The Induction of Antigen 85B-Specific CD8+ T Cells by Recombinant BCG Protects against Mycobacterial Infection in Mice.

Mycobacterium tuberculosis (Mtb) infection remains a major health problem worldwide. Although the Bacillus Calmette-Guérin (BCG) vaccine is the most widely used vaccination for preventing tuberculosis (TB), its efficacy is limited. We previously developed a new recombinant BCG (rBCG)-based vaccine encoding the Ag85B protein of M. kansasii (Mkan85B), termed rBCG-Mkan85B, and its administration is followed by boosting with plasmid DNA expressing the Ag85B gene (DNA-Mkan85B). Previously, we identified MHC-I (H2-Kd)-restricted epitopes that highly cross-react with those of Mtb in BALB/c (H2d) and CB6F1 (H2b/d) mice. We also reported that the rBCG-Mkan85B/DNA-Mkan85B prime-boost vaccination protocol protected CB6F1 mice against M. kansasii infection. In this study, to investigate the protective effect of our novel rBCG against Mtb infection, CB6F1 mice were either left unimmunized or immunized with the BCG, rBCG-Mkan85B, or rBCG-Mkan85B/DNA-Mkan85B vaccine for 10 weeks prior to inhalation exposure to the virulent Mtb Erdman strain for another 6 weeks. Compared with the BCG and rBCG-Mkan85B vaccinations, the rBCG-Mkan85B/DNA-Mkan85B prime-boost vaccination protocol significantly reduced the numbers of pulmonary colony-forming units (CFUs). Moreover, the rBCG-Mkan85B/DNA-Mkan85B prime-boost vaccination induced antigen-specific polyfunctional CD4+ and CD8+ T cells. These results suggest that CD8+ T-cell immunity to immunodominant epitopes of Mtb is enhanced by rBCG vector-based immunization. Thus, rBCG vector-based vaccinations may overcome the limited ability of the current BCG vaccine to elicit TB immunity.

Switching to tenofovir alafenamide for nucleos(t)ide analogue-experienced patients with chronic hepatitis B: week 144 results from a real-world, multi-centre cohort study.

BACKGROUND: Tenofovir alafenamide (TAF) may be preferable to other nucleos(t)ide analogues (NA) regarding outcomes against chronic hepatitis B virus (HBV) infection. AIMS: To evaluate the longer term virological/biochemical effectiveness of TAF and the renal safety of sequential therapy to TAF in real-world settings METHODS: This multi-centre, retrospective cohort study included consecutive adult patients who were switched from other NAs to TAF. We assessed the virological and biochemical responses up to 144 weeks. We performed sensitivity analyses for a subgroup with chronic kidney disease (CKD) at baseline. RESULTS: We analysed the data of 391 patients with chronic hepatitis B previously treated with entecavir (ETV) (n = 174), tenofovir disoproxil fumarate (TDF) (n = 116) or an NA combination (n = 101) for ≥ 24 months. HBV DNA <10 IU/ml at week 144 was found for 99% of patients, regardless of prior NA regimen or HBV DNA level at baseline. For patients who switched from TDF to TAF, total, low-density lipoprotein, high-density lipoprotein cholesterol and triglycerides were significantly increased after the switch. Patients who switched from a nucleotide analogue to TAF had an improved estimated glomerular filtration rate, although the rate of hypophosphataemia (<2.5 mg/dl) remained 9.7% at week 144. The virological and biochemical responses of patients with CKD were similar to the overall results. CONCLUSIONS: Switching to TAF remained effective and safe for up to 3 years. Given the increasing comorbidities related to ageing, it will be important to carefully follow the change in the lipid levels of patients with a prior TDF-based regimen.

Chronic Pulmonary Disease Caused by Tsukamurella toyonakaense.

Unidentified Mycobacterium species are sometimes detected in respiratory specimens. We identified a novel Tsukamurella species (Tsukamurella sp. TY48, RIMD 2001001, CIP 111916T), Tsukamurella toyonakaense, from a patient given a misdiagnosis of nontuberculous mycobacterial pulmonary disease caused by unidentified mycobacteria. Genomic identification of this Tsukamurella species helped clarify its clinical characteristics and epidemiology.

