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Liver transplantation is often the only lifesaving option for acute liver failure (ALF); however, the predictors of short-term mortality (death within one year) after living donor liver transplantation (LDLT) for ALF have yet to be defined. We retrospectively collected patients ≥18 years old who underwent LDLT for ALF between 2010 and 2020 at 35 centers in Asia. Univariate and multivariate logistic regression analyses were conducted to identify the clinical variables related to short-term mortality and establish a novel scoring system. The Kaplan-Meier method was performed to explore the association between the score and overall survival. Of the 339 recipients, 46 (13.6%) died within 1 year after LDLT. Multivariate analyses revealed 4 independent risk factors for death: use of vasopressors or mechanical ventilation, the higher model for end-stage liver disease score, and a lower graft-to-recipient weight ratio. The internally validated c-statistic of the short-term mortality after transplant (SMT) score derived from these 4 variables was 0.80 (95% confidence interval: 0.74-0.87). The SMT score successfully stratified recipients into low-, intermediate-, and high-risk groups with 1-year overall survival rates of 96%, 80%, and 50%, respectively. In conclusion, our novel SMT score based on 4 predictors will guide ALF recipient and living donor selection.
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AIM: To clarify the efficacy of atezolizumab (ATZ) plus bevacizumab (BEV) as the second-line therapy for patients with unresectable hepatocellular carcinoma (HCC). METHODS: The subjects were 82 patients with HCC receiving ATZ/BEV, including 33 patients with previous therapies with molecular-targeted agents (MTA). Therapeutic efficacy was evaluated using contrast-enhanced CT according to the mRECIST. RESULTS: The Child-Pugh scores were 5, 6,7 and 8 in 40, 35, 5 and 2 patients, respectively, and the extents of HCC progression were BCLC stage A, B and C in 3, 31 and 48 patients, respectively. Early therapeutic efficacy was evaluated in 67 patients, and percentages of patients achieving CR/PR/SD/PD until 12 weeks were 3.0%/29.9%/49.3%/17.9%, respectively, indicating ORR of 32.8% and DCR of 82.1%, The ORR was higher in MTA-naïve patients (40.5%) than in those after discontinuation of lenvatinib due to PD (7.7%, P = 0.0410), while the DCR was equivalent between both patients (83.3% vs 80.0%, P = 0.1184), and the multivariate analysis revealed previous MTA therapies with lenvatinib alone as a factor to deteriorate the ORR (HR of 4.846 (P = 0.0619)). The OS rates at 24 and 48 weeks were 86% and 72%, respectively, and the rates did not differ between MTA-naïve and MTA-experienced patients. Multivariate analyses revealed that achievement of CR, PR or SD and peripheral neutrophil/lymphocyte ratio were associated with a favorable outcome (HR of 0.124, P<0.0001 and 0.351, P = 0.0303). CONCLUSIONS: ATZ/BEV merits consideration even for MTA-experienced patients, since the OS was equivalent to those in MTA-naïve patients despite of an unfavorable early therapeutic efficacy.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Masculino , Femenino , Anciano , Persona de Mediana Edad , Bevacizumab/uso terapéutico , Bevacizumab/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adulto , Anciano de 80 o más Años , Resultado del Tratamiento , Estudios RetrospectivosRESUMEN
End-stage liver disease (ESLD) is a life-threatening clinical syndrome and when complicated with infection the mortality is markedly increased. In patients with ESLD, bacterial or fungal infection can induce or aggravate the occurrence or progression of liver decompensation. Consequently, infections are among the most common complications of disease deterioration. There is an overwhelming need for standardized protocols for early diagnosis and appropriate management for patients with ESLD complicated by infections. Asia Pacific region has the largest number of ESLD patients, due to hepatitis B and the growing population of alcohol and NAFLD. Concomitant infections not only add to organ failure and high mortality but also to financial and healthcare burdens. This consensus document assembled up-to-date knowledge and experience from colleagues across the Asia-Pacific region, providing data on the principles as well as evidence-based current working protocols and practices for the diagnosis and treatment of patients with ESLD complicated by infections.
