Direct-acting Antiviral Agents Therapy Research Articles

Benefits of Hepatitis C Viral Eradication: A Real-World Nationwide Cohort Study in Taiwan.

Chronic hepatitis C (CHC) increases the risk of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). This nationwide cohort study assessed the effectiveness of viral eradication of CHC. The Taiwanese chronic hepatitis C cohort and Taiwan hepatitis C virus (HCV) registry are nationwide HCV registry cohorts incorporating data from 23 and 53 hospitals in Taiwan, respectively. This study included 27,577 individuals from these cohorts that were given a diagnosis of CHC and with data linked to the Taiwan National Health Insurance Research Database. Patients received either pegylated interferon and ribavirin or direct-acting antiviral agent therapy for > 4weeks for new-onset LC and liver-related events. Among the 27,577 analyzed patients, 25,461 (92.3%) achieved sustained virologic response (SVR). The mean follow-up duration was 51.2 ± 48.4months, totaling 118,567 person-years. In the multivariable Cox proportional hazard analysis, the hazard ratio (HR) for incident HCC was 1.39 (95% confidence interval [CI]: 1.00-1.95, p = 0.052) among noncirrhotic patients without SVR compared with those with SVR and 1.82 (95% CI 1.34-2.48) among cirrhotic patients without SVR. The HR for liver-related events, including HCC and decompensated LC, was 1.70 (95% CI 1.30-2.24) among cirrhotic patients without SVR. Patients with SVR had a lower 10-year cumulative incidence of new-onset HCC than those without SVR did (21.7 vs. 38.7% in patients with LC, p < 0.001; 6.0 vs. 18.4% in patients without LC, p < 0.001). HCV eradication reduced the incidence of HCC in patients with and without LC and reduced the incidence of liver-related events in patients with LC.

Prospective Assessment of Serum Lipid Alterations in Chronic Hepatitis C Patients Treated with Direct Acting Antivirals: Insights Six Months Post Sustained Virological Response.

Background and Objectives: Chronic hepatitis C virus (HCV) infection is intricately linked with dysregulation of lipid metabolism. In particular, cholesterol plays a crucial role in HCV replication. Direct-acting antiviral agents (DAAs) therapy has revolutionized the hepatitis C treatment landscape, achieving high rates of sustained virological response (SVR). However, viral clearance comes with some alterations in lipid-related markers. This prospective study aimed to evaluate the impact of HCV clearance on lipid homeostasis and non-invasive liver fibrosis markers in hepatitis C patients treated with DAAs. Material and Methods: Fifty-two patients with varying degrees of fibrosis treated with DAAs therapy were evaluated at baseline and 24 weeks post-SVR. Lipid profiles and non-invasive liver fibrosis markers were assessed. Results: Our findings revealed an increase in total cholesterol, triglyceride, and LDLc (low-density lipoprotein cholesterol) levels at 24 weeks post-SVR, alongside an improvement in serum liver enzymes. Although improvements in liver stiffness were observed in non-invasive tests, there was an increase in lipid-related markers post-SVR. Conclusions: This suggests a potential increased cardiovascular risk despite improvements in liver function and fibrosis, highlighting the necessity for statin therapy in some cases and extended follow-ups for these patients. These findings underscore the importance of closely monitoring lipid profiles in chronic hepatitis C patients post-SVR, as well as the potential need for statin therapy to mitigate cardiovascular risk. Additionally, extended follow-up is essential to assess long-term outcomes and ensure the optimal management of these patients.

Angiopoietin-2 as a Predictor of Fibrosis Regression in Hepatitis C Virus-Patients after Direct Acting Antiviral Drugs

