A Retrospective Study of Long-Term Clinical Outcomes in Patients with Chronic Hepatitis C Treated with Interferon and Ribavirin.

BACKGROUND: The key endpoint for treatment efficacy in chronic hepatitis C (CHC) is the absence of a detectable virus at 24 weeks after treatment. This study aims to determine the long-term clinical outcomes in patients with CHC after interferon and ribavirin treatment and the factors that influence them. METHODS: A retrospective study was conducted on 259 patients with CHC between 2003 and 2021, and the patients were divided into treated (n = 159) and untreated (n = 100) groups. The median observation duration was four years for the treated group (range: 1-15 years) and four years for untreated groups (range: 1-14 years). RESULTS: The mean ages of the treated and untreated groups were 47.38 ± 9.07 and 51.17 ± 8.38 years, respectively. Regardless of whether antiviral therapy had been administered, patients with undetectable hepatitis C virus (HCV) load had a lower risk of developing liver cirrhosis and hepatocellular carcinoma (HCC) than patients with detectable HCV load (p < 0.05). Furthermore, patients with HCV genotype 1b were more likely to develop cirrhosis and HCC than patients with HCV non-genotype 1b (p < 0.05). Based on the results of multivariate analysis, age of 50 years and above (hazard ratio [HR] = 6.74, 95% confidence interval [CI] = 2.79-16.28) and infection with HCV genotype 1b (HR = 2.43, 95% CI = 1.06-5.56) were significant predictors of liver cirrhosis and HCC development, whereas undetectable HCV RNA load (HR = 0.14, 95% CI = 0.43-0.46) was a protective factor. CONCLUSIONS: During the long-term follow-up, no cases of HCC were discovered in patients with undetectable HCV RNA load. Nevertheless, long-term monitoring is still required in patients with liver cirrhosis, since it increases the risk for developing liver cancer.

Correlation Between Serum ESPL1 and Hepatitis B Virus-related Hepatocellular Carcinoma Histological Grade: A Chinese Single-center Case-control Study.

BACKGROUND/AIM: Serum markers to determine the histological grade of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) are still limited. This study aimed to investigate if serum extra spindle pole bodies-like 1 (ESPL1) protein could reflect the histological grade of HBV-related HCC. MATERIALS AND METHODS: A total of 154 patients with HBV-related HCC were enrolled in the experimental group and 41 non-HBV-related patients in the control. Enzyme-linked immunosorbent assay was used to detect serum ESPL1 levels. The differences in serological ESPL1, alpha-fetoprotein (AFP), and des-gamma-carboxy prothrombin (DCP) were compared between the two groups. HCC tumor diameter was measured, and pathological examination was performed to compare the relationship between ESPL1, AFP, and DCP and tumor size and histological grade. RESULTS: Serum AFP and DCP levels showed no significant difference between experimental group and control group, and increased when the tumor diameter increased but were not related to HCC histological grade. Serological ESPL1 levels were higher in the experimental group than those in the control group, and positively correlated with the histological grade. In the experimental group, tumor size and histological grade were almost independent (Kappa=0.000); patients with medium size tumors had the highest serum ESPL1 levels and the highest proportion of poorly differentiated carcinomas, whereas 75.6% of patients with small size tumors had moderately differentiated carcinomas and only 20% well differentiated carcinomas. CONCLUSION: Serum ESPL1 can reflect the malignant degree of HBV-related HCC and is helpful in identifying small size HCC tumors.

Structural insights into regulation of CNNM-TRPM7 divalent cation uptake by the small GTPase ARL15.

Cystathionine-ß-synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) are an evolutionarily conserved family of magnesium transporters. They promote efflux of Mg2+ ions on their own and influx of divalent cations when expressed with the transient receptor potential ion channel subfamily M member 7 (TRPM7). Recently, ADP-ribosylation factor-like GTPase 15 (ARL15) has been identified as CNNM-binding partner and an inhibitor of divalent cation influx by TRPM7. Here, we characterize ARL15 as a GTP and CNNM-binding protein and demonstrate that ARL15 also inhibits CNNM2 Mg2+ efflux. The crystal structure of a complex between ARL15 and CNNM2 CBS-pair domain reveals the molecular basis for binding and allowed the identification of mutations that specifically block binding. A binding deficient ARL15 mutant, R95A, failed to inhibit CNNM and TRPM7 transport of Mg2+ and Zn2+ ions. Structural analysis and binding experiments with phosphatase of regenerating liver 2 (PRL2 or PTP4A2) showed that ARL15 and PRLs compete for binding CNNM to coordinate regulation of ion transport by CNNM and TRPM7.