Mycobacterium senriense sp. nov., a slowly growing, non-scotochromogenic species, isolated from sputum of an elderly man.

A slowly growing mycobacteria, identified as strain TY59T, was isolated from sputum of an elderly man with pneumonia. Sequencing of the 16S rRNA gene indicated that this strain was similar to members of the Mycobacterium avium complex and closely related species. Strain TY59T has highest 16S rRNA gene sequence similarities to the type strains of Mycobacterium colombiense (99.80 % sequence similarity), Mycobacterium vulneris (99.74 %), Mycobacterium timonense (99.54 %), Mycobacterium avium subsp. avium (99.54 %) and Mycobacterium avium subsp. silvaticum (99.54 %). Analysis of the internal transcribed spacer (ITS) and DNA-directed RNA polymerase subunit beta (rpoB) sequences gave similar results to the 16S rRNA gene analysis. The closest species to strain TY59T were M. colombiense and M. vulneris with 97.90-98.25 % identity in ITS and 96.4-96.6 % in rpoB. The strain's 65 kDa heat shock protein (hsp65) gene was different from those of M. vulneris, M. colombiense and M. avium subsp. silvaticum with 72.4-74.2 % identity. Average nucleotide identity results showed a 93.4 % match to M. vulneris as the maximum value. Phenotypically, the non-chromogenicity, rough colonies, growth at 42 °C, negative results for nitrate reduction, ß-glucosidase and Tween 80 hydrolysis, and positive results for catalase activity set this strain apart from closely related species. We propose that Mycobacterium senriense sp. nov. is a novel species of slowly growing mycobacteria. The type strain is TY59T (RIMD 1371001T=CIP 111917T).

The Diagnosis of Nontuberculous Mycobacterial Pulmonary Disease by Single Bacterial Isolation Plus Anti-GPL-Core IgA Antibody.

Although serum anti-glycopeptidolipid (GPL)-core IgA antibody is a highly specific test for infection with Mycobacterium avium complex (MAC), Mycobacterium abscessus, and its subspecies abscessus, subsp. massiliense, and subsp. bolletii (MAB), its use for the definitive diagnosis of MAC pulmonary disease (PD) and MAB-PD are unknown. To clarify the diagnostic accuracy of the anti-GPL-core IgA antibody test among patients with radiologically suspected MAC-PD or MAB-PD who already have a single positive sputum culture test. The first isolations of MAC and MAB from patients with radiologically suspected MAC-PD or MAB-PD at the Osaka Toneyama Medical Center between January 2006 and December 2020 were collected. Patients were enrolled when their serum anti-GPL-core IgA antibody was measured during the 3 months before and after the first isolation. We retrospectively compared the results of anti-GPL-core IgA antibody testing with the final diagnoses based on the current guidelines. We included 976 patients for analysis. The serum anti-GPL-core IgA antibody was positive in 699 patients (71.6%). The positive predictive value of anti-GPL-core IgA antibody for the diagnosis of MAC-PD or MAB-PD was 97.4%. The median time required for the second positive culture after the first isolation was 51 days (interquartile range 12 to 196 days). The positive serum anti-GPL-core IgA antibody test allowed an early and definitive diagnosis of MAC-PD or MAB-PD in those who already had a single positive sputum culture test. IMPORTANCE To satisfy the microbiologic criteria of the current diagnostic guideline for nontuberculous mycobacterial pulmonary disease (PD), at least two positive sputum cultures of the same species of mycobacteria from sputum are required to avoid the casual isolation of mycobacteria. This study showed that the positivity of a serum anti-glycopeptidolipid (GPL)-core IgA antibody test has an excellent diagnostic ability among patients with radiologically suspected Mycobacterium avium complex (MAC)-PD or Mycobacterium abscessus (MAB)-PD who already had a single positive sputum culture test. The usage of single culture isolation plus anti-GPL-core IgA antibody as another diagnostic criterion has a time, cost, and effort-saving effect. Furthermore, it will facilitate the diagnosis of MAC-PD or MAB-PD in the early stage of disease because serum anti-GPL-core IgA antibody becomes high in these patients. Therefore, we proposed adding single culture isolation plus anti-GPL-core IgA antibody as "combined microbiological and serological criteria" to the diagnostic guidelines for MAC-PD and MAB-PD.

