Long-Term Outcomes after Switching to Tenofovir Alafenamide in Patients with Chronic Hepatitis B.

We sought to determine the long-term outcomes of chronic hepatitis B (CHB) cases switching to tenofovir alafenamide (TAF, n = 104, median age = 63.5 years). Data at switching to TAF (baseline) and those at 1, 2, 3, 4, and 5 years from switching to TAF were compared. At baseline, HB envelop antigen (HBeAg) seropositivity was found in 20 patients (19.2%), and undetectable HBV-DNA in 77 patients (74.0%). Percentage of detectable HBV-DNA significantly reduced at any time point. HB surface antigen (HBsAg) levels significantly reduced at 3, 4, and 5 years. The percentage of HBeAg seropositivity significantly reduced at 5 years. HB core related antigen levels did not significantly change. In patients with baseline HbeAg seropositivity, HbsAg levels significantly reduced at any time point, and a similar trend was found in patients without HBeAg seropositivity. In patients with baseline FIB4 index >1.85, HBsAg levels significantly reduced at 3, 4, and 5 years, and in patients with baseline FIB4 index <1.85, HBsAg levels significantly reduced at any time point. The estimated glomerular filtration rate significantly reduced only at 5 years. The discontinuation rate owing to the side effects of TAF was 0%. In conclusion, switching to TAF therapy in patients with CHB may be effective and safe at least up to 5 years.

Body Composition in Chronic Liver Disease.

Body composition has recently been attracting people's attention, not only from a cosmetic standpoint but also from the perspective of health and longevity. The body is classified into three components: fat, bone, and lean soft tissue, and it is common to see an increase in body fat and a decrease in total body muscle mass with aging. Aging-related loss of muscle mass and muscle function is referred to as primary sarcopenia, while sarcopenia caused by disease-specific conditions is referred to as secondary sarcopenia. On the other hand, the liver-muscle axis has been attracting attention in recent years, and it has become clear that the liver and the skeletal muscles interact with each other. In particular, patients with cirrhosis are prone to secondary sarcopenia due to protein-energy malnutrition, which is a characteristic pathophysiology of the disease, suggesting the importance of the organ-organ network. In this review, we would like to outline the latest findings in this field, with a focus on body composition in liver diseases such as liver cirrhosis, fatty liver disease, alcoholic liver disease, and hepatocellular carcinoma.

Liver Carcinogenesis Suppression in Chronic Hepatitis B in the Nucleoside Analogues Era.

There is a strong association between the distribution of Hepatitis B virus (HBV) carriers and the incidence of hepatocellular carcinoma (HCC). About 60% of HCC in Japan is caused by viral hepatitis. Ten to 15 percent of hepatitis virus-related HCCs derive from HBV. Recently, antiviral therapy against HBV has developed, and interferon therapy and nucleos(t)ide analogues (NAs) are currently the standard of care. NAs exhibit antiviral activity by inhibiting DNA polymerase and suppressing HBV replication. NAs are highly effective in suppressing HBV-DNA and improving alanine aminotransferase. The long-term treatment goal for chronic hepatitis B is HB surface antigen (HBsAg) loss. However, the number of patients who achieve HBsAg loss by NA (i.e., functional cure) is low and there have been cases of HCC incidence during (or after) NA therapy. In this article, we review the efficacy of NA therapy in suppressing HBV-derived carcinogenesis.

Insulin Resistance: A Marker for Fat-to-Lean Body Composition in Japanese Adults.

We sought to investigate the relationship between insulin resistance (IR) and body composition as assessed by bioelectrical impedance analysis in Japanese health check-up recipients (1186 men and 1441 women). IR was defined as a Homeostasis Model Assessment of IR (HOMA-IR) ≥ 2.5. In body-composition-related parameters, the fat mass index (F index) was defined as fat mass divided by the height squared (kg/m2). The fat-free mass index (FF index) was defined as fat-free mass divided by the height squared (kg/m2). The F index to FF index ratio (F-FF ratio) was defined as the F index divided by the FF index. Factors related to HOMA-IR were examined. The median HOMA-IR was 1.54 in men and 1.30 in women (p < 0.0001). The median F index was 4.9 kg/m2 in men and 6.1 kg/m2 in women (p < 0.0001). The median FF index was 18.2 kg/m2 in men and 15.1 kg/m2 in women (p < 0.0001). The median F-FF ratio was 0.272 in men and 0.405 in women (p < 0.0001). The F-FF ratio was an independent factor associated with HOMA-IR in the multivariate analysis in both genders, while the F index and FF index were not in both genders. In conclusion, fat and skeletal muscle balance can be controlled by IR in Japanese adults.

