Nucleos(t)ide analogues (NUCs) and interferon have been used for several decades to treat chronic hepatitis B; however, the therapeutic response remains unsatisfactory. Although NUC therapy exhibits potent on-treatment viral suppression, frequent off-therapy virological relapses suggest an indefinite treatment course. Interferon modulates the innate and adaptive antiviral immune responses and thus increases the chance of viral eradication. Interferon therapy has the advantage of a finite duration, absence of drug resistance, and durable posttreatment responses. Therefore, the combination of NUCs and interferon can theoretically facilitate a synergistic therapeutic effect. This paper summarizes the current strategies of various combination therapies into three categories: the simultaneous “dual” strategy, sequential combination “add-on” strategy, and “switch” strategy. Generally, dual therapy exhibits greater on-treatment and off-therapy viral suppression and lower drug resistance compared with NUC monotherapy. Compared with interferon monotherapy, dual therapy has greater on-treatment viral suppression but shows no difference in off-therapy sustained virological responses. Specific add-on or switch strategies provide promising on-treatment efficacy in select patients. Pretreatment or on-treatment quantitative hepatitis B surface antigen and e antigen are predictive for the treatment efficacy of combination therapy. The optimal schedule of combination regimens and individualized therapy remain to be comprehensively evaluated.
Appointments and Schedules ; Drug Resistance ; Hepatitis B Surface Antigens ; Hepatitis B, Chronic* ; Hepatitis, Chronic* ; Humans ; Interferons ; Recurrence ; Treatment Outcome

Nucleos(t)ide analogues (NUCs) and interferon have been used for several decades to treat chronic hepatitis B; however, the therapeutic response remains unsatisfactory. Although NUC therapy exhibits potent on-treatment viral suppression, frequent off-therapy virological relapses suggest an indefinite treatment course. Interferon modulates the innate and adaptive antiviral immune responses and thus increases the chance of viral eradication. Interferon therapy has the advantage of a finite duration, absence of drug resistance, and durable posttreatment responses. Therefore, the combination of NUCs and interferon can theoretically facilitate a synergistic therapeutic effect. This paper summarizes the current strategies of various combination therapies into three categories: the simultaneous “dual” strategy, sequential combination “add-on” strategy, and “switch” strategy. Generally, dual therapy exhibits greater on-treatment and off-therapy viral suppression and lower drug resistance compared with NUC monotherapy. Compared with interferon monotherapy, dual therapy has greater on-treatment viral suppression but shows no difference in off-therapy sustained virological responses. Specific add-on or switch strategies provide promising on-treatment efficacy in select patients. Pretreatment or on-treatment quantitative hepatitis B surface antigen and e antigen are predictive for the treatment efficacy of combination therapy. The optimal schedule of combination regimens and individualized therapy remain to be comprehensively evaluated.
Appointments and Schedules ; Drug Resistance ; Hepatitis B Surface Antigens ; Hepatitis B, Chronic* ; Hepatitis, Chronic* ; Humans ; Interferons ; Recurrence ; Treatment Outcome

The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) has increased among the general population and chronic hepatitis B (CHB) patients worldwide. Although fatty liver disease is a well-known risk factor for adverse liver outcomes like cirrhosis and hepatocellular carcinoma, its interactions with the hepatitis B virus (HBV) and clinical impacts seem complex. The presence of hepatic steatosis may suppress HBV viral activity, potentially leading to attenuated liver injury. In contrast, the associated co-morbidities like diabetes mellitus or obesity may increase the risk of developing adverse liver outcomes. These findings implicate that components of MAFLD may have diverse effects on the clinical manifestations of CHB. To this end, a clinical strategy is proposed for managing patients with concurrent CHB and MAFLD. This review article discusses the updated evidence regarding disease prevalence, interactions between steatosis and HBV, clinical impacts, and management strategies, aiming at optimizing holistic health care in the CHB population.

