Direct-acting antiviral therapy of chronic hepatitis C improves liver fibrosis, assessed by histological examination and laboratory markers.

BACKGROUND/PURPOSE: Direct-acting antiviral agents achieve sustained virological response in most chronic hepatitis C patients. However, histological responses are not consistent among all patients. We conducted an observational study to analyze the histological changes after direct-acting antiviral agent therapy. METHODS: We recruited 220 patients who achieved sustained virological response after direct-acting antiviral agent. Histology was assessed by liver biopsy and laboratory indices including fibrosis-4 and aspartate aminotransferase to platelet ratio index. Primary outcomes were change in the dynamic laboratory results. Secondary outcomes were histological changes on liver biopsy. We analyzed the factors predictive of histological regression. RESULTS: The mean fibrosis-4 index decreased from 4.78 at baseline to 3.30, 3.31, 3.65, and 3.66 at week 4, 8, end of treatment, and 12 weeks after treatment, respectively (all p < 0.01). Mean aspartate aminotransferase to platelet ratio index decreased from 1.62 at baseline to 0.61, 0.66, 0.64, and 0.82 at week 4, 8, end of treatment, and 12 weeks after treatment, respectively (all p < 0.01). Mean Histological Activity Index at baseline and post-treatment was 6.9 ± 1.9 and 5.0 ± 2.3. The METAVIR fibrosis scores improved in 61.9% of the patients. We compared patients who achieved fibrosis-regression with the non-regression group. There was no significant difference in the baseline host/virological factors between the groups. CONCLUSION: Reversal of liver inflammation and fibrosis was achieved in a significant number of patients who received direct-acting antiviral agent. No baseline host or virological factor was predictive of histological regression after antiviral treatment.

An Open-Label, Randomized, Active-Controlled Trial of 8 Versus 12 Weeks of Elbasvir/Grazoprevir for Treatment-Naive Patients With Chronic Hepatitis C Genotype 1b Infection and Mild Fibrosis (EGALITE Study): Impact of Baseline Viral Loads and NS5A Resistance-Associated Substitutions.

BACKGROUND: A 12-week grazoprevir/elbasvir regimen is highly effective against hepatitis C virus genotype 1 (HCV-1) infection. The efficacy of an 8-week regimen for treatment-naive HCV-1-infected patients with mild fibrosis has not been determined. METHODS: Treatment-naive HCV-1b-infected patients with mild fibrosis were randomly assigned to receive 8 (n = 41) or 12 (n = 41) weeks of grazoprevir/elbasvir therapy. The primary end point was a sustained virologic response, defined as an HCV RNA level of < 12 IU/mL, at posttreatment week 12 (SVR12). RESULTS: SVR12 was achieved by 87.8% of patients (36 of 41) in the 8-week arm and 100% (41 of 41) in the 8-week arm of the full-analysis population and by 90.0% (36 of 40) and 100% (41 of 41), respectively, in the per-protocol population (all P = .055). In the 8-week arm, a significantly lower SVR12 rate was observed among patients with a high HCV-1b load, defined as ≥1 500 000 IU/mL (79% vs 100%; P = .042), and among those with a baseline Y93H resistance-associated substitution (RAS) frequency of >15% in HCV nonstructural protein 5A (NS5A; 40.0% vs 97.1%; P = .004). Between-group analysis demonstrated that, among patient with a high HCV-1b load and a baseline Y93H RAS frequency of >15%, those in the 8-week arm had a substantially lower SVR12 rate than those in the 12-week arm (40.0% vs 100.0%). All 4 HCV-1b relapses had a Y93H RAS frequency of >99% at posttreatment week 12. CONCLUSIONS: Twelve weeks of grazoprevir/elbasvir therapy is highly effective for treatment-naive patients with mild fibrosis. A truncated, 8-week grazoprevir/elbasvir regimen might be applied for those with low viral loads or without a significant NS5A RAS frequency. CLINICAL TRIALS REGISTRATION: NCT03186365.

