Sex and ethnic disparities in hepatitis B evaluation and treatment across the world.

BACKGROUND & AIMS: Oral antiviral therapy with nucleos(t)ide analogues (NAs) for chronic hepatitis B (CHB) is well-tolerated and lifesaving, but real-world data on utilization are limited. We examined rates of evaluation and treatment in patients from the REAL-B consortium. METHODS: This was a cross-sectional study nested within our retrospective multinational clinical consortium (2000-2021). We determined the proportions of patients receiving adequate evaluation, meeting AASLD treatment criteria, and initiating treatment at any time during the study period. We also identified factors associated with receiving adequate evaluation and treatment using multivariable logistic regression analyses. RESULTS: We analyzed 12,566 adult treatment-naïve patients with CHB from 25 centers in 9 countries (mean age 47.1 years, 41.7% female, 96.1% Asian, 49.6% Western region, 8.7% cirrhosis). Overall, 73.3% (9,206 patients) received adequate evaluation. Among the adequately evaluated, 32.6% (3,001 patients) were treatment eligible by AASLD criteria, 83.3% (2,500 patients) of whom were initiated on NAs, with consistent findings in analyses using EASL criteria. On multivariable logistic regression adjusting for age, sex, cirrhosis, and ethnicity plus region, female sex was associated with adequate evaluation (adjusted odds ratio [aOR] 1.13, p = 0.004), but female treatment-eligible patients were about 50% less likely to initiate NAs (aOR 0.54, p <0.001). Additionally, the lowest evaluation and treatment rates were among Asian patients from the West, but no difference was observed between non-Asian patients and Asian patients from the East. Asian patients from the West (vs. East) were about 40-50% less likely to undergo adequate evaluation (aOR 0.60) and initiate NAs (aOR 0.54) (both p <0.001). CONCLUSIONS: Evaluation and treatment rates were suboptimal for patients with CHB in both the East and West, with significant sex and ethnic disparities. Improved linkage to care with linguistically competent and culturally sensitive approaches is needed. IMPACT AND IMPLICATIONS: Significant sex and ethnic disparities exist in hepatitis B evaluation and treatment, with female treatment-eligible patients about 50% less likely to receive antiviral treatment and Asian patients from Western regions also about 50% less likely to receive adequate evaluation or treatment compared to Asians from the East (there was no significant difference between Asian patients from the East and non-Asian patients). Improved linkage to care with linguistically competent and culturally sensitive approaches is needed.

Chronic Hepatitis C Related Steatotic Liver Disease Is More Than "Miscellaneous Steatotic Liver Disease".

The terminology and definition of fatty liver disease has evolved significantly. Recently, the overarching term of steatotic liver disease (SLD) has been endorsed by international societies.1,2 SLD further encompasses individuals with cardiometabolic risk factors (CMRFs), namely, metabolic dysfunction-associated steatotic liver disease (MASLD).

Chronic Viral Hepatitis B and C Outweigh MASLD in the Associated Risk of Cirrhosis and HCC.

BACKGROUND & AIMS: The impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on the development of cirrhosis and hepatocellular carcinoma (HCC) by chronic hepatitis B (CHB) or C infection and antiviral treatment statuses is not well-known. METHODS: A total of 336,866 adults aged ≥30 years were prospectively enrolled in a health screening program between 1997-2013. MASLD was identified by abdominal ultrasonography and cardiometabolic profiles. Data linkage was performed using 3 nationwide databases-National Health Insurance, Cancer Registry, and Death Certification System-to obtain information on antiviral treatment, vital status, and newly diagnosed cirrhosis and HCC. Follow-up was conducted until December 31, 2019. RESULTS: In the total population, 122,669 (36.4%) had MASLD. Over a mean follow-up of 15 years, 5562 new cases of cirrhosis and 2273 new cases of HCC were diagnosed. Although MASLD significantly increased the cumulative risks of cirrhosis or HCC (P < .0001), the associated risk was more pronounced when comparing CHB or C infection with the presence of MASLD. Stratifying the participants based on their MASLD and CHB or C statuses, hazard ratios (HRadj) with 95% confidence intervals for HCC were 8.81 (7.83-9.92) for non-steatotic liver disease (SLD) with CHB or C, 1.52 (1.32-1.74) for MASLD without CHB or C, and 8.86 (7.76-10.12) for MASLD with CHB or C, compared with non-SLD without CHB or C (all P < .0001). Among CHB or C patients who received antivirals during follow-up, MASLD was associated with increased risks of cirrhosis and HCC, with HRadj of 1.23 (1.01-1.49) and 1.32 (1.05-1.65), respectively. CONCLUSIONS: These findings underscore the need to prioritize treatment of chronic viral hepatitis before addressing MASLD.