Sequential HBV treatment with tenofovir alafenamide for patients with chronic hepatitis B: week 96 results from a real-world, multicenter cohort study.

BACKGROUND AND AIMS: Outcome data of sequential hepatitis B virus treatment with tenofovir alafenamide (TAF) are limited. We aimed to assess the effectiveness and renal safety of TAF in chronic hepatitis B (CHB) patients who were previously treated with entecavir (ETV), tenofovir disoproxil fumarate (TDF), or a nucleos(t)ide analogue (NA) combination. METHODS: This multicenter, retrospective, cohort study included 458 consecutive CHB patients who switched to TAF monotherapy after at least 2 years of treatment with another NA. The longitudinal virological/laboratory responses were evaluated up to 96 weeks after switchover. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. RESULTS: The proportions of complete viral suppression (CVS) (HBV DNA < 20 IU/mL) at week 96 were 99.0%, 98.5%, and 98.4% in the prior ETV (n = 198), TDF (n = 137), and NA combination (n = 123) groups, respectively. Almost all patients with HBV DNA of 20-2000 IU/mL at baseline achieved CVS at week 96. On multivariable generalized estimated equation analysis, a low quantitative hepatitis surface antigen (qHBsAg) level at baseline was associated with a lower follow-up qHBsAg level (coefficient 0.81, p < 0.001). The eGFR showed greater improvement in patients with CKD compared to those without (coefficient 21.7, p < 0.001). However, the increase of eGFR reached a peak between weeks 24 and 48. CONCLUSIONS: Based on this longitudinal data analysis up to 96 weeks, sequential NA therapy with a switch to TAF is a good option to achieve high viral suppression and renal safety.

Development of Hepatocellular Carcinoma in Patients Aged 75-84 Years With Chronic Hepatitis C Treated With Direct-Acting Antivirals.

BACKGROUND: Direct-acting antiviral (DAA) treatment has revolutionized hepatitis C virus (HCV) care. We aimed to evaluate the risk for the development of hepatocellular carcinoma (HCC) in patients aged 75-84 years with chronic hepatitis C after HCV elimination. METHODS: This multicenter cohort study included 2405 consecutive patients with chronic hepatitis C without a history of HCC who achieved HCV elimination by DAAs. Patients in whom HCC developed within 1 year of DAA initiation were excluded. Propensity score matching analysis was used to evaluate differences in HCC risk between patients aged 75-84 versus 60-74 years. RESULTS: The median observational period was 3.5 years. Among patients aged 75-84 years with a high Fibrosis-4 (FIB-4) index (≥3.25 at baseline), there was no significant difference in the annual incidence of HCCs between groups with an FIB-4 index ≥3.25 (2.75 per 100 person-years [PY]) versus <3.25 (2.16 per 100 PY) at 12 weeks after the end of treatment, unlike the results in those aged 60-74 years (3.61 and 1.51 per 100 PY, respectively) (adjusted hazard ratio, 2.20; P = .04). In 495 pairs matched by propensity score matching, in patients without cirrhosis, the cumulative HCC incidence was significantly higher in the 75-84-year than in the 60-74-year age group (P = .04). CONCLUSIONS: Older patients aged 75-84 years remained at high risk for the development of HCC, even after HCV elimination and the improvement of the FIB-4 index to <3.25.

Long-term hepatic function of patients with compensated cirrhosis following successful direct-acting antiviral treatment for hepatitis C virus infection.

BACKGROUND AND AIM: Direct-acting antivirals (DAAs) have contributed to the improvement of outcomes for all patients with chronic hepatitis C. The aim of this study was to evaluate the long-term hepatic benefits of hepatitis C virus (HCV) cure by DAAs in patients with compensated cirrhosis. METHODS: This multicenter cohort study consisted of consecutive patients with compensated cirrhosis who initiated interferon-free DAA treatment before September 2016. The impact of treatment on long-term hepatic function was followed for at least 4 years after the end of treatment, and the progression to decompensation was evaluated. RESULTS: The data of 394 patients were available for study. The median age was 70, and 41% had modified albumin-bilirubin (ALBI) grade 2b. During a short-term follow-up 1 year after the end of treatment, FIB-4 index and ALBI score significantly improved. The achievement rates of FIB-4 < 3.25 (40%) and ALBI grade 1 (70%) reached their plateau in the first year; however, there were significant further improvements in platelet count and α-fetoprotein level after the first year. The annual incidence of decompensation was 1.30 (95% confidence interval 0.83-2.02) per 100 person-years. In multivariable analysis, male sex and modified ALBI grade 2b at baseline were associated with decompensation. CONCLUSIONS: In a large real-world cohort of patients with compensated cirrhosis treated with a DAA, remarkable improvement in hepatic function was seen after HCV cure, especially during the first year after the end of treatment. Treatment in the early stage of cirrhosis would be of great benefit for preventing liver deterioration to decompensation.