Abstract Background HCV infection is a major health concern. Disease progression to fibrosis, cirrhosis, and HCC is aided by the persistence of inflammatory reactions and cellular damage. Moreover, angiogenesis was found to have a substantial pathogenic role in disease progression. Serum Angiopoietin-2 appears to be correlated with liver stiffness in chronic HCV and its elevation is linked to disease progression from chronic hepatitis to cirrhosis. Aim of the Work The aim of this study was to evaluate the role of serum Angiopoietin-2 in the prediction of regression of fibrosis in chronic HCV patients receiving direct-acting antiviral agents. Patients and Methods Forty Egyptian chronic HCV patients for whom direct-acting antiviral agent (DAA) therapy was planned were included. All patients underwent assessment twice, at baseline and at SVR12, for standard laboratory tests, measurement of fibrosis using FibroScan, FIB-4 and APRI scores, and Angiopoietin-2 level. Results Among 40 patients; 26 (65%) are males and 14 (35%) are females. Their age is ranged between 35 and 60 years old with a mean age of 52.35 ± 6.08 and a median of 53.0 (50.0 – 57.0). The HCV-RNA titer is ranged from 3.60 to 7.20 log IU/mL with a mean titer of 5.99 ± 0.87 before treatment. The median is 6.20 (5.30 – 6.65). There was a significant improvement concerning the fibrosis stage after DAA treatment. Liver fibrosis indices were significantly associated with regression of liver fibrosis stage based on FibroScan data after DAA therapy. Liver size, spleen size and portal vein diameter were improved significantly after successful HCV eradication by DAAs. There was improvement in the Child-Pugh score after successful HCV eradication by DAAs but the difference was no statistically significant (p = 0.500). Baseline Ang-2 was statistically significant after successful HCV eradication by DAAs (p &amp;lt; 0.001). Overall, there was a positive significant correlation between Ang-2 and all the fibrosis stages (p = 0.001) and there was a statistically significant higher mean of Ang-2 in higher stages of liver fibrosis before treatment. Indeed Ang-2 increase significantly when the fibrosis stage increased and vice-versa before treatment. Ang-2 in higher stages of liver fibrosis after treatment. Indeed Ang-2 increase significantly when the fibrosis stage increased and vice-versa after treatment. The correlation between Ang-2 and fibrosis group (F0, F1, F2 &amp; F3) were significant and the correlation between Ang-2 and the liver fibrosis stage (F4) were also significant before treatment. The correlations between Ang-2 levels and fibrosis group (F0, F1, F2 &amp; F3) were significant as well as the advanced liver fibrosis (F4) after DAA therapy. Conclusion Angiopoietin-2 can be a useful predictor of fbrosis regression in chronic HCV patients receiving direct acting antiviral agents. Elevated baseline Angiopoietin-2 and advanced ibrosis stages may predict non-regression of liver fibrosis.

632 Hepatitis C Positive Organ Donation and Direct Acting Antivirals in Pancreas Transplantation: A Systematic Review

Abstract Background Pancreas transplantation (PT) provides diabetic cure for patients with complicated diabetes mellitus. However, there is a paucity of suitable donor organs to fulfil requirements resulting in deaths on the waiting list. Organs from otherwise suitable hepatitis C virus positive (HCV+) donors alongside direct-acting antiviral agents (DAAs) have been used in kidney and liver transplants in small trials. We aimed to review this strategy in PT. Method A literature search was conducted on OVID MedLINE, PubMed and EMBASE to evaluate evidence on the use of HCV+ organ donors for PT in HCV- recipients alongside DAA therapy. Results Database analysis produced 5 articles (4 single centre retrospective, 1 case report). This included a total of 65 patients, 15 of which received PT. Two studies examined multiple organ transplants whilst 3 evaluated PT alone. Three studies employed prophylactic perioperative therapy, while 2 examined treatment post-transplantation. 100% of patients achieved a sustained virological response (SVR) at 12 weeks across all 5 studies. There were no episodes of acute rejection or complications directly associated with DAA therapy or HCV infection. HCV transmission occurred in only 1 of 15 patients, which was successfully treated. Pancreatic graft function and outcome after 7-12 months was good. Conclusions The use of DAA therapy is safe and effective for HCV+ donors to HCV- transplant in early reported studies. This approach could facilitate the successful utilisation of HCV+ organs for transplantation thereby minimising impact on supply and demand disparities. Pancreas transplantation specific studies are required to further analyse outcomes.

Natural history and clinical features of hepatitisC virus infection during childhood: A nationwide, observational survey in Japan.

Few data on spontaneous clearance rates of cases of mother-to-child transmission of hepatitisC viral (HCV) infection are available in Japan. Furthermore, the treatment courses of interferon-based and direct-acting antiviral agent (DAA) therapies for children are also unclear. Our aim was thus to clarify the long-term natural progression of HCV infection and the treatment outcomes of children in Japan. We conducted a combined multicenter, observational survey involving 65 pediatric institutions in Japan. Pediatric HCV infection cases with patients born between 1973 and 2021 were collected over the 11-year period from 2012 to 2022. A total of 563 patients were enrolled, with 190 excluded for having insufficient laboratory data or treatment information, resulting in 373 eligible cases. Of 328 cases of mother-to-child infection, 34 (10.4%) had spontaneous clearance, with a median time to spontaneous clearance of 3.1years (range 0.9-7.2years). Of the total 373 eligible cases, 190 received antiviral therapy (interferon-based therapy, 158; DAA therapy, 32). Sustained virologic response rates after first-line treatment were 75.3% (119/158) and 100% (32/32) for interferon-based therapy and DAA therapy, respectively, with the DAA group showing a shorter time from therapy initiation to viral negativity (2.7 vs. 1.0months; p=0.0031). Approximately 10% of Japanese children infected by mother-to-child transmission achieve spontaneous resolution of HCV infection. Our findings indicate that DAA therapy is safe and highly effective in Japanese children, achieving higher sustained virologic response rates and shorter time to clearance of the virus compared with interferon-based therapy.

