Decision tree algorithm predicts hepatocellular carcinoma among chronic hepatitis C patients following viral eradication.

Successful eradication of the hepatitis C virus (HCV) cannot eliminate the risk of hepatocellular carcinoma (HCC). Next-generation RNA sequencing provides comprehensive genomic insights into the pathogenesis of HCC. Artificial intelligence has opened a new era in precision medicine. This study integrated clinical features and genetic biomarkers to establish a machine learning-based HCC model following viral eradication. A prospective cohort of 55 HCV patients with advanced fibrosis, who achieved a sustained virologic response after antiviral therapy, was enrolled. The primary outcome was the occurrence of HCC. The genomic signatures of peripheral blood mononuclear cells (PBMC) were determined by RNA sequencing at baseline and 24 weeks after end-of-treatment. Machine learning algorithms were implemented to extract the predictors of HCC. HCC occurred in 8 of the 55 patients, with an annual incidence of 2.7%. Pretreatment PBMC DEFA1B, HBG2, ADCY4, and posttreatment TAS1R3, ABCA3, and FOSL1 genes were significantly downregulated, while the pretreatment ANGPTL6 gene was significantly upregulated in the HCC group compared to that in the non-HCC group. A gene score derived from the result of the decision tree algorithm can identify HCC with an accuracy of 95.7%. Gene score = TAS1R3 (≥0.63 FPKM, yes/no = 0/1) + FOSL1 (≥0.27 FPKM, yes/no = 0/1) + ABCA3 (≥2.40 FPKM, yes/no = 0/1). Multivariate Cox regression analysis showed that this gene score was the most important predictor of HCC (hazard ratio = 2.38, 95% confidence interval [CI] = 1.06-5.36, P = 0.036). Combining the gene score and fibrosis-4 index, a nomogram was constructed to predict the probability of HCC with an area under the receiver operating characteristic curve up to 0.950 (95% CI = 0.888-1.000, P = 7.0 × 10-5). Decision curve analysis revealed that the nomogram had a net benefit in HCC detection. The calibration curve showed that the nomogram had optimal concordance between the predicted and actual HCC probabilities. In conclusion, down-regulated posttreatment PBMC TAS1R3, ABCA3, and FOSL1 expression were significantly correlated with HCC development after HCV eradication. Decision-tree-based algorithms can refine the assessment of HCC risk for personalized HCC surveillance.

Dynamics of cytokines predicts risk of hepatocellular carcinoma among chronic hepatitis C patients after viral eradication.

BACKGROUND: Chronic hepatitis C virus (HCV) infection induces profound alterations in the cytokine and chemokine signatures in peripheral blood. Clearance of HCV by antivirals results in host immune modification, which may interfere with immune-mediated cancer surveillance. Identifying HCV patients who remain at risk of hepatocellular carcinoma (HCC) following HCV eradication remains an unmet need. We hypothesized that antiviral therapy-induced immune reconstruction may be relevant to HCC development. AIM: To investigate the impact of differential dynamics of cytokine expression on the development of HCC following successful antiviral therapy. METHODS: One hundred treatment-naïve HCV patients with advanced fibrosis (F3/4) treated with direct-acting antivirals (DAAs) or peginterferon/ribavirin who achieved sustained virologic response [SVR, defined as undetectable HCV RNA throughout 12 wk (SVR12) for the DAA group or 24 wk (SVR24) for the interferon group after completion of antiviral therapy] were enrolled since 2003. The primary endpoint was the development of new-onset HCC. Standard HCC surveillance (abdominal ultrasound and α-fetoprotein) was performed every six months during the follow-up. Overall, 64 serum cytokines were detected by the multiplex immunoassay at baseline and 24 wk after end-of-treatment. RESULTS: HCC developed in 12 of the 97 patients over 459 person-years after HCV eradication. In univariate analysis, the Fibrosis-4 index (FIB-4), hemoglobin A1c (HbA1c), the dynamics of tumor necrosis factor-α (TNF-α), and TNF-like weak inducer of apoptosis (TWEAK) after antiviral therapy were significant HCC predictors. The multivariate Cox regression model showed that ΔTNF-α (≤ -5.7 pg/mL) was the most important risk factor for HCC (HR = 11.54, 95%CI: 2.27-58.72, P = 0.003 in overall cases; HR = 9.98, 95%CI: 1.88-52.87, P = 0.007 in the interferon group). An HCC predictive model comprising FIB-4, HbA1c, ΔTNF-α, and ΔTWEAK had excellent performance, with 3-, 5-, 10-, and 13-year areas under the curve of 0.882, 0.864, 0.903, and 1.000, respectively. The 5-year accumulative risks of HCC were 0%, 16.9%, and 40.0% in the low-, intermediate-, and high-risk groups, respectively. CONCLUSION: Downregulation of serum TNF-α significantly increases the risk of HCC after HCV eradication. A predictive model consisting of cytokine kinetics could ameliorate personalized HCC surveillance strategies for post-SVR HCV patients.