Long-term histological change in chronic hepatitis C patients who had received peginterferon plus ribavirin therapy with sustained virological response.

BACKGROUND: The improvement in liver histology is an important aim in the management of hepatitis C virus (HCV) infection. Previous studies suggest that antiviral treatment could reduce the progression of hepatic fibrosis, especially in patients with sustained virological response (SVR). However, most studies were limited by short-term evaluations and the liver stiffness was assessed by non-invasive methods. In our study, we performed a paired liver biopsy study aimed at analyzing the long-term histological changes in patients with SVR. METHODS: We included 31 patients who had been previously treated with peginterferon plus ribavirin. All patients achieved SVR and had received pre- and post-treatment liver biopsies. The histological appearance of fibrosis and inflammation were assessed with METAVIR scoring system and Histological Activity Index (HAI) criteria. We analyzed several factors associated with the histological response. RESULTS: The median interval between two biopsies was 93.0 months. The percentage of patients with fibrosis regression, stable, and progression were 19%, 45%, and 36%. A total of 71% of patients achieved inflammation improvement, whereas 6% and 23% of patients had stable disease and disease-progression, respectively. We showed that the patients without baseline advanced fibrosis and those having a lower baseline HAI score had higher risk of fibrosis worsening. Baseline fibrosis and necroinflammation status did not influence HAI change significantly. CONCLUSION: The progression of hepatic fibrosis and inflammation can be reversed in some patients who had long-term virological suppression. Patients with advanced baseline fibrosis and higher inflammatory stages seemed to receive more histologic benefit from successful antiviral treatments.

Virus Elimination by Direct-Acting Antiviral Agents Impacts Glucose Homeostasis in Chronic Hepatitis C Patients.

Background and Aims: Chronic hepatitis C virus (HCV) infection is associated with dysregulation of glucose homeostasis, including insulin resistance (IR) and type 2 diabetes. However, independent risk factors associated with IR in chronic HCV-infected patients have not been detailly elucidated. Previous data regarding the impact of HCV elimination by direct-acting antiviral agents (DAAs) on glucose homeostasis is insufficient and controversial. This study aimed to analyze the independent factors associated with IR and to evaluate the changes in glucose homeostasis in chronic HCV-infected patients treated with DAAs therapies. Methods: We screened 704 patients with chronic HCV infection who underwent treatment with interferon-free DAAs. Patients' baseline characteristics, biochemical and virological data were collected. The outcome measurements were their IR and ß-cell function assessed by the homeostasis model assessment (HOMA) method at baseline and 12-weeks post-treatment. Results: High IR (HOMA-IR ≥ 2.5) was observed in 35.1% of the patients. Multivariable logistic regression analysis revealed that body mass index (BMI) >25 kg/m2, treatment experience, elevated baseline levels of alanine aminotransferase (ALT) and triglyceride, as well as Fibrosis-4 score >3.25 were independently associated with high IR. In patients who achieved sustained virological response (SVR), no significant change in mean HOMA-IR was observed from baseline to 12-weeks post-treatment (2.74 ± 2.78 to 2.54 ± 2.20, p = 0.128). We observed a significant improvement in ß-cell secretion stress from 121.0 ± 110.1 to 107.6 ± 93.0 (p = 0.015). Subgroup analysis revealed that SVR was associated with a significant reduction in mean HOMA-IR in patients with baseline HOMA-IR ≥ 2.5 (5.31 ± 3.39 to 3.68 ± 2.57, p < 0.001), HCV genotype 1 (3.05 ± 3.11 to 2.62 ± 2.05, p = 0.027), and treatment experience (4.00 ± 3.37 to 3.01 ± 2.49, p = 0.039). Conclusions: There were several independent factors associated with IR in patients with chronic HCV infection, including obesity, treatment experience, high serum ALT and triglyceride levels, as well as advanced hepatic fibrosis. After viral elimination by DAAs, we observed a significant reduction in mean HOMA-IR in patients with baseline high IR, HCV genotype 1, and treatment experience.