Sex Differences in Treatment Response to Nucleos(t)ide Therapy in Chronic Hepatitis B: A Multicenter Longitudinal Study.

BACKGROUND & AIMS: It is unclear if there may be sex differences in response to nucleos(t)ide analogs including virologic response (VR), biochemical response (BR), complete response (CR), and hepatocellular carcinoma (HCC) incidence among hepatitis B patients. We compared nucleos(t)ide analog treatment outcomes by sex. METHODS: We performed a retrospective cohort study of 3388 treatment-naïve adult hepatitis B patients (1250 female, 2138 male) from the Real-World Evidence from the Global Alliance for the Study of Hepatitis B Virus consortium who initiated therapy with either entecavir or tenofovir from 22 sites (Argentina, Korea, Japan, Taiwan, and the United States). We used propensity-score matching to balance background characteristics of the male and female groups and competing-risks analysis to estimate the incidence and subdistribution hazard ratios (SHRs) of VR, BR, CR, and HCC. RESULTS: Females (vs males) were older (52.0 vs 48.6 y); less likely to be overweight/obese (49.3% vs 65.7%), diabetic (9.9% vs 13.1%), or cirrhotic (27.9% vs 33.0%); and had a lower HBV DNA level (5.9 vs 6.0 log10 IU/mL) and alanine aminotransferase level (91 vs 102 IU/L) (all P < .01). However, after propensity-score matching, relevant background characteristics were balanced between the 2 groups. Females (vs males) had similar 5-year cumulative VR (91.3% vs 90.3%; P = .40) and HCC incidence rates (5.1% vs 4.4%; P = .64), but lower BR (84.0% vs 90.9%; P < .001) and CR (78.8% vs 83.4%; P = .016). Males were more likely to achieve BR (SHR, 1.31; 95% CI, 1.17-1.46; P < .001) and CR (SHR, 1.16; 95% CI, 1.03-1.31; P = .016), but VR and HCC risks were similar. CONCLUSIONS: Sex differences exist for treatment outcomes among hepatitis B patients. Male sex was associated with a 16% higher likelihood of clinical remission and a 31% higher likelihood of biochemical response than females, while virologic response and HCC incidence were similar between the 2 groups.

Long-term Risks of Cirrhosis and Hepatocellular Carcinoma Across Steatotic Liver Disease Subtypes.

INTRODUCTION: The prospective study aimed to investigate the long-term associated risks of cirrhosis and hepatocellular carcinoma (HCC) across various subtypes of steatotic liver disease (SLD). METHODS: We enrolled 332,175 adults who participated in a health screening program between 1997 and 2013. Participants were categorized into various subtypes, including metabolic dysfunction-associated SLD (MASLD), MASLD with excessive alcohol consumption (MetALD), and alcohol-related liver disease (ALD), based on ultrasonography findings, alcohol consumption patterns, and cardiometabolic risk factors. We used computerized data linkage with nationwide registries from 1997 to 2019 to ascertain the incidence of cirrhosis and HCC. RESULTS: After a median follow-up of 16 years, 4,458 cases of cirrhosis and 1,392 cases of HCC occurred in the entire cohort, resulting in an incidence rate of 86.1 and 26.8 per 100,000 person-years, respectively. The ALD group exhibited the highest incidence rate for cirrhosis and HCC, followed by MetALD, MASLD, and non-SLD groups. The multivariate adjusted hazard ratios for HCC were 1.92 (95% confidence interval [CI] 1.51-2.44), 2.91 (95% CI 2.11-4.03), and 2.59 (95% CI 1.93-3.48) for MASLD, MetALD, and ALD, respectively, when compared with non-SLD without cardiometabolic risk factors. The pattern of the associated risk of cirrhosis was similar to that of HCC (all P value <0.001). The associated risk of cirrhosis for ALD increased to 4.74 (95% CI 4.08-5.52) when using non-SLD without cardiometabolic risk factors as a reference. DISCUSSION: This study highlights elevated risks of cirrhosis and HCC across various subtypes of SLD compared with non-SLD, emphasizing the importance of behavioral modifications for early prevention.

Systematic integration of molecular and clinical approaches in HCV-induced hepatocellular carcinoma.