Outreach onsite treatment with a simplified pangenotypic direct-acting anti-viral regimen for hepatitis C virus micro-elimination in a prison.

BACKGROUND: Prisoners are at risk of hepatitis C virus (HCV) infection, especially among the people who inject drugs (PWID). We implemented an outreach strategy in combination with universal mass screening and immediate onsite treatment with a simplified pan-genotypic direct-acting antivirals (DAA) regimen, 12 wk of sofosbuvir/velpatasvir, in a PWID-dominant prison in Taiwan. AIM: To implement an outreach strategy in combination with universal mass screening and immediate onsite treatment with a simplified pan-genotypic DAA regimen in a PWID-dominant prison in Taiwan. METHODS: HCV-viremic patients were recruited for onsite treatment program for HCV micro-elimination with a pangenotypic DAA regimen, 12 wk of sofosbuvir/ velpatasvir, from two cohorts in Penghu Prison, either identified by mass screen or in outpatient clinics, in September 2019. Another group of HCV-viremic patients identified sporadically in outpatient clinics before mass screening were enrolled as a control group. The primary endpoint was sustained virological response (SVR12, defined as undetectable HCV ribonucleic acid (RNA) 12 wk after end-of-treatment). RESULTS: A total of 212 HCV-viremic subjects were recruited for HCV micro-elimination campaign; 91 patients treated with sofosbuvir/Ledipasvir or glecaprevir/ pibrentasvir before mass screening were enrolled as a control. The HCV micro-elimination group had significantly lower proportion of diabetes, hypertension, hyperlipidemia, advanced fibrosis and chronic kidney diseases, but higher levels of HCV RNA. The SVR12 rate was comparable between the HCV micro-elimination and control groups, 95.8% (203/212) vs 94.5% (86/91), respectively, in intent-to-treat analysis, and 100% (203/203) vs 98.9% (86/87), respectively, in per-protocol analysis. There was no virological failure, treatment discontinuation, and serious adverse event among sofosbuvir/velpatasvir-treated patients in the HCV micro-elimination group. CONCLUSION: Outreach mass screening followed by immediate onsite treatment with a simplified pangenotypic DAA regimen, sofosbuvir/velpatasvir, provides successful strategies toward HCV micro-elimination among prisoners.

Regorafenib for Taiwanese patients with unresectable hepatocellular carcinoma after sorafenib failure: Impact of alpha-fetoprotein levels.

BACKGROUND AND AIMS: Regorafenib has demonstrated its survival benefit for unresectable hepatocellular carcinoma (uHCC) patients in a phase III clinical trial. We aimed to assess the efficacy and tolerability of regorafenib and the predictors of treatment outcomes in Taiwanese patients. METHODS: We analyzed the survival, best overall response, predictors of treatment outcomes, and safety for uHCC patients who had tumor progression on sorafenib therapy and received regorafenib as salvage therapy between March 2018 and November 2020. RESULTS: Eighty-six patients with uHCC were enrolled (median age, 66.5 years; 76.7% male). The median regorafenib treatment duration was 4.0 months (95% confidence interval [CI], 3.6-4.6). The most frequently reported adverse events were hand-foot skin reaction (44.2%), diarrhea (36.0%), and fatigue (29.1%). No unpredictable toxicity was observed during treatment. The median overall survival (OS) with regorafenib was 12.4 months (95% CI, 7.8-17.0) and the median progression-free survival (PFS) was 4.2 months (95% CI, 3.7-4.7). Of 82 patients with regorafenib responses assessable, 4 patients (4.9%) achieved a partial response, and 33 (40.2%) had stable disease, leading to a disease control rate (DCR) of 45.1% (n = 37). Patients possessing baseline AFP < 400 ng/ml exhibited a markedly longer median OS, median PFS, and higher DCR compared with their counterparts (15.7 vs. 8.1 months, 4.6 vs. 3.7 months, 60.9% vs. 27.5%, respectively). Despite possessing high baseline AFP levels, patients with early AFP response (>10% reduction at 4 weeks or >20% reduction at 8 weeks after regorafenib administration) exhibited comparable treatment outcomes to those with baseline AFP < 400 ng/ml. CONCLUSIONS: The results of this real-world study verified the tolerability and efficacy of regorafenib treatment for uHCC patients who failed prior sorafenib therapy, especially for those with lower baseline AFP levels or with early AFP response.

