Investigating the Genetic Diversity of Hepatitis Delta Virus in Hepatocellular Carcinoma (HCC): Impact on Viral Evolution and Oncogenesis in HCC.

Hepatitis delta virus (HDV), an RNA virus with two forms of the delta antigen (HDAg), relies on hepatitis B virus (HBV) for envelope proteins essential for hepatocyte entry. Hepatocellular carcinoma (HCC) ranks third in global cancer deaths, yet HDV's involvement remains uncertain. Among 300 HBV-associated HCC serum samples from Taiwan's National Health Research Institutes, 2.7% (8/300) tested anti-HDV positive, with 62.7% (5/8) of these also HDV RNA positive. Genotyping revealed HDV-2 in one sample, HDV-4 in two, and two samples showed mixed HDV-2/HDV-4 infection with RNA recombination. A mixed-genotype infection revealed novel mutations at the polyadenylation signal, coinciding with the ochre termination codon for the L-HDAg. To delve deeper into the possible oncogenic properties of HDV-2, the predominant genotype in Taiwan, which was previously thought to be less associated with severe disease outcomes, an HDV-2 cDNA clone was isolated from HCC for study. It demonstrated a replication level reaching up to 74% of that observed for a widely used HDV-1 strain in transfected cultured cells. Surprisingly, both forms of HDV-2 HDAg promoted cell migration and invasion, affecting the rearrangement of actin cytoskeleton and the expression of epithelial-mesenchymal transition markers. In summary, this study underscores the prevalence of HDV-2, HDV-4, and their mixed infections in HCC, highlighting the genetic diversity in HCC as well as the potential role of both forms of the HDAg in HCC oncogenesis.

Preventing viral relapse with prophylactic tenofovir in hepatitis B carriers receiving chemotherapy: a phase IV randomized study in Taiwan.

BACKGROUND AND AIMS: This study aimed to compare the efficacy of shorter vs. longer tenofovir disoproxil fumarate (TDF) prophylaxis in preventing hepatitis B virus (HBV) relapse in cancer patients with chronic hepatitis B (CHB) undergoing chemotherapy. METHODS: This phase IV, prospective randomized trial enrolled cancer patients with CHB from 2014 to 2019 in Taiwan. Included patients were randomized to receive either 24- (Arm A) or 48-week (Arm B) post-chemotherapy TDF and compared for cumulative incidence of virological and clinical relapse. Logistic regressions were conducted to determine the factors associated with HBV relapse. RESULTS: One hundred patients were randomized, and 41 patients in Arm A and 46 in Arm B completed the TDF treatment. No significant difference was found in cumulative incidence of virological relapse (Arm A: 94.4%, Arm B: 93.1%, p = 0.110) or clinical relapse among patients with baseline HBV DNA > 2000 IU/mL (Arm A: 38.9%, Arm B: 26.7%, p = 0.420) between the two arms. High baseline HBV DNA ≥ 10,000 IU/mL (OR = 51.22) and HBsAg ≥ 1000 IU/mL (OR = 8.64) were independently associated with an increased virological relapse. Alanine aminotransferase (ALT), serum phosphorus, vitamin D, and estimated glomerular filtration rate (eGFR) remained stable throughout the study. CONCLUSIONS: The 24-week preventative TDF has comparable efficacy to the 48-week treatment in virologic and clinical relapse. High baseline HBsAg or HBV DNA is associated with a higher risk of HBV relapse. These findings imply a 24-week duration of TDF treatment with a close monitor for patients with a high baseline viral load. Hepatitis B virus infection is a prominent cause of liver cancer and chronic liver disease and affected millions of people worldwide. When HBV-infected people are exposed to immunosuppressive medication or chemotherapy for cancer, the chance of HBV reactivation rises considerably. This trial showed 24-week tenofovir disoproxil fumarate (TDF) may be sufficient for preventing HBV relapse in cancer patients receiving chemotherapy. CLINICAL TRIAL REGISTRATION NUMBER: NCT02081469.

Long-term renal function alterations in hepatitis C patients with SVRs: Impacts of therapies and mixed cryoglobulinemia.