HIV-1 RNA and DNA Genotyping Drug Resistance Detection in Patients with Low-Level Viremia in Liangshan, China.

In this study, we characterized HIV-1 RNA and HIV-1 DNA genotyping drug resistance detection in patients with low-level viremia (LLV) in Liangshan, China. Whole blood samples were collected from HIV/AIDS patients who had received antiretroviral therapy (ART) for ≥6 months and whose HIV-1 RNA loads were 50-1,000 copies/mL for two consecutive times at least 1-month apart. The patients were enrolled from a county in Liangshan Yi Autonomous Prefecture, Sichuan Province, between May 2021 and May 2022. Plasma and blood cells were separated. Plasma samples were tested for HIV-1 RNA genotyping drug resistance, while blood cell samples were tested for HIV-1 DNA genotyping drug resistance. Then, HIV-1 RNA and HIV-1 DNA genotyping drug resistance outcomes were compared. Among the 32 participants, 16 were males, while 16 were females, with the median age of 34.5 years. The main HIV-1 infection route was heterosexual transmission. The median ART duration was 3.9 years. Two types of nucleoside reverse transcriptase inhibitors (NRTIs) + one non-nucleoside reverse transcriptase inhibitor (NNRTI) were the main antiviral therapeutic options. Pol region genes for 28 HIV-1 DNA samples and 10 HIV-1 RNA samples were successfully amplified. The success rate of pol region gene amplification for HIV-1 DNA was significantly higher than that of HIV-1 RNA (χ2 = 20.988, p < .05). In HIV-1 RNA and HIV-1 DNA samples, M184 (4/8) and K103 (3/8) were the most frequent drug resistance mutation sites. Among the NNRTIs, the rates of drug resistance were highest to efavirenz (EFV) (6/8) and nevirapine (NVP) (6/8), while among the NRTIs, the rates of drug resistance were highest to abacavir (ABC) (4/8), emtricitabine (FTC) (4/8), and lamivudine (3TC) (4/8). In conclusion, detection of HIV-1 RNA genotyping drug resistance combined with HIV-1 DNA genotyping drug resistance can improve the success rate of drug resistance detection in patients with LLV.

The Impact of Urban Rail Transit Epidemic Prevention Measures on Passengers' Safety Perception.

In 2020, COVID-19 triggered concern about the safety of public transport. To meet passengers' expectations regarding safety, the public transport department has stepped up its pandemic prevention services. Some prevention services require passengers to follow mandatory requirements. However, whether and to what extent these requirements affect passenger satisfaction with public transportation services remains unclear. This study aims to construct an integrated framework to explore the direct and indirect relationships between four constructs (regular services quality, pandemic prevention service, psychological distance, and safety perception) and passengers' satisfaction in the context of urban rail transit services. Based on survey data collected from 500 passengers on the Shanghai Metro, this paper examines the relationships between routine service, pandemic prevention measures, safety perceptions, and satisfaction with the service. The results from the structural equation model indicate that routine service (0.608), pandemic prevention measures (0.56), and safety perception (0.05) have positive effects on passenger satisfaction. Psychological distance negatively impacts safety perception (-0.949) and has indirect effects on passenger satisfaction. Further, in order to identify the service improvements that public transportation departments should focus on, we use the three-factor theory to identify the services that should be improved: Basic factors, such as "punctual arrival of metros", "treatment of harmful garbage", "increasing frequency of platform disinfection", and "measurement of station temperature" should be treated as the first priority. As the second improvement priority, "the planning of metro stations can accommodate my travel scope" can be considered. Last, public transportation departments can enhance the exciting factor by installing "metro entrance signs" when resources are available.

Development and validation of a dynamic online nomogram for predicting acute kidney injury in cirrhotic patients upon ICU admission.