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Consenso , Enfermedad Hepática en Estado Terminal , Humanos , Infecciones Bacterianas/diagnóstico , Infecciones Bacterianas/complicaciones , Enfermedad Hepática en Estado Terminal/complicaciones , Enfermedad Hepática en Estado Terminal/diagnóstico , Micosis/diagnóstico , Micosis/complicacionesRESUMEN
AIM: Patients with chronic hepatitis B virus (HBV) infection experiencing viral breakthrough (BTH) or partial response (PR) during lamivudine (LAM) or entecavir hydrate (ETV) administration often took ETV plus tenofovir alafenamide fumarate (TAF) due to the emergence of a drug-resistance mutation. However, in patients lacking drug-resistance mutation against TAF, sufficient antiviral effects may be achievable with TAF monotherapy. We assessed the drug-resistance profile through nucleotide sequences of HBV pregenome RNA, and subsequently changed to TAF monotherapy from ETV plus TAF. METHODS: This prospective study included 25 patients with serum HBV-DNA below 20 IU/mL under ETV plus TAF administration. Pregenome RNA nucleotide sequences of HBV in the sera were analyzed using direct sequencing and deep sequencing. ETV was discontinued in patients without rtA194T and rtS106C + rtH126Y + rtD134E + rtL269I quadruple mutations in direct sequencing. RESULTS: LAM-PR, LAM-BTH, ETV-PR, and ETV-BTH were observed in 1, 16, 7, and 1 patient(s), respectively. Pregenome RNA nucleotide sequences were analyzable in 20 patients. Among the 12 patients classified as LAM-BTH, six patients showed rtL180M + rtM204V/I in direct sequencing, and one patient showed minor clones containing rtL180M + rtM204V + A194T in deep sequencing at a frequency of 0.3%. In the six patients classified as ETV-PR, one patient harbored rtM204I. No clones showing rtS106C + rtH126Y + rtD134E + rtL269I quadruple mutation were detected in deep sequencing. Subsequently, ETV was discontinued, and serum HBV-DNA remained undetectable up to 48 weeks in all patients. CONCLUSION: Patients receiving ETV plus TAF due to partial response or BTH during initial LAM or ETV administration were able to safely transition to TAF monotherapy based on nucleotide sequences of HBV pregenome RNA in the sera.
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AIM: There are few data regarding the safety and effectiveness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with intractable hepatobiliary diseases. We conducted a multicenter, questionnaire-based, cross-sectional study to determine the safety and effectiveness of the SARS-CoV-2 vaccines in Japanese patients with intractable hepatobiliary disease. METHODS: Patients aged ≥18 years with autoimmune hepatitis (AIH), primary biliary cholangitis, primary sclerosing cholangitis, Budd-Chiari syndrome, idiopathic portal hypertension, and extrahepatic portal vein obstruction at each center were consecutively invited to join the study. Participants were asked to complete a questionnaire regarding their characteristics, vaccination status, post-vaccination adverse effects, and SARS-CoV-2 infection. Additionally, liver disease status, treatment regimens, and liver function test values pre- and post-vaccination were collected. RESULTS: The survey was conducted from September 2021 to May 2022, and 528 patients (220 AIH, 251 primary biliary cholangitis, 6 AIH- primary biliary cholangitis/primary sclerosing cholangitis overlap, 39 primary sclerosing cholangitis, 4 Budd-Chiari syndrome, 5 idiopathic portal hypertension, and 3 extrahepatic portal vein obstruction) participated in the study. Post-vaccination adverse effects were comparable to those observed in the general population. Post-vaccination liver injuries classified as grade 1 or higher were observed in 83 cases (16%), whereas grades 2 and 3 were observed in only six cases (1.1%); AIH-like liver injury requiring treatment was not observed. Overall, 12 patients (2.3%) were infected with SARS-CoV-2, and only one patient was infected 6 months after the second vaccination. CONCLUSION: SARS-CoV-2 vaccines demonstrated satisfactory safety and effectiveness in Japanese patients with intractable hepatobiliary diseases.