Long-term assessment of recurrence of hepatocellular carcinoma in patients with chronic hepatitis C after viral cure by direct-acting antivirals.

BACKGROUND AND AIM: Early hepatocellular carcinoma (HCC) recurrence is common, even after achieving hepatitis C virus (HCV) cure. This study was carried out to assess the long-term trends and predictors of recurrence after HCV cure by direct-acting antivirals (DAAs). METHODS: This retrospective, multicenter cohort study enrolled 365 consecutive patients with chronic hepatitis C who required HCC treatment following sustained viral response (SVR) by DAA administration. Patients with HCC recurrence before SVR were excluded. Late HCC recurrence and its predictors beyond the post-treatment early phase (24 weeks after SVR) were evaluated. RESULTS: The data of 326 patients were available for the final analysis. The median follow-up duration from SVR determination was 2.7 years. Median age was 74, and 220 (67.5%) were 70 or over. The corresponding 5-year cumulative HCC recurrence rates of previous curative and palliative treatment groups were 45.4% and 65.7%, respectively (log-rank test: P < 0.001). Cox regression multivariable analysis revealed that cirrhosis (hazard ratio [HR] 1.85, P = 0.021), the number of HCC nodules (≥ 2) (HR 1.52, P = 0.031), and previous palliative HCC treatment (HR 1.71, P = 0.012) were independent predictors of late recurrence, in addition to the predictors of early recurrence; AFP > 7 ng/mL at 12 weeks after DAA administration, time from HCC complete response (CR) to DAA initiation (< 1 year), and the number of HCC treatments necessary to achieve CR (≥ 2). CONCLUSIONS: The evaluation of fibrosis and characteristics of the previous HCC would allow for better HCC recurrence stratification, which would be helpful for developing long-term surveillance strategies.

Pleural Effusion Caused by Mycolicibacterium mageritense in an Immunocompetent Host: A Case Report.

Mycolicibacterium mageritense (M. mageritense) is a rare species among rapidly growing mycobacteria, and M. mageritense pleurisy is very rare. Here, we report for the first time, an immunocompetent patient with pleurisy caused by M. mageritense. The patient had no history of immunodeficiency and no recurrence of lung cancer after surgery. However, 8 months after surgery, he developed a new lung shadow and pleurisy. Although whole-genome analysis of the colony cultured from the patient's pleural fluid revealed M. mageritense, we could not identify it in time, resulting in a poor outcome. M. mageritense pleurisy in this case might have occurred via a bulla rupture of the lung lesion because computed tomography of the patient's chest showed pneumothorax and a lung lesion in contact with thoracic cavity. This case emphasized that nontuberculous mycobacterial pleurisy should be considered in the differential diagnoses of pleural effusion even in immunocompetent patients. Advancement of comprehensive and rapid analyses of genomic data from clinical specimens will lead to better treatment strategies.

Pulmonary disease caused by a newly identified mycobacterium: Mycolicibacterium toneyamachuris: a case report.