BACKGROUND / AIMS: Effects of anti-hepatitis C virus (HCV) therapeutic regimens and mixed cryoglobulinemia on long-term renal function of HCV-infected patients with viral clearance have not been determined. METHODS/MATERIALS: A prospective 10-year cohort study of 1212 HCV-infected patients (interferon-based therapy, n = 615; direct-acting antiviral (DAA) therapy, n = 434) was conducted. RESULTS: At baseline, age, body mass index (BMI), hemoglobin (Hb) and uric acid (UA) levels, and fibrosis-4 score were associated with estimated glomerular filtration rates (eGFRs) in HCV-infected patients. At 24 weeks posttherapy, age, BMI, and Hb and UA levels were associated with eGFRs in patients with a sustained virological response (SVR) (n = 930). Compared with those at baseline, the eGFRs were lower in SVR patients at 24 weeks posttherapy, regardless of the therapeutic regimen. The eGFRs reverted to baseline levels in interferon-treated SVR patients up to 10 years posttherapy but remained decreased in DAA-treated SVR patients up to 4 years posttherapy. Longitudinally, repeated measures analyses with generalized estimating equations showed that the interactions between DAA-based therapy and mixed cryoglobulinemia (OR: 3.291) and Hb levels (1.778) were positively, while DAA-based therapy (0.442), age (0.956), UA levels (0.698), homeostasis model assessment-insulin resistance index (0.961) and complement 4 levels (0.9395) were negatively associated with the eGFR. Among DAA-treated SVR patients, the baseline eGFR (OR: 1.014; 95%CI OR: 1.004-1.023) and high-sensitivity C-reactive protein (HR: 1.082; 95%CI HR: 1.018-1.15) were associated with eGFR reduction at 24 weeks and 4 years posttherapy, respectively. CONCLUSIONS: Hepatic fibrosis was an HCV-related factor for renal function. Longitudinally, DAA therapy was negatively, while the interaction between DAA therapy and mixed cryoglobulinemia was positively associated with renal function in SVR patients; deteriorated renal function was recovered in interferon-treated SVR patients. Particularly in DAA-treated SVR patients, baseline renal function and systemic inflammation were associated with short- and long-term reductions in renal function, respectively.

Association of liver fibrosis with extrahepatic cancer in steatotic liver disease patients with PNPLA3 I148M GG genotype.

The impacts of patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M-rs738409, methylenetetrahydrofolate reductase (MTHFR) Ala222Val-rs1801133, and aldehyde dehydrogenase 2 (ALDH2) Glu504Lys-rs671 on the outcomes of Taiwanese patients with steatotic liver disease (SLD) have remained elusive. An 8-year prospective cohort study of patients with (n = 546) and without (n = 580) SLD (controls) was undertaken in a Taiwanese tertiary care center. The 546 SLD patients comprised 306 (56.0%) men and 240 (44.0%) women with mean ages of 53.3 and 56.4 years, respectively. Compared with the controls, SLD patients had an increased frequency of the PNPLA3 I148M-rs738409 GG genotype (25.5 vs. 5.9%, p = 0.001). Among the SLD patients, 236 (43.1%) suffered cardiovascular events, 52 (9.5%) showed extrahepatic cancers, 13 (2.38%) experienced hepatic events, including hepatocellular carcinoma (n = 3, 0.5%) and liver cirrhosis (n = 8, 1.47%), and none died. The Fibrosis-4 (FIB-4) scores were associated with extrahepatic cancer (hazard ratio [HR] 1.325; 95% confidence interval [CI], 1.038-1.691) and cirrhosis development (HR 1.532; 95% CI, 1.055-2.224), and the PNPLA3 I148M-rs738409 G allele (ß = 0.158, 95% CI, 0.054-0.325) was associated with the FIB-4 score. Stratified analyses showed that the impact of the FIB-4 score on extrahepatic cancer development was evident only in SLD patients with the PNPLA3 I148M-rs738409 GG genotype (HR 1.543; 95% CI, 1.195-1.993) and not in patients with the GC or CC genotype. Moreover, the ALDH2 Glu504Lys-rs671 G allele had a dose-dependent effect on alcoholism, and the MTHFR and ALDH2 genotypes were not significantly associated with SLD patient outcomes. In conclusion, special vigilance should be exercised for emerging extrahepatic cancer in SLD patients with the PNPLA3 I148M-rs738409 GG genotype and high FIB-4 scores.

Higher HBeAg-reversion virological relapse and lower sustained remission after treatment cessation in tenofovir-treated HBeAg-positive patients.

