9%, p < 0.05; respectively). The reduction in LDL-C levels with ezetimibe monotherapy was also correlated with the number of metabolic abnormalities (rho = 0.426, p = 0.013). CONCLUSIONS: Both ezetimibe monotherapy and combination therapy with ezetimibe and a statin were able to safely and effectively control LDL-C levels in Japanese patients with dyslipidaemia, including those with metabolic abnormalities.

Association of hyperhomocysteinemia and Chlamydia pneumoniae infection with carotid atherosclerosis and coronary artery disease in Japanese patients.

An elevated plasma level of homocysteine (Hcy) and infection by Chlamydia pneumoniae (C. pneumoniae) have been suggested as independent risk factors for carotid atherosclerosis (CA) and coronary artery disease (CAD), but the mechanisms involved are unclear. We investigated the correlation between positivity for antibody to C. pneumonia (anti-C. pneumoniae) and the Hcy level in patients with CA and CAD. The total plasma homocysteine (tHcy) concentration was determined in 99 patients with CA and 31 patients with CAD, as well as 119 controls with matched risk factors for atherosclerosis. The tHcy level was measured with a Bio-Rad microplate enzyme immunoassay. In the CAD group, the tHcy level (13.67 micromol/l) was significantly higher than that in other groups (CA group, 10.96 micromol/l; control group, 9.95 micromol/l; ANOVA, P = 0.0006). Positivity for anti-C. pneumoniae IgG was significantly more common in the CAD group (77.4%) than in the other groups (CA group, 53.5%; control group, 54.6%; ANOVA, P = 0.0490). There was no association between anti-C. pneumoniae IgA positivity or tHcy and conventional risk factors. However, anti-C. pneumoniae IgG positivity was significantly more common in subjects with higher tHcy levels than in those with low tHcy levels from each of the 3 groups. The CAD group had significantly higher tHcy levels, and tHcy was significantly associated with anti-C. pneumoniae IgG positivity. These findings indicate that elevation of tHcy is related to positivity for anti-C. pneumoniae IgG in patients with CAD.

Chronic Helicobacter pylori infection is associated with peripheral arterial disease.

It is reported that Helicobacter pylori infection is associated with coronary atherosclerosis both epidemiologically and pathogenetically, but no conclusions have yet been reached. Therefore, we investigated the relationship between H. pylori infection and peripheral arterial disease (PAD). Sixty-nine patients with PAD attending Harasanshin General Hospital (Fukuoka, Japan) were compared with 143 controls (age-matched asymptomatic outpatients with hyperlipidemia). H. pylori infection was diagnosed by the detection of IgG antibodies, the (13)C-urea breath test, and histological examination. Multiple logistic regression analysis was used to assess the data. The 69 PAD patients and 143 controls were aged from 50 to 92 years. According to the Fontaine classification, 43/69 PAD patients (62.3%) were grade I, 25 (36.2%) were grade II, and 1 (0.14%) was grade III. The prevalence of H. pylori infection was higher in the PAD patients than in the controls (79.7% versus 44.8%; P < 0.01). Stepwise logistic regression analysis revealed that H. pylori infection and hypertension had a significant influence on the occurrence of PAD. Our results suggest that chronic H. pylori infection may be one of the risk factors for PAD.

[Acute disseminated encephalomyelitis (ADEM) onset during meningitis and sepsis].

A 39-year-old man with a high fever, headache, and stiff neck, and Kernig and Brudzinski signs admitted in June 2004 had a WBC of 10,680/microL and CRP of 10.5mg/dL. Streptococcus pneumoniae was detected in blood and spinal fluid culture, but brain CT was normal. Meningitis was diagnosed and antibiotics and corticosteroids begun. After four days of treatment, his blood test and spinal fluid data had improved, but his consciousness had deteriorated. ADEM was diagnosed by the clinical course and brain MRI (T2-weighted image) that showed high-intensity lesions in the white cerebral matter, and steroid pulse treatment was begun on day 4 after admission. His consciousness disturbance rapidly disappeared and brain MRI showed that the multiple high-intensity lesions had ameliorated. The patient was released after 40 days of treatment.

Thymus and activation regulated chemokines in children with atopic dermatitis: Kyushu University Ishigaki Atopic Dermatitis Study (KIDS).

The purpose of this population-based study was to investigate the clinical significance of serum thymus and activation-regulated chemokine (TARC) in children with atopic dermatitis (AD). Between 2003 and 2004, 1359 Japanese children aged 5 years and under were prospectively followed. Serum levels of TARC by using an ELISA in each child were monitored throughout the study period. The first tested year, the mean serum level of TARC in children with sustained AD (mean; 691.7 pg/mL) was significantly higher than that of regressed AD children (569.9 pg/mL), newly developed AD children (380.1 pg/ mL), and healthy children (506.3 pg/mL). The changes of TARC levels in sustained AD children found no significance between 2003 (691.7 pg/mL) and 2004 (682.0 pg/mL). The mean levels of TARC of both regressed AD and healthy children significantly decreased from 2003 to 2004 (644.2 pg/mL to 448.7 pg/mL and 506.3 pg/mL to 442.1 pg/mL, respectively). The mean TARC level of newly developed AD children significantly increased from 2003 to 2004 (380.1 pg/mL to 491.8 pg/mL). We demonstrated strong associations between TARC levels and the natural course of childhood AD. Monitoring serum TARC levels of AD children may be useful for the biological evaluation of AD.