Association between the Suita Score and Body Composition in Japanese Adults: A Large Cross-Sectional Study.

The purpose of this study was to clarify the relationship between the Suita score (a prediction model for the development of cardiovascular disease) and body composition in Japanese health check-up subjects (6873 men and 8685 women). The Suita score includes 8 items (age, gender, smoking, diabetes, blood pressure, low-density lipoprotein, high-density lipoprotein, and chronic kidney disease). Factors associated with the Suita score within body composition-related parameters (body mass index (BMI), waist circumference (WC), fat mass index, fat-free mass index, fat mass to fat-free mass ratio (F-FF ratio), and water mass index) as assessed by bioelectrical impedance analysis were examined. The mean age of subjects was 54.8 years in men and 52.8 years in women (p < 0.0001). The mean BMI was 23.9 kg/m2 in men and 21.8 kg/m2 in women (p < 0.0001). Diabetes mellitus was found in 1282 subjects (18.7%) among men and 816 subjects (9.4%) among women (p < 0.0001). The mean Suita score was 42.0 in men and 29.6 in women (p < 0.0001). In multivariate analysis, WC (p < 0.0001), F-FF ratio (p < 0.0001), and water mass index (p < 0.0001) were independent factors linked to the Suita score for both genders. In conclusion, body composition can be associated with the Suita score in Japanese adults receiving health check-ups.

Hepatic Inflammatory Pseudotumor-Focusing on Its Heterogeneity.

Hepatic inflammatory pseudotumors (IPTs) are defined as benign, non-malignant, non-metastasizing tumors characterized by the presence of myofibroblastic spindle cells, hetorogenous populations of inflammatory cells, particularly plasma cells, lymphocytes and macrophages, as well as locations of fibrosis and necrosis without cellular anaplasia or atypical mitoses. Despite subsequent reports in the references, hepatic IPT remains difficult to diagnose; while posing major issues specifically for its differential diagnosis compared with that of other various benign diseases and malignant hepatic tumors. Histopathological findings are always a requisite for confirming the diagnosis, particularly given that the pathogenesis of IPT remains ambiguous to date. Hepatic IPT is a heterogeneous entity in terms of its clinical features, pathological findings, and pathogenesis. Once the diagnosis is confirmed, however, needless surgery such as wedge resection and lobectomy should be avoided. Here, we discuss the heterogeneity of hepatic IPT, its clinical features, pathological findings, and pathogenesis, and describe its differential diagnosis.

Body Composition Analysis in Patients with Metabolic Dysfunction-Associated Fatty Liver Disease.

We sought to examine body composition using bioimpedance analysis in patients with metabolic dysfunction-associated fatty liver disease (MAFLD, 2014 males and 949 females). Factors linked to the fat-free mass index (FF index) were examined using univariate and multivariate analysis. An FF index < 18 kg/m2 in males and an FF index < 15 kg/m2 in females were defined as having decreased skeletal muscle mass. The median age and body mass index (BMI) were 55 years and 25.4 kg/m2 in males, and 57 years and 25.4 kg/m2 in females, respectively. The FF index strongly correlated with muscle mass index both in males (r = 0.999) and females (r = 0.999). The prevalence of patients with an FF index < 18 kg/m2 in males and an FF index < 15 kg/m2 in females was well stratified according to age, BMI, severity of FL, and FIB4 index. In the males, in the multivariate analysis, BMI (p < 0.0001), fat mass index (p < 0.0001), and waist circumference (p = 0.0050) were found to be significant factors linked to FF index. In the females, in the multivariate analysis, BMI (p < 0.0001) and fat mass index (p < 0.0001) were found to be significant. In conclusion, fat accumulation as reflected by BMI, which is an easily available marker, could be a useful indicator for the skeletal muscle mass in MAFLD.

Real-world treatment outcome with protease inhibitor direct-acting antiviral in advanced hepatitis C cirrhosis: a REAL-C study.