Weight Gain and Increased Body Mass Index in Patients with Hepatitis C after Eradication Using Direct-Acting Antiviral Therapy in Taiwan.

Few studies have reported weight gain in patients with hepatitis C virus (HCV) infection treated with direct-acting antiviral agents (DAAs). This retrospective cohort study identified factors associated with substantial weight gain after DAA treatment in Taiwan. This study involved patients treated using DAAs at the Chiayi and Yunlin branches of Chang Gung Memorial Hospital from 1 January 2017 to 31 October 2020. Body weight data were collected at the start of DAA therapy and 2 years after the confirmation of a sustained virologic response. We performed multiple logistic regression to evaluate the clinical and laboratory parameters associated with a large body mass index (BMI) increase (≥5%). The mean BMI was 25.56 ± 4.07 kg/m2 at baseline and 25.77 ± 4.29 kg/m2 at the endpoint (p = 0.005). A considerable reduction in fibrosis-4 (FIB-4) score was a significant predictor of a large BMI increase (OR: 1.168; 95% CI: 1.047-1.304, p = 0.006). By contrast, older age (OR: 0.979; 95% CI: 0.963-0.996, p = 0.013) and a higher baseline BMI (OR: 0.907; 95% CI: 0.863-0.954, p < 0.001) were associated with a reduced risk of a large increase in BMI at the endpoint. In summary, a larger BMI increase was closely associated with a younger age, lower baseline BMI, and higher FIB-4 score reduction. Notably, differences in DAA regimens did not affect outcomes. Future studies are needed to elucidate the long-term effects and metabolic outcomes associated with this body weight change and investigate the exact underlying mechanisms.

Serum Angiopoietin-2 Levels Predict the Development of Hepatocellular Carcinoma following Hepatitis C Virus Eradication Using Direct-Acting Antiviral Agents

Plain Language SummaryOur previous studies showed that serum angiopoietin-2 (Ang-2) and C-X-C motif chemokine ligand 10 (CXCL10) levels predicted improvement in liver fibrosis following sustained virological response (SVR) of hepatitis C virus (HCV) obtained with administration of with direct-acting antiviral agents (DAAs). These levels were evaluated retrospectively as predictive indicators of hepatocellular carcinoma (HCC) development following SVR. We enrolled individuals from a historical cohort of 89 chronic HCV patients without history of HCC at baseline with SVR following DAA therapy and had baseline serum levels of Mac-2 binding protein glycosylation isomer ≥2.0 C.O.I. Multivariate analyses of patients revealed that only the Ang-2 level at 24 weeks following the end of treatment (EOT24W) was significantly related to HCC development (hazard ratio 2.27; p = 0.003). This result was reproduced in individuals with advanced liver fibrosis (M2BPGi level ≥3.3 C.O.I. at baseline). Time-dependent receiver operating characteristic curve analyses for the future risk of developing HCC within 5 years of follow-up (5y-HCC) showed the best cut-off Ang-2 level at EOT24W was 2,780 pg/mL, and significantly stratified the cumulative incidence of HCC (≥2,780 vs. < 2,780 pg/mL, 5y-HCC: 45.5 vs. 8.2%, p < 0.001). The serum Ang-2 level at EOT24W is a feasible predictor of HCC development after achieving SVR to DAAs therapy.

Effect of metabolic dysfunction on the risk of liver-related events in patients cured of hepatitis C virus.