Background: Acute kidney injury (AKI) is one of the most common and deadly complications among cirrhotic patients at intensive care unit (ICU) admission. We aimed to develop and validate a simple and clinically useful dynamic nomogram for predicting AKI in cirrhotic patients upon ICU admission. Methods: We analyzed the admission data of 4,375 patients with liver cirrhosis in ICU from 2008 to 2019 in the intensive care unit IV (MIMIC-IV) database. The eligible cirrhotic patients were non-randomly divided into derivation (n = 2,188) and validation (n = 2,187) cohorts at a ratio of 1:1, according to the order of admission. The least absolute shrinkage and selection operator regression model was used to identify independent predictors of AKI in the derivation cohort. A dynamic online nomogram was built using multivariate logistic regression analysis in the derivation cohort and then validated in the validation cohort. The C-index, calibration curve, and decision curve analysis were used to assess the nomogram's discrimination, calibration, and clinical usefulness, respectively. Results: The incidence of AKI in 4,375 patients was 71.3%. Ascites, chronic kidney disease, shock, sepsis, diuretic drugs, hepatic encephalopathy, bacterial infections, vasoactive drugs, admission age, total bilirubin, and blood urea nitrogen were identified using the multivariate logistic regression analysis as significant predictors of AKI upon ICU admission. In the derivation cohort, the model showed good discrimination (C-index, 0.786; 95% CI, 0.765-0.806) and good calibration. The model in the validation cohort yielded good discrimination (C-index, 0.774; 95% CI, 0.753-0.795) and good calibration. Decision curve analysis demonstrated that the dynamic online nomogram was clinically useful. Conclusion: Our study presents a dynamic online nomogram that incorporates clinical predictors and can be conveniently used to facilitate the individualized prediction of AKI in cirrhotic patients upon ICU admission.

Development and validation of a nomogram for survival prediction in hepatocellular carcinoma after partial hepatectomy.

BACKGROUND: The prognosis for hepatocellular carcinoma (HCC) is complex due to its high level of heterogeneity, even after radical resection. This study was designed to develop and validate a prognostic nomogram for predicting the postoperative prognosis for HCC patients following partial hepatectomy. PATIENTS AND METHODS: We extracted data on HCC patients and randomly divided them into two groups (primary and validation cohorts), using the Surveillance, Epidemiology and End Results (SEER) database. We developed the prediction model based on the data of the primary cohort and prognostic factors were evaluated using univariate and multivariate Cox regression analysis. A nomogram was constructed for predicting the 1-, 3-, and 5-year survival probability of HCC patients after surgery based on the results of the multivariate Cox regression analysis. The performance of the nomogram was evaluated in terms of its discrimination and calibration. To validated the model, discrimination and calibration were also evaluated in the validation cohort. Decision curve analysis (DCA) was performed to assess the clinical utility of the nomogram. RESULTS: A total of 890 patients who underwent partial hepatectomy for HCC were included in the study. The primary cohort enrolled 628 patients with a median follow-up time of 39 months, the 1-, 3-, and 5-year survival rate were 95.4%, 52.7% and 25.8% during follow-up. Multivariate Cox regression analysis showed that differentiation, tumor size, AFP and fibrosis were independently association with the prognosis of HCC patients after partial hepatectomy. The nomogram showed a moderate discrimination ith a C-index of 0.705 (95% CI 0.669 to 0.742), and good calibration. Similar discrimination with a C-index of 0.681 (95% CI 0.625 to 0.737), and calibration were also observed in the validation cohort. Decision curve analysis showed that the nomogram could be useful to predicting the prognosis in HCC patients following partial hepatectomy. CONCLUSIONS: The proposed nomogram is highly predictive and has moderate calibration and discrimination, potentially contributing to the process of managing HCC patients after partial hepatectomy in an individualized way.

Structural insights into regulation of TRPM7 divalent cation uptake by the small GTPase ARL15.

Cystathionine-ß-synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) are an evolutionarily conserved family of magnesium transporters. They promote efflux of Mg 2+ ions on their own or uptake of divalent cations when coupled to the transient receptor potential ion channel subfamily M member 7 (TRPM7). Recently, ADP-ribosylation factor-like GTPase 15 (ARL15) has been identified as CNNM binding partner and an inhibitor of divalent cation influx by TRPM7. Here, we characterize ARL15 as a GTP-binding protein and demonstrate that it binds the CNNM CBS-pair domain with low micromolar affinity. The crystal structure of the complex between ARL15 GTPase domain and CNNM2 CBS-pair domain reveals the molecular determinants of the interaction and allowed the identification of mutations in ARL15 and CNNM2 mutations that abrogate binding. Loss of CNNM binding prevented ARL15 suppression of TRPM7 channel activity in support of previous reports that the proteins function as a ternary complex. Binding experiments with phosphatase of regenerating liver 2 (PRL2 or PTP4A2) revealed that ARL15 and PRLs compete for binding CNNM, suggesting antagonistic regulation of divalent cation transport by the two proteins.

