Effectiveness of triple therapy with simeprevir for chronic hepatitis C genotype 1b patients with prior telaprevir failure.

Favourable efficacy and safety profiles for simeprevir in combination with pegylated interferon alpha (PEG-IFNα) and ribavirin (triple therapy) have been shown in clinical trials. This study was carried out to evaluate the effectiveness of simeprevir-based triple therapy for patients with prior telaprevir treatment failure. This multicentre, observational cohort consisted of 345 consecutive Japanese patients infected with HCV genotype 1b, including 20 who had experienced telaprevir-based triple therapy. Amino acid substitutions in the NS3/4A region were identified by direct sequencing at the time of relapse or breakthrough in treatment with telaprevir and at the initiation of treatment with simeprevir. Patients were stratified according to prior response to PEG-IFNα and ribavirin. Of the 20 patients with telaprevir treatment failure, 10 (50.0%) achieved sustained virological response at week 12 after the end of treatment (SVR12). For patients treatment naïve [3/4 (75.0%)] or with prior relapse [1/1 (100%)] or partial response [5/6 (83.3%)] to PEG-IFNα and ribavirin, almost all achieved SVR12, mainly because of the improvement of treatment adherence, especially to direct-acting antiviral agent and ribavirin. However, of the nine patients with prior null response to PEG-IFNα and ribavirin, only one (11.1%) achieved SVR12, despite all having received an adequate treatment dosage, and five (55.6%) achieved rapid virological response. The treatment outcome of simeprevir-based triple therapy for HCV genotype 1b patients with prior telaprevir failure depended on the prior response to PEG-IFNα and ribavirin. For patients with prior null response to PEG-IFNα and ribavirin, retreatment with simeprevir-based triple therapy is not a useful option.

Valuable antiviral therapeutic options for the treatment of chronic hepatitis C patients with thrombocytopenia.

Thrombocytopenia in patients with chronic hepatitis C may represent an obstacle for the initiation of antiviral treatment. The aim of this study was to evaluate factors predictive of successful pegylated interferon (PEG-IFN) α2b and ribavirin (RBV) treatment for patients with thrombocytopenia with no history of splenectomy or partial splenic embolization. One hundred and fifty-one chronic hepatitis C patients (genotype 1: n = 110, genotype 2: n = 41) with TCP (<100 × 10(9) /L) at baseline were enrolled. Pretreatment variables included interleukin 28B (IL28B) genotype (rs8099917) and homoeostasis model assessment of insulin resistance score (HOMA-IR). The kinetics of haemoglobin and platelets according to the inosine triphosphatase (ITPA) genotype (rs1127354) were investigated. Sustained virological response (SVR) was significantly more frequent in hepatitis C virus (HCV) genotype 2 (65.9%) than in genotype 1 (34.5%) patients (P < 0.0001). Multiple logistic regression analysis of HCV genotype 1 extracted IL28B TT genotype [odds ratio (OR) 5.97, P = 0.006] and HOMA-IR <2.5 (OR 7.14, P = 0.0016) as significant independent pretreatment predictors of SVR. The analyses of HCV genotype 2 showed that HOMA-IR was significantly related to SVR, but IL28B genotype was not. Patients with ITPA CC genotype showed a significant haemoglobin reduction and lower degree of platelets decrease than those with ITPA CA/AA genotypes. The most common reason for premature discontinuation of treatment was the development of hepatocellular carcinoma (n = 8, 5.3%). In conclusion, HOMA-IR is a useful predictor of SVR for patients with thrombocytopenia infected with HCV genotype 1 or 2 treated with PEG-IFNα2b and RBV. The inclusion of IL28B, ITPA genotypes and HOMA-IR adds valuable therapeutic information.

Serum pepsinogen and Helicobacter pylori infection--a Japanese population study.