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AIM: To determine the outcomes concerning portal venous blood flow and portosystemic shunts in patients with decompensated cirrhosis due to hepatitis C virus (HCV) infection who achieved sustained viral response (SVR) following antiviral therapy. METHODS: Portal hypertension-related events and liver function were evaluated in 24 patients achieving SVR following sofosbuvir plus velpatasvir therapy. RESULTS: Serum albumin level (median; g/dL) increased from 2.9 at baseline to 3.5 at 12 weeks after the end of treatment (EOT) (p = 0.005), while liver volumes (cm3 ) decreased from 1260 to 1150 (p = 0.0002). Portal hypertension-related events developed in 10 patients (41.7%), and the cumulative occurrence rates after the EOT were 29.2%, 33.3%, and 46.1% at 24, 48, and 96 weeks, respectively. Multivariate logistic regression analysis revealed that the maximal diameter of the shunts (p = 0.0235) was associated with the development of the events, with a cut-off value of 8.3 mm (p = 0.0105). Meanwhile, multiple linear regression analysis revealed that portal venous blood flow, liver volume, serum albumin, and bilirubin levels at baseline were associated with serum albumin levels at 12 weeks after EOT (p = 0.0019, p = 0.0154, p = 0.0010, and p = 0.0350, respectively). CONCLUSION: In patients with decompensated cirrhosis due to HCV infection, the baseline portal venous blood flow and liver volume and function were predictive of liver function following SVR, while the maximal diameter of portosystemic shunts predicted the occurrence of portal hypertension-related events.
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Background and Aims: Acute liver injury (ALI) due to autoimmune hepatitis (AIH) can be treated by immunosuppression. In contrast, idiosyncratic drug-induced liver injury (DILI) had a poor prognosis. DILI thus needs to be distinguished from non-DILI. Methods: Twenty-nine patients with DILI and 77 with non-DILI (42 of AIH and 35 with undetermined cause) diagnosed during 2005-2017 comprised the derivation cohort. 110 patients with ALI due to either AIH, DILI, or obscure causes at 6 liver centers during 2010-2015 were the validation cohort. Revised international AIH group scores (IAIHGs) and the Roussel-Uclaf Causality Assessment Method (RUCAM) were modified to calculate results using medical interviews and laboratory data without chronological changes. Diagnostic accuracy for the distinction of DILI and non-DILI was evaluated by receiver operating characteristic analysis and results were expressed as the area under the curve (AUC). This study received institutional institutional review board approval (MH2020-205). Results: The AUCs of modified IAIHGs and RUCAM scores for the diagnosis of DILI were 0.96 and 1.00 when cut-off values were set at 3 for the modified RUCAM and 5 for the modified IAIHGs in the derivation cohort. In the validation cohort, the AUCs of modified IAIHGs and RUCAM scores for the diagnosis of DILI were 0.95 and 0.97, respectively. The accuracy of the combination of the modified scores was 81% (89/110). Conclusion: Modified diagnostic scores based on detailed medical interviews and routine laboratory data can distinguish DILI from non-DILI in patients with ALI.
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The Intractable Hepato-Biliary Disease Study Group of Japan, sponsored by the Ministry of Health, Labor and Wealth, proposed in 2018 that patients with cirrhosis and a Child-Pugh score of 5-9 should be diagnosed as having acute-on-chronic liver failure (ACLF) when a deterioration of liver function ("serum bilirubin level of 5.0 mg/dl or more" and "prothrombin time value of 40% or less of the standardized values and/or international normalization rates of 1.5 or more") caused by severe liver damage develops within 28 days after an acute insult, including alcohol abuse, bacterial infection, gastrointestinal bleeding, and the exacerbation of underlying liver diseases. Disease severity can be classified into 4 grades depending on the extent of the deterioration in organ functions, including liver, kidney, cerebral, blood coagulation, circulatory and respiratory functions. The Study Group has since performed an annual nationwide survey of patients with ACLF diagnosed according to the proposed diagnostic criteria as well as those with disease conditions related to ACLF. A total of 501 patients, including 183 patients diagnosed as having ACLF, seen between 2017 and 2019 were enrolled, and univariate and multivariate analyses revealed that the proposed diagnostic criteria were useful for identifying cirrhotic patients with an unfavorable outcome following an acute insult. Consequently, the Study Group determined that the proposed diagnostic criteria should be used in both clinical practice and clinical research as formal diagnostic criteria.