The impact of metabolic dysfunction or metabolic dysfunction-associated fatty liver disease (MAFLD) on liver-related events (LREs) in patients with chronic hepatitis C (CHC) who had achieved a sustained virologic response (SVR) to direct-acting antiviral agents (DAAs) is unknown. A total of 924 patients with cured CHC and documented body mass index (BMI) were included in the analysis, and the data period was from September 2012 to April 2022. Hepatic steatosis was identified either through ultrasonography or blood biomarkers. Metabolic dysfunction was defined as the presence of overweight or obesity (BMI ≥ 23 kg/m2), type 2 diabetes mellitus (DM), and metabolic dysregulation. Patients may have more than one metabolic dysfunction. Variables at 12 or 24 weeks after DAA therapy (PW12) were used to identify predictors of LREs. The median age of the 924 patients was 58 (49-65) years. Of the participants, 418 (45.2%) were male. The median BMI was 24.01 (21.78-26.73) kg/m2, and 174 (18.8%) patients had DM. A multivariable Cox regression analysis revealed that age, male, albumin, total bilirubin, alpha-fetoprotein (AFP), metabolic dysfunction (hazard ratio: 1.709, 95% confidence interval: 1.128-2.591, P = .011), and FIB-4 > 3.25 were independent predictors of LREs. Type 2 DM and metabolic dysregulation exhibited a larger time-dependent area under the receiver operating characteristic curve for LREs than did overweight or obesity. Moreover, metabolic dysfunction was identified to be an independent predictor of hepatocellular carcinoma. Metabolic dysfunction increased the risk of LREs and HCC in patients with CHC who had achieved an SVR to DAA therapy.

Comparison of postoperative outcomes in cases achieving sustained virological response with direct-acting antiviral and interferon therapy.

The effect of direct-acting antiviral agents (DAAs) on hepatocellular carcinoma (HCC) recurrence after curative hepatectomy remains uncertain. This retrospective study aimed to evaluate the effect of sustained virological response (SVR) with DAAs or interferon (IFN) therapy on recurrence and overall survival (OS) after hepatectomy. We enrolled 593 patients who underwent curative resections between January 2010 and December 2017. Among them, 186 achieved SVR before hepatectomy: a total of 51 (27.4%) in the DAA-SVR group and 132 (72.6%) in the IFN-based SVR group. SVR before hepatectomy was an independent predictor of OS, and the 5-year OS rate was significantly higher in the SVR group than that in the non-SVR group (82.2% vs. 63.9%). There were no significant differences in the recurrence rates or OS between DAA and IFN treatments in achieving SVR before hepatectomy, regardless of poor hepatic function in the DAA therapy group. There was no significant difference in OS and recurrence-free survival (RFS) between the preoperative SVR achieved with DAA and IFN groups in this study, although liver function was significantly worse at the time of surgery in the DAA group compared to the IFN group.

Serum inducible protein 10kDa/C-X-C motif chemokine10 levels predict regression of M2BPGi-based liver fibrosis after hepatitisC virus eradication by direct-acting antiviral agents.

It is desirable to identify predictors of regression of liver fibrosis after achieving sustained virological response by anti-hepatitisC virus (anti-HCV) therapy. We retrospectively investigated the serum interferon-γ inducible protein 10kDa (IP-10) level as a predictive indicator of regression of liver fibrosis after successful hepatitis C virus eradication by direct-acting antiviral agents (DAAs) therapy. The study participants were recruited from a historical cohort of 116 chronically hepatitisC virus-infected patients who had achieved sustained virological response by DAAs therapy and whose serum Mac-2 binding protein glycosylation isomer (M2BPGi) levels at baseline (before DAAs therapy) were ≥2.0 cut-off index. We defined patients with M2BPGi levels <1.76 and ≥1.76 cut-off index at 2years after the end of treatment (EOT) as the regression (n=71) and non-regression (n=45) groups, respectively. Multivariate analyses revealed that the albumin-bilirubin score at baseline, and albumin-bilirubin score, Fibrosis-4 index at 24weeks after the EOT, and serum IP-10 change from baseline to 24weeks after the EOT (IP-10 change) were significantly associated with regression of M2BPGi-based liver fibrosis. In addition, IP-10 change was significantly associated with regression of M2BPGi-based liver fibrosis by a multivariate analysis, even when the serum M2BPGi levels were aligned by propensity score matching and in patients with advanced M2BPGi-based liver fibrosis: M2BPGi levels ≥3.3 cut-off index at baseline. Serum IP-10 change from baseline to 24weeks after the EOT is a feasible predictor of regression of M2BPGi-based liver fibrosis after achieving sustained virological response with DAA therapy.

Evaluation of Long-Term Outcomes of Direct Acting Antiviral Agents in Chronic Kidney Disease Subjects: A Single Center Cohort Study.

