Sustained Virological Response In Patients Research Articles

Impact of HCV eradication on recurrence pattern and long-term outcomes in patients with HCV-related hepatocellular carcinoma undergoing radiofrequency ablation.

The benefits of HCV eradication on distinct recurrence patterns and long-term hepatic outcomes in patients with hepatocellular carcinoma (HCC) undergoing radiofrequency ablation (RFA) remain uncertain. This study aims to assess the impact of HCV eradication on HCC recurrence patterns and long-term hepatic outcomes after RFA and to identify predictors of recurrence in patients achieving sustained virological response (SVR). We retrospectively enrolled 274 patients receiving RFA for HCV-related HCC, including 73 and 88 patients treated with interferon-based (IFN) and direct-acting antivirals (DAA) therapy, respectively. We analysed factors associated with local tumour progression (LTP), distant recurrence, overall survival, and hepatic decompensation. SVR was achieved in 49.3% of patients undergoing IFN therapy and 93.2% of patients undergoing DAA therapy. HCV eradication was not associated with LTP but significantly correlated with reduced risk of distant recurrence (by DAA: hazard ratio (HR) = 0.449, p = 0.006), overall survival (by IFN: HR = 0.242, p < 0.001; by DAA: HR = 0.274, p < 0.001) and hepatic decompensation (by IFN: HR = 0.313, p = 0.004; by DAA: HR = 0.281, p < 0.001). The benefits of achieving SVR in terms of overall survival and hepatic decompensation remained significant in subgroups of patients with and without recurrence. Patients with SVR showed a significant decline in FIB-4 score and a higher proportion of ALBI grade improvement. Among SVR patients, the IMbrave050 criteria predicted LTP but not distant recurrence, whereas the FIB-4 score after SVR, rather than the baseline FIB-4, predicted distant recurrence. HCV eradication was associated with a significant reduction in distant recurrence, mortality and hepatic decompensation following RFA in patients with HCV-related HCC.

Ratio of von Willebrand factor to ADAMTS13 is a useful predictor of esophagogastric varices progression after sustained virologic response in patients with hepatitis C virus-related liver cirrhosis.

Esophagogastric varices (EGV) are a serious complication of hepatitis C virus (HCV)-related liver cirrhosis (HCV-LC). In most cases, portal hypertension improves after a sustained virologic response (SVR) is achieved with direct-acting antiviral (DAA) treatment; however, in some cases, EGV exacerbation occurs after HCV elimination. We investigated whether von Willebrand factor (VWF) and a disintegrin-like metalloproteinase with thrombospondin type-1 motif 13 (ADAMTS13) can predict EGV progression with HCV-LC after SVR achievement. This retrospective study enrolled 47 patients with HCV-LC who achieved an SVR after DAA treatment. Eighteen patients experienced EGV progression after the SVR was achieved (EGV progression group). Twenty-nine patients did not experience EGV progression after the SVR was achieved (non-EGV progression group). Plasma VWF antigen levels and ADAMTS13 activity were measured the day before DAA treatment. The EGV progression group had significantly higher plasma VWF antigen levels (p=0.00331) and VWF-to-ADAMTS13 ratios (p=0.000249) than the non-EGV progression group. Multivariate logistic regression models found that a VWF-to-ADAMTS13 ratio >2.3 was the only risk factor for EGV progression after the SVR was achieved (hazard ratio [HR], 18.4; 95% confidence interval [CI], 3.08-109; p=0.00138). During the observation period, patients with a VWF-to-ADAMTS13 ratio >2.3 had a significantly higher cumulative incidence of EGV progression after SVR achievement than patients with a VWF-to-ADAMTS13 ratio ≤2.3 (HR, 6.4; 95% CI, 1.78-22.96; p=0.0044). The VWF-to-ADAMTS13 ratio before DAA treatment for HCV could predict EGV progression after SVR achievement.

ALBI score predicts morphological changes in esophageal varices following direct-acting antiviral-induced sustained virological response in patients with liver cirrhosis.