Hepatocellular carcinoma (HCC) is the fourth most common cancer and the second leading cause of cancer-related death in Taiwan. The Taiwan Liver Cancer Association and the Gastroenterological Society of Taiwan developed and updated the guidelines for HCC management in 2020. In clinical practice, we follow these guidelines and the reimbursement policy of the government. In Taiwan, abdominal ultrasonography, alpha-fetoprotein, and protein induced by vitamin K absence or antagonist-II (PIVKA-II) tests are performed for HCC surveillance every 6 months or every 3 months for high-risk patients. Dynamic computed tomography, magnetic resonance imaging, and contrast-enhanced ultrasound have been recommended for HCC surveillance in extremely high-risk patients or those with poor ultrasonographic visualization results. HCC is usually diagnosed through dynamic imaging, and pathological diagnosis is recommended. Staging of HCC is based on a modified version of the Barcelona Clinic Liver Cancer (BCLC) system, and the HCC management guidelines in Taiwan actively promote curative treatments including surgery and locoregional therapy for BCLC stage B or C patients. Transarterial chemoembolization (TACE), drug-eluting bead TACE, transarterial radioembolization, and hepatic artery infusion chemotherapy may be administered for patients with BCLC stage B or C HCC. Sorafenib and lenvatinib are reimbursed as systemic therapies, and regorafenib and ramucirumab may be reimbursed in cases of sorafenib failure. First-line atezolizumab with bevacizumab is not yet reimbursed but may be administered in clinical practice. Systemic therapy and external beam radiation therapy may be used in specific patients. Early switching to systemic therapy in TACE-refractory patients is a recent paradigm shift in HCC management.

Background/Aims: Fatty liver disease is defined as a cluster of diseases with heterogeneous etiologies, and its definition continues to evolve. The novel conceptional criteria for metabolic dysfunction-associated fatty liver disease (MAFLD) were proposed in 2020 to avoid the exclusion of a certain subpopulation, but their evaluations have been limited. We aimed to examine and compare the clinical as well as histologic features of MAFLD versus nonalcoholic fatty liver disease (NAFLD) in patients with biopsy-proven hepatic steatosis. Methods: From January 2009 to December 2019, 175 patients with histology-proven hepatic steatosis and 10 with cryptogenic cirrhosis who were treated at National Taiwan University Hospital, Taipei, Taiwan, were enrolled. Patients were classified into different groups according to the diagnostic criteria of MAFLD and NAFLD. The clinical and histologic features were then analyzed and compared. Results: In total, 76 patients (41.1%) were diagnosed with both MAFLD and NAFLD, 81 patients (43.8%) were diagnosed with MAFLD alone, nine patients (4.9%) were diagnosed with NAFLD alone, and 19 patients (10.3%) were diagnosed with neither. Those with MAFLD alone exhibited a higher degree of disease severity regarding histology and laboratory data than those with NAFLD alone. Advanced fibrosis was associated with the presences of hepatitis B virus infection and metabolic diseases. Conclusions The novel diagnostic criteria for MAFLD include an additional 38.9% of patients with hepatic steatosis and can better help identify those with a high degree of disease severity for early intervention than can the previous NAFLD criteria.

Background/Aims: Fatty liver disease is defined as a cluster of diseases with heterogeneous etiologies, and its definition continues to evolve. The novel conceptional criteria for metabolic dysfunction-associated fatty liver disease (MAFLD) were proposed in 2020 to avoid the exclusion of a certain subpopulation, but their evaluations have been limited. We aimed to examine and compare the clinical as well as histologic features of MAFLD versus nonalcoholic fatty liver disease (NAFLD) in patients with biopsy-proven hepatic steatosis. Methods: From January 2009 to December 2019, 175 patients with histology-proven hepatic steatosis and 10 with cryptogenic cirrhosis who were treated at National Taiwan University Hospital, Taipei, Taiwan, were enrolled. Patients were classified into different groups according to the diagnostic criteria of MAFLD and NAFLD. The clinical and histologic features were then analyzed and compared. Results: In total, 76 patients (41.1%) were diagnosed with both MAFLD and NAFLD, 81 patients (43.8%) were diagnosed with MAFLD alone, nine patients (4.9%) were diagnosed with NAFLD alone, and 19 patients (10.3%) were diagnosed with neither. Those with MAFLD alone exhibited a higher degree of disease severity regarding histology and laboratory data than those with NAFLD alone. Advanced fibrosis was associated with the presences of hepatitis B virus infection and metabolic diseases. Conclusions The novel diagnostic criteria for MAFLD include an additional 38.9% of patients with hepatic steatosis and can better help identify those with a high degree of disease severity for early intervention than can the previous NAFLD criteria.