Subgroup analysis of the predictive ability of aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 (FIB-4) for assessing hepatic fibrosis among patients with chronic hepatitis C.

BACKGROUND: There are many laboratory indices to assess liver fibrosis. Aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 (FIB-4) index have been used as well-known serum markers of liver fibrosis. With the increasing use of non-invasive fibrosis assessment, it is important to recognize the limitations of these tests. The factors influencing the diagnostic accuracy to evaluate liver fibrosis are not well-established. This study aimed to perform a subgroup analysis of the predictive ability of laboratory indices. METHODS: Overall, 113 patients with chronic hepatitis C infection who underwent liver biopsy were retrospectively examined. The histological assessment of liver fibrosis was performed using the METAVIR scoring system, and the values of several laboratory tests were also evaluated on the same day. We categorized our study population by treatment status, body mass index (BMI), and age. RESULTS: The two laboratory indices APRI and FIB-4 index could predict advanced (F3-4) liver fibrosis and cirrhosis (F4), with the area under the receiver operating characteristic curve (AUROC) > 0.8 and accuracy >70%. The AUROCs and accuracies were higher among patients with sustained virological response (SVR) than among those without SVR. A higher predictive ability was also observed among patients with BMI <25 kg/m2. Age did not appear to affect liver fibrosis predictability. CONCLUSIONS: The laboratory indices APRI and FIB-4 index exhibit good diagnostic performance for determining advanced fibrosis and cirrhosis among patients with hepatitis C infection. The diagnostic accuracy appears better among patients with SVR and those with BMI <25 kg/m2.

Evaluation of cost-effectiveness of peginterferon plus ribavirin for chronic hepatitis C treatment and direct-acting antiviral agents among HIV-infected patients in the prison and community settings.

BACKGROUND: In Taiwan, the majority of chronic hepatitis C carriers with HIV co-infection are intravenous drug users and inmates in correctional facilities. Peginterferon and ribavirin (PegIFN/RBV) have been the standard-of-care for chronic hepatitis C virus (HCV) infection more than decades. We evaluated the estimated cost-effectiveness of PegIFN/RBV from the National Health Insurance Research Database, covering the population of Taiwan from 1998 to 2013. MATERIALS AND METHODS: This is an observational study, and study during was 2010-2016 and a total of 239 patients were treated with PegIFN/RBV. Of them, 156 patients were treated in the correctional facilities of Taipei, Taoyuan, Taichung and Taitung prisons, and 83 patients were treated in communities. The cost-effectiveness was analyzed in regimens of PegIFN/RBV and direct-acting antiviral agents. RESULTS: By multivariate analysis, the patients completed PegIFN/RBV in prison (adjusted odds ratio [aOR]: 4.56, 95% confidence interval [CI]: 1.58-13.12, p = 0.005), HCV RNA level <800,000 IU/mL (aOR: 4.0, 95% CI: 1.27-12.66, p = 0.02) at baseline, and the presence of early virologic response (EVR) (aOR: 7.67, 95% CI: 1.89-31.06, p = 0.004) were independent predictors for sustained virologic response (SVR). For the subgroups of prisoners, HIV-infected prisoners and HIV-infected patients in communities, the SVR rate was 73.8%, 72.0% and 36.8%, and the average medical-care cost was US$7,701, $7,893, and $15,443 per SVR achieved, respectively. Also, the estimated medical-care cost for genotype 6 was US$9211. CONCLUSIONS: Chronic HCV/HIV co-infected patients with genotype 1 and 6 in the community setting could benefit from DAAs in Taiwan.

Genotype distribution and treatment response among incarcerated drug-dependent patients with chronic hepatitis C infection.