BACKGROUND: MicroRNAs (miRNAs) play a crucial role in gene expression and regulation, with dysregulation of miRNA function linked to various diseases, including hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). There is still a gap in understanding the regulatory relationship between miRNAs and mRNAs in HCV-HCC. This study aimed to investigate the function and effects of persistent HCV-induced miRNA expression on gene regulation in HCC. METHODS: MiRNA array data were used to identify differentially expressed miRNAs and their targets, and miRNAs were analyzed via DIANA for KEGG pathways, gene ontology (GO) functional enrichment, and Ingenuity Pathways Analysis (IPA) for hepatotoxicity, canonical pathways, associated network functions, and interactive networks. RESULTS: Seventeen miRNAs in L-HCV and 9 miRNAs in S-HCV were differentially expressed, and 5 miRNAs in L-HCV and 5 miRNAs in S-HCV were significantly expressed in liver hepatocellular carcinoma (LIHC) tumors. Grouped miRNA survival analysis showed that L-HCV miRNAs were associated with survival in LIHC, and miRNA‒mRNA targets regulated viral carcinogenesis and cell cycle alteration through cancer pathways in LIHC. MiRNA-regulated RCN1 was suppressed through miRNA-oncogene interactions, and suppression of RCN1 inhibited invasion and migration in HCC. CONCLUSION: Persistent HCV infection induced the expression of miRNAs that act as tumor suppressors by inhibiting oncogenes in HCC. RCN1 was suppressed while miRNAs were upregulated, demonstrating an inverse relationship. Therefore, hsa-miR-215-5p, hsa-miR-10b-5p, hsa-let-7a-5p and their target RCN1 may be ideal biomarkers for monitoring HCV-HCC progression.

Antiviral therapy substantially reduces HCC risk in patients with chronic hepatitis B infection in the indeterminate phase.

BACKGROUND AND AIMS: HCC risk in chronic hepatitis B (CHB) is higher in the indeterminate phase compared with the inactive phase. However, it is unclear if antiviral therapy reduces HCC risk in this population. We aimed to evaluate the association between antiviral therapy and HCC risk in the indeterminate phase. APPROACH AND RESULTS: We analyzed 855 adult (59% male), treatment-naïve patients with CHB infection without advanced fibrosis in the indeterminate phase at 14 centers (USA, Europe, and Asia). Inverse probability of treatment weighting (IPTW) was used to balance the treated (n = 405) and untreated (n = 450) groups. The primary outcome was HCC development. The mean age was 46±13 years, the median alanine transaminase was 38 (interquartile range, 24-52) U/L, the mean HBV DNA was 4.5±2.1 log 10 IU/mL, and 20% were HBeAg positive. The 2 groups were similar after IPTW. After IPTW (n = 819), the 5-, 10-, and 15-year cumulative HCC incidence was 3%, 4%, and 9% among treated patients (n = 394) versus 3%, 15%, and 19%, among untreated patients (n = 425), respectively ( p = 0.02), with consistent findings in subgroup analyses for age >35 years, males, HBeAg positive, HBV DNA>1000 IU/mL, and alanine transaminase

The interplay of metabolic dysfunction-associated fatty liver disease and viral hepatitis on liver disease severity: A large community-based study in a viral endemic area.

BACKGROUND AND AIM: The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) and its interplay with hepatitis B virus (HBV) and hepatitis C virus (HCV) in terms of liver disease severity is elusive. METHODS: A mass surveillance program was conducted in a viral hepatitis endemic area. The objective was to identify MAFLD/non-MAFLD subjects with advanced liver disease. RESULTS: Two thousand two hundred and forty-two (41.7%) of the 5378 subjects were identified as having MAFLD, and 375 (7.0%) had advanced liver disease. The proportions of anti-HCV and HBsAg seropositivity were 19.3% and 9.7%, respectively. The proportions of advanced fibrosis in subjects with non-viral hepatitis (NBNC), HBV and HCV infection were 2.8%, 5.7% and 23.4%, respectively. Subjects with MAFLD had a significantly higher proportion of advanced fibrosis (8.7% vs 5.7%, P < 0.001). Factors associated with advanced fibrosis included age (odds ratio [OR]/95% confidence interval [CI]: 4.8/3.7-6.0, P < 0.001), male sex (OR/CI: 1.3/1.0-1.7, P = 0.019), anti-HCV seropositivity (OR/CI: 5.9/4.6-7.5, P = 0.019), MAFLD-lean metabolic dysregulation (MS) (OR/CI: 2.6/1.3-5.2, P = 0.005; compared with the non-MAFLD group) and MAFLD-diabetes (OR/CI: 1.5/1.1-2.1, P = 0.008; compared with the non-MAFLD group). MAFLD did not aggravate liver disease severity in patients with viral hepatitis. However, among NBNC subjects, factors associated with advanced liver disease included MAFLD-lean MS group (OR/CI: 9.1/2.4-34.6, P = 0.001; compared with non-MAFLD group) and MAFLD-DM group (OR/CI: 2.0/1.2-3.2, P = 0.004; compared with non-MAFLD group). CONCLUSIONS: MAFLD patients with diabetes and metabolic dysregulation had a higher risk of advanced liver disease. The effect was more significant in non-viral hepatitis subjects in a community level.