BACKGROUND: Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is becoming a significant health burden. Recent advances in analysis techniques have allowed the accurate identification of previously unknown NTM species. Here, we report a case of NTM-PD caused by a newly identified mycobacteria in an immunocompetent patient. CASE PRESENTATION: A 44-year-old woman was referred to our hospital due to the frequent aggravation of her chronic respiratory symptoms, with NTM-PD-compatible computed tomography findings. Unidentified mycobacterium was repeatedly isolated from respiratory specimens and we diagnosed her as NTM-PD of unidentified mycobacterium. Subsequent whole-genome analysis revealed that the unidentified mycobacterium was a novel mycobacterium genetically close to Mycolicibacterium mucogenicum. We started combination therapy with clarithromycin, moxifloxacin, amikacin, and imipenem/cilastatin, referring to drug sensitivity test results and observed its effect on M. mucogenicum infection. Her symptoms and radiological findings improved significantly. CONCLUSION: We report a case of NTM-PD caused by a newly identified mycobacteria, Mycolicibacterium toneyamachuris, genetically close to M. mucogenicum. This pathogenic mycobacterium showed different characteristics from M. mucogenicum about clinical presentation and drug sensitivity. The clinical application of genomic sequencing will advance the identification and classification of pathogenic NTM species, and enhance our understanding of mycobacterial diseases.

Vaccination with Intradermal Bacillus Calmette-Guérin Provides Robust Protection against Extrapulmonary Tuberculosis but Not Pulmonary Infection in Cynomolgus Macaques.

Recently, the efficacy of Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccination is being reassessed in accordance with the achievements of clinical tuberculosis (TB) vaccine research. However, the mechanisms ultimately determining the success or failure of BCG vaccination to prevent pulmonary TB remain poorly understood. In this study, we analyzed the protective effects of intradermal BCG vaccination by using specific pathogen-free cynomolgus macaques of Asian origin that were intradermally vaccinated with BCG (Tokyo strain) followed by Mycobacterium tuberculosis (Erdman strain) infection. Intradermal BCG administration generated TB Ag-specific multifunctional CD4 T cell responses in peripheral blood and bronchoalveolar lavage and almost completely protected against the development of TB pathogenesis with aggravation of clinical parameters and high levels of bacterial burdens in extrapulmonary organs. However, interestingly, there were no differences in bacterial quantitation and pathology of extensive granulomas in the lungs between BCG-vaccinated monkeys and control animals. These results indicated that the changes in clinical parameters, immunological responses, and quantitative gross pathology that are used routinely to determine the efficacy of TB vaccines in nonhuman primate models might not correlate with the bacterial burden and histopathological score in the lung as measured in this study.

Incidence of Hepatocellular Carcinoma after Treatment with Sofosbuvir-Based or Sofosbuvir-Free Regimens in Patients with Chronic Hepatitis C.

Advanced fibrosis/cirrhosis and related biomarkers have been recognized as useful predictors of the development of hepatocellular carcinoma (HCC) by patients with chronic hepatitis C (CHC) following hepatitis C virus (HCV) cure by direct-acting antivirals (DAAs). However, it remains unclear if DAAs themselves have an influence on or facilitate the development of HCC. This multicenter cohort study included CHC patients without a history of HCC who achieved HCV elimination by DAAs. Cohorts of 835 patients treated with a sofosbuvir (SOF)-based regimen and 835 treated with a SOF-free regimen were matched 1:1 by propensity scoring with nine variables to evaluate differences in HCC incidence. The median observation period was 3.5 years. Sixty-nine cases of HCC were found during 5483.9 person-years (PY) over the entire follow-up period. The annual incidence was similar for both groups (SOF-based 1.25 and SOF-free 1.27 per 100 PY, respectively: adjusted hazard ratio (HR) 1.26, 95% confidence interval (CI) 0.75-2.12, p = 0.39). However, the annual incidence within the first two years was higher for patients treated with SOF than for those without, but did not reach significance (1.50 and 0.97 per 100 PY incidence rates, respectively: adjusted HR 2.05, 95% CI 0.98-4.25, p = 0.06). In summary, DAA treatment with SOF was not associated with an increase in the development of de novo HCC.

Tenofovir alafenamide after switching from entecavir or nucleos(t)ide combination therapy for patients with chronic hepatitis B.