Artificial intelligence based on serum biomarkers predicts the efficacy of lenvatinib for unresectable hepatocellular carcinoma.

Lenvatinib has been effective not only as a first-line but also as a later-line systemic therapy for unresectable hepatocellular carcinoma (uHCC) in real-world clinical practice. How to predict the efficacy of lenvatinib and guide appropriate therapy selection in patients with uHCC have become important issues. This study aimed to investigate the impact of serum biomarkers on the treatment outcomes of patients with uHCC treated with lenvatinib in a real-world setting using an artificial intelligence algorithm. We measured serum biomarkers, including alpha-fetoprotein (AFP), albumin-bilirubin (ALBI) grade, and circulating angiogenic factors (CAFs [i.e., vascular endothelial growth factor, angiopoietin-2, fibroblast growth factor-19 [FGF19], and FGF21]) and analyzed treatment outcomes, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in patients with uHCC treated with lenvatinib. The results of this study demonstrated that an AFP reduction ≥ 40% from baseline within 8 weeks after lenvatinib induction was associated with a higher ORR. With baseline biomarkers using a decision tree-based model, we identified patients with high, intermediate, and low ORRs (84.6%, 21.7% and 0%, respectively; odds ratio, 53.04, P < 0.001, high versus intermediate/low groups). Based on the decision tree-based survival predictive model, baseline AFP was the most important factor for OS, followed by ALBI grade and FGF21.

Role of hepatitis D virus infection in development of hepatocellular carcinoma among chronic hepatitis B patients treated with nucleotide/nucleoside analogues.

Hepatitis D virus (HDV) infection increases the risk of hepatocellular carcinoma (HCC) in the natural course of chronic hepatitis B (CHB) patients. Its role in patients treated with nucleotide/nucleoside analogues (NAs) is unclear. We aimed to study the role of hepatitis D in the development of HCC in CHB patients treated with NAs. Altogether, 1349 CHB patients treated with NAs were tested for anti-HDV antibody and RNA. The incidence and risk factors of HCC development were analyzed. Rates of anti-HDV and HDV RNA positivity were 2.3% and 1.0%, respectively. The annual incidence of HCC was 1.4 per 100 person-years after a follow-up period of over 5409.5 person-years. The strongest factor association with HCC development was liver cirrhosis (hazard ratio [HR]/95% confidence interval [CI] 9.98/5.11-19.46, P < 0.001), followed by HDV RNA positivity (HR/ CI 5.73/1.35-24.29, P = 0.02), age > 50 years old (HR/CI 3.64/2.03-6.54, P < 0.001), male gender (HR/CI 2.69/1.29-5.60, P: 0.01), and body mass index (BMI, HR/CI 1.11/1.03-1.18, P = 0.004). The 5-year cumulative incidence of HCC was 7.3% for patients with HDV RNA negativity compared to that of 22.2% for patients with HDV RNA positivity (P = 0.01). In the subgroup of cirrhotic patients, the factors associated with HCC development were HDV RNA positivity (HR/CI 4.45/1.04-19.09, P = 0.04) and BMI (HR/CI 1.11/1.03-1.19, P = 0.01). HDV viremia played a crucial role in HCC development in CHB patients who underwent NA therapy.

Changing epidemiology and viral interplay of hepatitis B, C and D among injecting drug user-dominant prisoners in Taiwan.