Structural basis of 3'-end poly(A) RNA recognition by LARP1.

La-related proteins (LARPs) comprise a family of RNA-binding proteins involved in a wide range of posttranscriptional regulatory activities. LARPs share a unique tandem of two RNA-binding domains, La motif (LaM) and RNA recognition motif (RRM), together referred to as a La-module, but vary in member-specific regions. Prior structural studies of La-modules reveal they are pliable platforms for RNA recognition in diverse contexts. Here, we characterize the La-module of LARP1, which plays an important role in regulating synthesis of ribosomal proteins in response to mTOR signaling and mRNA stabilization. LARP1 has been well characterized functionally but no structural information exists for its La-module. We show that unlike other LARPs, the La-module in LARP1 does not contain an RRM domain. The LaM alone is sufficient for binding poly(A) RNA with submicromolar affinity and specificity. Multiple high-resolution crystal structures of the LARP1 LaM domain in complex with poly(A) show that it is highly specific for the RNA 3'-end, and identify LaM residues Q333, Y336 and F348 as the most critical for binding. Use of a quantitative mRNA stabilization assay and poly(A) tail-sequencing demonstrate functional relevance of LARP1 RNA binding in cells and provide novel insight into its poly(A) 3' protection activity.

Tenofovir is superior to entecavir in reducing HCC for patients with HBV-related compensated cirrhosis at high HCC risk scores.

Background: Both tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are known to reduce the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This study aimed to compare the difference in HCC risk reduction between TDF and ETV in treatment-naïve patients with CHB-related compensated cirrhosis. Methods: Patients with compensated cirrhosis initially treated with TDF or ETV at nine Chinese hospitals between June 2014 and March 2021 were enrolled in this retrospective study. The cumulative HCC incidence rates for the two drugs were compared for the entire cohort, and a subgroup analysis was performed according to the HCC risk scores. Propensity score matching (PSM) was used to control confounding biases. Results: The analysis included 1453 patients (TDF group, n = 188; ETV group, n = 1265). Ninety-five patients developed HCC, with a median follow-up period of 26.1 months. The 3-year HCC incidence was 2.0% in the TDF group and 7.5% in the ETV group (log-rank p = 0.005). TDF treatment was associated with a lower risk of HCC than ETV treatment [hazard ratio (HR) = 0.222, 95% confidence interval (CI), 0.070-0.702, p = 0.010] but was similar after PSM (HR = 0.483, 95% CI, 0.144-1.626, p = 0.240; log-rank p = 0.230). However, subgroup analysis showed that the cumulative HCC incidence was lower in the TDF group than in the ETV group among patients with a modified PAGE-B score (mPAGE-B) ⩾9, either before or after PSM (log-rank p = 0.048 and p = 0.023, respectively). Conclusion: Among patients with an mPAGE-B score ⩾9, TDF is associated with a lower HCC incidence than ETV in patients with CHB-related compensated cirrhosis.

The NLRP3 inflammasome mediates liver failure by activating procaspase-1 and pro-IL-1 ß and regulating downstream CD40-CD40L signaling.

OBJECTIVES: In this prospective case-control study, we explored the regulatory roles of the NLRP3 inflammasome in hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF). METHODS: Thirty patients with HBV-ACLF, 30 patients with chronic hepatitis B, and 30 healthy individuals were enrolled. Real-time reverse transcription polymerase chain reaction was used to assess mRNA levels in peripheral blood mononuclear cells and serum protein levels were assessed by enzyme-linked immunosorbent assay. RESULTS: Serum levels of alanine aminotransferase, asparagine aminotransferase, total bilirubin, and direct bilirubin in patients with HBV-ACLF were increased. Transcript levels of NLRP3 and ASC and protein levels of interleukin (IL)-1ß, IL-18, and sCD40L were elevated in patients with HBV-ACLF. Expression of the NLRP3 inflammasome signaling pathway components procaspase-1 and pro-IL-1ß was elevated in patients with HBV-ACLF. CONCLUSIONS: This prospective case-control study demonstrated that significant activation of the NLRP3 inflammasome occurs in patients with HBV-ACLF. The activated NLRP3 inflammasome mediated liver failure by stimulating procaspase-1 and pro-IL-1 ß and regulating downstream CD40-CD40L signaling.