A complete investigation of the clinical outcomes after treatment cessation in HBeAg-positive patients with HBeAg loss is limited. We retrospectively recruited 242 HBeAg-positive patients with HBeAg loss after a median duration of 37.2 months with tenofovir (TDF, n = 77) or entecavir (ETV, n = 165) treatment. There were 77 (31.8%) patients with sustained virological remission (SVR), 85 (35.1%) with HBeAg-reversion virological relapse, 80 (33.1%) with HBeAg-negative virological relapse after treatment cessation, and 23 (9.5%) with HBsAg loss. Clinical data at baseline, on-treatment and during off-treatment follow-up were analyzed. The 3-year cumulative incidences of overall, HBeAg-reversion and HBeAg-negative virological relapse were 70.2%, 54%, and 53.5%, respectively. The common factors associated with HBeAg-reversion and HBeAg-negative virological relapse were tenofovir treatment (hazard ratio [HR] = 5.411, p < 0.001; HR = 2.066, p = 0.006, respectively) and HBsAg at end of treatment (EOT) (HR = 1.461, p = 0.001; HR = 1.303, p = 0.019, respectively). The 5-year cumulative incidence of HBsAg loss in SVR patients was 13.7% and EOT HBsAg was the only associated factor (HR = 0.524, p = 0.024). Compared to that of ETV-treated patients, TDF-treated patients had a significantly higher 3-year cumulative incidence of virological relapse (87.3% vs. 62.8%, p < 0.001), earlier HBeAg-reversion virological relapse (2.9 vs. 7.8 months, p < 0.001), a higher rate of HBeAg-reversion virological relapse (53.2% vs. 26.7%) and a lower SVR rate (15.6% vs. 39.4%) (p < 0.001). In summary, the clinical outcomes after treatment cessation in HBeAg-positive patients with HBeAg loss were composed of HBeAg-reversion virological relapse, HBeAg-negative virological relapse and SVR. TDF was significantly associated with off-treatment virological relapse. EOT HBsAg plays an important role in HBsAg loss among SVR patients and posttreatment virological relapse.

Unbranched rod-like RNA is required for RNA editing of hepatitis delta virus genotype 2 and genotype 4.

RNA editing of the hepatitis delta virus (HDV) is essential for generating the large delta antigen, which is crucial for virion assembly. In HDV genotype 1 (HDV-1), editing occurs within the context of the unbranched rod-like structure characteristic of HDV RNA, while RNA editing in HDV-3 requires a branched double-hairpin structure. The regulation of RNA editing in HDV-2 and HDV-4 remains uncertain. Based on predictions of the unbranched rod-like RNA structures of HDV-2 and HDV-4, the editing site occurs as an A.C mismatch pair, surrounded by four base pairs upstream and two base pairs downstream of the editing site, respectively. To investigate HDV-2 and HDV-4 RNA editing, cultured cells were transfected with non-replicating editing reporters carrying wild-type sequences or specific mutations. The results revealed that the editing rates observed for wild-type HDV-2 and HDV-4 were fairly similar, albeit lower than that of HDV-1. Like HDV-1, both HDV-2 and HDV-4 showed a reduction in editing rate when the A.C mismatch pair and the immediately upstream base-paired region were disturbed. Notably, extending the downstream base-paired region from two to three or four (forming a structure identical to that of HDV-1) base pairs increased editing rate. Furthermore, we presented novel evidence that indicates the importance of the first bulge's size, located upstream of the editing site, and the base-pairing length within 7-13 and 28-39 nucleotides downstream of the editing site in influencing the HDV-4 editing rate. To summarize, our analyses suggest that the unbranched rod-like structures surrounding the editing site of HDV-2 and HDV-4 play a crucial role in regulating their RNA editing rates.

Adding nutritional status to the original BCLC stage improves mortality prediction for hepatocellular carcinoma patients in HBV-endemic regions.

Hepatocellular carcinoma (HCC) is associated with high mortality, especially in Asian populations where chronic HBV infection is a major cause. Accurate prediction of mortality can assist clinical decision-making. We aim to (i) compare the predicting ability of Barcelona Clinic Liver Cancer classification (BCLC) stage, neutrophil-to-lymphocyte ratio (NLR), and Albumin-Bilirubin (ALBI) score in predicting short-term mortality (one- and two-year) and (ii) develop a novel model with improved accuracy compared to the conventional models. This study enrolled 298 consecutive HCC patients from our hepatology department. The prognostic values for mortality were assessed by area under the receiver operating characteristic curve (AUROC) analysis. A novel model was established and internally validated using 5-fold cross-validation, followed by external validation in a cohort of 100 patients. The primary etiology of cirrhosis was hepatitis B virus (HBV), with 81.2% of HCC patients having preserved liver function. Significant differences were observed in hemoglobin (Hb) and serum albumin levels, which reflect patients' nutrition status, between patients who survived for one year and those who died. BCLC exhibited superior predictive accuracy compared to NLR but had borderline superiority to the ALBI score. Therefore, a novel model incorporating BCLC, Hb, and serum albumin was developed, internally and externally validated, as well as subgroup sensitivity analysis. The model exhibited significantly higher predictive accuracy for one- and two-year mortality than conventional prognostic predictors, with AUROC values of 0.841 and 0.805, respectively. The novel "BCLC-Nutrition Model", which incorporates BCLC, Hb, and serum albumin, may provide improved predictive accuracy for short-term mortality in HCC patients compared to commonly used prognostic scores. This emphasizes the importance of nutrition in the management of HCC patients.