Prevalence, proportions of elevated liver enzyme levels, and long-term cardiometabolic mortality of patients with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND AND AIM: This study estimated the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) according to cardiometabolic risk factors. The long-term impacts of MASLD on all-cause and cardiometabolic-specific mortality were evaluated. METHODS: We enrolled 343 816 adults aged ≥30 years who participated in a health screening program from 1997 through 2013. MASLD was identified on the basis of abdominal ultrasonography and metabolic profiles. The participants were further categorized by liver enzyme elevation. Baseline cardiometabolic comorbidities were classified on the basis of self-reported medication use and clinical seromarkers. All-cause and cardiometabolic-specific deaths were determined through computerized data linkage with nationwide death certifications until December 31, 2020. RESULTS: The overall prevalence of MASLD was 36.4%. Among patients with MASLD, 35.9% had abnormal liver enzyme levels. Compared with patients without MASLD, abnormal liver enzymes were positively associated with cardiometabolic comorbidities in patients with MASLD (Pfor trend < 0.001). After follow-up, patients with MASLD had a 9%-29% higher risk of all-cause, cardiovascular-related, or diabetes-related mortality. In the groups with MASLD and elevated and normal liver enzyme levels, the multivariate-adjusted hazard ratios for cardiovascular deaths were 1.14 (1.05-1.25) and 1.10 (1.03-1.17), respectively, and those for diabetes deaths were 1.42 (1.05-1.93) and 1.24 (0.98-1.57), respectively, compared with those in the non-MASLD group (Pfor trend < 0.001). DISCUSSION: Individuals with MASLD and elevated liver enzyme levels exhibited significantly higher risks of all-cause and cardiometabolic deaths and should be monitored and given consultation on cardiometabolic modifications.

Mortality in patients with chronic hepatitis B treated with tenofovir or entecavir: A multinational study.

BACKGROUND AND AIM: The benefits of entecavir (ETV) versus tenofovir disoproxil fumarate (TDF) in reducing the development of chronic hepatitis B (CHB)-related hepatocellular carcinoma remain controversial. Whether mortality rates differ between patients with CHB treated with ETV and those treated with TDF is unclear. METHODS: A total of 2542 patients with CHB treated with either ETV or TDF were recruited from a multinational cohort. A 1:1 propensity score matching was performed to balance the differences in baseline characteristics between the two patient groups. We aimed to compare the all-cause, liver-related, and non-liver-related mortality between patients receiving ETV and those receiving TDF. RESULTS: The annual incidence of all-cause mortality in the entire cohort was 1.0/100 person-years (follow-up, 15 757.5 person-years). Patients who received TDF were younger and had a higher body mass index, platelet count, hepatitis B virus deoxyribonucleic acid levels, and proportion of hepatitis B e-antigen seropositivity than those who received ETV. The factors associated with all-cause mortality were fibrosis-4 index > 6.5 (hazard ratio [HR]/confidence interval [CI]: 3.13/2.15-4.54, P < 0.001), age per year increase (HR/CI: 1.05/1.04-1.07, P < 0.001), alanine aminotransferase level per U/L increase (HR/CI: 0.997/0.996-0.999, P = 0.003), and γ-glutamyl transferase level per U/L increase (HR/CI: 1.002/1.001-1.003, P < 0.001). No significant difference in all-cause mortality was observed between the ETV and TDF groups (log-rank test, P = 0.69). After propensity score matching, no significant differences in all-cause, liver-related, or non-liver-related mortality were observed between the two groups. CONCLUSIONS: Long-term outcomes of all-cause mortality and liver-related and non-liver-related mortality did not differ between patients treated with ETV and those receiving TDF.

A therapeutic dose and its pharmacokinetics of ropeginterferon Alfa-2b for hepatitis C treatment.