The spreading of viral hepatitis among injecting drug users (IDU) is an emerging public health concern. This study explored the prevalence and the risks of hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus (HDV) among IDU-dominant prisoners in Taiwan. HBV surface antigen (HBsAg), antibodies to HCV (anti-HCV) and HDV (anti-HDV), viral load and HCV genotypes were measured in 1137(67.0%) of 1697 prisoners. 89.2% of participants were IDUs and none had HIV infection. The prevalence of HBsAg, anti-HCV, dual HBsAg/anti-HCV, HBsAg/anti-HDV, and triple HBsAg/anti-HCV/anti-HDV was 13.6%, 34.8%, 4.9%, 3.4%, and 2.8%, respectively. HBV viremia rate was significantly lower in HBV/HCV-coinfected than HBV mono-infected subjects (66.1% versus 89.9%, adjusted odds ratio/95% confidence intervals [aOR/CI] = 0.27/0.10-0.73). 47.5% anti-HCV-seropositive subjects (n = 396) were non-viremic, including 23.2% subjects were antivirals-induced. The predominant HCV genotypes were genotype 6(40.9%), 1a(24.0%) and 3(11.1%). HBsAg seropositivity was negatively correlated with HCV viremia among the treatment naïve HCV subjects (44.7% versus 72.4%, aOR/CI = 0.27/0.13-0.58). Anti-HCV seropositivity significantly increased the risk of anti-HDV-seropositivity among HBsAg carriers (57.1% versus 7.1%, aOR/CI = 15.73/6.04-40.96). In conclusion, IUDs remain as reservoirs for multiple hepatitis viruses infection among HIV-uninfected prisoners in Taiwan. HCV infection increased the risk of HDV infection but suppressed HBV replication in HBsAg carriers. An effective strategy is mandatory to control the epidemic in this high-risk group.

Role of hepatitis D virus in persistent alanine aminotransferase abnormality among chronic hepatitis B patients treated with nucleotide/nucleoside analogues.

BACKGROUND: The biochemical response is a crucial indicator of prognosis in chronic hepatitis B (CHB) patients treated with nucleotide/nucleoside analogues (NAs). The impact of hepatitis D virus (HDV) infection on alanine aminotransferase normalization is elusive. METHODS: The longitudinal study recruited 1185 CHB patients who received NAs. These patients were tested for anti-HDV antibody and HDV RNA at the initiation of anti-hepatitis B virus (HBV) therapy and annually for patients who were HDV-seropositive. ALT levels were examined at the first and second year of anti-HBV therapy. ALT abnormality was defined as ALT levels above 40 IU/mL in both male and female, and the risk factors associated with ALT abnormality were analysed. RESULTS: Rates of seropositivity for anti-HDV and HDV RNA were 2.0% and 0.8% among 1185 NA-treated CHB patients, respectively. The strongest factor associated with ALT abnormality (>40 IU/mL) after first year treatment with NAs was HDV RNA seropositivity at year 1 (odds ratio [OR]/95% confidence interval [CI]: 31.44/3.49-283.56, P = 0.002), followed by liver cirrhosis (2.18/1.51-3.15, P < 0.001), detectable HBV DNA at year 1 (OR/CI: 1.99/1.36-2.92, P < 0.001), diabetes (OR/CI: 1.75/1.10-2.78, P = 0.02), body mass index (BMI) (OR/CI: 1.13/1.09-1.18, P < 0.001) and age (OR/CI: 0.97/0.96-0.98, P < 0.001). Among patients who were seronegative for HBV DNA at year 1, the strongest factor associated with ALT abnormality was HDV RNA seropositivity at year 1 (OR/CI: 30.00/3.28-274.05, P = 0.003), followed by liver cirrhosis (OR/CI: 1.83/1.21-2.75, P = 0.004), BMI (OR/CI: 1.16/1.11-1.21, P < 0.001) and age (OR/CI: 0.97/0.96-0.99, P < 0.001). Similarly, the impact of HDV RNA seropositivity on ALT abnormality was noted in patients without detectable HBV DNA but not in those with hepatitis B viremia at treatment year 2 (OR/CI: 10.16/1.33-77.74, P = 0.03). CONCLUSION: HDV infection played an important role in ALT abnormality in CHB patients receiving 1-year and 2-year NAs. The impact was particularly noted in patients who had successfully suppressed HBV DNA.

Serial serologic changes of hepatitis D virus in chronic hepatitis B patients receiving nucleos(t)ides analogues therapy.

BACKGROUND AND AIM: The serial serologic changes of hepatitis D virus (HDV) infection among chronic hepatitis B virus (HBV) infected patients who received oral nucleotide/nucleoside analogues are elusive. METHODS: Serum anti-HDV and HDV RNA among chronic hepatitis B (CHB) patients were tested at the time of initiating anti-HBV therapy and subsequently during the follow-up period. RESULTS: The seropositive rate of anti-HDV and HDV RNA among 2850 CHB patients, was 2.7% and 0.9%, respectively. Factors associated with anti-HDV seropositivity were platelet counts (odds ratio [OR]/95% confidence intervals [CI]: 0.995/0.992-0.999; P = 0.006), HBV DNA levels (OR/CI: 0.81/0.70-0.94; P = 0.005), and hepatitis B e-antigen (HBeAg) seropositivity (OR/CI: 0.22/0.05-0.95; P = 0.04). The only factor associated with HDV RNA positivity among anti-HDV seropositive patients was age (OR/CI: 0.95/0.90-1.00; P = 0.03). The spontaneous clearance rate of serum anti-HDV antibody was 3.0 per 100 person-years with a median follow-up period of 3.5 years (range 2-12 years), whereas the seroclearance rate of HDV RNA was 4.3 per 100 person-years among anti-HDV seropositive patients after a median follow-up period of 6.0 years (range 2-11 years). A baseline anti-HDV titer < 0.5 cut-off index was the only factor predictive of anti-HDV seroclearance (hazard ratio [HR]/CI: 30.11/3.73-242.85; P = 0.001). CONCLUSIONS: HDV infection was not common among patients treated for HBV in Taiwan. Seroclearance of anti-HDV and HDV RNA did occur over time, albeit the chance is rare.