A Validated Composite Score Demonstrates Potential Superiority to MELD-Based Systems in Predicting Short-Term Survival in Patients with Liver Cirrhosis and Spontaneous Bacterial Peritonitis-A Preliminary Study.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a severe complication in cirrhosis patients with ascites, leading to high mortality rates if not promptly treated. However, specific prediction models for SBP are lacking. AIMS: This study aimed to compare commonly used cirrhotic prediction models (CTP score, MELD, MELD-Na, iMELD, and MELD 3.0) for short-term mortality prediction and develop a novel model to improve mortality prediction. METHODS: Patients with the first episode of SBP were included. Prognostic values for mortality were assessed using AUROC analysis. A novel prediction model was developed and validated. RESULTS: In total, 327 SBP patients were analyzed, with HBV infection as the main etiologies. MELD 3.0 demonstrated the highest AUROC among the traditional models. The novel model, incorporating HRS, exhibited superior predictive accuracy for in-hospital in all patients and 3-month mortality in HBV-cirrhosis, with AUROC values of 0.827 and 0.813 respectively, surpassing 0.8. CONCLUSIONS: MELD 3.0 score outperformed the CTP score and showed a non-significant improvement compared to other MELD-based scores, while the novel SBP model demonstrated impressive accuracy. Internal validation and an HBV-related cirrhosis subgroup sensitivity analysis supported these findings, highlighting the need for a specific prognostic model for SBP and the importance of preventing HRS development to improve SBP prognosis.

Predicting Hepatocellular Carcinoma Risk in Chronic Hepatitis B Patients Receiving Finite Periods of Antiviral Therapy.

PURPOSE: Hepatocellular carcinoma (HCC) is one of the most severe complications in chronic hepatitis B virus (HBV) infection. HCC can still develop in patients with chronic HBV (CHB) infection undergoing antiviral therapy. Several effective scoring systems for the prediction of HCC risk in CHB patients have been established. However, very few of them are designed for CHB patients receiving nucleos(t)ide analogues (NAs) therapy. Furthermore, none are available for HCC risk prediction in CHB patients receiving finite periods of antiviral therapy. METHODS: This study enrolled 790 consecutive treatment-naïve patients with CHB infection who had visited our liver clinics from 2008 to 2012 for pretreatment assessment before receiving antiviral therapies. The treatments were provided at finite periods according to the National Health Insurance Policy in Taiwan. The last follow-up date was 31 December 2021. We analyzed the virological and clinical factors in these 790 CHB patients receiving finite periods of NA treatments and identified the most significant risk factors for HCC to establish a novel predictive scoring system. By using stepwise selection in a multivariate Cox proportional hazards model, we divided the patients into three risk groups. RESULTS: Our predictive scoring system included five independent variables: genotype C (adjusted HR [aHR] = 2.23), NA-withdraw-related hepatitis relapse (aHR = 6.96), male (aHR = 4.19), liver cirrhosis (aHR = 11.14), and T1768A core promoter mutation (aHR = 3.21). This model revealed significant differences in HCC incidence among the three risk groups. The 5-year cumulative HCC risk significantly differed among the three risk groups (low risk: 1.33%, moderate risk: 4.99%, and high risk: 17.46%), with log-rank test p < 0.001. CONCLUSION: Our predictive scoring system is a promising tool for the prediction of HCC in CHB patients receiving finite NA treatments. Genotype C, NA-withdraw-related hepatitis relapse, male gender, liver cirrhosis, and the T1768A HBV core promoter mutation were significant independent risk factors.

Hepatitis C micro-elimination through the retrieval strategy of patients lost to follow-up.

BACKGROUND AND AIM: World Health Organization sets up an ambitious and attainable goal to eliminate hepatitis C (HCV) by 2030. The previous diagnosed HCV patients lost to follow-up were considered as an important target group for HCV elimination. We conducted a call back program to retrieve the lost to follow-up HCV patients and link them to care in our hospital. By analyzing and comparing our result with that from other studies, we wish to improve our retrieval strategy and provide our experience to the general communities. METHODS: A list of the patients with a medical record showing seropositive for antibody to HCV (anti-HCV Ab) from 2004 to 2017 was retrieved by the department of intelligent technology of our hospital. Three dedicated staff members reviewed the patients' electronic medical records (EMRs) and recruited the patient lost follow-up to the call back program. The staff members contacted the qualified patients by telephone and inquired about their opinions for treating their chronic HCV infection. We also informed the patients about the retrieval strategy and why we contact them. As our National Health Insurance request, we gave all patient one informed consent for hepatitis C treatment. Informed consents have been obtained from all patients. Referrals to our gastroenterology unit (GU) were arranged for the patients who would like to continue their chronic HCV care in our hospital. RESULTS: There were 31,275 anti-HCV positive patients. We included 11,934 patients (38.2%) into the call back system and contacted them by telephone. Based on the response to our call, we ascertained 1277 eligible cases (10.7%) for retrieval. The patients who were younger (< 55), lived in Taoyaun City or had tested positive for anti-HCV Ab at the department of internal medicine department had an increased rate of successful call back. There were 563 patients (44.1%) returning to our GU. Of them, 354 patients (62.9%) were positive for HCV viremia. 323 patients (91.2%) received the DAAs treatment. The SVR12 with Grazoprevir + elbasvir, Glecaprevir + pibrentasvir, Sofosbuvir + ledipasvir and Sofosbuvir + velpatasvir were 97.9%, 98.8%, 100% and 97.5%, respectively. CONCLUSIONS: Call back system can expand our reach to those unaware or ignoring chronic HCV infection patients and link them to treatment.