High molecular weight form of adiponectin levels of Japanese patients with chronic hepatitis C virus infection.

AIM: The aim of the present study was to clarify the correlation between serum adiponectin level and the properties of hepatitis C virus (HCV). METHODS: A meal test was carried out for insulin resistance assessment in 81 patients with chronic HCV infection. Blood samples were taken before and after the test to measure serum insulin and plasma glucose (PG). The adiponectin level was measured by enzyme-linked immunosorbent assay in each patient. RESULTS: Serum adiponectin levels were significantly correlated with the area under the insulin curve (AUC-insulin)during the meal test and with serum HCV-RNA level. Multiple regression analysis showed age to be a significant independent parameter associated with an increased adiponectin level, whereas male sex, fasting insulin, and serum HCV-RNA level were significant independent parameters associated with a decreased adiponectin level. CONCLUSION: It is possible that insulin resistance in patients with chronic HCV infection is related to adiponectin secretion.

Effect on carotid atherosclerosis of probucol plus levofloxacin for Chlamydia pneumoniae infection.

To investigate the effect of levofloxacin on carotid atherosclerosis, patients with hypercholesterolemia whose carotid atherosclerosis was not improved by probucol therapy (500 mg/day) for 24 months were enrolled. All patients were seropositive for anti C. pneumoniae IgA and/or IgG. Carotid atherosclerosis was evaluated by ultrasonic measurement of the maximum intima-media thickness (Max-IMT). All subjects were prescribed three courses of levofloxacin (each course, 400 mg/day for 2 weeks, followed by 14 days off drug treatment). At 12 months after combined therapy with probucol and levofloxacin, Max-IMT was significantly decreased compared with the value before treatment (P < 0.01). These results suggest that the combination therapy was effective for improving carotid atherosclerosis in C. pneumoniae-seropositive patients.

Impact of peripheral arterial disease and acute ischemic stroke.

Peripheral arterial disease (PAD) is associated with coronary artery disease (CAD) and stroke, but data on the relationship between PAD and acute ischemic stroke are lacking. Therefore, we investigated this relationship. A total of 101 patients were enrolled on admission to Harasanshin General Hospital (Fukuoka, Japan) with their first ischemic stroke. All 101 patients underwent cranial CT and/or brain magnetic resonance imaging, duplex ultrasonography of the extracranial carotid arteries, and transthoracic echocardiography. The subjects were aged 41 to 92 years. PAD was present in 81/101 patients (80.2%), including 57/73 (78.1%) with small artery occlusion, 11/13 (84.6%) with large artery occlusion, and 13/15 (86.7%) with cardiogenic embolism. In 42 of these 81 patients (51.9%), PAD was asymptomatic. Serum apoprotein A1 levels were significantly higher and the intima-media thickness was significantly greater in the patients with PAD than in those without PAD. The modified Rankin scale score was significantly higher on admission in patients with PAD than in those without PAD. Stepwise logistic regression analysis revealed that the apoprotein A1 level and the modified Rankin scale score on admission were strongly associated with the occurrence of stroke in patients with PAD. Our results suggest that PAD is frequently associated with acute ischemic stroke. It may be important to perform screening for PAD in patients who have suffered an ischemic stroke.

Both hepatitis C virus and Chlamydia pneumoniae infection are related to the progression of carotid atherosclerosis in patients undergoing lipid lowering therapy.

Recent experimental and epidemiological findings suggest that infectious agents may play a role in the development and progression of atherosclerosis. We previously reported that Chlamydia pneumoniae (C. pneumoniae) infection reduces the effectiveness of lipid-lowering therapy for carotid atherosclerosis and that this micro-organism may play a role in the progression of atherosclerosis. In this study, we investigated the possible association between hepatitis C virus (HCV) infection and carotid arteriosclerosis. A total of 165 asymptomatic hypercholesterolemic patients were randomized to receive probucol (500 mg/day, n=82) or pravastatin (10 mg/day, n=83) and were followed for 2 years. The 2-year change of the maximum common carotid artery intima-media thickness (Max-IMT) was the primary endpoint, while the Max-IMT and the incidence of major cardiovascular events were secondary endpoint. All serum samples were tested for antibody to HCV (anti-HCV) by enzyme-linked immunosorbent assay (ELISA), and all anti-HCV-positive samples were assayed for HCV RNA. Patients without HCV infection (n=25) showed a significant reduction of Max-IMT (-10.9%) (p<0.0001), while a small decrease of Max-IMT was noted in the patients with HCV infection (n=25) (-0. 3%). Significant differences in the reduction of serum total cholesterol and LDL cholesterol were found between patients with and without HCV infection (both p<0.0001). No significant difference in therapeutic effect was noted between the probucol and the pravastatin groups. After adjustment for confounding risk factors, both C. pneumoniae infection and anti-HCV positivity were associated with a greater risk of an increase in Max-IMT (8.5635 [1.3738-15.7532], p<0.05, 9.5040 [0.2886-18.7194], p<0.05, respectively). These findings suggest that both chronic HCV infection and C. pneumoniae infection can reduce the effectiveness of lipid-lowering therapy for carotid atherosclerosis, and that the HCV may play a role in the progression of atherosclerosis in HCV infected patients.