The chronic kidney disease (CKD) population, including kidney transplant recipients (KTRs) and subjects on renal replacement therapy, is particularly vulnerable to unfavorable outcomes from chronic hepatitis C (CHC). Currently, there are oral direct-acting antiviral agents (DAAs) available to eradicate the virus with favorable short-term outcomes; however, their long-term effects are lacking. The aim of the study is to assess the long-term efficacy and safety of DAA therapy in the CKD population. An observational, cohort single-center study was performed. Fifty-nine CHC subjects with CKD, treated with DAAs between 2016 and 2018, were enrolled in the study. Safety and efficacy profiles were assessed, including sustained virologic response (SVR), occult hepatitis C infection (OCI) incidence, and liver fibrosis. SVR was achieved in 96% of cases (n = 57). OCI was diagnosed only in one subject following SVR. Significant liver stiffness regression was observed 4 years after SVR compared to baseline values (Mdn = 6.1 kPa, IQR = 3.75 kPa; 4.9 kPa, IQR = 2.9 kPa), p < 0.001. The most common adverse events were anemia, weakness, and urinary tract infection. DAAs provide a safe and effective cure for CHC in both CKD patients and KTRs with a favorable safety profile in the long-term follow-up.

Collaborative Referral Model for Hepatitis C Screening and Treatment in a Remote Mountainous Region of Taiwan during the COVID-19 Pandemic.

Community-based screening for the hepatitis C virus (HCV) decreased during the COVID-19 pandemic. We developed a collaborative referral model between a primary clinic (Liouguei District Public Health Center, LDPHC) and a tertiary referral center to increase HCV screening and treatment uptake in a mountainous region of Taiwan. Once-in-a-lifetime hepatitis B and C screening services established by the Taiwan National Health Insurance were performed at LDPHC. Antibody-to-HCV (anti-HCV)-seropositive patients received scheduled referrals and took a shuttle bus to E-Da hospital for HCV RNA testing on their first visit. Direct-acting antiviral agents (DAAs) were prescribed for HCV-viremic patients on their second visit. From October 2020 to September 2022, of 3835 residents eligible for HCV screening in Liouguei District, 1879 (49%) received anti-HCV testing at LDPHC. The overall HCV screening coverage rate increased from 40% before referral to 69.4% after referral. Of the 79 anti-HCV-seropositive patients, 70 (88.6%) were successfully referred. Of the 38 HCV-viremic patients, 35 (92.1%) received DAA therapy, and 32 (91.4%) achieved sustained virological response. The collaborative referral model demonstrates a good model for HCV screening and access to care and treatment in a Taiwan mountainous region, even during the COVID-19 pandemic. Sustained referral is possible using this routine referral model.

Effect of gender difference on psychiatric outcomes for hepatitis C virus patients receiving direct-acting antivirals in Egyptian population: a cohort study

Abstract Background Chronic liver disease is primarily caused by hepatitis C virus (HCV). HCV produces extrahepatic psychiatric problems. So, patients with CHC who received sofosbuvir-based direct-acting antiviral agents (DAAs) were evaluated for psychiatric manifestations, specifically depression and anxiety symptoms. Additionally, evaluate the impact of gender on psychiatric manifestations of sofosbuvir-based DAAs and identify their potential risk factors for psychiatric manifestations. In this prospective study, 170 CHC patients without prior treatment received DAA therapy who categorized into 2 groups, group 1 comprised male participants (Nb = 97), and group two comprised female participants (Nb = 73). All participants were evaluated with the five-factor model of personality (SIFFM), Hamilton Depression Rating Scale (HDS), and Hamilton Anxiety Rating Scale (HAS) at baseline and repeated follow up until 3 months after treatment end. Results Our findings indicated that, a progressive decline in the mean HADS-A and HADS-D scores between baseline (before treatment) and consequence follow-up (during and after treatment) measurements without significant difference regarding gender. No statistically significant difference between the groups regarding the mean values of SIFFM. High levels of extraversion were more likely to increase depression levels. Conclusions DAA treatment significantly improved anxiety and depression symptoms in CHC patients. Gender did not affect sofosbuvir-based DAA psychiatric symptoms. High extraversion increased depression risk.

Serum angiopoietin-2 levels predict regression of Mac-2 binding protein glycosylation isomer-based liver fibrosis after hepatitis C virus eradication by direct-acting antiviral agents.