This study aimed to clarify the morphological changes in esophageal varices after achieving sustained virological response (SVR) with direct-acting antivirals (DAAs) in patients with cirrhosis. A total of 243 patients underwent esophagogastroduodenoscopy before DAA treatment and after achieving SVR. Morphological changes in esophageal varices were investigated using esophagogastroduodenoscopy. This study comprised 125 males and 118 females with a median age of 68years. Esophageal varices at baseline were classified into no varix in 155 (63.8%), F1 in 59 (24.3%), F2 in 25 (10.3%) and F3 in 4 (1.6%) patients. The improvement, unchanged, and aggravation rates of esophageal varices after SVR were 11.9%, 73.3%, and 14.8%, respectively. High ALBI score at SVR12 was an independent factor associated with post-SVR esophageal varices aggravation (p = 0.045). Time-dependent receiver operating characteristic (ROC) curve analysis revealed a cut-off value of - 2.33 for ALBI score at SVR12 in predicting post-SVR esophageal varices aggravation. Of the 155 patients without esophageal varices at baseline, 17 developed de novo post-SVR esophageal varices. High ALBI score at SVR12 was a significant independent factor associated with de novo post-SVR esophageal varices (p = 0.046). ROC curve analysis revealed a cut-off value of - 2.65 for ALBI score at SVR12 in predicting de novo post-SVR esophageal varices. Patients with cirrhosis can experience esophageal varices aggravation or de novo esophageal varices, despite achieving SVR. In particular, patients with high ALBI score at SVR12 have a high likelihood of developing post-SVR esophageal varices aggravation or de novo post-SVR esophageal varices.

Reduction of the Risk of Hepatocellular Carcinoma over Time Using Direct-Acting Antivirals: A Propensity Score Analysis of a Real-Life Cohort (PITER HCV).

The treatment of hepatitis C virus (HCV) with direct-acting antivirals (DAA) leads to high sustained virological response (SVR) rates, but hepatocellular carcinoma (HCC) risk persists in people with advanced liver disease even after SVR. We weighted the HCC risk in people with cirrhosis achieving HCV eradication through DAA treatment and compared it with untreated participants in the multicenter prospective Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. Propensity matching with inverse probability weighting was used to compare DAA-treated and untreated HCV-infected participants with liver cirrhosis. Kaplan-Meier analysis and competing risk regression analysis were performed. Within the first 36 months, 30 de novo HCC cases occurred in the untreated group (n = 307), with a weighted incidence rate of 0.34% (95%CI: 0.23-0.52%), compared to 63 cases among SVR patients (n = 1111), with an incidence rate of 0.20% (95%CI: 0.16-0.26%). The 12-, 24-, and 36-month HCC weighted cumulative incidence rates were 6.7%, 8.4%, and 10.0% in untreated cases and 2.3%, 4.5%, and 7.0% in the SVR group. Considering death or liver transplantation as competing events, the untreated group showed a 64% higher risk of HCC incidence compared to SVR patients (SubHR 1.64, 95%CI: 1.02-2.62). Other variables independently associated with the HCC occurrence were male sex, increasing age, current alcohol use, HCV genotype 3, platelet count ≤ 120,000/µL, and albumin ≤ 3.5 g/dL. In real-life practice, the high efficacy of DAA in achieving SVR is translated into high effectiveness in reducing the HCC incidence risk.

Effect of previous infection with hepatitis B virus on the incidence of hepatocellular carcinoma after sustained virologic response in patients with chronic hepatitis C virus infection.

Previous infection with hepatitis B virus (HBV), which is assessed by HBV core antibody (HBcAb) or surface antibody (HBsAb) titres, has reportedly been associated with an increased risk of developing hepatocellular carcinoma (HCC). We investigated the influence of previous HBV infection on the incidence of HCC in patients with hepatitis C virus (HCV) infection who achieved eradication of HCV, that is sustained virologic response (SVR). Both HBcAb and HBsAb were measured in a total of 1214 patients with HCV infection who had not been coinfected with HBV, as determined by both negative HBs antigen and HBV DNA, and in whom SVR was confirmed. Patients were followed up for a median of 5.7 years, and the incidence of post-SVR HCC was compared based on HBcAb and/or HBsAb. In both univariate and multivariate analyses, the incidence of post-SVR HCC did not differ based on the presence of HBcAb or HBsAb. In conclusion, previous HBV infection has no impact on the incidence of HCC in patients with HCV after SVR.

Predicting de-novo portal vein thrombosis after HCV eradication: A long-term competing risk analysis in the ongoing PITER cohort.