The decreased ratio of serum pepsinogen (PG) I and II has good correlation with the presence of atrophic gastritis. A total of 1,540 residents aged 30-89 years were enrolled into this study to investigate which serum PG level of residents with Helicobacter pylori infection would represent an adjunct to the diagnosis and progression of atrophic gastritis. All participants received esophagogastroduodenoscopy. Serum antibody to H. pylori (anti-H. pylori) was measured by an enzyme-linked immunosorbent assay (ELISA). Serological atrophic gastritis was defined as serum PG I isozyme level ≤70 ng/ml and a PG I/II ratio of ≤3.0. Of the 1,540 participants, 923 (59.9%) were positive for anti-H. pylori. Serological atrophic gastritis was found significantly more often in anti-H. pylori-positive participants (40.8%) than in anti-H. pylori-negative participants (7.9%) (p ≤ 0.0001). The endoscopic findings of anti-H. pylori-positive participants with serological atrophic gastritis were significantly more frequent by 4.06 times for atrophic gastritis (p ≤ 0.0001) than anti-H. pylori-negative participants without serological atrophic gastritis. Eight anti-H. pylori-positive participants were diagnosed with gastric cancer, but no cancer was found in anti-H. pylori-negative participants without serological atrophic gastritis. Serum PG testing is clinically useful for the prediction of gastric lesions in H. pylori-infected persons.

Utility of glycated albumin for the diagnosis of diabetes mellitus in a Japanese population study: results from the Kyushu and Okinawa Population Study (KOPS).

AIMS/HYPOTHESIS: Glycated albumin is a measure of the mean plasma glucose concentration over approximately 2-3 weeks. We determined reference values for glycated albumin, and assessed its utility for the diagnosis of type 2 diabetes mellitus in the general population. METHODS: We studied 1,575 men and women (mean age, 49.9 years; range, 26-78 years) who participated in a periodic health examination in a suburban Japanese town. HbA(1c) and fasting plasma concentrations of glucose (FPG) and glycated albumin were measured. Participants with FPG ≥ 7.0 mmol/l or HbA(1c) ≥ 6.5% (48 mmol/mol) were diagnosed as having diabetes. In our laboratory, the glycated albumin assay had intra-assay and inter-assay CVs of 1.1% and 1.6%, respectively. RESULTS: Glycated albumin levels were significantly correlated with HbA(1c) levels (r = 0.766, p < 0.001) and FPG (r = 0.706, p < 0.001). The presence of diabetes was significantly higher in participants with glycated albumin levels between 15.0% and 15.9% (five of 276, 1.81%) than in those with glycated albumin <14% (three of 672, 0.45%) (p = 0.037), and was markedly increased in those with a glycated albumin level >16% (58 of 207, 28.0%). Receiver operating characteristic curve analysis indicated that a glycated albumin level of ≥15.5% was optimal for predicting diabetes, with a sensitivity of 83.3% and a specificity of 83.3%. CONCLUSIONS/INTERPRETATION: There is merit to further investigating the potential for glycated albumin to be used as an alternative measure of dysglycaemia for future research and clinical practice.

Systematic review with meta-analysis: effectiveness and tolerability of interferon-free direct-acting antiviral regimens for chronic hepatitis C genotype 1 in routine clinical practice in Asia.

BACKGROUND: Direct-acting antiviral (DAA) regimens have shown high efficacy and tolerability for patients with HCV genotype 1/1b (GT1/1b) in clinical trials. However, robust real-world evidence of interferon (IFN)-free DAA treatment for HCV GT1-infected patients in Asia is still lacking. AIM: To systematically review and meta-analyse the effectiveness and tolerability of IFN-free DAA therapy for HCV GT1 infection in Asia. METHODS: We included studies that enrolled adult patients with HCV GT1 infection in routine clinical practice in Asia, using IFN-free DAA regimens, and reported sustained virological response (SVR) after 12/24 weeks end-of-treatment by 31 May 2017. The pooled SVR rates were computed with a random-effects model. Subgroup analysis and meta-regression as previously registered in PROSPERO were performed to determine how pre-planned variables might have affected the pooled estimates. RESULTS: We included 41 studies from eight countries and regions, comprising of 8574 individuals. The pooled SVR rates for GT1 were 89.9% (95% CI 88.6-91.1, I2  = 55.1%) with daclatasvir/asunaprevir (DCV/ASV) and 98.1% (95% CI 97.0-99.0, I2  = 41.0%) with ledipasvir/sofosbuvir ± ribavirin (LDV/SOF ± RBV). Baseline cirrhosis but not prior treatment history and age, attenuated the effectiveness of both regimens. Baseline resistance associated substitutions (RASs) severely attenuated SVR of DCV/ASV (65.4% vs 94.3%, P < 0.001) and only minimally with LDV/SOF ± RBV (94.5% vs 99.2%, P = 0.003). Patients with renal dysfunction treated with DCV/ASV showed a higher SVR rate (93.9% vs 89.8%, P = 0.046). Patients with hepatocellular carcinoma (HCC) LDV/SOF ± RBV achieved a lower SVR than those without HCC (94.1% vs 98.7%, P = 0.001). CONCLUSION: All oral DAA treatment of HCV GT1 resulted in high cure rates in Asian patients in routine clinical practice setting including elderly patients and those with end-stage renal disease.

Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting anti-viral treatment.

BACKGROUND: With the development of direct-acting anti-virals (DAAs), almost all patients with chronic hepatitis C virus (HCV) infection can achieve sustained viral response (SVR). AIM: To evaluate the short-term risk of HCC among patients with SVR by DAAs, including those with cirrhosis or previous HCC. METHODS: This large-scale, multicentre cohort study included 1,675 consecutive patients who achieved SVR by treatment with interferon-free sofosbuvir-based regimens, divided into groups with (n = 152) or without previous HCC (n = 1,523). The Kaplan-Meier method and Cox proportional hazard analysis were used to calculate the cumulative HCC incidence and related factors of HCC. RESULTS: During the follow-up period (median: 17 months), 46 (2.7%) patients developed HCC. The 1-year cumulative rates of de novo HCC were 0.4% and 4.9% for the noncirrhosis and cirrhosis groups respectively (log-rank test: P < 0.001). For cirrhotic patients, serum α-fetoprotein level at the end of treatment (EOT-AFP) was the strongest predictor of de novo HCC. The 1-year cumulative de novo HCC rates were 1.4% and 13.1% in the EOT-AFP < 9.0 ng/mL and ≥ 9.0 ng/mL groups (cut-off value) respectively (log-rank test: P < 0.001). The 1-year cumulative rates of HCC recurrence were 6.5% and 23.1% for the noncirrhosis and cirrhosis groups respectively (log-rank test: P = 0.023). For cirrhotic patients, previous HCC characteristics were significantly associated with HCC recurrence. In contrast, sex, age and metabolic features did not influence de novo HCC or recurrence. CONCLUSIONS: For cirrhotic patients after elimination of HCV, serum EOT-AFP level and previous HCC characteristics would be useful markers for predicting de novo HCC or recurrence.

Serum WFA(+) -M2BP is a non-invasive liver fibrosis marker that can predict the efficacy of direct-acting anti-viral-based triple therapy for chronic hepatitis C.

BACKGROUND: The Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA(+) -M2BP) is a new liver fibrosis glycobiomarker with unique fibrosis-related glyco-alteration. WFA(+) -M2BP is also a useful surrogate marker for the risk of developing hepatocellular carcinoma and for the liver functional reserve. AIM: To evaluate the diagnostic ability of WFA(+) -M2BP for liver fibrosis in the clinical setting and the clinical utility of WFA(+) -M2BP for predicting the efficacy of direct-acting anti-viral (DAA) treatment for chronic hepatitis C patients. METHODS: The study included 159 genotype 1 hepatitis C patients who received DAA-based treatment (telaprevir or simeprevir) combined with pegylated-interferon alpha plus ribavirin (108 telaprevir- and 51 simeprevir-based triple treatment). The relation between baseline serum WFA(+) -M2BP and treatment efficacy was evaluated. RESULTS: The serum WFA(+) -M2BP level significantly increased with the progress of liver fibrosis. Area under the receiver operating characteristic curve analysis identified 2.17 as the cut-off index (COI) for WFA(+) -M2BP for diagnosing advanced fibrosis. The sustained virological response (SVR) rate was significantly, negatively correlated with the serum WFA(+) -M2BP level. Multiple logistic regression analysis found a low serum WFA(+) -M2BP level (<2.17 COI) to be independently associated with SVR (odds ratio, 4.35, P = 0.027). Even for prior nonresponders and patients with the interleukin-28B minor allele or histological advanced fibrosis, treatment outcome was favourable for patients with a low serum WFA(+) -M2BP level. CONCLUSION: Serum WFA(+) -M2BP is a non-invasive liver fibrosis marker useful for predicting the efficacy of DAA-based triple therapy for chronic hepatitis C patients.