It is desirable to identify predictors of regression of liver fibrosis after achieving a sustained virologic response (SVR) by direct-acting antiviral agents (DAAs) to antihepatitis C virus (HCV) therapy. Here, we retrospectively investigated the serum angiopoietin-2 (Ang-2) level as a predictive indicator of regression of liver fibrosis after successful HCV eradication by DAA therapy. The study subjects were recruited from a historical cohort of 109 chronically HCV-infected patients who had achieved SVR by DAA therapy and whose serum Mac-2 binding protein glycosylation isomer (M2BPGi) levels at baseline (before DAA therapy) were ≥2.0 the cut-off index (COI). We defined patients with M2BPGi levels <1.76 and≥1.76 COI at 2years after the end of treatment (EOT) as the regression (R, n=69) and nonregression (NR, n=40) groups, respectively. Multivariate analyses revealed that the Ang-2 level at baseline and the Ang-2 level, albumin-bilirubin score, and FIB-4 index at 24weeks after the EOT were significantly associated with regression of M2BPGi-based liver fibrosis. Receiver operating characteristic curve analyses showed that the Ang-2 level at 24weeks after the EOT had the largest area under the curve values (0.859). The same results were obtained even when the serum M2BPGi levels were aligned by propensity score matching and in patients with advanced M2BPGi-based liver fibrosis: M2BPGi levels ≥3.3 COI at baseline. The serum Ang-2 level at 24weeks after the EOT is a feasible predictor of regression of M2BPGi-based liver fibrosis after achieving SVR by DAA therapy.

Enhanced liver fibrosis score as a noninvasive biomarker in hepatitis C virus patients after direct-acting antiviral agents.

Background: In more than 90% of chronic viral hepatitis C (HCV) patients treated with direct-acting antiviral agents (DAAs), a sustained viral response (SVR) was observed. Unfortunately, there are subgroups of subjects who display enduring liver fibrosis and are at high risk of developing hepatocellular carcinoma (HCC). Thus, liver fibrosis evaluation during the follow-up of these patients plays a pivotal role. The gold standard to evaluate hepatic fibrosis is liver biopsy, which is an invasive procedure. Imaging techniques and serum biomarkers have been proposed as safer and cheaper procedures. Objectives: In this study, we evaluated the concordance of transient elastography (TE) with ELF score ( enhanced liver fibrosis) in a cohort of patients with HCV before and after direct-acting antiviral (DAAs) treatment. ELF score has been validated in other chronic liver diseases; the evidence is not available in HCV patients treated with DAAs. Study design: We prospectively recruited all consecutive HCV patient candidates for DAAs therapy at the University of Naples “Federico II” between April 2015 and July 2016. TE and ELF scores were assessed at baseline, at SVR24, and at SVR48. Results: One-hundred-nineteen patients were treated with DAAs, and 94.1% of them reached SVR. A total of 55.5% of patients were males with a mean age of 64.7 ± 9.6 years. TE results revealed that 12 patients (10%) had F1-2 mild/moderate fibrosis, and 107 (90%) had F3-4 advanced fibrosis. At baseline, SVR24, and SVR48, the concordance between ELF test and TE was poor: 0.11 (p = 0.086), 0.15 (p = 0.124), and 0.034 (p = 0.002), respectively. However, at SVR24 and SVR48, both methods showed a significant amelioration of liver fibrosis compared to baseline (p < 0.001). In addition, both ELF index and TE were significantly associated with portal hypertension at baseline, but not with varices and ascites. Conclusions: Our findings suggested that ELF test could predict changes in liver fibrosis, independently of TE. In case of TE unavailability, ELF score could represent an appropriate tool. Notably, in the context of the COVID-19 pandemic, ELF testing should be encouraged to reduce unnecessary access to the hospital and prolonged physical contact.

Hepatocytes infected with hepatitis C virus change immunological features in the liver microenvironment.

Hepatitis C virus (HCV) infection is remarkably efficient in establishing viral persistence, leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC). Direct-acting antiviral agents (DAAs) are promising HCV therapies to clear the virus. However, recent reports indicate potential increased risk of HCC development among HCV patients with cirrhosis following DAA therapy. CD8+ T-cells participate in controlling HCV infection. However, in chronic hepatitis C patients, severe CD4+ and CD8+ T-cell dysfunctions have been observed. This suggests that HCV may employ mechanisms to counteract or suppress the host T-cell responses. The primary site of viral replication is within hepatocytes where infection can trigger the expression of costimulatory molecules and the secretion of immunoregulatory cytokines. Numerous studies indicate that HCV infection in hepatocytes impairs antiviral host immunity by modulating the expression of immunoregulatory molecules. Hepatocytes expressing whole HCV proteins upregulate the ligands of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and transforming growth factor β (TGF-β) synthesis compared to those in hepatocytes in the absence of the HCV genome. Importantly, HCV-infected hepatocytes are capable of inducing regulatory CD4+ T-cells, releasing exosomes displaying TGF-β on exosome surfaces, and generating follicular regulatory T-cells. Recent studies report that the expression profile of exosome microRNAs provides biomarkers of HCV infection and HCV-related chronic liver diseases. A better understanding of the immunoregulatory mechanisms and identification of biomarkers associated with HCV infection will provide insight into designing vaccine against HCV to bypass HCV-induced immune dysregulation and prevent development of HCV-associated chronic liver diseases.