Reduction of ACE2 Serum Concentrations by Telbivudine in Chronic Hepatitis B Patients.

BACKGROUND: Coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has wreaked havoc worldwide since December 2019. Currently, no effective medical treatments have been approved. As the epidemic continues to spread, SARS-CoV-2 mutants emerge, some of which become more infectious with increasing vaccine resistance. The main route for SARS-CoV-2 to enter the host cells is by binding its spike protein to the host receptor, angiotensin-converting enzyme 2 (ACE2). Besides the membrane-bound form of ACE2, the soluble form of ACE2 (sACE2) can also bind SARS-CoV-2 for viral endocytosis. OBJECTIVE: Previously, we found that telbivudine reduced the concentrations of ACE1 in blood. Therefore, we speculated that this drug might also reduce the concentrations of sACE2. METHODS: In this retrospective study, serum samples from 39 hepatitis B patients receiving telbivudine were collected and examined for sACE2 concentrations using an ELISA kit.. RESULTS: It was found that the serum concentrations of sACE2 were significantly declined in chronic hepatitis B patients treated with telbivudine. CONCLUSION: Telbivudine treatment reduced sACE2 concentrations, which could potentially reduce the infection risk of SARS-CoV-2.

One-year efficacy of tenofovir alafenamide in patients with chronic hepatitis B: An observational study.

ABSTRACT: Non-inferior antiviral efficacy and better renal safety have been reported in chronic hepatitis B patients with tenofovir alafenamide (TAF) treatment. The experience in real-world clinical practice is limited.We aimed to explore the efficacy after 1-year TAF treatment.A total of 148 patients (42 HBeAg-positive and 106 HBeAg-negative) with TAF treatment ≥1 year were included. Virological suppression (<20 IU/mL or undetectable), HBsAg level, alanine aminotransferase (ALT) normalization (≤36 U/L), and estimated glomerular filtration rate (eGFR) were analyzed at 1 year. Multivariate logistic regression analysis was performed to determine the associated factors for virological suppression and ALT normalization.Virological suppression was achieved in 83% and the 1-year median decline of hepatitis B virus DNA was 5.18 log IU/mL. ALT normalization occurred in 75.7%. HBsAg level decreased at a median of 0.27 log IU/mL with significant difference from baseline (P < .001). Baseline ALT (odds ratio [OR] 1.005, 95% confidence interval [CI] 1.000-1.010, P = .036) and hepatitis B virus DNA (OR 0.222, 95% CI 0.079-0.621, P = .004) were significant factors for 1-year virological suppression. Age (OR 1.064, 95% CI 1.003-1.130, P = .041) was associated with ALT normalization. Significant changes were observed in creatinine (mean increase 0.03 mg/dL, P = .011) and eGFR (mean decrease 2.6 mL/min/1.73 m2, P = .004) after 1-year TAF treatment.One-year TAF treatment came to good virological response, modest ALT normalization rate and significant HBsAg decline. The observation of significant changes in eGFR warranted further studies.

Proton beam radiotherapy combined with anti-PD1/PDL1 immune checkpoint inhibitors for advanced hepatocellular carcinoma.

Anti-Programmed cell Death protein 1 (Anti-PD1) or Programmed Death-Ligand 1 (PDL1) immune checkpoint inhibitors provide treatment options for advanced HCC patients with low response rates. Combination therapy is becoming a major issue to improve the unmet need. Proton beam radiotherapy (PBT) could effectively control the local tumor with a low-risk injury to peripheral liver parenchyma. We retrospectively reviewed the patients who have received PBT combined with anti-PD1/PDL1 to evaluate the efficacy and safety of the advanced HCC patients. This study reviewed 29 advanced HCC patients who have received PBT and anti-PD1/PDL1 during 2016 and 2019. All were Child-Pugh A and performance status 0-1. Seventeen patients (58.6%) had extrahepatic spreading. Concurrent PBT started during anti-PD1/PDL1 with a median of 96.6 grays equivalent dose. The PBT field covered all tumors in 13 (44.8%) patients under curative intent. Other patients (55.2%) received palliative PBT that covered only the principal tumors. All patients have completed the concurrent PBT protocol. The median anti-PD1/PDL1 duration was 3.9 months. After a median follow-up of 13.2 months, the rates of 1-year PBT infield tumor control, 1-year outfield tumor control, and overall response were 90.5%, 90.9%, and 61.5%, and 70.8%, 69.2%, and 43.8%, respectively for curative-intent and palliative-control PBT. Complete response was found in 4 (30.8%) curative-intent and 1 (6.3%) palliative-control patients. The median overall progression-free survival was 27.2 months for curative-intent patients and 15.9 months for palliative-control patients. The overall survival was non-reached for both groups. The ALBI grade and Child-Pugh score change at 3-month and 6-month after PBT initiation were nonsignificant. No unexpected adverse event occurred except nine patients (31.0%) had treatment-related adverse events higher than or equal to Grade 3, including 2 (6.9%) had a radiation-induced liver injury. PBT combined with anti-PD1/PDL1 was safe without unexpected adverse events. The concurrent therapy could effectively treat advanced HCC through sustained local tumor necrosis and effective systemic tumor control for the patients who received curative-intent or palliative-control PBT combined with anti-PD1/PDL1.