INTRODUCTION: Current guidelines discourage the use of direct-acting antiviral (DAA) containing protease-inhibitor (PI) in advanced HCV cirrhosis. We aimed to compare the real-world tolerability of PI vs. non-PI DAA regimens in this population. METHODS: We identified advanced cirrhosis patients treated with DAA from the REAL-C registry. The primary outcome was significant worsening or improvement in CPT or MELD scores following DAA treatment. RESULTS: From the REAL-C registry of 15,837 patients, we included 1077 advanced HCV cirrhosis patients from 27 sites. 42% received PI-based DAA. Compared to non-PI group, the PI group was older, had higher MELD and higher percentage with kidney disease. Inverse probability of treatment weighting (IPTW; matching on age, sex, history of clinical decompensation, MELD, platelet, albumin, Asia site, Asian ethnicity, hypertension, hemoglobin, genotype, liver cancer, ribavirin) was used to balance the two groups. In the IPTW-matched cohorts, the PI and non-PI groups had similar SVR12 (92.9% vs. 90.7%, p = 0.30), similar percentages of significant worsening in CTP or MELD scores at posttreatment week 12 and 24 (23.9% vs. 13.1%, p = 0.07 and 16.5% vs. 14.6%, p = 0.77), and similar frequency of new HCC, decompensating event, and death by posttreatment week 24. In multivariable analysis, PI-based DAA was not associated with significant worsening (adjusted odds ratio = 0.82, 95% CI 0.38-1.77). CONCLUSION: Tolerability and treatment outcomes were not significantly different in advanced HCV cirrhosis treated with PI-based (vs. non-PI) DAA up to CTP-B or MELD score of 15. Safety of PI-based DAA in those with CTP-C or MELD beyond 15 awaits further data.

Accurate SARC-F Score in Patients with Liver Disease.

SARC-F is a well-accepted screening tool for sarcopenia. A SARC-F value of 1 point is reported to be more discriminating in identifying sarcopenia than 4 points (recommended cutoff point). The prognostic impact of the SARC-F score was investigated in patients with liver disease (LD, n = 269, median age = 71 years, 96 hepatocellular carcinoma (HCC) cases). Factors associated with SARC-F ≥ 4 points and SARC-F ≥ 1 point were also examined. In the multivariate analysis, age (p = 0.048), and Geriatric Nutritional Risk Index (GNRI) score (p = 0.0365) were significant factors linked to SARC-F ≥ 1 point. In our patients with LD, the SARC-F score is well correlated with the GNRI score. The 1-year cumulative overall survival ratio in patients with SARC-F ≥ 1 (n = 159) and SARC-F 0 (n = 110) was 78.3% and 90.1% (p = 0.0181). After excluding 96 HCC cases, similar tendencies were found (p = 0.0289). In the receiver operating curve (ROC) analysis based on the prognosis for the SARC-F score, the area under the ROC was 0.60. The sensitivity was 0.57, the specificity was 0.62, and the optimal cutoff point of the SARC-F score was 1. In conclusion, sarcopenia in LDs can be affected by nutritional conditions. A SARC-F score of ≥1 is more useful than a score of 4 in predicting the prognosis of patients with LD.

Drug Delivery with Hyaluronic Acid-Coated Polymeric Micelles in Liver Fibrosis Therapy.

Developing delivery vehicles that achieve drug accumulation in the liver and transferability into hepatic stellate cells (HSCs) across the liver sinusoidal endothelium is essential to establish a treatment for hepatic fibrosis. We previously developed hyaluronic acid (HA)-coated polymeric micelles that exhibited affinity to liver sinusoidal endothelial cells. HA-coated micelles possess a core-shell structure of self-assembled biodegradable poly(l-lysine)-b-poly(lactic acid) AB-diblock copolymer (PLys+-b-PLLA), and its exterior is coated with HA through polyion complex formation via electrostatic interaction between anionic HAs and cationic PLys segments. In this study, we prepared HA-coated micelles entrapping olmesartan medoxomil (OLM), an anti-fibrotic drug, and evaluated their possibility as drug delivery vehicles. HA-coated micelles exhibited specific cellular uptake into LX-2 cells (human HSC line) in vitro. In vivo imaging analysis after intravenous (i.v.) injection of HA-coated micelles into mice revealed that the micelles exhibited high accumulation in the liver. Observation of mouse liver tissue sections suggested that HA-coated micelles were distributed in liver tissue. Furthermore, i.v. injection of HA-coated micelles entrapping OLM showed a remarkable anti-fibrotic effect against the liver cirrhosis mouse model. Therefore, HA-coated micelles are promising candidates as drug delivery vehicles for the clinical management of liver fibrosis.