Effect of Direct-Acting Antiviral Agents on Gastroesophageal Varices in Patients with Hepatitis C Virus-Related Cirrhosis.

Aim: In patients with hepatitis C virus-related liver cirrhosis (LC) who achieve sustained virological responses (SVRs) through treatment with direct-acting antiviral agents (DAAs), it remains unclear whether there are improvements in gastroesophageal varices (GEVs) and portal hypertension. We investigated changes in liver function and GEVs that occurred after DAA therapy. Materials and Methods: We evaluated the medical records of 195 patients with hepatitis C virus-related LC who received DAAs. A total of 171 patients achieved SVRs, among whom 36 had GEVs before or after receiving DAA therapy. The liver function, fibrosis, and GEVs were re-evaluated every 6 months after receiving DAA therapy. The risk factors for progressive GEVs were investigated. Results: DAA therapy resulted in improvements in liver function (indicated by aspartate transaminase, alanine transaminase, and serum albumin levels) and fibrosis (indicated by type IV collagen levels and the Fibrosis-4 index). After receiving DAA therapy, 27 patients had stable GEVs and 9 had progressive GEVs. With respect to GEV grades before DAA therapy, there was a significant difference between patients with stable and progressive GEVs (p = 0.027). Presence of grade-2 GEVs before starting DAA therapy was a risk factor for GEV progression (odds ratio: 5.83; p = 0.04). Patients with grade-2 GEVs had significantly shorter progression-free periods than those with grade < 2 GEVs (p = 0.025). Conclusions: DAA therapy does not ameliorate GEVs. Furthermore, grade-2 GEVs can worsen after DAA therapy. Therefore, patients with GEVs of grades ≥ 2 should undergo endoscopic surveillance after receiving DAAs.

IP-10 Interferes With the Antiviral Response of Direct-Acting Antiviral Agents for Hepatitis C Virus Infection.

BackgroundIncreased interferon (IFN)-gamma inducible protein-10 (IP-10) level has been shown to be associated with sustained virologic responses (SVRs) to pegylated interferon-alpha 2a/ribavirin-based therapy in patients with chronic hepatitis C (CHC). We investigated the relationship between IP-10 and treatment response in patients with CHC treated with direct-acting antiviral agents (DAAs) therapy.MethodsWe measured the dynamic changes of IP-10 in samples from 90 patients with CHC. The serum IP-10 levels, intrahepatic expressions of IP-10 mRNA, and protein were determined, respectively. For the in vitro experiments, the expression changes of IP-10 in hepatitis C virus (HCV)-replicating Huh-7 cells with or without non-structural protein 5A (NS5A) inhibitor were analyzed using real-time reverse transcription-polymerase chain reaction and Western blotting.ResultsPatients with chronic hepatitis C had increased baseline IP-10 levels, intrahepatic IP-10 mRNA, and protein expression. After initiating DAAs therapy, serum IP-10 levels decreased gradually in patients who achieved cure, whereas in patients who failed the therapy, IP-10 levels did not change significantly or recovered from the initial decline. Multivariate logistic regression analysis confirmed that baseline IP-10 level ≤ 450 pg/ml and decline >30% at 12 weeks independently predicted the SVR in patients with CHC who received DAAs. In vitro, the expression of IP-10 mRNA and protein in HCV-replicating Huh-7 cells increased significantly. However, such activities were downregulated by NS5A inhibitor, followed by the reduction of HCV RNA levels and a decline in IP-10 levels.ConclusionIP-10 interfered with HCV replication in hepatocytes and the dynamic decline in IP-10 levels during DAA treatment predicted the SVR in patients with CHC.