The Novel Finding of Dynamic Change in eGFR Up to One Year after End of Treatment in HCV-Infected Patients Receiving Sofosbuvir and Velpatasvir.

Background: The results of long-term renal evolution in HCV-infected patients using sofosbuvir and velpatasvir (SOF/VEL), with or without ribavirin (RBV), are lacking. Aims: We evaluated the renal safety for HCV-infected patients receiving SOF/VEL. Methods: Between 1 June 2019 and 6 July 2020, we included 594 HCV-infected patients receiving SOF/VEL +/- RBV for 12 weeks in Taiwan. Viral eradication rate (defined by sustained virological response at week 12 post-treatment; SVR12) and changes to renal function were considered. Results: SVR12 was achieved in 99.3% (590/594) upon per-protocol analysis. Patients saw improved hepatobiliary function and fibrosis after the start of SOF/VEL therapy. For renal function, those with baseline estimated glomerular filtration rate (eGFR) ≥ 60 (mL/min/1.73 m2) experienced transient on-treatment reduction in renal function that improved upon ending treatment, but recurrent eGFR degradation during one-year follow-up. The use of RBV (OR = 5.200, 95% CI: 1.983-13.634, p = 0.001) was a significant risk factor at SVR24, while diabetes mellitus (OR = 2.765, 95% CI: 1.104-6.922, p = 0.030) and the use of RBV (OR = 3.143, 95% CI: 1.047-9.435, p = 0.041) were identified as significant risk factors of worsening renal function at SVR48. SOF/VEL did not worsen renal function among those with stage 4-5 chronic kidney disease (CKD) who were not receiving dialysis. Conclusions: A trend of decline in eGFR at 1 year after SOF/VEL treatment was observed among diabetic patients with baseline eGFR ≥ 60 (mL/min/1.73 m2) and concomitant use of RBV. The close monitoring of renal function is warranted. Further study should be conducted in order to weigh the risks and benefit of RBV.

Clinical characteristics and outcomes of drug-induced liver injury in Taiwan: With emphasis on the impact of chronic hepatitis B infection.

BACKGROUND: Whether hepatitis B virus (HBV) infection can affect the outcomes of drug-induced liver injury (DILI) is controversial. This study aimed to evaluate the characteristics and outcomes of DILI in Taiwan, with an emphasis on the impact of HBV infection. METHODS: We prospectively recruited patients with DILI from multiple centers in Taiwan from 2010 to 2018. RESULTS: A total of 1,014 patients were enrolled. The leading culprit drug category was antimicrobials (481, 47.4%), followed by nonsteroidal anti-inflammatory drugs, anticonvulsants, and statins. Among the antimicrobials, antituberculosis agents were most likely to induce liver injury (257, 25.3%), followed by antibacterial, antifungal, and antiviral agents. The liver-related mortality rate was 8.2% (83/1,014). The patients who died had higher rates of hepatocellular-type liver injury, elevated liver biochemical tests, preexisting liver cirrhosis, jaundice, chronic HBV infection, and antituberculosis drug-induced liver injury (ATDILI) than the survivors. A total of 131 patients (12.9%) with DILI were HBV carriers, of whom 23 (17.6%) died of hepatic failure. The rate of HBV-DNA > 2000 IU/mL was higher in the patients who died (47.8% vs. 26.9%, p = 0.047) than in the survivors. After adjusting for possible risk factors, active HBV infection with HBV-DNA > 2000 IU/mL was the most significant risk factor for liver-related mortality (adjusted HR, 4.40, 95% CI, 2.31%-8.38%, p < 0.001). The other independent risk factors for mortality were ATDILI and albumin-bilirubin (ALBI) score (adjusted HR, 1.25 and 4.09, respectively, p < 0.003). CONCLUSION: Antituberculosis agents were the leading cause of DILI in Taiwanese, and they were associated with poorer outcomes than other drug categories. Active HBV infection, ATDILI and ALBI score were independent risk factors for fatal DILI. Close monitoring of liver tests and timely antiviral therapy should be implemented in HBV carriers during the administration of high-risk drugs, such as antituberculosis agents.