Age-related response to interferon alfa treatment in women vs men with chronic hepatitis C virus infection.

BACKGROUND: Interferon alfa is used widely for patients with chronic hepatitis C virus (HCV) infection. Little is known, however, of the relationship between patients' sex and the effectiveness of interferon alfa treatment in these patients. METHODS: We treated 311 patients (199 men and 112 women) with human lymphoblastoid interferon (6 million units subcutaneously every day for 2 weeks and 3 times a week for 22 weeks) and observed them for an additional 6 months. Serum HCV RNA levels and genotype were tested by polymerase chain reaction before treatment. A liver biopsy was also done. For the purposes of this study, a complete response was defined as the elimination of HCV RNA for at least 6 months after the termination of treatment. RESULTS: The rate of complete response was 27.1% for men and 24.1% for women. With multiple logistic regression analysis, the HCV RNA level (P < .001), genotype (P < .001), patients' sex (P < .05), and the interaction between sex and age were associated with a complete response to interferon alfa. The rate of complete response was 33.3% in men aged 39 years and younger, 25.0% in men aged 40 years and older. 75.0% in women aged 39 years and younger, and 15.6% in women aged 40 years and older. The odds ratio by group was 1.00, 0.72, 4.38, and 0.21, respectively. CONCLUSIONS: Our finding that women aged 39 years and younger are responsive to interferon alfa treatment suggests that hormonal activity, in particular the level of estrogen, may be associated with the sustained elimination of HCV.

Hepatitis B surface antigen disappearance and hepatitis B surface antigen subtype: a prospective, long-term, follow-up study of Japanese residents of Okinawa, Japan with chronic hepatitis B virus infection.

To determine the natural course of hepatitis B surface antigen (HBsAg) disappearance in chronic hepatitis B virus (HBV) infection and the factors related to its disappearance, 946 HBsAg carriers in Okinawa, Japan were prospectively followed for up to 19 years (mean = 9.2 years). The disappearance of HBsAg, as determined by radioimmunoassay (RIA), was observed in 62 (6.6%) and the overall annual disappearance rate was 0.79%/year. Its disappearance was more frequent in 60 (7.4%) of 815 serum samples negative for hepatitis B e antigen (HBeAg) by RIA at entry compared with only two (1.5%) of 131 serum samples that were HBeAg positive by RIA at entry (P < 0.05). Stepwise logistic regression analysis showed that age and HBsAg subtype were significantly associated with HBsAg disappearance (both P < 0.05), and that carriers with subtype adr (odds ratio = 2.87) had an increased probability of clearing HBsAg compared with carriers with subtype adw. Conversely, HBeAg disappearance was earlier in those with the adw subtype than in those with adr. Hepatitis B virus DNA was not detected by the polymerase chain reaction after HBsAg disappearance in any of the 62 from whom it had disappeared. The HBsAg titer, as measured by reverse passive hemagglutination, was related to the time to its disappearance; the higher the titer, the longer the time to disappearance. These findings suggest that HBeAg negativity, a more advanced age, and low titers of HBsAg are favorable factors for HBsAg disappearance in the natural course of chronic HBV infection. Moreover, HBsAg subtype adr was a predictive factor for HBsAg disappearance, whereas subtype adw was predictive of early HBeAg disappearance.

Correlation between human T cell lymphotropic virus type-1 and Strongyloides stercoralis infections and serum immunoglobulin E responses in residents of Okinawa, Japan.