AIM: Ropeginterferon alfa-2b is a novel mono-pegylated proline-interferon. Its biweekly dosing schema has demonstrated tolerability and clinical efficacy for treating chronic hepatitis in previous clinical studies. This trial evaluates the pharmacokinetics of 400 µg ropeginterferon alfa-2b in patients with chronic hepatitis C virus (HCV) and provides the data to support the clinical utility of ropeginterferon alfa-2b at 400 µg. METHODS: Seventeen patients with chronic HCV genotype 2 were enrolled to receive a single injection of 400 µg ropeginterferon alfa-2b plus 14-day treatment of ribavirin. Pharmacokinetics, safety, and HCV RNA reduction/clearance were assessed. RESULTS: Tmax was 154.003 h and T1/2 was 114.273 h. The Cmax was 29.823 ng mL-1. AUClast was 9364.292 h∗ng mL-1 and AUCinf was 11084.317 h∗ng mL-1. All adverse events were mild or moderate, and there were no serious adverse events. A 1000-fold reduction in the geometric mean of HCV RNA was observed 14 d after the single injection of ropeginterferon alfa-2b. Two patients achieved clearance of HCV RNA, and the other five patients had HCV RNA levels lower than 200 IU mL-1. CONCLUSION: Ropeginterferon alfa-2b at 400 µg led to PK exposures associated with safety and notable clinical activity in patients with chronic HCV. This study suggests that ropeginterferon alfa-2b at 400 µg is an acceptable dosing regimen for treating chronic HCV and also provides supporting data for the clinical use of ropeginterferon alfa-2b at a higher starting dose for other indications.

Hepatitis D double reflex testing of all hepatitis B carriers in low-HBV- and high-HBV/HDV-prevalence countries.

Hepatitis D virus (HDV) infection occurs as a coinfection with hepatitis B and increases the risk of hepatocellular carcinoma, decompensated cirrhosis, and mortality compared to hepatitis B virus (HBV) monoinfection. Reliable estimates of the prevalence of HDV infection and disease burden are essential to formulate strategies to find coinfected individuals more effectively and efficiently. The global prevalence of HBV infections was estimated to be 262,240,000 in 2021. Only 1,994,000 of the HBV infections were newly diagnosed in 2021, with more than half of the new diagnoses made in China. Our initial estimates indicated a much lower prevalence of HDV antibody (anti-HDV) and HDV RNA positivity than previously reported in published studies. Accurate estimates of HDV prevalence are needed. The most effective method to generate estimates of the prevalence of anti-HDV and HDV RNA positivity and to find undiagnosed individuals at the national level is to implement double reflex testing. This requires anti-HDV testing of all hepatitis B surface antigen-positive individuals and HDV RNA testing of all anti-HDV-positive individuals. This strategy is manageable for healthcare systems since the number of newly diagnosed HBV cases is low. At the global level, a comprehensive HDV screening strategy would require only 1,994,000 HDV antibody tests and less than 89,000 HDV PCR tests. Double reflex testing is the preferred strategy in countries with a low prevalence of HBV and those with a high prevalence of both HBV and HDV. For example, in the European Union and North America only 35,000 and 22,000 cases, respectively, will require anti-HDV testing annually.

Influence of Nonalcoholic Fatty Liver Disease With Increased Liver Enzyme Levels on the Risk of Cirrhosis and Hepatocellular Carcinoma.

BACKGROUND & AIMS: The influence of nonalcoholic fatty liver disease (NAFLD) on the long-term risk of cirrhosis and hepatocellular carcinoma (HCC) in Asian populations has not been widely investigated. METHODS: We enrolled 129,374 adults aged 30 years and older, all of whom participated in a health screening program from 2008 through 2013, were seronegative for hepatitis B surface antigen and anti-hepatitis C virus antibodies, and had limited daily alcohol consumption (<20 g/d for men and <10 g/d for women). Abdominal ultrasonography was performed to determine the presence of NAFLD. The participants were divided into the following groups: NAFLD with increased or normal liver enzyme levels, and non-NAFLD with normal liver enzyme levels. The incidences of cirrhosis and HCC were determined through computerized data linkage with nationwide registries. Cox proportional hazard models were used to estimate the hazard ratios of NAFLD on the risks of cirrhosis and HCC. RESULTS: The incidence rates of cirrhosis and HCC increased as follows: non-NAFLD with normal liver enzyme levels (n = 66,801; 51%), NAFLD with normal liver enzyme levels (n = 41,461; 32%), and NAFLD with increased liver enzyme levels (n = 21,112; 16%). In the NAFLD group with increased liver enzyme levels and the NAFLD group with normal liver enzyme levels, the corresponding multivariate-adjusted hazard ratios for cirrhosis were 3.51 (95% confidence interval [CI]: 2.36-5.22) and 0.73 (95% CI: 0.46-1.16), and for HCC were 1.91 (95% CI: 1.08-3.38) and 0.57 (95% CI: 0.31-1.04), respectively, compared with the non-NAFLD group (P for trend < .001). The findings were consistent after restricting the analysis to nonobese individuals (body mass index, <25 kg/m2) and nonobese individuals without diabetes (P < .05). CONCLUSIONS: Individuals with NAFLD and increased liver enzyme levels showed significantly higher risks for cirrhosis and HCC and should be monitored.