Study the response of Qurevo (ombitasvir, paritaprevir, and ritonavir) in end-stage renal disease patients with hepatitis C virus

BackgroundOut of the 185 million people infected with hepatitis C virus (HCV) worldwide according to the World Health Organization (WHO), Egypt had the highest prevalence of HCV reaching 13% of its population with an estimated number of 12 million people. The prevalence of HCV infection among hemodialysis (HD) patients ranged from 6 to 60%. HD patients have an increased overall mortality risk if they have chronic HCV when compared to those without HCV infection. Treatment of HCV with the new direct-acting antiviral agent (DAA) therapy Qurevo “ombitasvir/paritaprevir/ritonavir” with ribavirin in ESRD was approved in many countries compared to traditional HCV treatment that faced restrictions in the setting of chronic kidney disease (CKD).Aim of the studyTo evaluate the efficacy and safety of Qurevo/ribavirin regimen in HCV-infected HD patients.Patients and methodsA prospective cohort study evaluated the outcome of 12-week ombitasvir (NS5A inhibitor)/paritaprevir (NS3/4A protease inhibitor)/ritonavir with ribavirin combination therapy for 50 HCV-infected HD patients, over a period of 15 months from December 2016 to February 2018. The primary endpoint was sustained virologic response 12 weeks after therapy (SVR12) and after 24 weeks of therapy (SVR24).ResultsThe SVR12 rate was 96% (48/50); 2 patients (4%) were non-responders to treatment at SVR12, and another 2 (4%) were relapsers after SVR12. As regards the adverse events, the most frequent were fatigue/asthenia in 44 patients (88%) and worsening anemia (Hb dropped to < 10 g/dl) in 42 patients (84%). GIT upset occurred in 10 patients (20%), sleep disorders in 8 patients (16%), decreased appetite in 8 patients (16%), respiratory distress in 6 patients (12%), headache and dizziness in 6 patients (12%), and muscle spasms in 4 patients (8%). Itching (pruritus) occurred in 3 patients (6%). Death occurred in 4 patients (8%) after SVR24 most probably not due to DAA but may be due to myocardial infarction, pulmonary edema, severe hypotension on hemodialysis sessions, and shock due to blood loss in retroperitoneal hematoma following peritoneal dialysis not related to DAA therapy. Hepatic decompensation, hypersensitivity (angioedema), teratogenicity, and drug interactions did not occur in any patient (0%). Other events occurred in 11 patients (22%). They were parenchymal liver changes in ultrasound at the end of therapy after being normal before therapy (in 3 patients), thrombocytopenia, increased alkaline phosphatase, hiccough, deterioration of hypertension, urinary tract infection, lower limb cellulitis, vaginal bleeding, and chest infection (in 1 patient each). SVR12 was achieved in 100% of patients who had to stop or modify the ribavirin dose; this means that ribavirin absence did not affect the SVR in these patients.ConclusionOur results confirm the efficacy of Qurevo “ombitasvir/paritaprevir/ritonavir” with ribavirin combination therapy in ESRD patients (on regular hemodialysis) with HCV infection with anemia as the most frequent adverse event.

Posttreatment nonalcoholic fatty liver disease fibrosis scores for predicting liver-related complications in patients with chronic hepatitis C receiving direct-acting antiviral agents.

Patients with chronic hepatitis C (CHC) have a higher prevalence of hepatic steatosis and dyslipidaemia than healthy individuals. We analysed noninvasive fibrosis assessments, especially nonalcoholic fatty liver disease (NAFLD)-related noninvasive fibrosis tests, for predicting liver-related complications and hepatocellular carcinoma (HCC) occurrence in patients with CHC. This retrospective study enrolled 590 consecutive patients with CHC having a sustained virologic response (SVR) to direct-acting antiviral agent (DAA) therapy. The NAFLD fibrosis score (NFS) exhibiting the highest value of area under the receiver operating characteristic curve (AUROC) was selected for comparison with the fibrosis-4 index (FIB-4). Of the 590 patients, 188 had metabolic syndrome. A multivariate Cox regression analysis identified total bilirubin at 3 or 6months after DAA therapy (PW12), NFS at PW12 (hazard ratio [HR]: 2.125, 95% confidence interval [CI]: 1.058-4.267, p=.034) and alpha-fetoprotein (AFP) at PW12 (HR: 1.071, 95% CI: 1.005-1.142, p=.034) as the independent predictors of liver-related complications in all patients. In patients with metabolic syndrome, NFS and AFP values at PW12 were independent predictors of liver-related complications and HCC occurrence. Time-dependent NFS AUROC values at PW12 for 1-, 2- and 3-year liver-related complications were higher than NFS values at baseline in patients with metabolic syndrome. NFS at baseline or PW12 is a more effective predictor of liver-related complications than FIB-4 values in all patients. NFS at PW12 may be a useful predictor of liver-related complications and HCC development in patients with CHC with an SVR to DAA therapy, especially in those with metabolic syndrome.