To clarify the relationship between Strongyloides stercoralis, infection with human T cell lymphotropic virus type-1 (HTLV-1), and serum immunoglobulin E (IgE) levels, epidemiologic investigations of these two infections were conducted in inhabitants of Okinawa, a subtropical zone in Japan. Blood and feces samples were taken from 1,347 healthy inhabitants (554 males and 793 females). Antibody to HTLV-1 was measured by particle agglutination, enzyme-linked immunosorbent assay, and Western blotting. The presence of Strongyloides was determined by direct detection of rhabditiform larvae in fresh stool on agar-plate cultures. Serum IgE levels in 127 inhabitants were measured by a fluoroenzyme immunoassay. Antibody to HTLV-1 was detected in 23.0% of the blood samples and was more frequent in females (25.1%) than in males (20.0%) (P < 0.05). Strongyloides were detected in 21.9% of the feces samples and were more frequent in males (31.9%) than in females (14.9%) (P < 0.001). The prevalence of both infections increased with age, especially in persons 50 years of age and older: The prevalence of Strongyloides infection was significantly higher in HTLV-1 carriers (31.6%) than in those without HTLV-1 infection (P < 0.001). The level of IgE was low in HTLV-1 carriers, and significantly lower in HTLV-1 carriers than in noncarriers among inhabitants with Strongyloides infection. Both HTLV-1 and Strongyloides infections are endemic in the area studied.

The elimination of hepatitis B virus infection: changing seroepidemiology of hepatitis A and B virus infection in Okinawa, Japan over a 26-year period.

Serial changes in hepatitis A virus (HAV) and B virus (HBV) markers were determined from 1970 to 1996 in healthy Japanese residents of a rural area of Okinawa, Japan. All 190 serum samples taken in 1970, 791 in 1980, 708 in 1988, and 523 in 1996 from residents 0 to more than 60 years of age were tested for antibody to HAV (anti-HAV), antibody to hepatitis B core antigen (anti-HBc), and hepatitis B surface antigen (HBsAg). The age-adjusted prevalences of anti-HAV and anti-HBc decreased significantly from 83.9% and 74.9%, respectively, in 1970 to 39.7% and 36.6%, respectively, in 1996. In residents < or = 29 years of age, the prevalences of anti-HAV and anti-HBc decreased significantly from 65.3% and 83.8%, respectively, in 1970 to 0.7% and 8.2%, respectively, in 1996. The age-adjusted HBsAg prevalence decreased significantly from 8.2% in 1980 to 4.1% in 1988. These results indicate that exposure to HAV and HBV infections among Okinawa residents less than 29 years of age is decreasing, probably because of improvements in socioeconomic conditions since 1970. Infection with HBV may be eliminated there in the near future.

Markedly high seroprevalence of hepatitis B virus infection in comparison to hepatitis C virus and human T lymphotropic virus type-1 infections in selected Solomon Islands populations.

To determine the prevalences of hepatitis B virus (HBV), hepatitis C virus (HCV), and human T lymphotropic virus type-1 (HTLV-1) infections in residents of the Solomon Islands, we surveyed 1,610 serum samples from 1,113 outpatients and 497 healthy volunteer blood donors at the Central Hospital in Honiara, the Solomon Islands. The prevalence of hepatitis B surface antigen (HBsAg) by radioimmunoassay (RIA) (n = 315, 19.6%) was significantly different from that of antibody to HCV (anti-HCV) by a second-generation enzyme immunoassay (EIA) (n = 4, 0.2%) and antibody to HTLV-1 (anti-HTLV-1) by an ELISA with Western blot analysis to verify the positivity (n = 49, 3.0%) (P < 0.0001, respectively). There were no significant differences in the prevalences of these markers between outpatients and blood donors. Hepatitis B e antigen (HBeAg) was detected by RIA in 130 (41.3%) of 315 HBsAg-positive samples. The distribution of HBsAg subtypes by EIA was 190 adr (60.3%), 111 ayw (35.2%), and 14 (0.4%) other subtypes. The HBeAg prevalence decreased with age in all groups for each subtype. There were no significant differences in the prevalence of HBeAg among HBsAg subtypes. We conclude that HBV infection is highly endemic in selected Solomon Islands populations, and that the high prevalence of HBeAg may be associated with the spread of HBV infection there.

Human lymphoblastoid interferon treatment for patients with hepatitis C virus-related cirrhosis.