Ribavirin facilitates early viral kinetics in chronic hepatitis C patients receiving daclatasvir/asunaprevir.

BACKGROUND AND AIM: Ribavirin (RBV) remains crucial in difficult-to-cure chronic hepatitis C patients receiving directly acting antivirals (DAAs). The current study aimed to address whether RBV enhanced early viral kinetics in patients with DAAs. METHODS: Hepatitis C virus (HCV) genotype-1b patients were allocated to daclatasvir/asunaprevir +weight-based RBV (1000-1200 mg/day) for 12-24 weeks. HCV RNA levels were compared at day 1, week 1, week 2, and week 4 of treatment. RESULTS: The sustained virological response rate was 100% (67/67) and 96.7% (59/61) in the RBV and non-RBV group, respectively. The HCV RNA levels at treatment week 2 (W2) were significantly lower in the RBV group than in the non-RBV group (0.42 ± 0.81 log IU/mL vs 0.79 ± 1.03 log IU/mL, P = 0.04). Among the intermediate responders who remained to have detectable RNA after W1 of treatment, patients with RBV had a significantly higher rate of undetectable HCV RNA (71.4% vs 36.0%, P = 0.003) and lower HCV RNA level at W2 (0.55 ± 0.89 log IU/mL vs 1.32 ± 1.04 log IU/mL, P = 0.001). A more significant magnitude of HCV RNA reduction was also noted from baseline to day 1 (3.15 ± 0.38 log IU/mL vs 2.80 ± 0.70 log IU/mL, P = 0.009) and W1 to W2 (1.40 ± 0.65 log IU/mL vs 0.88 ± 0.78 log IU/mL, P = 0.007) in the RBV group compared to the non-RBV group among the intermediate responders. Logistic regression analysis revealed that adding RBV independently predicted undetectable HCV RNA at W2 (odds ratio/confidence interval: 4.74/1.54-14.57, P = 0.007) in the intermediate responders. CONCLUSIONS: Adding RBV to DAAs improved early viral kinetic, in particular, for intermediate responders.

Identification of treatment-experienced hepatitis C patients with poor cost-effectiveness of pegylated interferon plus ribavirin from a real-world cohort.

BACKGROUND/PURPOSE: Pegylated interferon (PegIFN) plus ribavirin (RBV) combination therapy has been the standard of care since 2002. Although a better viral response has been achieved among chronic hepatitis C (CHC) patients in Taiwan, approximately 25% of hepatitis C virus (HCV) genotype 1 (G1) patients and 15% of G2 patients failed to achieve a sustained virological response (SVR) at the first therapy. The actual cost-effectiveness of the retreatment remains elusive. The present study conducted a real-world cost-effectiveness analysis of a large cohort among different pre-specified subgroups of treatment-experienced CHC patients. METHODS: A total of 117 patients with CHC who failed to achieve SVR at the first IFN-based therapy and received a second IFN-based therapy were enrolled. The inpatient and outpatient costs were acquired from National Health Insurance Research Database of Taiwan. The related medical care costs per treatment and per SVR were calculated. RESULTS: We demonstrated that the average cost per SVR achieved was $13,722 in treatment-experienced CHC patients. Especially, patients with HCV G1 infection, baseline viral loads > 400,000 IU/mL, advanced hepatic fibrosis, not achieving a rapid viral response at week 4 or complete early viral response at week 12, had poorer cost-effectiveness for PegIFN/RBV retherapy, ranging from around $15,520 to as high as $72,546 per SVR achieved. CONCLUSION: In the current study, we explored the real-world cost-effectiveness data of PegIFN/RBV for different subgroups of treatment-experienced HCV patients. These findings provide information for policy-makers for making decisions on treatment strategies of costly direct-acting antiviral agents for retreating CHC patients.