BACKGROUND AND AIMS: Tenofovir alafenamide (TAF) has been newly approved for the treatment of chronic hepatitis B (CHB). We aimed to assess the effectiveness and renal safety of switching from entecavir (ETV) or nucleos(t)ide analogue (NA) combination therapy to TAF. METHODS: This multicentre, retrospective, cohort study included 313 consecutive CHB patients who switched to TAF monotherapy after treatment with ETV or a nucleos(t)ide analogue (NA) combination for over 2 years. Virological/laboratory responses were evaluated for 48 weeks after switchover. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 . Differences in longitudinal parameters were compared by the generalized estimating equation method. RESULTS: In the prior ETV group (n = 191), the HBV DNA suppression rate at week 48 was significantly increased, from 75.9% to 96.9% (P < .001). Additionally, mean changes in the HBsAg level at week 48 in HBsAg ≥ 3.0 logIU/mL and < 3.0 logIU/mL groups were -0.09 and -0.13 logIU/mL respectively. In the prior NA combination group (n = 122), the mean changes in HBsAg level at week 48 in the HBsAg ≥ 3.0 logIU/mL and <3.0 logIU/mL groups were -0.08 and -0.11 logIU/mL respectively. For patients with CKD, the eGFR at week 48 was significantly improved compared to those with non-CKD (adjusted slope coefficient difference: 2.75 mL/min/1.73 m2 /48 weeks; P = .001). CONCLUSIONS: Switching from ETV or an NA combination to TAF was effective for HBV suppression and continued HBsAg reduction. Moreover, the renal glomerular function of patients in the prior NA combination group with CKD was significantly improved compared to those with non-CKD. LAY SUMMARY: Nucleos(t)ide analogues, such as entecavir, tenofovir disoproxil fumarate and tenofovir alafenamide, inhibit hepatitis B virus (HBV) replication and are recommended as first-line oral agents for chronic HBV infection. We evaluated the virological/biochemical effects and renal safety when patients are switched from entecavir or nucleoside-nucleotide analogue combination therapy to tenofovir alafenamide. Our findings suggest that switching to tenofovir alafenamide was effective for HBV suppression and the improvement in renal function for patients with chronic kidney disease.

Ledipasvir and sofosbuvir for 12 weeks for hepatitis C virus genotype 2 infection: A propensity score matched analysis.

AIM: Hepatitis C virus genotype 2 is common in East Asia, sub-Saharan Africa, and Latin America. However, many countries in these areas lag behind other areas of the world in government approval for new direct-acting antivirals. The aim of this study was to evaluate the treatment outcome of ledipasvir/sofosbuvir (LDV/SOF) for patients with chronic hepatitis C virus genotype 2 infection. METHODS: This is a two-part multicenter, real-world cohort study. Study 1 consisted of 58 consecutive patients who were treated with LDV/SOF for 12 weeks. Study 2 used propensity score matching for LDV/SOF (n = 58) and glecaprevir/pibrentasvir (n = 207) treatment groups (1:1) with a set of clinically important variables. Sustained viral response 12 weeks after the end of treatment (SVR12) and adverse events were evaluated in both studies. RESULTS: In study 1, the overall SVR12 rates of the intention-to-treat and modified intention-to-treat populations were 94.8% (55/58) and 96.5% (55/57), respectively. High SVR12 rates were observed in almost all subgroups, including older age, compensated cirrhosis, and treatment experience. In study 2, propensity score matching of the entire study population yielded 52 matched pairs with similar baseline characteristics. There were no statistically significant differences between the LDV/SOF (96.1%) and glecaprevir/pibrentasvir (98.0%) groups in the overall SVR12 rates of the modified intention-to-treat populations, and their rates of treatment discontinuation and adverse events were similar. CONCLUSIONS: Treatment with LDV/SOF for hepatitis C virus genotype 2 resulted in a high rate of SVR12 and excellent tolerability. The outcomes of LDV/SOF were very similar to those of glecaprevir/pibrentasvir.

Cost-effectiveness analysis of sofosbuvir plus ribavirin in patients with genotype 2 chronic hepatitis C: an analysis with real world outcomes from a multicentre cohort in Japan.