Sustained virological response (SVR) by direct-acting antivirals (DAAs) may reverse the hypercoagulable state of HCV cirrhosis and the portal vein thrombosis (PVT) risk. We evaluated the incidence and predictive factors of de novo, non-tumoral PVT in patients with cirrhosis after HCV eradication. Patients with HCV-related cirrhosis, consecutively enrolled in the multi-center ongoing PITER cohort, who achieved the SVR using DAAs, were prospectively evaluated. Kaplan-Meier and competing risk regression analyses were performed. During a median time of 38.3months (IQR: 25.1-48.7months) after the end of treatment (EOT), among 1609 SVR patients, 32 (2.0%) developed de novo PVT. Aplatelet count ≤120,000/μL, albumin levels ≤3.5mg/dL, bilirubin >1.1mg/dL, a previous liver decompensation, ALBI, Baveno, FIB-4, and RESIST scores were significantly different (p<0.001), among patients who developed PVT versus those who did not. Considering death and liver transplantation as competing risk events, esophageal varices (subHR: 10.40; CI 95% 4.33-24.99) and pre-treatment ALBI grade ≥2 (subHR: 4.32; CI 95% 1.36-13.74) were independent predictors of PVT. After HCV eradication, a significant variation in PLT count, albumin, and bilirubin (p<0.001) versus pre-treatment values was observed in patients who did not develop PVT, whereas no significant differences were observed in those who developed PVT (p>0.05). After the EOT, esophageal varices and ALBI grade ≥2, remained associated with de novo PVT (subHR: 9.32; CI 95% 3.16-27.53 and subHR: 5.50; CI 95% 1.67-18.13, respectively). In patients with HCV-related cirrhosis, a more advanced liver disease and significant portal hypertension are independently associated with the de novo PVT risk after SVR.

Sustained virologic response from hepatitis C from an emergency department screening & linkage program: A retrospective review

IntroductionThe role of the Emergency Department (ED) as a vital constituent in Hepatitis C (HCV) screening has become increasingly evident. A key component of the ED's role in HCV screening is the ability to effectively link HCV-RNA positive patients to definitive, HCV-specific care, to include direct-acting antiviral (DAA) medication with resultant sustained virologic response (SVR). We sought to consider the rate of HCV-specific linkage, DAA initiation, and SVR obtained in HCV patients identified from an ED screening program. MethodsA retrospective chart review was conducted in February of 2022 of all individuals who participated in an opt-out ED-based HCV screening program between January 2018 and December 2019. Data was disaggregated by race, gender, age/birth cohort, insurance status, and achievement of sustained virologic response (SVR). Bivariate analysis using Pearson's chi-square was utilized to compare outcomes based on insurance status, race, sex, and birth cohort. ResultsOf 66,634 individuals screened for HCV during the study period, 885 (1.33%) patients were RNA-positive. Of those individuals, 121 (13.67%) were linked to HCV-specific care. Of those linked, the majority (66.9%) were male, white (66.1%; 33.1% Black), baby boomers or older (53.7%) and publicly insured (57.9%; private insurance 23.1%, self-pay 19%). Among linked patients, 88 (72.7%) started DAA medication. Mirroring linked demographics, majority were male (64.8%), white (64.8%), baby boomers or older (52.3%), and publicly insured (57.6%). White patients initiated on DAA were more likely to obtain SVR (64.9% versus 41.9% Black; p = .04) and uninsured patients were more likely to obtain SVR (82.4% versus 50.7% insured; p = .02). Bivariate consideration of SVR-patients specifically demonstrates that Black patients tended to be older, with significant overrepresentation of Baby boomers (77.5%) as compared to whites (37.5%; p < .0001). Black patients were also more likely to be publicly insured (82.5%) while white patients were more likely to have private insurance (28.8%) or be uninsured (26.3%) than their Black counterparts (12.5% and 5% respectively; p < .05). ConclusionAn ED-based HCV screening program can result in successful HCV-specific linkage and care, to include DAA initiation and ultimately, SVR. Among linked patients, specific cohort considerations may demonstrate differences in age and insurance status which may have implications on DAA application and adherence, and therefore, individual ability to achieve SVR.

Hepatocellular organellar abnormalities following elimination of hepatitis C virus.