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We herein report two patients with hepatocellular carcinoma (HCC) who exhibited intraabdominal bleeding caused by tumor rupture soon after lenvatinib initiation. A hypervascular nodule was present in the lateral segment manifesting extrahepatic protrusion in an 81-year-old-man and in the caudate lobe, which was completely occupied by the tumor, in an 83-year-old-man. Both patients were given lenvatinib, and epigastralgia occurred suddenly three and five days later. Computed tomography revealed high-attenuation areas suggesting bleeding around the left and caudate lobes. Considering the strong antiangiogenic effects by lenvatinib, transcatheter arterial embolization should be performed before lenvatinib initiation in patients with subcapsular HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Quinolinas , Anciano de 80 o más Años , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Hemoperitoneo , Humanos , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Compuestos de Fenilurea/efectos adversos , Quinolinas/efectos adversos , RoturaRESUMEN
AIM: To establish a therapeutic strategy for cirrhosis patients with gastric variceal bleeding. METHODS: The outcomes of 137 patients with bleeding gastric varices were evaluated. RESULTS: The bleeding source was gastroesophageal varices (GOV) in 86 patients, and gastric fundal varices (FV) in 51 patients. The Child-Turcotte-Pugh classes were A, B, and C in 26, 79, and 32 patients, respectively; 34 patients (24.8%) had hepatocellular carcinoma (HCC), of which 11 also had complicating portal venous tumor thrombosis (PVTT). Patients with GOV were treated by endoscopic variceal ligation or endoscopic injection sclerotherapy (EIS) with ethanolamine oleate, while those with FV were treated by EIS with cyanoacrylate; 29 patients with FV also underwent additional balloon-occluded retrograde transvenous obliteration (BRTO). Hemostasis was successfully achieved in 136 patients (99.3%), and the cumulative 1-year, 3-year, and 5-year rebleeding rates were 18.1%, 30.8%, and 30.8%, respectively, in the patients with GOV, and 2.2%, 12.5% and 12.5%, respectively, in the patients with FV. The overall 1-year, 3-year, and 5-year survival rates were 79.7%, 71.5% and 64.4%, respectively, in the patients with GOV, and 91.0%, 76.9% and 59.5%, respectively, in the patients with FV. Multivariable analysis identified PVTT and alcoholic cirrhosis as a significant risk factor associated with rebleeding, model for end-stage liver disease (MELD) score and PVTT as significant factors associated with survival. CONCLUSIONS: Endoscopic therapies with or without BRTO appeared to be useful therapeutic strategies to prevent rebleeding in patients with gastric variceal bleeding, and favorable outcomes were obtained, except in patients with underlying HCC associated with PVTT and/or severe liver damage.
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Oclusión con Balón , Carcinoma Hepatocelular , Enfermedad Hepática en Estado Terminal , Várices Esofágicas y Gástricas , Neoplasias Hepáticas , Várices , Trombosis de la Vena , Oclusión con Balón/efectos adversos , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/terapia , Enfermedad Hepática en Estado Terminal/complicaciones , Várices Esofágicas y Gástricas/complicaciones , Várices Esofágicas y Gástricas/terapia , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/terapia , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/terapia , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/terapia , Recurrencia Local de Neoplasia/terapia , Recurrencia , Escleroterapia , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Várices/terapia , Trombosis de la Vena/etiologíaRESUMEN
BACKGROUND: The Japanese guidelines for the treatment of cirrhosis suggest zinc supplementation to prevent hepatic encephalopathy in patients with cirrhosis and zinc deficiency, although the factors that are associated with therapeutic efficacy remain unknown. METHOD: A total of 159 patients with chronic liver diseases but without previous zinc supplementation were analyzed. Factors associated with serum zinc levels as well as the therapeutic efficacy of zinc supplementation were evaluated. RESULT: Serum zinc levels decreased with the progression of liver diseases. A multiple linear regression analysis revealed that the serum levels of albumin and cholinesterase and the daily furosemide dose were independently associated with the serum zinc levels. The optimal furosemide cut-off dosage for patients with zinc deficiency (<60 µg/dl) was 5 mg/day. Among 34 patients receiving zinc acetate hydrate, overt hepatic encephalopathy occurred in 12 patients (35.4%). A multivariate analysis identified a minimal serum zinc level of 50 µg/dl after more than 12 weeks of zinc supplementation as a factor associated with overt encephalopathy development, while furosemide use was not associated. The Child-Pugh score at baseline was the only factor associated with the maintenance of sufficient serum zinc levels. CONCLUSION: Although the furosemide dose was negatively correlated with the serum zinc level in patients with chronic liver diseases, furosemide use was not associated with the occurrence of overt encephalopathy in those receiving zinc supplementation. Serum zinc levels of ≥50 µg/dl were required to prevent overt encephalopathy development during zinc supplementation in both patients with and those without furosemide administration.