The prevalence of hepatitis C virus (HCV) infection is disproportionately high among prisoners, especially among those who are drug-dependent. However, current screening and treatment recommendations are inconsistent for this population, and appropriate care is not reliably provided. To address these problems, the present study aimed to identify unique characteristics and clinical manifestations of incarcerated patients with HCV infection. We included incarcerated patients who received treatment with pegylated-interferon combined with ribavirin at Mackay Memorial Hospital in Taitung and were serving sentences at either the Taiyuan Skill Training Institute or the Yanwan Training Institute. HCV genotypes 1 (41.4%), 3 (25.9%), and 6 (24.1%) were the most prevalent in the incarcerated patients. During the study period, we analyzed treatment response among 58 incarcerated patients and compared obtained results with treatment response among 52 patients who were living in the community. Higher sustained virological response rate was observed among patients with incarceration and HCV genotype other than 1. The odds ratios (corresponding 95% confidence intervals) for incarceration and genotype 1 were 2.75 (1.06-7.11) and 0.37 (0.14-0.99), respectively. Better treatment compliance among incarcerated patients might partially explain these results. The results of this study suggest that treatment of prisoners with HCV infection is feasible and effective. More appropriate and timely methods are needed to prevent HCV transmission among injection drug users inside prisons.

Is endotracheal intubation a non-beneficial treatment in patients with respiratory failure due to paraquat poisoning?

INTRODUCTION: Paraquat poisoning can result in dysfunction of multiple organs, and pulmonary fibrosis with respiratory failure is the major cause of mortality. For terminally ill patients, some life-prolonging treatments can be non-beneficial treatments (NBT). The objective of this study was to determine if intubation is a NBT for patients with respiratory failure due to paraquat poisoning. METHODS: The study included 68 patients with respiratory failure due to paraquat poisoning. Patients were hospitalized at MacKay Memorial Hospital, Taitung Branch, Taiwan, between 2005 to April 2016. Composite outcomes of intra-hospital mortality, the rate of do-not-resuscitate (DNR) orders, prescribed medications, length of stay, and medical costs were recorded and compared between the do-not-intubate (DNI) group and endotracheal intubation (EI) group. RESULTS: Intra-hospital mortality rate for the entire population was 100%. There were significantly more patients with DNR orders in the DNI group (P = 0.007). There were no differences in the length of hospital stay. However, patients in DNI group had significantly less vasopressor use and more morphine use, shorter time in the intensive care unit, and fewer medical costs. CONCLUSION: The procedure of intubation in patients with respiratory failure due to paraquat poisoning can be considered inappropriate life-prolonging treatment.

Application of chronic liver failure-sequential organ failure assessment score for the predication of mortality after esophageal variceal hemorrhage post endoscopic ligation.

BACKGROUND: Esophageal variceal hemorrhage (EVH) is one of the high mortality complications in cirrhotic patients. Endoscopic variceal ligation (EVL) is currently the standard therapy for EVH. However, some patients have expired during hospitalization or survived shortly after management. AIM: To evaluate hospital and 6-week mortality by receiver operating characteristic (ROC) curve of chronic liver failure-sequential organ failure assessment (CLIF-SOFA) score compared to a model for end-stage liver disease (MELD) score and Child-Turcotte-Pugh (CTP) class. METHODS: We retrospectively collected 714 cirrhotic patients with EVH post EVL between July 2010 and June 2016 at Taitung MacKay Memorial Hospital, Taiwan. CLIF-SOFA score, MELD score, and CTP class were calculated for all patients admitted. RESULTS: Among the 714 patients, the overall hospital and 6-week mortality rates were 6.9% (49/715) and 13.1% (94/715) respectively. For predicting hospital death, area under receiver operating characteristic curve (AUROC) values of CLIF-SOFA score, MELD score, and CTP class were 0.964, 0.876, and 0.846. For predicting 6-week death, AUROC values of CLIF-SOFA score, MELD score, and CTP class were 0.943, 0.817, and 0.834. CLIF-SOFA score had higher AUROC value with statistical significance under pairwise comparison than did MELD score and CTP class in prediction of not only hospital but also 6-week mortality. The history of hepatocellular carcinoma was the risk factor for 6-week mortality. For patients with hepatocellular carcinoma the cut-point of CLIF-SOFA score was 5.5 for 6-week mortality and 6.5 for hospital mortality on admission. For patients without hepatocellular carcinoma, the cut-point of CLIF-SOFA score was 6.5 for both 6-week and hospital mortality. CONCLUSION: CLIF-SOFA score predicted post-EVL prognosis well. For patients without hepatocellular carcinoma, CLIF-SOFA score ≥6 suggests higher 6-week mortality and CLIF-SOFA score ≥7 suggests higher hospital mortality. For patients with hepatocellular carcinoma, CLIF-SOFA score ≥7 suggests higher 6-week and hospital mortality.