Combined therapeutic effect of YHO-1701 with PD-1 blockade is dependent on natural killer cell activity in syngeneic mouse models.

The signal transducer and activator of transcription 3 (STAT3) signaling pathway is a key mediator of cancer cell proliferation, survival, and invasion. We discovered YHO-1701 as a small molecule inhibitor of STAT3 dimerization and demonstrated its potent anti-tumor activity using xenograft mouse models as monotherapy and combination therapy with molecular targeted drugs. STAT3 is also associated with cancer immune tolerance; therefore, we used the female CT26 syngeneic mouse model to examine the effect of combining YHO-1701 administration with PD-1/PD-L1 blockade. Pretreatment of the mice with YHO-1701 before starting anti-PD-1 antibody administration resulted in a significant therapeutic effect. In addition, the effect of monotherapy and combination treatment with YHO-1701 was significantly abolished by depleting natural killer (NK) cell activity. YHO-1701 was also found to restore the activity of mouse NK cells under inhibitory conditions in vitro. Furthermore, this combination therapy significantly inhibited tumor growth in an immunotherapy-resistant model of murine CMS5a fibrosarcoma. These results suggest that the combination of YHO-1701 with PD-1/PD-L1 blockade might be a new candidate for cancer immunotherapy involving the enhancement of NK cell activity in the tumor microenvironment.

HB Surface Antigen Level as a Useful Predictor for the Treatment Response to Tenofovir Alafenamide in Nucleoside Analogue Naïve Chronic Hepatitis B.

AIM: To elucidate factors contributing to hepatitis B virus (HBV)-DNA clearance following tenofovir alafenamide (TAF) therapy in nucleoside analogue (NA) naïve patients with chronic hepatitis B (CHB) (n=92, 11 cirrhotic cases). PATIENTS AND METHODS: The time interval between the start of TAF therapy and first confirmed undetectable HBV-DNA after TAF therapy was calculated. Univariate and multivariate analyses of factors related to undetectable HBV-DNA after TAF therapy were performed. RESULTS: HB envelop antigen seropositivity was found in 12 patients (13.0%). The cumulative undetectable HBV-DNA rate at 1- and 2- year was 74.9% and 90.9%. In the multivariate Cox regression analysis of the undetectable HBV-DNA after TAF therapy, HBsAg level >1,000 IU/ml (p=0.0082, HBsAg level <100 IU/ml as a reference standard) was an independent predictor of the undetectable HBV-DNA after TAF therapy. CONCLUSION: Baseline higher HBsAg level can be an adverse predictor for the undetectable HBV-DNA after TAF therapy in NA naïve CHB patients.

Crystal structure of the motor domain of centromere-associated protein E in complex with a non-hydrolysable ATP analogue.

Centromere-associated protein E (CENP-E) is a kinesin motor protein essential for mitosis and a new target for anticancer agents with less side effects. To rationally design anticancer drug candidates based on structure, it is important to determine the three-dimensional structure of the CENP-E motor domain bound to its inhibitor. Here, we report the first crystal structure of the CENP-E motor domain in complex with a non-hydrolysable ATP analogue, adenylyl-imidodiphosphate (AMPPNP). Furthermore, the structure is compared with the ADP-bound form of the CENP-E motor domain as well as the AMPPNP-bound forms of other kinesins. This study indicates that helix α4 of CENP-E participates in the slow binding of CENP-E to microtubules. These results will contribute to the development of anticancer drugs targeting CENP-E.

Selectively bred rodent models for studying the etiology of type 2 diabetes: Goto-Kakizaki rats and Oikawa-Nagao mice.

Type 2 diabetes (T2D) is a polygenic disease and studies to understand the etiology of the disease have required selectively bred animal models with polygenic background. In this review, we present two models; the Goto-Kakizaki (GK) rat and the Oikawa-Nagao Diabetes-Prone (ON-DP) and Diabetes-Resistant (ON-DR) mouse. The GK rat was developed by continuous selective breeding for glucose tolerance from the outbred Wistar rat around 50 years ago. The main cause of spontaneous hyperglycemia in this model is insulin secretion deficiency from pancreatic ß-cells and mild insulin resistance in insulin target organs. A disadvantage of the GK rat is that environmental factors have not been considered in the selective breeding. Hence, the GK rat may not be suitable for elucidating predisposition to diabetes under certain environmental conditions, such as a high-fat diet. Therefore, we recently established two mouse lines with different susceptibilities to diet-induced diabetes, which are prone and resistant to the development of diabetes, designated as the ON-DP and ON-DR mouse, respectively. The two ON mouse lines were established by continuous selective breeding for inferior and superior glucose tolerance after high-fat diet feeding in hybrid mice of three inbred strains. Studies of phenotypic differences between ON-DP and ON-DR mice and their underlying molecular mechanisms will shed light on predisposing factors for the development of T2D in the modern obesogenic environment. This review summarizes the background and the phenotypic differences and similarities of GK rats and ON mice and highlights the advantages of using selectively bred rodent models in diabetes research.