To evaluate the efficacy and safety of human lymphoblastoid interferon treatment (interferon alfa) for patients with compensated cirrhosis caused by hepatitis C virus (HCV) infection, we randomly assigned 82 cirrhotic patients with chronic HCV infection (44 men, 38 women; mean age, 58.6 years) to two groups: 41 patients were treated with interferon alfa (480 million U over 6 months), and the other patients received no drug treatment. HCV RNA genotypes were determined by polymerase chain reaction (PCR) testing using type-specific primers. HCV RNA levels were measured by competitive PCR testing. No untreated patients eliminated HCV RNA from the serum or had a decrease in the level of alanine aminotransferase to normal during the observation period. Of the 34 patients who completed interferon alfa treatment, 6 (17.6%) who were considered complete responders eliminated HCV RNA from the serum by the end of treatment and sustained this elimination throughout a 6-month follow-up period. Complete responders constituted 6 (46.2%) of 13 patients with HCV RNA levels < or = 10(5) copies/50 microL, but none of the 21 patients with levels > 10(5) copies/50 microL were complete responders. Two (7.1%) of 28 patients with genotype 1b infection and 4 (66.7%) of 6 with genotype 2a were complete responders. Five patients withdrew because of interferon alfa-induced side effects (1 for thrombocytopenia, 3 for severe general malaise, and 1 for impotence), and 2 withdrew after being diagnosed with hepatocellular carcinoma. Hepatic failure did not occur in any treated patient in the present study. These findings indicate that interferon alfa treatment is useful for compensated cirrhosis caused by HCV infection if the HCV RNA levels are low and the infection is of genotype 2a.

Rapidly growing primary gastric B-cell lymphoma after eradication of Helicobacter pylori.

Helicobacter pylori (H. pylori) infection plays a decisive role in primary gastric B-cell lymphoma especially of mucosa-associated lymphoid tissue (MALT)-type. We treated a 47-year-old male patient with primary gastric B-cell lymphoma associated with H. pylori infection. Although antibiotic therapy for eradication of H. pylori caused great improvement in the low-grade MALT lymphoma-like lesion, the small areas of high-grade lesion rapidly formed a new bulky mass in only 8 weeks. This suggests that eradication of H. pylori is not effective for high-grade lymphoma.

Large dose natural interferon alpha therapy for patients with chronic hepatitis C.

To evaluate the efficacy of large dose interferon treatment for patients with chronic hepatitis C virus (HCV) infection, we studied 99 Japanese patients treated with either 6 million units (MU) or 9 MU natural interferon alpha. Serum samples were tested for HCV RNA by polymerase chain reaction (PCR). HCV RNA genotypes were determined by PCR with type-specific preimers, and the HCV RNA level was measured by competitive PCR. HCV RNA was detected in all patients, prior to the initiation of treatment. We examined interleukin-1 receptor antagonist (IL-1 Ra) by enzyme-linked immunosorbent assay. Forty-four patients were treated with 9 MU natural interferon alpha for 24 weeks (group A), and fifty-five patients were treated with 6 MU natural interferon alpha for 24 weeks (group B). There were no significant differences in HCV RNA levels, HCV RNA genotype or histological activity index (HAI) score between the two groups. Of the 94 patients who completed this treatment, nine (23.1%) in group A and 14 (25.5%) in group B sustained elimination of HCV RNA throughout a 6-month follow-up. There were no differences in the rate of complete response when comparing HCV RNA genotype, levels and HAI score and no significant differences in elevation of IL-1 Ra levels between the two groups. Five of group A patients refused further treatment because of severe side effects such as retinal hemorrhage, while no patient in group B had severe side effects. Thus, large dose natural interferon alpha treatment confers no additional benefit to the patient, compared with the current use of a lower dose.

Telaprevir-based triple therapy for chronic hepatitis C patients with advanced fibrosis: a prospective clinical study.