OBJECTIVETo emphasize early differential diagnosis from patients with hyperphenylalaninemia (HPA) and to evaluate the treatment and long-term outcome of patients with tetrahydrobiopterin synthase (BH4) deficiency in Northern Chinese population.

METHODSFrom 1992 to 2005, a total of 618 patients with HPA were diagnosed and/or cared for in our outpatient clinic. Urinary pterin analysis, detection of dihydropteridine reductase (DHPR) activity in blood, and then BH4 loading tests were carried out to differentiate BH4 deficiency in these patients from classical phenylketonuria. BH4 deficient patients were treated with BH4, levodopa and 5-hydroxytryptophane (5-HTP) immediately while the diagnosis was done to disease. Patientso blood phenylalanine levels, psychomotor and intelligence development were followed up.

RESULTSA total of 38 cases were diagnosed as BH4 deficiency, all of them were revealed as 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency from the extremely decreased urine biopterin, normal DHPR activities and drop down of blood phenylalanine level to normal range within 4 to 8 hours after BH4 loading. The most common manifestations were progressively psychomotor and mental retardation to patients even after taking early dietary treatment. The patients were diagnosed and treated with drugs at the ages of 2.1 months to 13 years. With 4 patients died of pneumonia, 7 patients refused to treatment, only 27 patients were under treatment and followed up. The average full scale development or intelligence quotient (DQ/IQ) of patients who were treated within and after 6 months were 86+/- 10 or 66+/- 7 respectively. Development was not even in different aspects. A significant negative correlation was observed between the level of the DQ and the age of treatment commenced (r was -0.714, P< 0.01). Eleven patients experienced the extrapyramidal movement disorders, 3 of them combined with epilepsy. The extrapyramidal disorders were controlled by administration of levodopa.

CONCLUSIONThe differential diagnosis for BH4 deficiency should be carried out in all patients with HPA. PTPS deficiency is the most common form of BH4 deficiency in Northern Chinese population. The long-term outcome of these patients benefits from diagnosis and treatment with BH4, levodopa and 5-HTP as early as possible.

5-Hydroxytryptophan ; therapeutic use ; Asian Continental Ancestry Group ; genetics ; Biopterin ; analogs & derivatives ; deficiency ; therapeutic use ; Child, Preschool ; China ; Dihydropteridine Reductase ; blood ; Humans ; Infant ; Levodopa ; therapeutic use ; Phenylalanine ; blood ; Phenylketonurias ; drug therapy ; genetics ; metabolism ; Phosphorus-Oxygen Lyases ; deficiency ; genetics

Background: Shared decision making using patient decision aids (PtDAs) was established over a decade ago, but few studies have evaluated its efficacy in Asian countries. We therefore evaluated the application of PtDAs in a decision conflict between two muscle relaxant reversal agents, neostigmine and sugammadex, and sequentially analyzed the regional differences and operating room turnover rates. Methods: This multicenter, outcome-assessor-blind, randomized controlled trial included 3,132 surgical patients from two medical centers admitted between March 2020 and August 2020. The patients were randomly divided into the classical and PtDA groups for pre-anesthesia consultations. Their clinicodemographic characteristics were analyzed to identify variables influencing the choice of reversal agent. On the day of the pre-anesthesia consultation, the patients completed the four SURE scale (sure of myself, understand information, risk-benefit ratio, encouragement) screening items. The operating turnover rates were also evaluated using anesthesia records. Results: Compared with the classical group, the PtDA group felt more confident about receiving sufficient medical information (P < 0.001), felt better informed about the advantages and disadvantages of the medications (P < 0.001), exhibited a superior understanding of the benefits and risks of their options (P < 0.001), and felt surer about their choice (P < 0.001). Moreover, the PtDA group had a significantly greater tendency to choose sugammadex over neostigmine (P < 0.001). Conclusions PtDA interventions in pre-anesthesia consultations provided surgical patients with clear knowledge and better support. PtDAs should be made available in other medical fields to enhance shared clinical decision-making.