Long-term Treatment With Tenofovir Alafenamide for Chronic Hepatitis B Results in High Rates of Viral Suppression and Favorable Renal and Bone Safety.

OBJECTIVES: Results from two Phase 3 studies, through 2 years, in chronic hepatitis B infection (CHB) showed tenofovir alafenamide (TAF) had similar efficacy to tenofovir disoproxil fumarate (TDF) with superior renal and bone safety. Here, we report updated results through 5 years. METHODS: Patients with HBeAg-negative or -positive CHB with or without compensated cirrhosis were randomized (2:1) to TAF 25 mg or TDF 300 mg once daily in double-blind (DB) fashion for up to 3 years, followed by open-label (OL) TAF up to 8 years. Efficacy (antiviral, biochemical, serologic), resistance (deep sequencing of polymerase/reverse transcriptase and phenotyping), and safety, including renal and bone parameters, were evaluated by pooled analyses. RESULTS: Of 1298 randomized and treated patients, 866 receiving TAF (DB and OL) and 432 receiving TDF with rollover to OL TAF at year 2 (n = 180; TDF→TAF3y) or year 3 (n = 202; TDF→TAF2y) were included. Fifty (4%) TDF patients who discontinued during DB were excluded. At year 5, 85%, 83%, and 90% achieved HBV DNA < 29 IU/mL (missing = failure) in the TAF, TDF→TAF3y, and TDF→TAF2y groups, respectively; no patient developed TAF or TDF resistance. Median eGFR (by Cockcroft-Gault) declined < 2.5 mL/min, and mean declines of < 1% in hip and spine bone mineral density were seen at year 5 in the TAF group; patients in the TDF→TAF groups had improvements in these parameters at year 5 after switching to OL TAF. CONCLUSIONS: Long-term TAF treatment resulted in high rates of viral suppression, no resistance, and favorable renal and bone safety.

Impact of comorbidities on the serological response to COVID-19 vaccination in a Taiwanese cohort.

BACKGROUND/AIMS: Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the best policies to control COVID-19 pandemic. The serological response to COVID-19 vaccination in Taiwanese patients with different comorbidities is elusive. METHODS: Uninfected subjects who received 3 doses of mRNA vaccines (BNT162b2 [Pfizer-BioNTech, BNT] and mRNA-1273 [Moderna]), viral vector-based vaccines (ChAdOx1-S (AZD1222, AZ) or protein subunit vaccines (Medigen COVID-19 vaccine) were prospectively enrolled. The SARS-CoV-2-IgG spike antibody level was determined within three months after the 3rd dose of vaccination. The Charlson Comorbidity Index (CCI) was applied to determine the association between vaccine titers and underlying comorbidities. RESULTS: A total of 824 subjects were enrolled in the current study. The proportions of CCI scores of 0-1, 2-3 and > 4 were 52.8% (n = 435), 31.3% (n = 258) and 15.9% (n = 131), respectively. The most commonly used vaccination combination was AZ-AZ-Moderna (39.2%), followed by Moderna-Moderna-Moderna (27.8%). The mean vaccination titer was 3.11 log BAU/mL after a median of 48 days after the 3rd dose. Factors associated with potentially effective neutralization capacity (IgG level ≥ 4160 AU/mL) included age ≥ 60 years (odds ratio [OR]/95% confidence interval [CI]: 0.50/0.34-0.72, P < 0.001), female sex (OR/CI: 1.85/1.30-2.63, P = 0.001), Moderna-Moderna-based vaccination (compared to AZ-AZ-based vaccination, OR/CI: 6.49/3.90-10.83, P < 0.001), BNT-BNT-based vaccination (compared to AZ-AZ-based vaccination, OR/CI: 7.91/1.82-34.3, P = 0.006) and a CCI score ≥ 4 (OR/CI: 0.53/0.34-0.82, P = 0.004). There was a decreasing trend in antibody titers with increasing CCI scores (trend P < 0.001). Linear regression analysis revealed that higher CCI scores (ß: - 0.083; 95% CI: - 0.094-0.011, P = 0.014) independently correlated with low IgG spike antibody levels. CONCLUSIONS: Subjects with more comorbidities had a poor serological response to 3 doses of COVID-19 vaccination.

Ledipasvir/Sofosbuvir for Patients Coinfected With Chronic Hepatitis C and Hepatitis B in Taiwan: Follow-up at 108 Weeks Posttreatment.