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BACKGROUND: To evaluate the long-term efficacy of switching of the nucleos(t)ide analog used for treatment from entecavir (ETV) to tenofovir alafenamide fumarate (TAF) in patients with chronic HBV infection. METHODS: A total of 103 patients with serum HBsAg levels of ≥100 IU/mL who had received ETV were enrolled. The nucleos(t)ide analog used for the treatment was switched from ETV to TAF, and the changes in serum HBsAg levels during the 144-week period before and after the drug switching were compared in 74 patients who had received ETV at least for 192 weeks. RESULTS: Significant decreases of serum HBsAg levels were observed during both the ETV and the TAF administration period, although the degree of reduction was greater during the latter period than during the former period (P<0.001). Significant decreases of serum HBsAg levels were seen in both patients with genotype B HBV infection and genotype C HBV infection, irrespective of the serum HBsAg and HBcrAg levels at the time of the drug switching. CONCLUSION: Switching of the nucleos(t)ide analog used for treatment from ETV to TAF merits consideration in patients with chronic HBV infection, since the extent of reduction of the serum HBsAg level was greater during the TAF treatment period than during the ETV treatment period.
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Alanina/uso terapéutico , Sustitución de Medicamentos/métodos , Fumaratos/uso terapéutico , Guanina/análogos & derivados , Antígenos de Superficie de la Hepatitis B/sangre , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/sangre , Hepatitis B Crónica/tratamiento farmacológico , Nucleósidos/uso terapéutico , Tenofovir/análogos & derivados , Anciano , Antivirales/uso terapéutico , Femenino , Estudios de Seguimiento , Genotipo , Guanina/uso terapéutico , Virus de la Hepatitis B/genética , Hepatitis B Crónica/virología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tenofovir/uso terapéutico , Resultado del TratamientoAsunto(s)
Insuficiencia Hepática Crónica Agudizada , Carcinoma Hepatocelular , Hepatopatías Alcohólicas , Neoplasias Hepáticas , Insuficiencia Hepática Crónica Agudizada/epidemiología , Insuficiencia Hepática Crónica Agudizada/etiología , Humanos , Japón/epidemiología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/epidemiología , Cirrosis Hepática Alcohólica/complicaciones , Cirrosis Hepática Alcohólica/epidemiología , Hepatopatías Alcohólicas/complicaciones , Hepatopatías Alcohólicas/epidemiologíaRESUMEN
BACKGROUND: The significance of the 2018 Japanese diagnostic criteria for acute-on-chronic liver failure (ACLF) has not yet been evaluated. METHODS: A nationwide survey was performed for patients with ACLF occurring between 2017 and 2019. Cirrhotic patients with a Child-Pugh score of 5-9 were diagnosed as having ACLF when liver failure (serum bilirubin level of ≥ 5.0 mg/dL and a prothrombin time international normalization rate [INR] of ≥ 1.5) occurred within 28 days after an acute insult. Patients who fulfilled either criterion (total serum bilirubin or INR) and/or those with indeterminate Child-Pugh scores at baseline were also enrolled. RESULTS: Among the 501 enrolled patients, 183 patients (37%) were diagnosed as having ACLF. The etiologies of the cirrhosis and acute insults were alcohol intake/abuse in 114 (62%) and 75 (41%) patients, respectively. Sixty-eight patients (37%) were also diagnosed as having severe alcoholic hepatitis. The survival rate without liver transplantation was 48% among the ACLF patients and 71% in the remaining patients (P < 0.01). A multivariate analysis revealed that the disease condition was significantly associated with mortality, with an odds ratio of 2.025 in ACLF patients relative to the remaining patients (P < 0.01), and patient age and the number of organs with functional failure were also associated with mortality among the ACLF patients. CONCLUSION: The proposed diagnostic criteria for ACLF were useful for identifying cirrhotic patients with an unfavorable outcome following acute insults. A therapeutic strategy for patients with severe alcoholic hepatitis should be established, since such patients accounted for the majority of ACLF patients.