Multi-Omics Analyses Identify Signatures in Patients with Liver Cirrhosis and Hepatocellular Carcinoma.

Gut bacterial/viral dysbiosis, changes in circulating metabolites, and plasma cytokines/chemokines have been previously associated with various liver diseases. Here, we analyzed the associations between fecal microbial composition, circulating metabolites, and plasma cytokines/chemokines in patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC). We recruited 10 HCC patients, 18 LC patients, and 17 healthy individuals. Their stool samples were used for gene sequencing of bacterial 16S rRNA and viral genomes, while plasma samples were utilized for the determination of endotoxin, zonulin, metabolite, and cytokine/chemokine levels. Dysbiosis was observed among gut bacteria and viruses, with significant changes in abundance at the genus and species levels, respectively. However, no differences were found between cohorts in the alpha and beta diversity. Plasma lipopolysaccharides and zonulin, but not trimethylamine N-oxide, were progressively increased in LC and HCC subjects. Profiling plasma metabolites and selected cytokines/chemokines revealed differential changes in the LC and HCC cohorts. Following joint correlation and correlation network analyses, regardless of etiology, common network signatures shared by LC and HCC patients were characterized by the gut virus Stenotrophomonas virus DLP5 and the uncultured Caudovirales phage, plasma metabolites pyruvic acid and acetic acid, and plasma cytokines/chemokines eotaxin and PDGF-AB/BB, respectively. Additionally, LC- and HCC-specific correlation networks were also identified. This study provides novel insights into altered gut microbial/viral composition that may contribute to pre-HCC disorders, metabolic reprogramming, or inflammatory microenvironments for hepatocarcinogenesis.

Herbal and dietary supplement-induced liver injury in Taiwan: comparison with conventional drug-induced liver injury.

BACKGROUND AND AIMS: Whether herbal and dietary supplements (HDS) are safer than Western conventional drugs is controversial. The aim of this study was to explore the characteristics and risk factors for HDS-induced liver injury (HILI) in Taiwan. METHODS: This is a 9-year multi-center prospective study conducted in Taiwan from 2011 to 2019. Patients with HILI were compared to those with conventional drug-induced liver injury (CILI). RESULTS: A total of 1,297 patients were enrolled, of whom 285 (22.0%) had HILI and 1,012 (78.0%) had CILI. Compared to the CILI group, the HILI group had higher initial serum alanine aminotransferase, alkaline phosphatase (ALP), peak ALP and bilirubin levels, and higher rates of jaundice, ascites, encephalopathy, coagulopathy, sepsis and acute liver failure. In addition, the HILI group had a higher mortality rate than the CILI group (12.6 vs. 8.0%, p = 0.016). Hepatitis B carrier status, elevated baseline liver biochemical tests and the use of crude herbs (without processing) were associated with an increased risk of HILI-related mortality (adjusted hazard ratios [95% confidence intervals]: 2.90 [1.43-5.99], 2.40 [1.01-5.68] and 2.94 [1.45-5.97], respectively). CONCLUSIONS: HDS are popular and incriminated in more than one-fifth of drug-induced liver injuries in Taiwan. The patients with HILI were more severe than those with CILI in terms of liver biochemical tests, complications and mortality. Hepatitis B carriers, those with elevated baseline liver tests and crude herb users may have a higher risk of HILI-related mortality. The prudent use of HDS is suggested in these high-risk subjects.

Ropeginterferon alfa-2b in patients with genotype 1 chronic hepatitis C: Pharmacokinetics, safety, and preliminary efficacy.