Voriconazole Versus Amphotericin B as Induction Therapy for Talaromycosis in HIV/AIDS Patients: A Retrospective Study.

Disseminated talaromycosis caused by Talaromyces marneffei is a life-threatening opportunistic infection. Although amphotericin B deoxycholate (dAmB) remains the first-line induction treatment, voriconazole can also be used. However, no clinical trials have compared dAmB and voriconazole in the administration of talaromycosis. We retrospectively evaluated the efficacy and safety of voriconazole or dAmB as induction therapy for talaromycosis in HIV-infected patients. We enrolled HIV-infected patients with a confirmed Talaromyces marneffei infection who received intravenous dAmB (0.6 to 0.7 mg/kg daily for 2 weeks) or voriconazole (6 mg/kg every 12 h on day 1 and 4 mg/kg every 12 h afterward) as induction therapy, followed by oral itraconazole as consolidation and maintenance therapy. Drug efficacy was evaluated based on response rate. Drug safety was evaluated based on the occurrence of adverse events. In total, 58 patients who received voriconazole and 82 who received dAmB were enrolled from two hospitals. The voriconazole and dAmB treatment groups had similar response rates at the primary and follow-up efficacy evaluations. However, the durations of induction antifungal therapy and hospital stay were shorter for patients in the voriconazole group than in the dAmB group. Few adverse reactions occurred in either the voriconazole or dAmB group. Our retrospective study indicated that voriconazole is an effective and safe induction antifungal drug for HIV-associated disseminated talaromycosis. The duration of induction treatment with voriconazole was shorter, indicating its potential as a better choice in clinical practice. The duration of voriconazole induction therapy is 11 to 13 days.

Serum ESPL1 Can Be Used as a Biomarker for Patients With Hepatitis B Virus-Related Liver Cancer: A Chinese Case-Control Study.

AIMS: To investigate the feasibility of serum extra spindle pole bodies-like 1 (ESPL1) used as a biomarker for patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). METHODS: 131 chronic HBV-infection patients were recruited and divided into HBV S gene integration, non-HBV S gene integration, chronic hepatitis B (CHB), HBV-related liver cirrhosis (LC) and HBV-related HCC group, 24 non-HBV-related HCC patients were selected as HCC control group, 30 people without HBV-infection as healthy control group. Serum ESPL1 were detected and compared. RESULTS: ESPL1 level of integration group was significantly higher than that of non-integration group (346.7 vs 199.6 ng/ml, P = 0.000) and healthy control group (346.7 vs 41.3 ng/ml, P = 0.000). ESPL1 level of non-integration group was significantly higher than that of healthy control group (199.6 vs 41.3 ng/ml, P = 0.000); ESPL1 levels in chronic HBV-infection related groups were increased in turn according to CHB group (95.8 ng/ml), HBV-related LC group (268.2 ng/ml), HBV-related HCC group (279.9 ng/ml) and integration group (346.7 ng/ml). Except that there was no significant difference in ESPL1 levels between HBV-related LC and HCC group (P = 0.662), pairwise comparisons between other groups showed significant differences (P < 0.05). ESPL1 level of HBV-related HCC group was significantly higher than that of non-HBV-related HCC group (279.9 vs 46.6 ng/ml, P = 0.000), there was no noticeable difference between non-HBV-related HCC and healthy control group (46.6 vs 41.3 ng/ml, P = 0.848). ESPL1 level of HBV-related HCC group after resection was significantly lower than that of before resection (178.4 vs 260.8 ng/ml, P = 0.000). CONCLUSIONS: Chronic HBV-infection patients with high ESPL1 level may indicate HBV S gene integration and is a high-risk population for HBV-related HCC. Serum ESPL1 can be used as a biomarker for screening HBV-related HCC high-risk population and monitoring recurrence.

RNA sequencing of plasma exosomes revealed novel functional long noncoding RNAs in hepatocellular carcinoma.