BACKGROUND: For patients coinfected with hepatitis C virus (HCV) and hepatitis B virus (HBV), HCV treatment with direct-acting antivirals can lead to HBV reactivation. We evaluated HBV reactivation during ledipasvir/sofosbuvir treatment and 108-week follow-up. METHODS: In Taiwan, 111 patients with HCV genotype 1 or 2 and HBV received ledipasvir/sofosbuvir (90mg/400mg) once daily for 12 weeks. HBV virologic reactivation was defined as postbaseline increase in HBV DNA from either less than the lower limit of quantification (LLOQ, 20 IU/mL) to equal to or more than LLOQ or equal to or more than LLOQ to >1 log10 IU/mL. HBV clinical reactivation was HBV virologic reactivation with alanine aminotransferase (ALT) >2× upper limit of normal. Factors associated with development of HBV virologic or clinical reactivation were evaluated with logistic regression analysis. RESULTS: All patients (100%, 111/111) maintained HCV suppression through 108 weeks after treatment. HBV virologic reactivation occurred in 73% of patients (81/111). Clinical reactivation occurred in 9% (10/111). The majority of HBV virologic reactivations (86%, 70/81) occurred by follow-up week 12, whereas clinical reactivation was generally more delayed. Eight (7%, 8/111) initiated HBV therapy. In regression analyses, baseline HBV DNA and hepatitis B surface antigen (HBsAg) levels were associated with HBV virologic reactivation and baseline ALT and HBV DNA, and HBsAg levels were associated with HBV clinical reactivation. CONCLUSION: Among HCV/HBV coinfected patients treated with direct-acting antivirals for HCV, HBV virologic reactivation occurred in a majority of patients during treatment and follow-up. In most patients, HBV virologic reactivation was asymptomatic; only a small proportion initiated HBV treatment. Notably, clinical reactivation may still occur >3 months after end of therapy. CLINICAL TRIALS REGISTRATION: NCT02613871.

Impact of Sofosbuvir-Based Direct-Acting Antivirals on Renal Function in Chronic Hepatitis C Patients With Impaired Renal Function: A Large Cohort Study From the Nationwide HCV Registry Program (TACR).

BACKGROUND & AIMS: Sofosbuvir is approved for chronic hepatitis C (CHC) patients with severe chronic kidney disease (CKD). The impact of sofosbuvir-based therapy on renal function augmentation on a real-world nationwide basis is elusive. METHODS: The 12,995 CHC patients treated with sofosbuvir-based (n = 6802) or non-sofosbuvir-based (n = 6193) regimens were retrieved from the Taiwan nationwide real-world HCV Registry Program. Serial estimated glomerular filtration rate (eGFR) levels were measured at baseline, end of treatment (EOT), and end of follow-up (EOF) (3 months after EOT). RESULTS: The eGFR decreased from baseline (91.4 mL/min/1.73 m2) to EOT (88.4 mL/min/1.73 m2; P < .001) and substantially recovered at EOF (88.8 mL/min/1.73 m2) but did not return to pretreatment levels (P < .001). Notably, a significant decrease in eGFR was observed only in patients with baseline eGFR ≥90 mL/min/1.73 m2 (from 112.9 to 106.4 mL/min/1.73 m2; P < .001). In contrast, eGFR increased progressively in patients whose baseline eGFR was <90 mL/min/1.73 m2 (from 70.0 to 71.5 mL/min/1.73 m2; P < .001), and this increase was generalized across different stages of CKD. The trend of eGFR amelioration was consistent irrespective of sofosbuvir usage. Multivariate adjusted analysis demonstrated that baseline eGFR >90 mL/min/1.73 m2 was the only factor independently associated with significant slope coefficient differences of eGFR (-1.98 mL/min/1.73 m2; 95% confidence interval, -2.24 to -1.72; P < .001). The use of sofosbuvir was not an independent factor associated with eGFR change. CONCLUSIONS: Both sofosbuvir and non-sofosbuvir-based regimens restored renal function in CHC patients with CKD, especially in those with significant renal function impairment.

Clinical characteristics and treatment outcomes of SARS-CoV-2 delta variant outbreak, Pingtung, Taiwan, June 2021.