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Insuficiencia Hepática Crónica Agudizada , Insuficiencia Hepática Crónica Agudizada/diagnóstico , Insuficiencia Hepática Crónica Agudizada/epidemiología , Insuficiencia Hepática Crónica Agudizada/etiología , Niño , Humanos , Japón/epidemiología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/epidemiología , Oportunidad Relativa , PronósticoRESUMEN
BACKGROUND AND AIM: In Japan, corticosteroids have been commonly used as a part of multidisciplinary therapy for patients with acute liver failure and late-onset hepatic failure. However, there is controversy regarding the development of infections and other complications. In this study, the influence of corticosteroids on patient outcomes after liver transplantation was investigated. METHODS: This study included 167 patients with acute liver failure and late-onset hepatic failure who underwent liver transplantation between 2010 and 2015. The effects of pretransplant corticosteroid therapy on patient outcomes were evaluated using a database constructed by the subcommittee for fulminant hepatitis in the Intractable Hepato-Biliary Diseases Study Group of Japan. RESULTS: The subacute type and the median total bilirubin levels were higher in those receiving corticosteroids than in those not receiving corticosteroids. Although infections tended to be higher in patients receiving corticosteroids, pretransplant corticosteroid administration did not affect the survival rates. The duration from corticosteroid initiation to liver transplantation was longer in patients who developed infections. The survival rates, however, did not differ between patients with and without infections. CONCLUSIONS: Corticosteroids were administered to patients with poor prognoses. Otherwise, the overall outcome in those administered corticosteroids was not significantly different from that in those administered without corticosteroids. Although infectious complications tended to occur, they were generally controllable and nonfatal. Pretransplant corticosteroid therapy may be permissible, with regarding for infections and performed within the minimum duration.
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AIM: To optimize the therapeutic strategy for patients with decompensated cirrhosis manifesting hepatic ascites and/or edema, factors affecting the outcome of patients receiving tolvaptan were evaluated. METHODS: The subjects were 165 patients receiving tolvaptan including 116 patients (70%) also treated with furosemide. The therapeutic efficacy of tolvaptan was defined as "effective" when a body weight reduction of 1.5 kg or more was obtained within 1 week. The long-term outcome was defined as "favorable" when the ascites-related events-free duration was prolonged following tolvaptan treatment, compared with that before treatment, or ascites-related events were absent for at least 120 days during treatment based on the hazard function analysis. RESULTS: Tolvaptan was effective in 115 patients (70%). Among them, the long-term outcome was evaluated in 99 patients and was favorable in 70 patients (71%). A multivariate analysis revealed that the serum blood urea nitrogen levels at baseline (odds ratio 0.960 per +1 mg/dL, P = 0.021) and the type of tolvaptan initiation (planned vs. emergent; 3.695, P < 0.001) were associated with therapeutic efficacy, while the furosemide dose (0.280 per +20 mg/day, P = 0.014) and previous ascites-related events (0.074, P < 0.001) were associated with the long-term outcome. Receiver operating curve analyses identified the optimal cut-off values for the furosemide dose as 15 mg/day (P < 0.001). Furthermore, the cumulative survival rates in patients receiving furosemide at 15 mg/day or less were significantly higher than those in the remaining patients (P = 0.048). CONCLUSION: Furosemide given at baseline contributed to an unfavorable outcome in patients receiving tolvaptan; consequently, tolvaptan should be given before increasing the furosemide dose.