BACKGROUND AND AIM: Ropeginterferon alfa-2b (P1101) is a novel long-acting mono-PEGylated recombinant proline interferon (IFN) conjugated to a 40 kDa branched polyethylene glycol (PEG) chain at its N-terminus, allowing every-two-week injection. It received European Medicines Agency and Taiwan marketing authorization for the treatment of polycythemia vera in 2019 and 2020, respectively. This phase 2 study aimed to evaluate the pharmacokinetics, safety, and preliminary efficacy of ropeginterferon alfa-2b as compared with PEG-IFN-α2a in patients with chronic hepatitis C virus genotype 1 infection. METHODS: One hundred six treatment naive patients were enrolled in this phase 2 study and randomized to four treatment groups: subcutaneous weekly PEG-IFN-α2a 180 µg (group 1), weekly ropeginterferon alfa-2b 180 µg (group 2), weekly ropeginterferon alfa-2b 270 µg (group 3), or biweekly ropeginterferon alfa-2b 450 µg (group 4) plus ribavirin for 48 weeks. RESULTS: After multiple weekly administration, serum exposure (AUC0-τ) in ropeginterferon alfa-2b 180 µg was approximately 41% greater and the accumulation ratio of 2-fold greater than PEG-IFN-α2a 180 µg. The incidences of flu-like symptoms were 66.7% (18/27), 53.3% (16/30), 55.0% (11/20), and 48.3% (14/29), anxiety were 14.8% (4/27), 6.7% (2/30), 0%, and 0%, and depression were 25.9% (7/27), 13.3% (4/30), 0%, and 3.4% (1/29), for groups 1-4, respectively. Two grade 2 of 3 depression were noted in PEG-IFN-α2a arm, but none in ropeginterferon arms. The SVR24 rates were 77.8% (21/27), 66.7% (20/30), 80% (16/20), and 69% (20/29), respectively. CONCLUSIONS: Ropeginterferon alfa-2b showed longer effective half-life and superior safety profile than PEG-IFN-α2a. Biweekly injection of ropeginterferon alfa-2b will be studied in larger viral hepatitis patient population.

Drug-induced liver injury associated with severe cutaneous adverse drug reactions: A nationwide study in Taiwan.

BACKGROUND & AIMS: Severe cutaneous adverse drug reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP) are high-mortality adverse drug reactions. The risk factors and prognosis of drug-induced liver injury (DILI) concomitant with SCAR warrant clarification. We aimed to evaluate the characteristics and outcomes of DILI with SCAR. METHODS: We analysed the database of a 10-year multi-centre prospective study in Taiwan from 2011 to 2020. RESULTS: A total of 1415 patients with DILI were enrolled, including 81 cases combined with SJS/TEN, 74 with DRESS, 3 with AGEP and 1257 with pure DILI. Approximated 11.2% of patients had SCAR, of which allopurinol was the leading incriminated drug, followed by sulphonamides and carbamazepine. The SJS/TEN group had the highest mortality (34.6%). Jaundice, acute kidney injury and SJS/TEN were independent risk factors of mortality (odds ratio: 29.54, 4.43 and 4.86, respectively, P < .003). Chronic kidney disease with high-dose allopurinol also contributed to high mortality (78.9%) in cases of allopurinol-induced DILI with SCAR. The HLA-B*5801 was associated with a high risk and mortality of allopurinol-induced DILI with SCAR. Likewise, the HLA-B*1502 was closely related to carbamazepine-induced DILI with SCAR. CONCLUSIONS: DILI patients combined with SCAR are common and have a high mortality in Taiwan. Allopurinol is the leading incriminated drug. Jaundice, acute kidney injury and SJS/TEN are risk factors of mortality. HLA-B*5801, chronic kidney disease and high drug dosage also contribute to high mortality in allopurinol-induced DILI with SCAR.

Alpha-fetoprotein response at different time-points is associated with efficacy of nivolumab monotherapy for unresectable hepatocellular carcinoma.

Nivolumab monotherapy has a modest objective response rate (ORR) in hepatocellular carcinoma (HCC). To overcome the lack of biomarkers that predict delayed alpha-fetoprotein (AFP) response beyond 4 weeks, we applied a novel 50-10 rule of AFP response for unresectable HCC patients under nivolumab monotherapy and proposed an algorithm based on on-treatment AFP reduction at different time-points. Ninety unresectable HCC patients who underwent nivolumab monotherapy in 2015-2019 were retrospectively recruited and divided into four classes: rapid AFP decrease of ≥ 50% of baseline at week 4 (class I), AFP changes within ± 50% of baseline at week 4 that later decreased to ≥ 10% of baseline (class II) or not (class III) at week 12, and rapid AFP increase of ≥ 50% of baseline at week 4 (class IV). ORR was 47.4%, 36.0%, 7.7%, and 5.0% in class I-IV patients, respectively. Rapid (class I) and delayed (class II) AFP responders had significantly higher ORR, overall survival (OS) and progression-free survival (PFS) than non-responders (class III and IV) (ORR: 40.9% vs. 6.5%, P<0.001; median OS: not reached vs. 9.6 months, log-rank P<0.001; median PFS: 9.6 vs. 2.8 months, log-rank P<0.001). In multivariate analysis, AFP response was an independent factor associated with good OS (hazard ratio [HR]=0.301, P=0.001) and PFS (HR=0.332, P<0.001). Moreover, AFP responders had higher ORR and better OS as well as PFS than non-responders, regardless of nivolumab as a first- or more than a second-line therapy (all P<0.05). In conclusion, the novel 50-10 rule of AFP response provides practical guidance for nivolumab monotherapy in unresectable HCC patients. However, this algorithm remains to be verified in a large prospective cohort.