The future development of hepatocellular carcinoma (HCC) in patients after sustained virologic response (SVR) is an important issue. The purposes of this study were to investigate pathological alterations in organelle of the liver of SVR patients and to characterize organelle abnormalities that may be related to carcinogenesis after SVR. The ultrastructure of liver biopsy specimens from patients with chronic hepatitis C (CHC) and SVR were compared to cell and mouse models and assessed semi-quantitatively using transmission electron microscopy. Hepatocytes in patients with CHC showed abnormalities in the nucleus, mitochondria, endoplasmic reticulum, lipid droplet, and pericellular fibrosis, comparable to those seen in hepatitis C virus (HCV)-infected mice and cells. DAA treatment significantly reduced organelle abnormalities such as the nucleus, mitochondria, and lipid droplet in the hepatocytes of patients and mice after SVR, and cured cells, but it did not change dilated/degranulated endoplasmic reticulum and pericellular fibrosis in patients and mice after SVR. Further, samples from patients with a post-SVR period of >1 year had significantly larger numbers of abnormalities in the mitochondria and endoplasmic reticulum than those of <1 year. A possible cause of organelle abnormalities in patients after SVR could be oxidative stress of the endoplasmic reticulum and mitochondria associated with abnormalities of the vascular system due to fibrosis. Interestingly, abnormal endoplasmic reticulum was associated with patients with HCC for >1 year after SVR. These results indicate that patients with SVR exhibit a persistent disease state and require long-term follow-up to detect early signs of carcinogenesis.

Significance of pretreatment alpha-fetoprotein in patients with compensated severe fibrosis after hepatitis C viral eradication.

We aimed to investigate the factors associated with improvement of liver functional reserve after sustained virological response using interferon-free, direct-acting antiviral combination treatment in patients with compensated, severe fibrosis. Between September 2014 and April 2020, 492 patients received direct-acting antiviral combination treatment in our hospital. Among them, 173 patients who had severe fibrosis based on a fibrosis-4 index ≥3.25, showed sustained virological response after treatment. We investigated the dynamic change in albumin-bilirubin score and the baseline factors associated with its improvement, 48 weeks after treatment. The baseline significant factors associated with albumin-bilirubin≦ -0.5 were lower albumin (HR: 15.625, 95% CI: 4.273-58.824, P < .001), higher hepatitis C virus RNA (HR: 4.995, 95% CI: 1.882-13.260, P=.001), and higher alpha-fetoprotein (HR: 1.033, 95% CI: 1.011-1.055, P=.003). Patients with alpha-fetoprotein ≧10ng/mL showed significant improvement of albumin-bilirubin score from baseline to 48 weeks after treatment compared to those with alpha-fetoprotein <10ng/mL (P < .001). Baseline serum alpha-fetoprotein might be a predictive factor for improvement of liver function after sustained virological response in patients with severe fibrosis.

Low-Cost Predictors for Liver Function and Clinical Outcomes after Sustained Virological Response in Patients with HCV-Related Cirrhosis and Thrombocytopenia.

Background and Objectives: To find low-cost markers that can identify the hepatitis C virus cirrhotic patients that are at risk for long-term severe adverse liver effects (ascites, ascites or upper gastrointestinal bleeding, hepatocellular carcinoma), after treatment. There is established evidence for the benefits of treating hepatitis C virus cirrhotic patients, but there is still some need for clarification concerning the real impact on the long-term evolution after achieving sustained virological response; there is no general consensus in the literature about identifying the patients that do not improve post-treatment. Materials and Methods: Our retrospective analysis investigated the long-term (2 years) evolution of 46 patients with cirrhosis with thrombocytopenia, previously infected with VHC, treated and who obtained an SVR after DAA treatment. Results: Despite the overall improvement, 8.7% patients developed hepatocellular carcinoma and 6.5% patients ascites/upper GI bleeding. We found that FIB-4, MELD and AFP changes at 1 year were the most significant predictors for these outcomes. Additionally, a drop in leukocyte count after 1 year seemed to indicate a risk for hepatocellular carcinoma, but this was not consistent. Conclusions: It might be beneficial to intensify the surveillance for post-treatment adverse liver effects for the patients with these marker changes at 1 year.

Induction Therapy with Natural Interferon-Beta and a Protease Inhibitor Restores Innate-Immune Responses and Suppresses Chronic Hepatitis C Infection