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AIM: To optimize the therapeutic strategy for cirrhotic patients manifesting hepatic encephalopathy, factors affecting the outcome of patients receiving rifaximin were evaluated. METHODS: The subjects were 95 patients receiving rifaximin. Serum ammonia levels were measured serially during rifaximin treatment. Factors associated with long-term outcomes and cumulative survival rates were evaluated. RESULTS: Serum ammonia levels were decreased at 4 weeks after rifaximin treatment compared to the levels at baseline even in patients receiving rifaximin as an add-on therapy with lactitol hydrate (P < 0.001) and reduction values were negatively correlated with the maximal diameter of portosystemic shunts (r = -0.275, P = 0.009). Overt encephalopathy occurred in 37 patients (38.9%) during rifaximin treatment, and the hazard function analysis identified 90 days as a high-risk term for developing the first-time overt encephalopathy. Thus, the long-term outcome was judged as favorable in 77 patients (81.1%) in whom overt encephalopathy was absent for at least 90 days during rifaximin initiation. A multivariate analysis revealed that furosemide, especially at daily doses of ≥20 mg both at baseline and during rifaximin treatment, was a significant factor associated with unfavorable outcome (P = 0.009 and P = 0.022, respectively) as well as occurrence and recurrence of overt encephalopathy (P = 0.012). Moreover, furosemide treatment significantly deteriorated the cumulative survival rate of patients receiving rifaximin (P = 0.026). CONCLUSION: Furosemide contributed to the deteriorated outcome of patients receiving rifaximin. Consequently, rifaximin should be given before increasing the furosemide dose, and the furosemide dose should not be increased during rifaximin treatment.
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BACKGROUND & AIMS: We aimed to clarify the features of resistance-associated substitutions (RASs) after failure of multiple interferon (IFN)-free regimens in HCV genotype 1b infections. METHODS: A total of 1,193 patients with HCV for whom direct-acting antiviral (DAA) treatment had failed were enrolled from 67 institutions in Japan. The RASs in non-structural protein (NS)3, NS5A, and NS5B were determined by population sequencing. RESULTS: Failure of 1, 2, and 3 regimens was observed in 1,101; 80; and 12 patients, respectively. Among patients with failure of 1 regimen, Y56H and D168V in NS3 were more frequently detected after failure of paritaprevir, whereas D168E was more frequently detected after failure of regimens including asunaprevir. R30H and L31-RAS in NS5A were frequently detected after failure of regimens including daclatasvir. The prevalence of Y93-RAS was high irrespective of the regimen. S282T RAS in NS5B was detected in 3.9% of ledipasvir/sofosbuvir failures. The prevalence of D168-RAS increased significantly according to the number of failed regimens (p <0.01), which was similar to that seen with L31-RAS and Y93-RAS. The prevalence of patients with RASs in either NS3 or NS5A, or in both, increased significantly with increasing numbers of failed regimens. The P32del, which is unique to patients for whom DAA had failed, was linked to the absence of Y93H, the presence of L31F, and previous exposure to IFN plus protease inhibitor regimens. CONCLUSIONS: Failure of multiple DAA regimens can lead to the generation of multiple RASs in the NS3 and NS5A regions of the HCV 1b genome. These mutations contribute to viral resistance to multiple treatment regimens and, therefore, should be considered during decision making for treatment of chronic HCV. LAY SUMMARY: Resistance-associated substitutions (RAS) in the genome of the hepatitis C virus are 1 of the major causes for failed treatment. We investigated RASs after failure of various treatments for chronic hepatitis C, and found that more complicated RASs accumulated in the viral genome with successive failed treatments. The highly resistant P32del RAS at NS5A region was uniquely found in patients for whom DAA treatments had failed, and was linked to the presence and absence of specific RASs.