Background/Aims: Real-world studies assessing the effectiveness and safety of sofosbuvir/velpatasvir (SOF/VEL) plus ribavirin (RBV) for Child-Pugh B/C hepatitis C virus (HCV)-related cirrhosis are limited. Methods: We included 107 patients with Child-Pugh B/C HCV-related cirrhosis receiving SOF/VEL plus RBV for 12 weeks in Taiwan. The sustained virologic response rates at off-treatment week 12 (SVR12) for the evaluable population (EP), modified EP, and per-protocol population (PP) were assessed. Thesafety profiles were reported. Results: The SVR12 rates in the EP, modified EP and PP were 89.7% (95% confidence interval [CI], 82.5–94.2%), 94.1% (95% CI, 87.8–97.3%), and 100% (95% CI, 96.2–100%). Number of patients who failed to achieve SVR12 were attributed to virologic failures. The SVR12 rates were comparable regardless of patient characteristics. One patient discontinued treatment because of adverse events (AEs). Twenty-four patients had serious AEs and six died, but none were related to SOF/VEL or RBV. Among the 96 patients achieving SVR12, 84.4% and 64.6% had improved Child-Pugh and model for endstage liver disease (MELD) scores. Multivariate analysis revealed that a baseline MELD score ≥15 was associated with an improved MELD score of ≥3 (odds ratio, 4.13; 95% CI, 1.16–14.71; P=0.02). Patients with chronic kidney disease (CKD) stage 1 had more significant estimated glomerular filtration rate declines than patients with CKD stage 2 (-0.42 mL/min/1.73 m2/month; P=0.01) or stage 3 (-0.56 mL/min/1.73 m2/month; P<0.001). Conclusions SOF/VEL plus RBV for 12 weeks is efficacious and well-tolerated for Child-Pugh B/C HCV-related cirrhosis.

Background/Aims: Real-world studies assessing the effectiveness and safety of sofosbuvir/velpatasvir (SOF/VEL) plus ribavirin (RBV) for Child-Pugh B/C hepatitis C virus (HCV)-related cirrhosis are limited. Methods: We included 107 patients with Child-Pugh B/C HCV-related cirrhosis receiving SOF/VEL plus RBV for 12 weeks in Taiwan. The sustained virologic response rates at off-treatment week 12 (SVR12) for the evaluable population (EP), modified EP, and per-protocol population (PP) were assessed. Thesafety profiles were reported. Results: The SVR12 rates in the EP, modified EP and PP were 89.7% (95% confidence interval [CI], 82.5–94.2%), 94.1% (95% CI, 87.8–97.3%), and 100% (95% CI, 96.2–100%). Number of patients who failed to achieve SVR12 were attributed to virologic failures. The SVR12 rates were comparable regardless of patient characteristics. One patient discontinued treatment because of adverse events (AEs). Twenty-four patients had serious AEs and six died, but none were related to SOF/VEL or RBV. Among the 96 patients achieving SVR12, 84.4% and 64.6% had improved Child-Pugh and model for endstage liver disease (MELD) scores. Multivariate analysis revealed that a baseline MELD score ≥15 was associated with an improved MELD score of ≥3 (odds ratio, 4.13; 95% CI, 1.16–14.71; P=0.02). Patients with chronic kidney disease (CKD) stage 1 had more significant estimated glomerular filtration rate declines than patients with CKD stage 2 (-0.42 mL/min/1.73 m2/month; P=0.01) or stage 3 (-0.56 mL/min/1.73 m2/month; P<0.001). Conclusions SOF/VEL plus RBV for 12 weeks is efficacious and well-tolerated for Child-Pugh B/C HCV-related cirrhosis.