Background: Persistent hepatitis C virus (HCV) infection results from inefficient innate and adaptive immune responses and exhausted virus-specific T-cell responses. Host cytokines and innate immune responses play important roles in controlling HCV infection. Innate immune responses modulate adaptive immune responses. These responses have recently been shown to have roles in antiviral therapy for chronic HCV infection. My previous study has indicated that viral clearance early in the course of therapy is associated with the restoration of innate and adaptive immune responses, and thus has potential as a novel therapeutic strategy for chronic hepatitis C (CHC). Methods: The efficacy and safety of induction therapy (IT) with natural (n)-interferon (IFN)-beta followed by pegylated-IFN-alpha and ribavirin (PR) alone (group A, n = 30) were compared with those of IT with a protease inhibitor (PI) (Simeprevir or Vaniprevir) plus PR (group B, n = 13) in patients with CHC with genotype 1b and high viral load. Results: During IT with n-IFN-beta, the virologic response rates in group A and group B were 10% and 8% (p = 0.6792) at week 4; 30% and 16% (p = 0.6989) at week 12; and 47% and 20% (p = 0.0887) at week 24. During and after treatment with PR alone, or PI plus PR, the virologic response rates in groups A and B were 50% and 82% (p = 0.01535) at week 4: 53% and 91% (p = 0.006745) at week 8; 57% and 91% (p = 0.001126) at week 12; 57% and 100% (p = 0.001845) at the end of the treatment; and 57% and 80% (p = 0.005166) after treatment cessation. Conclusion: IT with PI plus PR restored the innate immune response, was tolerated well, overcame virological breakthrough, enhanced early virologic responses, and resulted in a sustained virologic response in patients with intractable CHC. Thus, IT with PI plus PR is beneficial for patients with intractable CHC. Steps for augmenting immune responses must be identified.

Normalization of circulating plasma levels of miRNAs in HIV-1/HCV co-infected patients following direct-acting antiviral–induced sustained virologic response

In a previous recent work, we recognized three plasma circulating microRNAs (miRNAs)—miR-100-5p_iso3p:-2, miR-122-5p, and miR-192-5p—that correlate largely with liver fibrosis evolution in human immunodeficiency virus type 1 (HIV-1)/hepatitis C virus (HCV) co-infected patients. Here, we investigated whether levels of these three circulating miRNAs can be associated to liver disease evolution in HIV-1/HCV co-infected patients which have achieved HCV sustained virologic response (SVR) 12 weeks after finishing treatment. Eighty-one chronic HIV-1/HCV co-infected patients were longitudinally recruited at baseline (T0) of DAA therapy and 12 weeks (T12) after finishing therapy. At T0 most of the study patients displayed transient elastography values linked to an advanced stage of liver fibrosis (F0-1 9%, F2 11%, F3 32%, F4 48%). Significant reductions in the levels of circulating miR-100-5p_iso3p:-2, miR-122-5p, and miR-192-5p were detected at T12 in SVR patients, in the overall cohort (P < 0.0001, P < 0.0001, and P = 0.0008, respectively) and in patients with advanced (F3-4) liver fibrosis (p < 0.0001, p < 0.0001, and P = 0.0011, respectively). Of note, no significant reduction in the study miRNA levels was found at T12 in patients who did not achieve SVR (P = 0.8750, P = 0.1250, and P = 0.1260, respectively). HCV-cured patients, in contrast to non-responders, significantly reduced their liver stiffness after two years of achieving SVR (p < 0.0001). DAA-induced SVR is linked with a significant reduction in circulating levels of miR-100-5p_iso3p:-2, miR-122-5p, and miR-192-5p. Our results indicate that miRNA plasma levels may be a useful biomarker of liver damage progression in HIV-1/HCV co-infected individuals that reach DAA-induced SVR.

Persistent epigenetic alterations in transcription factors after a sustained virological response in hepatocellular carcinoma.

The risk of hepatocellular carcinoma (HCC) persists in a condition of sustained virologic response (SVR) after hepatitis C virus (HCV) eradication. Comprehensive molecular analyses were performed to test the hypothesis that epigenetic abnormalities present after an SVR play a role in hepatocarcinogenesis. Whole-genome methylome and RNA sequencing were performed on HCV, SVR, and healthy liver tissue. Integrated analysis of the sequencing data focused on expression changes in transcription factors and their target genes, commonly found in HCV and SVR. Identified expression changes were validated in demethylated cultured HCC cell lines and an independent validation cohort. The coincidence rates of the differentially methylated regions between the HCV and SVR groups were 91% in the hypomethylated and 71% in the hypermethylated regions in tumorous tissues, and 37% in the hypomethylated and 36% in the hypermethylated regions in non-tumorous tissues. These results indicate that many epigenomic abnormalities persist even after an SVR was achieved. Integrated analysis identified 61 transcription factors and 379 other genes that had methylation abnormalities and gene expression changes in both groups. Validation cohort specified gene expression changes for 14 genes, and gene ontology pathway analysis revealed apoptotic signaling and inflammatory response were associated with these genes. This study demonstrates that DNA methylation abnormalities, retained after HCV eradication, affect the expression of transcription factors and their target genes. These findings suggest that DNA methylation in SVR patients may be functionally important in carcinogenesis, and could serve as biomarkers to predict HCC occurrence.

Improvement of patient-reported outcomes in patients achieving sustained virologic response with direct-acting antivirals for hepatitis C virus infection.