Exosomal long noncoding RNA (lncRNA) has been found to be associated with the development of cancers. However, the expression characteristics and the biological roles of exosomal lncRNAs in hepatocellular carcinoma (HCC) remain unknown. Here, by RNA sequencing, we found 9440 mRNAs and 8572 lncRNAs were differentially expressed (DE-) in plasma exosomes between HCC patients and healthy controls. Exosomal DE-lncRNAs displayed higher expression levels and tissue specificity, lower expression variability and splicing efficiency than DE-mRNAs. Six candidate DE-lncRNAs (fold change 6 or more, P ≤ .01) were high in HCC cells and cell exosomes. The knockdown of these candidate DE-lncRNAs significantly affected the migration, proliferation, and apoptosis in HCC cells. In particular, a novel DE-lncRNA, RP11-85G21.1 (lnc85), promoted HCC cellular proliferation and migration by targeted binding and regulating of miR-324-5p. More importantly, the level of serum lnc85 was highly expressed in both Alpha-fetoprotein (AFP)-positive and AFP-negative HCC patients and allowed distinguishing AFP-negative HCC from healthy control and liver cirrhosis (area under the receiver operating characteristic curve, 0.869; sensitivity, 80.0%; specificity, 76.5%) with high accuracy. Our finding offers a new insight into the association between the dysregulation of exosomal lncRNA and HCC, suggesting that lnc85 could be a potential biomarker of HCC.

High Rate of Detection of Human ESPL1-HBV S Fusion Gene in Patients With HBV-related Liver Cancer: A Chinese Case-Control Study.

AIM: It has been shown that the integration of hepatitis B virus (HBV) gene into the host genome is a high-risk factor for development of hepatocellular carcinoma (HCC). However, the relationship between HBV S-integrated human extra spindle pole bodies-like 1 (ESPL1) gene and HCC is unknown. This study was designed to detect HBV S-integrated human ESPL1 fusion gene in patients with HCC for potentially using this fusion gene as a biomarker for HCC diagnosis. PATIENTS AND METHODS: Nineteen and 70 patients with chronic hepatitis B (CHB) were recruited to the experimental and control groups, respectively, and both groups underwent an effective nucleoside/nucleotide analog therapy and follow-up for HCC occurrence for up to 11 years. HCC tissues were obtained by surgical resection from the experimental group, while liver tissues were collected by liver biopsy in the control group prior to treatment with nucleoside/nucleotide analogs. Alu polymerase chain reaction was used to assess HBV S gene integration in the liver tissues from both groups. HBV S-integrated human ESPL1 fusion gene was then detected in patients with HBV S gene integration using a gene database. RESULTS: All patients in the experimental group developed HCC, whereas no HCC was diagnosed in the control group. HBV S gene integration was identified in 12 out of 19 HCC tissues in the experimental group, giving a detection rate of 63.2%, which was significantly greater than that of 15.7% (11/70) in the control group (p<0.001). We further showed that HBV S-integrated human ESPL1 fusion gene was detected in eight patients (rate of 66.7%) among the 12 patients with HCC with HBV S gene integration in the experimental group, whereas the fusion gene was not detectable in any of the patients in the control group (p=0.001). CONCLUSION: This research demonstrates a high detection rate of HBV S-integrated human ESPL1 fusion gene in patients with HBV-related HCC and shows that this fusion gene appears to be associated with HCC development in patients with CHB. These findings suggest that HBV S-integrated human ESPL1 fusion gene may potentially serve as a biomarker for early detection of HCC in HBV-infected populations.

Real-world clinical outcomes among individuals with chronic HCV infection in China: CCgenos study.

BACKGROUND: This 5-year follow-up of the CCgenos cross-sectional study aimed to observe real-life outcomes in a cohort of 997 Han Chinese patients with chronic HCV infection and to explore the impacts of HCV genotype, patient characteristics and treatment status. METHODS: Clinical information and centralized HCV RNA measures were collected every 6/3 months for untreated/treated patients. Overall disease progression was defined as ≥1 of: de novo development of cirrhosis, Child-Turcotte-Pugh score increased by ≥2 points (if cirrhosis at baseline), progression to decompensated cirrhosis, hepatocellular carcinoma (HCC), liver transplant or death. Cox regression assessed risk factors for the time from estimated infection to cirrhosis or HCC. Logistic regression assessed risk factors for incidence rates of cirrhosis and overall disease progression. RESULTS: 281 of 514 patients enrolled across China completed 5 years of follow-up. Overall disease progression occurred in 36/364 (9.9%) treated patients and 35/148 (23.6%) untreated patients (odds ratio = 0.35; 95% CI 0.21, 0.59; P<0.0001). Overall disease progression occurred in 6/231 (2.6%) patients achieving sustained virological response at 24 weeks (SVR24) versus 11/82 (13.4%) who did not (P=0.0002). Cirrhosis development was significantly associated with abnormal aspartate aminotransferase (AST), age ≥40 years, body mass index ≥28 kg/m2, HCV GT1, platelet count <100×109/l, and AST to platelet ratio index (APRI) ≥2 (multivariate Cox regression, P<0.05). HCC was significantly associated with HCV GT1 and platelet count <100×109/l (multivariate Cox regression, P<0.05). CONCLUSIONS: Achieving SVR24 significantly reduced the probability of overall disease progression but no significant difference was seen for both cirrhosis and HCC during 5 years of follow-up.

