Shear-wave elastography to predict hepatocellular carcinoma after hepatitis C virus eradication:A systematic review and meta-analysis

BACKGROUND Direct-acting antiviral agents(DAAs)are highly effective treatment for chronic hepatitis C(CHC)with a significant rate of sustained virologic response(SVR).The achievement of SVR is crucial to prevent additional liver damage and slow down fibrosis progression.The assessment of fibrosis degree can be performed with transient elastography,magnetic resonance elastography or shear-wave elastography(SWE).Liver elastography could function as a predictor for hepato-cellular carcinoma(HCC)in CHC patients treated with DAAs.AIM To explore the predictive value of SWE for HCC development after complete clearance of hepatitis C virus(HCV).METHODS A comprehensive literature search of clinical studies was performed to identify the ability of SWE to predict HCC occurrence after HCV clearance.In accordance with the study protocol,a qualitative and quantitative analysis of the evidence was planned.RESULTS At baseline and after 12 wk of follow-up,a trend was shown towards greater liver stiffness(LS)in those who go on to develop HCC compared to those who do not[baseline LS standardized mean difference(SMD):1.15,95%confidence interval(95%CI):020-2.50;LS SMD after 12 wk:0.83,95%CI:0.33-1.98].The absence of a statistically significant difference between the mean LS in those who developed HCC or not may be related to the inability to correct for confounding factors and the absence of raw source data.There was a statist-ically significant LS SMD at 24 wk of follow-up between patients who developed HCC vs not(0.64;95%CI:0.04-1.24).CONCLUSION SWE could be a promising tool for prediction of HCC occurrence in patients treated with DAAs.Further studies with larger cohorts and standardized timing of elastographic evaluation are needed to confirm these data.

Tenofovir amibufenamide vs tenofovir alafenamide for treating chronic hepatitis B:A real-world study

BACKGROUND The efficacy and safety profile of tenofovir amibufenamide(TMF)in chronic hepatitis B(CHB)patients is not well-established.AIM To compare the efficacy and safety of TMF and tenofovir alafenamide(TAF)over a 48-wk period in patients with CHB.METHODS A total of 215 subjects meeting the inclusion criteria were enrolled and divided into two groups:TMF group(n=106)and the TAF group(n=109).The study included a comparison of virological response(VR):Undetectable hepatitis B virus DNA levels,alanine transaminase(ALT)normalization rates,renal function parameters,and blood lipid profiles.RESULTS At 24 and 48 wk,VR rates for the TMF group were 53.57%and 78.57%,respectively,compared with 48.31%and 78.65%for the TAF group(P>0.05).The VR rates were also similar in both groups among patients with low-level viremia,both hepatitis B e antigen(HBeAg)-positive and HBeAg-negative subgroups.The TMF cohort showed ALT normalization and renal safety profiles similar to the TAF group.There was a notable increase in total cholesterol levels in the TAF group(P=0.045),which was not observed in the TMF group(P>0.05).In patients with liver cirrhosis,both groups exhibited comparable VR and ALT normalization rates and renal safety profiles.However,the fibrosis 4 score at 48 wk showed a significant reduction in the TAF group as compared to the TMF group within the liver cirrhosis subgroup.CONCLUSION Our study found TMF is as effective as TAF in treating CHB and has a comparable safety profile.However,TAF may be associated with worsening lipid profiles.

Stages of care for patients with chronic hepatitis C at a hospital in southern Brazil

BACKGROUND Hepatitis C virus(HCV)is defined as a public health problem by the World Health Organization(WHO)and since then has defined targets through the HCV elimination.The HCV cascade of care highlights the progress towards these goals and essential interventions that need to be delivered along this continuum care.AIM To document the treatment cascade for patients with HCV infection at the Hospital Nossa Senhora da Conceição(HNSC),defining the percentage of antibody-positive patients who collected molecular biology tests(polymerase chain reaction),attended outpatient clinic assistance,underwent treatment,and achieved a virologic cure termed sustained virologic response(SVR).METHODS With the retrospective cohort design,patients diagnosed with HCV infection in the period between January 1,2015 and December 31,2020 were included.Data from HCV notification forms,electronic medical records,Computerized Laboratory Environment Manager System,and Medicine Administration System(evaluation of special medications)were collected in 2022 and all information up to that period was considered.The data were analyzed with IBM SPSS version 25,and Poisson regression with robust simple variance was performed for analysis of variables in relation to each step of the cascade.Variables with P<0.20 were included in the multivariate analysis with P<0.05 considered significant.Pearson’s chi-square test was applied to compare the groups of patients who persisted in follow-up at the HNSC and who underwent follow-up at other locations.RESULTS Results were lower than expected by the WHO with only 49%of candidates receiving HCV treatment and only 29%achieving SVR,despite the 98%response rate to direct acting antivirals documented by follow-up examination.The city of origin and the place of follow-up were the variables associated with SVR and all other endpoints.When comparing the cascade of patients who remained assisted by the HNSC vs external patients,we observed superior data for HNSC patients in the SVR.Patients from the countryside and metropolitan region were mostly assisted at the HNSC and the specialized and continuous care provided at the HNSC was associated with superior results,although the outcomes remain far from the goals set by the WHO.CONCLUSION With the elaboration of the HCV cascade of care using local data,it was possible to stratify and evaluate risk factors associated with losses between each step of the cascade,to inform new strategies to guide elimination efforts in the future.