Patient-reported outcome (PRO) in patients with chronic hepatitis C virus (HCV) infection (CHC) after successful direct-acting antiviral (DAA) therapy remains elusive. The study aimed to investigate the impact of DAA therapy on health-related quality of life (HRQoL). We also assess the associated factors predictive of HRQoL change after sustained virologic response (SVR) to HCV therapy. CHC patients receiving DAA therapy were prospectively recruited. They completed paired HRQoL assessments which included Short-Form-36 (SF-36), Pittsburgh Sleep Quality Index (PSQI) score, Taiwanese Depression Questionnaire score, and State Trait Anxiety Inventory (STAI) score before treatment and at Week 12 off-treatment. Clinical data and characteristics were compared in a paired manner. A total of 158 patients achieved SVR (SVR rate: 96.6%) were enrolled into the final analysis. Improvement of depression, anxiety, digestive symptoms, and SF-36 items of vitality, body pain, physical functioning, emotional functioning, social functioning, and mental health were demonstrated among SVR patients. Sleep quality, or other SF-36 items were not significantly changed after the treatment. Multivariate analysis revealed that improvement of sleep quality, depression, and anxiety were associated with better HRQoL. SVR to HCV therapy by DAA significantly improved PROs including HRQoL.

Hepatocellular carcinoma incidence in chronic hepatitis C patients according to sustained virological response (SVR) with interferon‐based therapies and baseline characteristics

AbstractIntroductionHepatocellular carcinoma (HCC) is the second most common cause of cancer‐related death worldwide with increasing incidence. Effective antiviral treatment for chronic hepatitis C (CHC) became available in the last 7 years but despite the WHO Hepatitis elimination targets, they are not universally available today in all regions for all the patients, indicating still a bleak outlook for CHC‐associated HCC in the next decades.AimTo assess the HCC incidence in relation to interferon (IFN)‐based antiviral treatment response and baseline characteristics of a large cohort of chronic hepatitis C (CHC) patients from a single institution.MethodsWe retrospectively collected data of CHC patients, who were diagnosed between 1989 and 2011 and treated at the AKH‐University Hospital of Vienna before the introduction of direct‐acting antiviral (DAA) only therapy. We analysed the HCC incidence in patients with a sustained virological response (SVR) and without SVR according to the patients' baseline characteristics.ResultsOur study included 2134 patients, who were treated or not treated with IFN‐based antiviral treatment and had long‐term follow‐up available. The overall HCC incidence in this cohort was 6.2% (132 HCC cases over a median follow‐up period of 9 years). According to the baseline fibrosis stage, the overall HCC incidence was: 1.1% in patients with baseline fibrosis stage F0‐2, 8.2% in F3 and 20.6% in F4 patients. The HCC incidence was significantly higher in non‐SVR and no‐treatment group as compared with SVR patients: 12.4% vs 1.9%, P &lt; .0001, 7.3% vs 1.9%, P &lt; .0001. In multivariate analysis, lower platelet count (odds ratio‐OR = ‐0.1, 95% CI: 0.15‐0.63), for the SVR group and presence of cirrhosis (OR = 3.6, 95% CI: 1.59‐8.17), ALBI grade &gt;=2 (OR = 2.3, 95% CI: 1.0‐5.3) for the non‐SVR group were independently associated with HCC occurrence. For the group of patients with no treatment, the only predictor for HCC was high baseline alpha‐fetoprotein values (OR = 10.2, 95% CI: 2.2‐47.9).ConclusionThe achievement of SVR significantly reduces the risk for HCC occurrence during long‐term follow‐up. However, the risk remains high in successfully treated patients with low platelet count and in patients who did not achieve SVR with more advanced liver disease. These risk factors should be considered in decision‐making of HCC surveillance in this settling.

Liver Disease Outcomes after Sustained Virological Response in Patients with Chronic Hepatitis C Infection Treated with Generic Direct-Acting Antivirals.