Prognostic Nutritional Index Correlates with Liver Function and Prognosis in Chronic Liver Disease Patients.

The Prognostic Nutritional Index (PNI) is widely recognized as a screening tool for nutrition. We retrospectively examined the impact of PNI in patients with chronic liver disease (CLD, n = 319, median age = 71 years, 153 hepatocellular carcinoma (HCC) patients) as an observational study. Factors associated with PNI < 40 were also examined. The PNI correlated well with the albumin-bilirubin (ALBI) score and ALBI grade. The 1-year cumulative overall survival rates in patients with PNI ≥ 40 (n = 225) and PNI < 40 (n = 94) were 93.2% and 65.5%, respectively (p < 0.0001). In patients with (p < 0.0001) and without (p < 0.0001) HCC, similar tendencies were found. In the multivariate analysis, hemoglobin (p = 0.00178), the presence of HCC (p = 0.0426), and ALBI score (p < 0.0001) were independent factors linked to PNI < 40. Receiver operating characteristic (ROC) curve analysis based on survival for the PNI yielded an area under the ROC curve of 0.79, with sensitivity of 0.80, specificity of 0.70, and an optimal cutoff point of 42.35. In conclusion, PNI can be a predictor of nutritional status in CLD patients. A PNI of <40 can be useful in predicting the prognosis of patients with CLD.

Identification and Characterization of a Novel Dual Inhibitor of Indoleamine 2,3-dioxygenase 1 and Tryptophan 2,3-dioxygenase.

Kynurenine (Kyn), a metabolite of tryptophan (Trp), is a key regulator of mammal immune responses such as cancer immune tolerance. Indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are main enzymes regulating the first and rate-limiting step of the Kyn pathway. To identify new small molecule inhibitors of TDO, we selected A172 glioblastoma cell line constitutively expressed TDO. Characterization of this cell line using kinase inhibitor library resulted in identification of MEK/ERK pathway-dependent TDO expression. After knowing the properties for TDO expression, we further proceeded to screen chemical library for TDO inhibitors. We previously determined that S-benzylisothiourea derivatives are enzymatic inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) and suggested that the isothiourea moiety could be an important pharmacophore for binding to heme. Based on this premise, we screened an in-house library composed of various isothiourea derivatives and identified a bisisothiourea derivative, PVZB3001, as an inhibitor of TDO. Interestingly, PVZB3001 also inhibited the enzymatic activity of IDO1 in both cell-based and cell-free assays but did not inhibit other heme enzymes. Molecular docking studies suggested the importance of isothiourea moieties at the ortho position of the phenyl ring for the inhibition of catalytic activity. PVZB3001 showed competitive inhibition against TDO, and this was supported by the docking simulation. PVZB3001 recovered natural killer (NK) cell viability and functions by inhibiting Kyn accumulation in conditioned medium of both IDO1- and TDO-expressing cells. Furthermore, oral administration of IDO1-overexpressing tumor-bearing mice with PVZB3001 significantly inhibited tumor growth. Thus, we identified a novel selective dual inhibitor of IDO1 and TDO using the Kyn production assay with a glioblastoma cell line. This inhibitor could be a useful pharmacological tool for modulating the Kyn pathway in a variety of experimental systems.

The Significance of Zinc in Patients with Chronic Liver Disease.