BACKGROUND: An outbreak of SARS-CoV-2 Delta variant infection occurred in Pingtung, Taiwan, in June 2021. In this study, we aimed to elucidate the clinical characteristics of the Delta-variant SARS-CoV-2 infection and the treatment outcome of antiviral agents in patients from Pingtung County in Southern Taiwan. METHODS: A total of 11 patients with Delta-variant COVID-19 were consecutively admitted to a governmental hospital in June 2021. Baseline characteristics and treatment outcome were evaluated. RESULTS: All patients were symptomatic. The most common symptoms were cough (72.7%), followed by fever (54.5%), headache (18.2%) and dysosmia/dysgeusia (18.2%). Two patients developed pneumonia without mechanical ventilation requirement. Compared to patients without pneumonia, those with pneumonia had higher aspartate aminotransferase (AST) (21.0 vs. 126.0 IU/L, P = 0.03) and lactate dehydrogenase (LDH) (143.1 vs. 409.0 IU/mL, P = 0.03), and ferritin (0.2 vs. 2.0 mg/L, P = 0.046) levels. Pneumonia improved after 2-week treatment, and no mortality occurred after 30 days of diagnosis. The median duration of viral shedding duration of viral shedding was 16.5 days (range 11-42 days) (defined by time to repeated negative real-time reverse transcriptase polymerase chain reaction (RT-PCR) or a cycle threshold (CT) value ≥ 30). CONCLUSION: We demonstrated the clinical characteristics of Delta-variant COVID-19 and treatment outcome of antiviral agents. The risk factors attributed to pneumonia were higher serum AST, ferritin, and LDH levels.

Body weight changes in treated hepatitis B patients switching to tenofovir alafenamide☆.

BACKGROUND/PURPOSE: Switching to a tenofovir alafenamide (TAF)-containing regimen has been reported to be associated with body weight gain in human immunodeficiency virus-infected subjects. We aimed to investigate the body weight change and virological, hepatic, and renal outcomes of TAF switching among chronic hepatitis B (CHB) patients. METHODS: This retrospective study included 121 CHB patients who were switched to TAF after >12 months of treatment with another nucleot(s)ide analog (NUC). All patients were monitored for 12 months. RESULTS: The cohort was mostly Asian (96.7%) with a mean age of 55 years, 72% male, 14% cirrhosis, 21% HBeAg positive, and 75% with prior use of tenofovir disoproxil fumarate. At 12 months after TAF switching, their body weight significantly increased from 66.4 ± 11.8 to 67.8 ± 12.3 kg (p < 0.001), and 21.1% of the subjects had a ≥5% weight gain. Patients without diabetes or hypertension were more likely to have a body weight gain. Meanwhile, the complete viral suppression rate increased significantly from 89.3% to 96.2% (p = 0.016). The rate of alanine aminotransferase normalization also increased significantly from 71.1% to 87.6% (p < 0.001) by local criteria and from 58.7% to 70.2% (p = 0.029) by AASLD criteria. The mean eGFR (mL/min/1.73 m2) did not change (88.2 ± 18.8 vs. 87.2 ± 17.5, p = 0.28). However, for the subgroup with GFR <90 at TAF switching, there was a significant improvement in eGFR (72.9 ± 12.0 vs. 75.7 ± 14.2, p = 0.027). CONCLUSION: In real-world NUC-experienced CHB patients, unexpected body weight gain was observed after TAF switching. The mechanism needs to be investigated in the future.

Ledipasvir/sofosbuvir for HCV genotype 1, 2, 4-6 infection: Real-world evidence from a nationwide registry in Taiwan.

BACKGROUND/PURPOSE: The Taiwan Association for the Study of the Liver (TASL) HCV Registry (TACR) is a nationwide registry of chronic hepatitis C patients in Taiwan. This study evaluated antiviral effectiveness of ledipasvir (LDV)/sofosbuvir (SOF) in patients in the TACR. METHODS: Patients enrolled in TACR from 2017-2020 treated with LDV/SOF were eligible. The primary outcome was the proportion of patients with sustained virologic response 12 weeks after end of treatment (SVR12). RESULTS: 5644 LDV/SOF ± ribavirin-treated patients were included (mean age: 61.4 years; 54.4% female). Dominant viral genotypes were GT1 (50.8%) and GT2 (39.3%). 1529 (27.1%) patients had liver cirrhosis, including 201 (3.6%) with liver decompensation; 686 (12.2%) had chronic kidney disease. SVR12 was achieved in 98.6% of the overall population and in 98.2% and 98.7% of patients with and without cirrhosis, respectively. SVR12 rates in patients with compensated cirrhosis treated with LDV/SOF without RBV were >98%, regardless of prior treatment experience. SVR12 was 98.6%, 98.4%, 100%, 100%, and 98.7% among those with GT1, GT2, GT4, GT5, and GT6 infections, respectively. Although patient numbers were relatively small, SVR12 rates of 100% were reported in patients infected with HCV GT2, GT5, and GT6 with decompensated cirrhosis and 98% in patients with severely compromised renal function. LDV/SOF adherence ≤60% (P < 0.001) was the most important factor associated with treatment failure. Incidence of adverse events was 15.8%, with fatigue being the most common. CONCLUSION: LDV/SOF is effective and well tolerated in routine clinical practice in Taiwan. Cure rates were high across patient populations.