The introduction of generic direct-acting antivirals (DAAs) in Egypt is associated with a superior cure rate of hepatitis C virus (HCV) infection. However, the course of progressive liver damage and developing liver related complications in patients with sustained virologic response (SVR) remain unclear. This study was designed to examine the long-term outcomes of generic DAA-induced virological cure in a real-life cohort of HCV patients with or without comorbid schistosomiasis. We prospectively enrolled a cohort of 506 recently cured HCV patients (437 Child-Pugh class A [Child-A] and 69 Child-Pugh class B [Child-B]). All patients were clinically evaluated at different time points during a 2-year follow-up (November 2018 to February 2021). Over the course of treatment and follow-up, 77 (15.2%) patients (42 [9.6%] Child-A and 35 [50.7%] Child-B) experienced complications at different time points. The overall mortality rate was approximately 1/1,000 person-years. The incidence of hepatic insufficiency was approximately 5.5/1,000 person-years, and that of de novo hepatocellular carcinoma (HCC) was approximately 8.3/1,000 person-years. A sustained improvement in liver indices up to 2 years of follow-up was observed. In the Cox regression model, pretreatment decompensated cirrhosis predicted the occurrence of adverse liver events and HCC after therapy. In conclusion, in HCV patients with advanced cirrhosis or coexisting hepatic schistosomiasis, generic DAA-induced SVR remains robust with favorable clinical outcomes although the risk of hepatocarcinogenesis cannot be eliminated. Surveillance of patients with treated HCV infection is an important aspect of postcure care for early detection and management of liver disease-related adverse events.

Factors Influencing the Intracellular Concentrations of the Sofosbuvir Metabolite GS-331007 (in PBMCs) at 30 Days of Therapy.

Sofosbuvir (SOF) is an HCV NS5B polymerase inhibitor, and GS-331007 is its major metabolite. The aim of this study was to investigate whether clinical and pharmacological factors could influence GS-331007 intracellular (IC) concentrations in peripheral blood mononuclear cells (PBMCs) associated with a sustained virological response in patients treated with SOF and ribavirin (RBV). Drug levels were analyzed using liquid chromatography at different days of therapy, whereas variants in genes encoding transporters and nuclear factors were investigated using real-time PCR. This study enrolled 245 patients treated with SOF; 245 samples were analyzed for pharmacogenetics and 50 were analyzed for IC pharmacokinetics. The GS-331007 IC concentration at 30 days was associated with its plasma concentration determinate at 30, 60 and 90 days of SOF-therapy and with daclatasvir concentrations at 7 days of therapy. No genetic polymorphism affected IC exposure. In linear multivariate analysis, ledipasvir treatment, baseline albumin and estimated glomerular filtration rate were significant predictors of IC exposure. This study presents data on an IC evaluation in a cohort of patients treated with SOF, also considering pharmacogenetics. These results could be useful for regions where SOF–RBV treatment is considered the standard of care; moreover, they could further deepen the knowledge of IC exposure for similar drugs in the future.

Evolution of Cryoglobulinemia in Direct-Acting Antiviral-Treated Asian Hepatitis C Patients With Sustained Virological Responses: A 4-Year Prospective Cohort Study.

BackgroundHow cryoglobulinemia evolves after sustained virological response (SVR) following direct-acting antiviral (DAA) treatment in Asian hepatitis C virus (HCV)-infected patients remains elusive.MethodsA prospective cohort study was conducted in 422 Taiwanese patients (358 completed DAA therapy and 353 experienced SVRs). Serum cryoglobulins were surveyed at baseline and every 3-6 months posttherapy.ResultsOf 422, 227 (53.8%) had cryoglobulinemia, 8 (1.89%) had cryoglobulinemic vasculitis. Of 227, 54 (23.8%), 57 (25.1%) and 116 (51.1%) had 1, 2 and 3 cryoglobulins, respectively; those with 3 cryoglobulins had the highest alanine aminotransferase, immunoglobulin G (IgG) and fibrosis-4 index. During a 4-year follow-up, among SVR patients, cryoglobulinemia rates decreased from 56.4% to 15.4%, single cryoglobulin rates increased (21.6% to 63.9%) and 3 cryoglobulin rates decreased (55.7% to 11.1%). Compared with baseline values, among SVR patients with baseline cryoglobulinemia, complement component 4 levels increased, and IgG and IgM levels decreased until 48 weeks posttherapy for those without posttherapy cryoglobulinemia. All 8 cryoglobulinemic vasculitis patients exhibited SVRs; 5 (62.5%) achieved complete clinical response 12 weeks posttherapy, of whom, 2 (40%) experienced clinical relapse 24~48 weeks posttherapy. Baseline IgM levels were associated with posttherapy cryoglobulinemia in SVR patients (cut-off values at 12, 24, 48 weeks and 4 years posttherapy: 130, 105, 118 and 168 mg/dL, respectively).ConclusionsAmong DAA-treated SVR patients, in 4 years, cryoglobulinemia rates decreased from 56.4% to 15.4%, multiple cryoglobulin rates decreased, cryoglobulinemia signals reversed, 62.5% of cryoglobulinemic vasculitis patients achieved complete clinical response (40% had relapse), and baseline IgM levels indicated posttherapy cryoglobulinemia.