BACKGROUND: Antiviral treatment is recommended for chronic hepatitis C patients with advanced fibrosis to reduce and prevent cirrhosis-related complications. AIM: To evaluate the efficacy and safety of telaprevir (TVR)-based triple therapy for patients with advanced fibrosis in a clinical practice setting. METHODS: This prospective, multicentre study consisted of 102 patients with advanced fibrosis (METAVIR score F3-4) who were infected with HCV genotype 1b. All received 12 weeks of TVR in combination with 24 weeks of pegylated interferon (PEG-IFN) α2b and ribavirin (RBV). RESULTS: The sustained virological response (SVR) rate was 69.6% (71 of 102). Notably, for treatment-naïve and prior relapse patients the SVR rate was over 80%. Previous treatment response, interleukin 28B polymorphism (rs8099917) and rapid virological response (undetectable HCV RNA at week 4) were independently associated with SVR. To achieve SVR, an adequate dosage of PEG-IFNα2b (≥1.2 µg/kg/week) and RBV (≥7.5 mg/kg/day) is preferable; however, the mean weight-adjusted TVR dosage had little impact on treatment outcome. Although severe blood cytopaenia and a dermatological disorder were frequently found, the rate of discontinuation due to adverse effects was 12.7%. The inosine triphosphatase CC allele (rs1127354) was independently associated with the development of severe anaemia, and lower serum albumin level (<35 g/L) was associated with the occurrence of infection. CONCLUSIONS: The great gain in the SVR rate by telaprevir-based triple therapy offsets the problems with adverse effects; thus, it should be considered as a potent treatment protocol for patients with advanced fibrosis, especially for those with treatment-naïve and prior relapse.

Seroepidemiology of TT virus infection and relationship between genotype and liver damage.

TT virus (TTV) has been identified in patients with posttransfusion hepatitis of unknown etiology and is thought to be a new hepatitis virus. We determined the extent of TTV infection in the Japanese general population and the relationship between TTV DNA genotype and liver damage. In 1998, we tested 847 serum samples for TTV. TTV DNA was assayed by a nested polymerase chain reaction and classified into three different genotypes and eight subtypes. TTV DNA was detected in 25.3% and 32.4% of the inhabitants of the two areas studied, respectively. The genotype distribution was similar in both areas. G1, G2, and G3 were 60%, 20%, and 5%, respectively. Of the 20 subjects with TTV DNA alone and elevated serum ALT levels, 18 were G1, one was G2, and one was G3. TTV infection is endemic in the Japanese general population studied. The main TTV genotype, G1, may be related to the ensuing liver damage.

Human T lymphotropic virus type 1 infection influences hepatitis C virus clearance.

To explore the effect of human T lymphotropic virus type 1 (HTLV-1) infection on hepatitis C virus (HCV) infection, a survey for these viral infections was conducted that involved 2280 residents in an area in which HTLV-1 and HCV are endemic. The response of patients with HCV and HTLV-1 to interferon (IFN)-alpha treatment was also assessed. Antibody to HCV was detected in 13.8% of the residents tested, and antibody to HTLV-1 was detected in 15.4%. The prevalence of HCV RNA was significantly higher among residents who had antibodies to both HCV and HTLV-1 than in those who had antibodies to HCV only (P<.05). Sustained elimination of HCV RNA by IFN was significantly more frequent among patients with HCV alone than among those with HCV and HTLV-1. By logistic regression analysis, HTLV-1 infection was associated with nonresponse to IFN treatment. Thus, HTLV-1 infection affects the clearance, both natural and in association with IFN treatment, of HCV.

A relationship between the evolution of hepatitis C virus variants, liver damage, and hepatocellular carcinoma in patients with hepatitis C viremia.

To clarify the mechanism of liver damage induced by hepatitis C virus (HCV) and to determine whether the damage is related to hepatocellular carcinoma (HCC), HCV RNA levels were measured serially, and HCV genome mutations were analyzed from serum of 274 Japanese patients with chronic HCV viremia during 1993-1998. All patients had alanine aminotransferase (ALT) levels measured during 1986-1998. Patients with consistently normal ALT levels had identical and highly conserved HCV core regions; however, those with consistently abnormal ALT levels had quasi species, and the population of the quasi species changed over time. HCV RNA levels did not change in the 274 patients. HCC developed in 31% of 80 patients with consistently abnormal ALT levels and in 4% of 92 patients with intermittently abnormal ALT levels but never in 102 patients with ALT levels consistently normal during 1993-1998. In patients with chronic HCV viremia, persistent liver damage plays an important role in the development of HCC.