Identification of groups with poor cost-effectiveness of peginterferon plus ribavirin for naïve hepatitis C patients with a real-world cohort and database.

BACKGROUND: For decades, peginterferon and ribavirin (PegIFN/RBV) have been the standard-of-care for chronic hepatitis C virus (CHC) infection. However, the actual cost-effectiveness of this therapy remains unclear. We purposed to explore the real-world cost effectiveness for subgroups of treatment-naïve CHC patients with PegIFN/RBV therapy in a large real-world cohort using a whole population database. METHODS: A total of 1809 treatment-naïve chronic hepatitis C virus (HCV) patients (829 HCV genotype 1 [G1] and 980 HCV G2) treated with PegIFN/RBV therapies were linked to the National Health Insurance Research Database, covering the entire population of Taiwan from 1998 to 2013 to collect the total medical-care expenses of outpatient (antiviral agents, nonantiviral agents, laboratory, and consultation costs) and inpatient (medication, logistic, laboratory, and intervention costs) visits. The costs per treatment and the cost per sustained virological response (SVR) achieved were calculated. RESULTS: The average medical-care cost was USD $4823 (±$2984) per treatment and $6105 (±$3778) per SVR achieved. With SVR rates of 68.6% and 87.8%, the cost/SVR was significantly higher in G1 than those in G2 patients, respectively ($8285 vs $4663, P < .001). Treatment-naïve G1 patients of old ages, those with advanced fibrosis, high viral loads, or interleukin-28B unfavorable genotypes, or those without a rapid virological response (RVR: undetectable HCV RNA at week 4), or those with complete early virological response (cEVR: undetectable HCV RNA at week 12). Treatment-naïve G2 patients with high viral loads or without RVR or cEVR incurred significantly higher costs per SVR than their counterparts. The cost/SVR was extremely high among patients without RVR and in patients without cEVR. CONCLUSION: We investigated the real-world cost effectiveness data for different subgroups of treatment-naïve HCV patients with PegIFN/RBV therapies, which could provide useful, informative evidence for making decisions regarding future therapeutic strategies comprising costly direct-acting antivirals.

Diversity of the association of serum levels and genetic variants of MHC class I polypeptide-related chain A with liver fibrosis in chronic hepatitis C.

BACKGROUND/AIMS: Genetic variants of MHC class I polypeptide-related chain A (MICA) at rs2596542 have been associated with hepatocellular carcinoma. The linkage between serum MICA (sMICA) and liver fibrosis in chronic hepatitis C is elusive. RESULTS: Linear regression analysis revealed that sMICA were independently correlated to α-fetoprotein (ß: 0.149; 95% confidence interval [CI]: 0.001, 0.003; P = 0.007)and MICA rs2596542 GG genotype (ß: 0.209; 95% CI: 0.153, 0.483; P < 0.001). While patients were stratified by MICA genetic variants, advanced fibrosis was the only factor independently correlated to sMICA among A allele carriers (ß: 0.234; 95% CI: 0.107, 0.543; P = 0.004) but not among non-A allele carriers. Logistic regression analysis revealed that factors associated with advanced liver fibrosis was sMICA (OR/CI: 2.996/1.428-6.287, P = 0.004) and platelet counts (OR/CI: 0.988/0.982-0.994, P < 0.001) in MICA rs2596542 A allele carriers. sMICA > 50 pg/mL provided a positive predictive value of 72 % in predicting advanced liver fibrosis (F3-4) and of 90% in significant fibrosis (> F2) in MICA rs2596542 A allele carriers. MATERIALS AND METHODS: Serum level and single nucleotide polymorphism at rs2596542 of MICA were tested for the association with liver fibrosis in 319 biopsy proven chronic hepatitis C patients. CONCLUSIONS: Levels of sMICA were highly correlated to liver disease severity in chronic hepatitis C patients who carried the MICA rs738409 A allele. Patients possessing the genetic predisposition had a higher likelihood of progressed liver fibrosis if they expressed higher sMICA levels.

25-Hydroxy vitamin D suppresses hepatitis C virus replication and contributes to rapid virological response of treatment efficacy.