Modern Treatment of Hepatitis C Infection

Abstract In 2016, the World Health Organization set „Viral hepatitis elimination by 2030” as a goal, which is predicated upon 2 advances: on the one hand, the efficacy of hepatitis B vaccine and, on the other, the sustained viral response to direct-acting antiviral (DAA) therapy for infection with hepatitis C virus (HCV). Romania also adopted this initiative considering the available results confirming the efficiency of this policy. Viral clearance results in reduced morbidity and mortality by liver injury and also by any associated HCV infection manifestations. In order to fulfill the target stated by the WHO any patient with detectable viremia must be treated. Unlike interferon-based regimes, DAA therapy for HCV infection is applicable to all groups of patients, regardless of the severity of their liver injury. Other advantages are high efficiency levels, proved in clinical trials as well as in the real world, oral administration route, good safety profile, a very good rate of sustained virological response in patients with decompensated cirrhosis and the possibility of prescribing them to children older than 8. Despite the remarkable progress, an ideal antiviral therapy has not yet been discovered. The direct-acting antiviral therapy in use today has 3 targets: NS3/4A, NS5A, NS5B. None of the drugs is designed to be used alone. For convenience, the pharmaceutical industry has developed pills containing combinations of 2 or 3 active drugs, which completely changed the hepatitis C treatment paradigm.

A relation between T cell phenotypic profile and virus genotype in patients with chronic viral hepatitis (before and after treatment with direct antiviral agents)

The aim of the study was to investigate the phenotype of effector T lymphocytes in patients with chronic viral hepatitis C (CVHC) before and after of treatment with direct antiviral drugs depending on the genotype of the virus. 50 patients with CVHC without signs of liver cirrhosis were examined. The diagnosis was made on the basis of epidemiological and clinical laboratory data as recommended by the European Association for the Study of the Liver when specific serological markers of CHCV and RNA of hepatitis C virus (HCV) were detected (EASL, 2016). The determination of HCV RNA was carried out by the method of quantitative polymerase chain reaction in real time. The degree of liver fibrosis in patients with CVHC was assessed using ultrasound elastography. Patients were treated for 3 months with direct antiviral drugs according to the recommendations of the European Association for the Study of the Liver (2016). The control group included 46 practically healthy individuals with severe chronic diseases of various organs and systems excluded during a routine examination, no health complaints, having normal clinical and biochemical blood tests in the absence of markers for viral hepatitis B and C, antibodies to opisthorchis and denying history of alcohol abuse. The study of the subpopulation composition of helper and cytotoxic T lymphocytes was carried out by direct immunofluorescence of whole peripheral blood. We obtained a 100% sustained virological response in patients with 1, 2 and genotypes of CHCV without signs of liver cirrhosis when using therapy with Sofosbuvir (400 mg) and Daclatasvir (60 mg) for 12 weeks. It was found that in CVHC patients were found characteristic features in the phenotypic composition of effector T lymphocytes before and after treatment with direct antiviral drugs in depending on the genotype of HCV. Patients with HCV genotypes 1 and 3 had an increase in the content of terminal differentiated effector (TEMRA) T helpers and effector memory (EM). Only patients with HCV genotype 2 had a decrease in the level of EM T-helper cells in the blood. A decrease in the relative number of T helpers of central memory (СM) was independent of the HCV genotype. The level of effector subpopulations of cytotoxic T lymphocytes in patients with CVHC was consistent with or exceeded control levels in depending on the genotype of HCV. The level of all investigated subpopulations of effector cytotoxic T lymphocytes in patients with HCV genotype 1 was equal to the control values. The number of naïve cytotoxic T cells and CM in peripheral blood in patients with HCV genotype 2 was increased. The content of naïve cytotoxic T lymphocytes, CM and TEMRA in patients with genotype 3 HCV in the blood was increased. The highest viral load was detected in patients with CVHC with genotype 1 HCV. Liver fibrosis was most pronounced in patients with CVHC infection with HCV genotypes 2 and 3. After 3 months of treatment with direct antiviral drugs the patients with CVHC had a reduced content of CM T helpers regardless of the HCV genotype. In addition, patients with HCV genotypes 1 and 3 had a decrease in the number of naïve T helpers and patients with HCV genotypes 2 and 3 had a normalization of the content of naïve cytotoxic T lymphocytes.