Zinc is an essential trace element for the maintenance of life because it acts as a center of activity or cofactor for hundreds of enzymes. Zinc deficiency causes a variety of symptoms, including anemia, dermatitis, stomatitis, alopecia, bedsores, decreased appetite, impaired growth, gonadal dysfunction, susceptibility to infection, and taste disorders, etc. In March 2017, zinc acetate hydrate, which had been approved for Wilson disease in Japan, received an additional indication for hypozincemia. Hypozincemia is frequently observed in patients with chronic liver disease (CLD), especially cirrhosis, and it has recently been shown that hypozincemia is closely related to the development of liver fibrosis and increased risk of liver carcinogenesis, in addition to the appearance of various subjective symptoms. Moreover, hypozincemia in CLD may be associated with sarcopenia (i.e., decrease in muscle strength and muscle mass) and frailty (i.e., vulnerability), which receive much attention these days. It is assumed that treatment with zinc acetate hydrate will become widespread in patients with CLD. Zinc acetate hydrate may also have potential for improving sarcopenia in patients with CLD. This review primarily outlines the significance of zinc in patients with CLD.

The Impacts of Cholesterol, Oxysterols, and Cholesterol Lowering Dietary Compounds on the Immune System.

Cholesterol and its oxidized forms, oxysterols, are ingested from foods and are synthesized de novo. Cholesterol and oxysterols influence molecular and cellular events and subsequent biological responses of immune cells. The amount of dietary cholesterol influence on the levels of LDL cholesterol and blood oxysterols plays a significant role in the induction of pro-inflammatory state in immune cells, leading to inflammatory disorders, including cardiovascular disease. Cholesterol and oxysterols synthesized de novo in immune cells and stroma cells are involved in immune homeostasis, which may also be influenced by an excess intake of dietary cholesterol. Dietary compounds such as ß-glucan, plant sterols/stanols, omega-3 lipids, polyphenols, and soy proteins, could lower blood cholesterol levels by interfering with cholesterol absorption and metabolism. Such dietary compounds also have potential to exert immune modulation through diverse mechanisms. This review addresses current knowledge about the impact of dietary-derived and de novo synthesized cholesterol and oxysterols on the immune system. Possible immunomodulatory mechanisms elicited by cholesterol-lowering dietary compounds are also discussed.

CD34+CD10+CD19- Cells in Patients with Unhealthy Alcohol Use Stimulate the M2b Monocyte Polarization.

M2b monocytes commonly isolated from patients with unhealthy alcohol use (Alc) have been described as cells that make the host susceptible to opportunistic infections. CD34+CD10+CD19- cells are multilineage progenitors of CD19+ cells, and we show that the effect of these cells from the peripheral blood on M2b monocyte polarization differed between healthy donors and Alc in this study. In healthy donors, these cells consistently differentiated into high-mobility group box-1 (HMGB1)-nonproducing cells (CD19+ cells) in response to retinoic acid (RA). However, owing to the lack of expression of RA receptor (RAR), these cells from Alc failed to differentiate into CD19+ cells under the same RA stimulation. Conditioned medium (CM) of these cells from Alc induced the polarization of M2b monocytes, which increases the susceptibility of hosts to opportunistic infections in Alc. When the alcoholic individuals were subjected to 2 weeks of abstinence from alcohol, these cells from Alc recovered their RAR expression and differentiated into CD19+ cells. Moreover, the CM of these cells from Alc after abstinence lost its ability to induce M2b monocyte polarization. These results indicate that these cells from Alc have different properties from those of healthy donors. In Alc, these cells without RAR stimulate M2b monocyte polarization through the production of HMGB1.

Effect of an Electronic Alert System on Hepatitis B Virus Reactivation in Patients Receiving Immunosuppressive Drug Therapy.

Hepatitis B virus (HBV) reactivation (HBVr) can occur in patients receiving immunosuppressive drug therapies, causing significant morbidity and mortality. Although the guidelines for HBVr have been proposed by several academic societies, some providers do not follow them, resulting in HBVr and death. As HBV-DNA levels increase before liver enzyme levels do, we previously constructed an electronic alert system that recommends the measurement of HBV-DNA. Here, we investigated whether this alert system improves the HBV-DNA measurement rate and elicits responses according to guidelines. A total of 5329 patients were divided into two groups, before and after the introduction of the alert system, and the HBV-DNA measurement rates in both groups were compared. Because of the introduction of the alert system, the HBV-DNA measurement rate among HBsAg-negative patients with anti-HBs and/or anti-HBc before immunosuppressive drug therapy improved significantly. The HBV-DNA monitoring rate within 3 months also improved significantly (p = 0.0034) in HBV-remission phase patients. HBVr was detected immediately, and the affected patients were treated with nucleotide analogs before severe hepatitis onset. The introduction of the alert system for HBVr improved the HBV-DNA measurement rates in patients receiving immunosuppressive drug therapy, leading to the rapid treatment of patients with HBVr.