Efficacy and Safety of 12-week Interferon-based Danoprevir Regimen in Patients with Genotype 1 Chronic Hepatitis C.

Background and Aims: Genotype (GT) 1 remains the predominant hepatitis c virus (HCV) GT in Chinese patients. Over 80% of those Chinese patients harbor the interferon-sensitive CC allele of IFNL4rs12979860, which is favorable for interferon-based treatment regimens. This phase III clinical trial aimed to evaluate the efficacy and safety of the ritonavir-boosted danoprevir plus pegylated-interferon α-2a and ribavirin regimen for 12 weeks in treatment-naïve mainland Chinese patients infected with HCV GT1 without cirrhosis. Methods: One hundred and forty-one treatment-naïve, non-cirrhotic HCV GT1 Chinese patients (age ≥18 years) were enrolled for this single-arm, multicenter, phase III MANASA study (NCT03020082). Patients received a combination of ritonavir-boosted danoprevir (100 mg/100 mg) twice a day plus subcutaneous injection of weekly pegylated-interferon α-2a (180 µg) and oral ribavirin (1000/1200 mg/day body weight <75/≥75 kg) for 12 weeks. The primary end-point was sustained virologic response rate at 12 weeks after the end of treatment. The secondary end-points were safety outcomes, tolerability, virologic response over time and relapse rate. Results: All enrolled patients were HCV GT1-infected, and most among them (97.9%, 123/141) had the HCV GT1b subtype. Single-nucleotide polymorphism test showed that the majority of patients were of the IFNL4 rs12979860 CC genotype (87.2%, 123/141). Overall, 140 patients completed the 12-week treatment, and 97.1% (136/140) patients achieved sustained virologic response at 12 weeks (per protocol population group, 95% confidence interval: 92.9-99.2%). Only drug-related serious adverse event occurred. Most of the adverse events were grade 1 and grade 2 alanine aminotransferase elevation or liver dysfunction. One patient discontinued treatment because of severe head injury in a car accident. Conclusions: The triple regimen of ritonavir-boosted danoprevir plus pegylated-interferon α-2a and ribavirin produced a sustained virologic response rate of 97.1% after 12 weeks treatment in noncirrhotic HCV GT1-infected Chinese patients, and was safe and well tolerated. Trial Registration Clinical-Trials.gov Identifier: NCT03020082.

Hepatitis C screening in hospitals: find the missing patients.

BACKGROUND: Hepatitis C virus (HCV) infection is one of the leading causes of liver cancer, creating enormous economic and social burdens. The Chinese government recommends routine screening of inpatients for HCV before invasive procedures to prevent iatric infections. However, the diagnosis and treatment rates for HCV remain low. The aim of this study was to use available routine screening data to understand the HCV screening of inpatients in different regions of China. METHODS: Inpatient information and HCV screening results were collected from January 2016 to December 2016 at eight tertiary hospitals in different regions of China to compare the HCV-positivity of hospitalized patients among different regions and age groups. RESULTS: The HCV screening rate of inpatients was more than 50%. A total of 467,008 inpatients were enrolled in the study (51.20% were male), and the HCV antibody (anti-HCV) -positive rate was 0.88% (95% confidence interval [CI], 0.85-0.91%) among the total population. This rate was significantly higher among all males compared with all females (0.91% vs 0.85%). Moreover, the HCV antibody-positive rate increased with age and was highest for the 60-64-year age group. Notably, 90.14% (3722/4129) of the anti-HCV seropositive patients were 40 years of age or older. HCV screening for people over 40 years old is recommended. CONCLUSIONS: This study highlights the key role of routine examination for HCV infection in hospitalized patients. Full use of inpatient screening results to manage HCV antibody-positive patients and a screening strategy targeting inpatients 40 years and older were found to be low-cost and effective, which will help to find the missing millions of yet unaware patients and also accelerate the elimination of HCV in China.