AIM: 25-Hydroxy vitamin D (Vit D) plays a role in treatment outcomes in chronic hepatitis C virus (HCV) infection. We aimed to clarify whether HCV replication is inhibited by Vit D in HCV replicon cells. Clinical implication was assessed for rapid virological response (RVR) and sustained virological response (SVR) among those patients receiving antiviral therapy. METHODS: Cell survival and viral loads were observed in Con1 (genotype 1b) and J6/JFH (genotype 2a) cells treated with different doses of Vit D. Three groups of patients with different treatment responses were recruited to assess their Vit D levels: group A, RVR-/SVR-; group B, RVR+/SVR-; and group C, RVR+/SVR+. RESULTS: The viral load of Con1 cells decreased by 69%, 80%, and 86% following treatment with 1 µM, 5 µM, and 10 µM Vit D, respectively (P < 0.0001). In J6/JFH cells, it decreased by 12%, 55%, and 80.5% following treatment with 1 µM, 5 µM, and 10 µM Vit D, respectively (P < 0.0001). There was a significant increase of Vit D between chronic hepatitis C groups, ranging from 4.4 ± 5.6 ng/mL in group A (n = 44), to 17.2 ± 11.6 ng/mL in group B (n = 44), and 32.5 ± 37.5 ng/mL of group C (n = 44) (P < 0.001). Advanced fibrosis (odds ratio = 0.13, 95% confidence interval = 0.04-0.41, P < 0.001) and Vit D deficiency (<10 ng/mL) (odds ratio = 0.11, 95% confidence interval = 0.03-0.43, P = 0.001) were predictive of SVR in the multivariate regression analysis. CONCLUSION: Vitamin D decreases HCV replication and also contributes to early treatment viral kinetics.

Reactivation of hepatitis B in patients of chronic hepatitis C with hepatitis B virus infection treated with direct acting antivirals.

BACKGROUND AND AIM: Hepatitis B virus (HBV) may reactivate when treating chronic hepatitis C (CHC) with direct acting antivirals (DAA). We aim to investigate the risk of HBV reactivation during DAA therapy. METHODS: Chronic hepatitis C patients receiving pan-oral DAA therapy from December 2013 to August 2016 were evaluated. Fifty-seven patients that had a past HBV infection (negative hepatitis B surface antigen [HBsAg] and positive hepatitis B core antibody) and seven patients that had a current HBV infection (positive HBsAg) were enrolled. Serum HBV and hepatitis C virus (HCV) markers were regularly measured. The endpoints were the HCV sustained virological response (SVR) and the HBV virological/clinical reactivation. RESULTS: The overall SVR12 rate was 96.9%, and two patients, one with positive HBsAg, had a relapse of HCV. No episodes of HBV virological reactivation were observed among the patients with a past HBV infection. For the seven patients with a current HBV infection, HBV virological reactivation was found in four (57.1%) of the seven patients. Clinical reactivation of HBV was observed in one patient with pretreatment detectable HBV DNA and recovered after entecavir administration. For the other three patients with HBV virological reactivation, the reappearance of low level HBV DNA without clinical reactivation was observed. HBsAg levels demonstrated only small fluctuations in all the patients. CONCLUSIONS: There was a minimal impact of hepatitis B core antibody seropositivity on HCV efficacy and safety. For CHC patients with current HBV infection, the risk of HBV reactivation was present, and monitoring the HBV DNA level during therapy is warranted.

Genetics Variants and Serum Levels of MHC Class I Chain-related A in Predicting Hepatocellular Carcinoma Development in Chronic Hepatitis C Patients Post Antiviral Treatment.

BACKGROUND/AIMS: The genome-wide association study has shown that MHC class I chain-related A (MICA) genetic variants were associated with hepatitis C virus (HCV) related hepatocellular carcinoma (HCC). The impact of the genetic variants and its serum levels on post-treatment cohort is elusive [corrected]. METHODS: MICA rs2596542 genotype and serum MICA (sMICA) levels were evaluated in 705 patients receiving antiviral therapy. RESULTS: Fifty-eight (8·2%) patients developed HCC, with a median follow-up period of 48·2 months (range: 6­129 months). The MICA A allele was associated with a significantly increased risk of HCC development in cirrhotic non-SVR patients but not in patients of non-cirrhotic and/or with SVR. For cirrhotic non-SVR patients, high sMICA levels (HR/CI: 5·93/1·86­26·38, P = 0·002) [corrected] and the MICA rs2596542 A allele (HR/CI: 4·37/1·52­12·07, P = 0·002) were independently associated with HCC development. The risk A allele or GG genotype with sMICA > 175 ng/mL provided the best accuracy (79%) and a negative predictive value of 100% in predicting HCC. CONCLUSIONS: Cirrhotic patients who carry MICA risk alleles and those without risk alleles but with high sMICA levels possessed the highest risk of HCC development once they failed antiviral therapy.