OBJECTIVES: A number of publications have demonstrated the cost-effectiveness of sofosbuvir plus ribavirin (SOF+RBV) compared with the former standard therapy with interferon (IFN)-containing regimens. Unlike these cost-effective analyses, where efficacy parameters were obtained from registration trials for drug approval, this analysis is a cost-effectiveness analysis of SOF+RBV for genotype (GT) 2 non-cirrhosis (NC) and compensated cirrhosis (CC) patients using efficacy parameters obtained from a multicentre cohort study (Kyushu University Liver Disease Study; KULDS) in Kyushu area in Japan in order to reflect real-world clinical practice in Japan. METHOD: A Markov model followed 10 000 patients (62 years old) over their lifetime. Four populations were followed: treatment-naïve (TN)-NC, treatment-experienced (TE)-NC, TN-CC and TE-CC. Comparators were Peg-IFNα2b+RBV for TN-NC and CC patients and telaprevir (TVR)+Peg-IFNα2b+RBV for TE-NC patients. The sustained virological response (SVR) rates of SOF+RBV were taken from KULDS and those of comparators were obtained from systematic literature reviews. There were nine states (NC, CC, decompensated cirrhosis [DC], hepatocellular carcinoma [HCC], SVR [NC], SVR [CC], liver transplantation [LT], post-LT and death) in this model, and an increase in the progression rate to HCC due to ageing was also considered. The analysis was conducted from the perspective of a public healthcare payer, and a discount rate of 2% was set for both cost and effectiveness. RESULTS: Incremental cost-effectiveness ratios (ICERs) of SOF+RBV versus Peg-IFNα2b+RBV were ¥323 928 /quality-adjusted life year (QALY) for TN-NC patients, ¥92 256/QALY for TN-CC patients and ¥1 519 202/QALY for TE-CC patients. The ICER of SOF+RBV versus TVR+Peg-IFNα2b+RBV was ¥849 138/QALY for TE-NC patients. The robustness of the results was determined by sensitivity analysis. CONCLUSIONS: The results of this analysis strongly demonstrate the robustness of our previous findings that SOF+RBV regimens are cost-effective in the real world and clinical trial settings for Japanese GT2 NC and CC patients.

Glecaprevir and pibrentasvir for Japanese patients with chronic hepatitis C genotype 1 or 2 infection: Results from a multicenter, real-world cohort study.

AIM: Glecaprevir (GLE) and pibrentasvir (PIB) are new direct-acting antiviral agents (DAAs) with pangenotypic inhibitors that respectively target the hepatitis C virus (HCV) NS3/4 protease and NS5A. The aim of this study was to evaluate the effectiveness and safety of combining GLE and PIB for patients with HCV genotype (GT) 1 or 2 infection in the clinical setting, including patients DAA-experienced or on hemodialysis. METHODS: This multicenter, real-world, retrospective, cohort study consisted of 314 Japanese patients who were treated with GLE (300 mg) and PIB (120 mg) for a fixed 8- or 12-week duration. We evaluated the sustained virologic response rate 12 weeks after the end of treatment (SVR12) and adverse events. RESULTS: Among the treated patients, 122 had GT1 and 192 GT2 infection. The overall SVR12 rates in the per-protocol populations were 99.2% (119/120) for GT1 and 98.9% (183/185) for GT2. High SVR12 rates were observed in almost all subgroups, including cirrhosis, receiving hemodialysis, or previous all-oral DAA groups treated with asunaprevir and daclatasvir (GT1b), ledipasvir/sofosbuvir (GT1), or sofosbuvir and ribavirin (GT2). Virological relapse occurred in only 1.0% (3/305) of the patients who completed treatment. The most common adverse events were pruritus and fatigue (>5% of patients). Serious adverse events were rare and discontinuation due to an adverse event was required for 1.6% of the patients. CONCLUSIONS: In this real-world cohort study, treatment with GLE/PIB achieved high SVR12 rates with a low rate of serious adverse events among patients with HCV GT1 or 2 infection.

Elbasvir plus grazoprevir for patients with chronic hepatitis C genotype 1: A multicenter, real-world cohort study focusing on chronic kidney disease.