A cross-sectional assessment of health-related quality of life in Chinese patients with chronic hepatitis c virus infection with EQ-5D.

BACKGROUND: Hepatitis C virus (HCV) infection is one of the most common liver infections, with a decrement in HRQoL of HCV patients. This study aims to assess Health-related quality of life (HRQoL) in Chinese patients with chronic HCV infection, and to identify significant predictors of the HRQoL in these patients of China. METHODS: In this cross-sectional observational study, treatment-naïve Han ethnic adults with chronic HCV infection were enrolled. Adopting European Quality of Life scale (EQ-5D) and EuroQOL visual analogue scale (EQ-VAS) were used to qualify HRQoL. Results were reported in descriptive analyses to describe sociodemographic and clinical characteristics. Multiple linear regression analysis was applied to investigate the associations of these variables with HRQoL. Binary logistic regression analysis was performed to identify associations of these variables with HRQoL by dimensions of EQ-5D. RESULTS: Nine hundred ninety-seven patients were enrolled in the study [median age 46.0 (37.0, 56.0) years; male 54.8%]. Mean EQ-5D index and EQ-VAS score were 0.780 ± 0.083 and 77.2 ± 14.8. Multiple Linear regression analysis showed that income (< 2000 RMB, ß = - 0.134; 2000-4999 RMB, ß = - 0.085), moderate or severe symptoms of discomfort (more than one symptoms, ß = - 0.090), disease profile (cirrhosis, ß = - 0.114), hyperlipidemia (ß = - 0.065) and depression (ß = - 0.065) were independently associated with EQ-5D index. Residence (the west, ß = 0.087), income (< 2000 RMB, ß = - 0.129; 2000-4999 RMB, ß = - 0.052), moderate or severe symptoms of discomfort (more than one symptoms, ß = - 0.091), disease profile and depression (ß = - 0.316) were the influencing factors on EQ-VAS. Binary logistic regression indicated that disease profile and clinical depression were the major influencing factors on all five dimensions of EQ-5D. CONCLUSIONS: In this cross-sectional assessment of HCV patients in China, we indicated HRQoL of Chinese HCV patients. Significant negative associations between HRQoL and sociodemographic and clinical factors such as moderate or severe symptoms of discomfort, disease profile and depression emerged. We have to focus on optimally managing care of HCV patients and improving their HRQoL. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01293279. Date of registration: February 10, 2011.

Ledipasvir/sofosbuvir for treatment-naive and treatment-experienced Chinese patients with genotype 1 HCV: an open-label, phase 3b study.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is a significant medical burden in China, affecting more than 10 million persons. In clinical trials and real-world settings, treatment with ledipasvir/sofosbuvir in patients with genotype 1 HCV infection resulted in high sustained virologic response rates. Ledipasvir/sofosbuvir may provide a highly effective, short-duration, single-tablet regimen for Chinese patients with HCV infection. METHODS: Chinese patients with genotype 1 HCV infection who were HCV treatment naive or treatment experienced, without cirrhosis or with compensated cirrhosis, were treated with open-label ledipasvir/sofosbuvir for 12 weeks. The primary efficacy endpoint was sustained virologic response 12 weeks after completing treatment (SVR12). For treatment-naive patients, SVR12 was compared to a historical rate of 57%. The primary safety endpoint was adverse events leading to permanent discontinuation of study drug; serious adverse events were also evaluated. The presence of resistance-associated substitutions (RASs) was evaluated by viral sequencing. RESULTS: All 206 enrolled patients achieved SVR12 (100%; 95% CI 98-100%), including 106 treatment-naive patients (100%; 95% CI 97-100%), which was superior to a historical SVR rate of 57% (p < 0.001). All patients with baseline NS5A and NS5B RASs (14 and 1% of patients, respectively) achieved SVR12. The most common adverse events were viral upper respiratory tract infection (17%), upper respiratory tract infection (14%), and cough (6%). There were no discontinuations due to adverse events; and no treatment-related serious adverse events were reported. CONCLUSION: Ledipasvir/sofosbuvir is a well tolerated and highly effective treatment for Chinese patients with genotype 1 HCV, regardless of prior treatment experience, cirrhosis status, or the presence of pretreatment RASs.