High frequencies of a favorable IL-28B rs8099917 polymorphism and the clinical implications in patients with HCV in one multiracial area of Taiwan.

There is a strong association between hepatitis C virus (HCV) treatment efficacy and the interleukin (IL)-28B gene. However, the IL-28B variant's distribution and potential role in the therapeutic response are not well established in Taitung, a racially diverse county in Taiwan. Here, we investigated the distribution pattern of IL-28B rs8099917 and its influence on treatment efficacy. In this retrospective study, we enrolled 180 patients who had been treated with pegylated-interferon plus ribavirin. Patients' general information, virological characteristics, IL-28B status, laboratory results, treatment course, and outcome were analyzed. Of the patients enrolled, 56.7% were male, with a mean age of 54.11 years. A total of 24.4% of the population were indigenous people. The majority of patients had the favorable IL-28B polymorphism (rs8099917 TT/TG/GG: 94.4%/5.6%/0%). The proportion of patients with the TT genotype seemed to be higher in indigenous patients. The rate of sustained virological response (SVR) among included patients was 73.0%. Univariate analysis showed that genotype non-1, patients achieved rapid virological response (RVR), lower body mass index (BMI), and lower baseline HCV viral load were significantly associated with SVR. Multivariate analysis revealed that BMI <25 and RVR are the independent predictor of success treatment. In conclusion, the favorable IL-28B rs8099917 polymorphism occurs in high frequency in this multiracial area, which might be important to help guide physicians and patients in their future clinical decisions.

The genotype distribution of hepatitis C in southeastern Taiwan: Clinical characteristics, racial difference, and therapeutic response.

The genotypes of hepatitis C virus (HCV) are associated with the therapeutic response. The racial diversity of Taitung, Taiwan is heterogeneous and a distinguishing feature; how such racial differences influence the genotype distribution and treatment outcome has not been well studied. The objective of this study is to elucidate the HCV genotype distribution in southeastern Taiwan and to analyze the racial differences influencing genotypes and clinical implications. In this retrospective cohort study, we included 343 patients who had been treated with peginterferon-alpha plus ribavirin. The predominant HCV genotype in the southeastern area was type 1 (43.7%), followed by type 2 (37.0%). The proportion of patients mixed with genotype 1 was lower in indigenous vis-à-vis nonindigenous groups (46.1% and 60.2%, p = 0.02). The prevalence of genotype 6 (5.2%) seems higher than in the general population of Taiwan and showed no difference between indigenous and nonindigenous people. The sustained virological response rate was higher in patients without genotype 1, low baseline HCV RNA (≤ 400,000 IU/mL), and in patients who achieved rapid virological response. Racial differences did not influence the therapeutic response. In this retrospective study, the proportion of HCV genotype 6 appeared slightly higher in southeastern areas than in the general population in Taiwan. The prevalence of genotype 1 in indigenous people was statistically lower than in nonindigenous people. Sustained virological response rate did not show any significant difference between indigenous and nonindigenous people in the current study.