The real-world effectiveness and safety of all-oral direct-acting antivirals (DAAs) for chronic hepatitis C (HCV) infection and chronic kidney disease (CKD) have not been fully elucidated. This study assesses elbasvir (EBR) plus grazoprevir (GZR) for patients with HCV genotype 1 infection in the clinical setting, focusing on CKD stage 3-5D. This multicenter, real-world cohort study consisted of 282 Japanese patients who were treated with EBR (50 mg) plus GZR (100 mg) for a fixed 12-week duration. We evaluated the sustained viral response rate 12 weeks after the end of treatment (SVR12), longitudinal liver and renal parameters, and adverse effects according to the cirrhosis and CKD status. Of those enrolled, 89 (31.6%) were CKD stage 3-5 and 21 (7.4%) were CKD stage 5D (hemodialysis-dependent). The overall and CKD stage 3-5D SVR12 rates in the per protocol populations were 98.6% (272/276) and 98.1% (101/103). High SVR12 rates were observed in almost all groups, except for prior all-oral DAA failure with NS5A resistance-associated substitutions. There was no significant change during treatment or follow-up period in estimated glomerular filtration rate, irrespective of CKD status. In contrast, the serum complement level (C3 and C4) increased, with significance for C3. Serious adverse effects were very rare, both in the groups with normal eGFR and CKD, and discontinuation was required for only six (2.1%) patients. EBR plus GZR for HCV genotype 1 was highly effective with a low rate of adverse effects, regardless of CKD status. In addition, liver parameters and complement levels improved longitudinally.

Diabetes Mellitus Prevents an Improvement in the Serum Albumin Level During Interferon-free Sofosbuvir-based Therapy for Chronic Hepatitis C Patients: A Multi-institutional Joint Study.

Objective Interferon-free regimens of direct-acting antiviral agents have improved the treatment response for chronic hepatitis C virus (HCV) infection, and improvement in the serum albumin level during interferon-free therapy has been reported. The aim of this study was to identify the factors that influence the improvement in the serum albumin level in patients receiving interferon-free antiviral therapy. Methods This retrospective, multicenter study consisted of 471 Japanese patients with chronic hepatitis and compensated liver cirrhosis infected with HCV who completed 12-week interferon-free sofosbuvir (SOF)-based therapy [SOF plus ledipasvir for genotype 1 (n=276) and SOF with ribavirin for genotype 2 (n=195)]. We evaluated the changes in the serum albumin level from baseline to the end of treatment (ΔAlb). Results When compared with the normal-albumin group (baseline serum albumin >35 g/L, n=406), the low-albumin group (baseline serum albumin ≤35 g/L, n=65) showed a significant increase in the mean ΔAlb (5.5 g/L vs. 1.0 g/L, p<0.001). In the low-albumin group, a multivariate logistic regression analysis extracted diabetes mellitus as a negative predictive factor of median ΔAlb >5.0 g/L (odds ratio: 0.19, 95% confidence interval: 0.048-0.79, p=0.020). In the low-albumin group, the mean ΔAlb was significantly lower in the diabetic patients (n=14) than in the non-diabetic patients (n=51) (3.9 g/L and 5.7 g/L, p=0.049). Conclusion Interferon-free SOF-based therapy significantly improved the serum albumin in the low-albumin group patients with chronic HCV infection. However, the improvement in the serum albumin level was significantly lower in the diabetic patients than in the non-diabetic patients.

Preoperative evaluation of bone quality for dental implantation using an ultrasound axial transmission device in an ex vivo model.

This study investigated the clinical utility of an ultrasound axial transmission device in preoperative evaluation of bone quality for dental implantation, by clarifying the relationship between cortical bone speed of sound (cSOS), insertion torque values (ITV), and implant stability quotient (ISQ) in porcine femur bone. Eleven fresh porcine femurs, without soft tissue, were prepared. The cSOS of these bones were measured using the axial transmission device. Bone mineral density (BMD) and porosity (Po) were measured in cortical bone samples obtained from the region of ultrasound measurements by X-ray microcomputed tomography. Thirty-three implants were inserted into these samples (three implants per bone sample), and ITV and ISQ were measured for all implants. Then, cortical bone thickness (CbTh) of the area for implantation was measured for all implants using a micrometer. The mean cSOS was 3962 m/s; mean BMD and Po were 0.822 g/cm2 and 0.185%, respectively. cSOS and BMD values were positively correlated, and cSOS values and Po values were negatively correlated. Mean ITV, ISQ, and CbTh were 37.95 Ncm, 71.172, and 2.869 mm, respectively. There was a positive correlation between cSOS values and ISQ values. The cSOS of each bone did not correlate with ITV for all of the bone samples. However, when the CbTh ranges from 3.0 to 3.5 mm, ITV are correlated with cSOS. These findings suggest that cSOS, which reflects the cortical bone quality, may be clinical utility as a preoperative diagnosis of the implant.