Pretreatment glucose status determines HCC development in HCV patients with mild liver disease after curative antiviral therapy.

Although diabetes mellitus (DM) is known to increase the risk of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC), the impact of dynamic glucose status on HCC occurrence in chronic hepatitis C (CHC) patients receiving antiviral therapy is unclear. In total, 1112 biopsy-proven patients treated with peginterferon/ribavirin were enrolled in this study. Both pretreatment and post-treatment glucose status, including 75 g oral glucose tolerance test (OGTT), were measured to evaluate the association between glucose status and the development of HCC. Of the 1112 patients evaluated, 93 (8.4%) developed HCC >5183.8 person-years of follow-up (annual incidence rate: 1.79%). DM only influenced the risk of developing CC in patients with mild liver disease (F0-2) and a sustained virological response (SVR) but not in other patient subpopulations. Cox-regression analysis demonstrated that the strongest factor associated with HCC in patients with mild liver disease and SVR was the presence of DM (hazard ratio [HR]/95 % confidence intervals [CI]: 3.79/1.420-10.136, P = 0.008), followed by age (HR/CI: 1.06/1.001-1.117, P = 0.046) and platelet count (HR/CI: 0.989/0.979-1.000, P = 0.05). The percentages of SVR patients with F0-2 with normoglycemia, pre-DM, sub-DM (pre-sDM), and DM before treatment were 45.3% (n = 267), 29.9% (n = 176), 15.6% (n = 92), and 9.2% (n = 54), respectively. The percentages of HCC in patients with normoglycemia, pre-sDM, and DM were 1.1%, 3.7%, and 11.1%, respectively (trend P < 0.001). Sixteen of the 19 (84.2 %) HCC patients possessed glucose abnormality (including 6 patients with DM and 10 patients with pre-sDM) before antiviral therapy. Compared to patients with normoglycemia, the incidence of HCC increased gradually from pre-sDM (HR: 3.6, P = 0.05) to DM (HR: 11.6, P = 0.001) (adjusted trend P = 0.004). We concluded that DM is a critical determinant for the development of HCC in SVR patients with mild liver disease. Pre-sDM status carried an additional risk for HCC, and these patients should also be carefully monitored for HCC after viral eradication.

Time-varying Changes in Pulmonary Function with Exposure to Prolonged Sitting.

OBJECTIVES: The purpose of this study was to quantify the time-varying changes in pulmonary function with exposure to prolonged sitting. METHODS: Twenty-one healthy volunteers were recruited. The pulmonary function of all participants was measured three times in order to assess changes over time; pulmonary function was measured before sitting, after participants had been seated for 1 hour, and after they had been seated for 2 hours. A spirometer was used to measure pulmonary function. The recorded values were forced vital capacity, forced expiratory volume in 1 second, ratio of forced expiratory volume in 1 second to forced vital capacity (forced expiratory volume in 1 second/forced vital capacity), and peak expiratory flow. RESULTS: All measured values were significantly different before sitting and after 1 hour of sitting. There were also significant differences between all measurements taken before sitting and after 2 hours of sitting. However, the measurements taken after 1 hour and 2 hours of sitting did not significantly differ. CONCLUSION: These findings suggest that significant changes in pulmonary function occur relatively quickly when human beings are seated.

Differences in onset time between the vastus medialis and lateralis during stair stepping in individuals with genu varum or valgum.

[Purpose] We investigated the difference in onset time between the vastus medialis and lateralis according to knee alignment during stair ascent and descent to examine the effects of knee alignment on the quadriceps during stair stepping. [Subjects] Fifty-two adults (20 with genu varum, 12 with genu valgum, and 20 controls) were enrolled. Subjects with > 4 cm between the medial epicondyles of the knees were placed in the genu varum group, whereas subjects with > 4 cm between the medial malleolus of the ankle were placed in the genu valgum group. [Methods] Surface electromyography was used to measure the onset times of the vastus medialis and vastus lateralis during stair ascent and descent. [Results] The vastus lateralis showed more delayed firing than the vastus medialis in the genu varum group, whereas vastus medialis firing was more delayed than vastus lateralis firing in the genu valgum group. Significant differences in onset time were detected between stair ascent and descent in the genu varum and valgum groups. [Conclusion] Genu varum and valgum affect quadriceps firing during stair stepping. Therefore, selective rehabilitation training of the quadriceps femoris should be considered to prevent pain or knee malalignment deformities.