Combining the age-male-albumin-bilirubin-platelets score and shear wave elastography stratifies carcinogenic risk in hepatitis C patients after viral clearance

BACKGROUND The treatment of hepatitis C with direct-acting antiviral agents(DAAs)produces a high rate of sustained virological response(SVR)with fewer adverse events than interferon(IFN)therapy with a similar effect in inhibiting carcinogenesis as IFN therapy.The age-male-albumin-bilirubin-platelets(aMAP)score is useful for stratifying the risk of hepatocellular carcinoma in chronic hepatitis patients,and the velocity of shear waves(Vs)measured by shear wave elastography has also been shown to be useful for diagnosing the level of fibrotic progression in hepatitis C and predicting carcinogenic risk.Combining these two may improve the prediction of carcinogenic risk.AIM To determine whether combining the aMAP score with Vs improves carcinogenic risk stratification in medium-to-high-risk hepatitis C patients.METHODS This retrospective,observational study involved hepatitis C patients treated with DAAs who achieved SVR.Vs was measured before treatment(baseline),at the end of treatment(EOT),and 12 wk(follow-up 12)and 24 wk(follow-up 24)after treatment.The patients were followed for at least six months after EOT to determine whether cancer developed.Multiple regression analysis was used to identify factors contributing to hepatic carcinogenesis.The diagnostic performances of clinical parameters for predicting the presence of hepatocellular carcinoma were evaluated using receiver-operating characteristic(ROC)curve analyses.RESULTS A total of 279 patients(mean age 65.9 years,118 males,161 females)were included in the analysis.Multiple regression analysis was performed with carcinogenesis as the target variable and alanine aminotransferase,platelets,α-fetoprotein,Vs,and the Fib-4 index as explanatory variables;only Vs was found to be significant(P=0.0296).The cut-off value for Vs for liver carcinogenesis calculated using the ROC curve was 1.53 m/s.Carcinoma developed in 2.0%(3/151)of those with Vs<1.53 m/s and in 10.5%(9/86)of those with Vs≥1.53 m/s.CONCLUSION In hepatitis C patients after SVR,combining the aMAP score and Vs to stratify the risk of carcinogenesis is more efficient than uniform surveillance of all patients.

Efficacy and safety of tenofovir alafenamide in patients with chronic hepatitis B exhibiting suboptimal response to entecavir

BACKGROUND Entecavir(ETV)is a potent and safe antiviral agent for patients with chronic hepatitis B(CHB);however,some patients may exhibit suboptimal response or resistance to ETV.Tenofovir alafenamide(TAF)is a novel tenofovir prodrug with improved pharmacokinetics and reduced renal and bone toxicity compared with tenofovir disoproxil fumarate.AIM To evaluate the efficacy and safety of switching from ETV to TAF in patients with CHB exhibiting suboptimal response to ETV.METHODS A total of 60 patients with CHB who had been treated with ETV for at least 12 mo and had persistent or recurrent viremia[Hepatitis B virus(HBV)DNA≥20 IU/mL]or partial virologic response(HBV DNA<20 IU/mL,but detectable)were enrolled in the study.The patients were randomly assigned to either continue ETV(0.5 mg)daily or switch to TAF(25 mg)daily for 48 wk.The primary endpoint was the proportion of patients who achieved a virologic response(HBV DNA level<20 IU/mL)at week 48.Secondary endpoints included changes in serum alanine aminotransferase(ALT),hepatitis B surface antigen(HBsAg),hepatitis B e antigen(HBeAg),and anti-HBe levels,and renal and bone safety parameters.RESULTS At week 48,the proportion of patients who achieved a virologic response was significantly higher in the TAF group than in the ETV group(93.3%vs 66.7%,P=0.012).The mean reduction in HBV DNA from baseline was also significantly greater in the TAF group than in the ETV group(-3.8 vs-2.4 Log10 IU/mL,P<0.001).The rates of ALT normalization,HBeAg loss,HBeAg seroconversion,and HBsAg loss were not found to significantly differ between the two groups.None of the patients developed genotypic resistance to ETV or TAF.Both drugs were well tolerated,with no serious adverse events or discontinuations caused by adverse events.No significant changes were observed in the estimated glomerular filtration rate,serum creatinine level,or urine protein-to-creatinine ratio in either group.The TAF group had a significantly lower decrease in bone mineral density at the lumbar spine and hip than the ETV group(-0.8%vs-2.1%,P=0.004;-0.6%vs-1.8%,P=0.007,respectively).CONCLUSION Switching from ETV to TAF is effective and safe for patients with CHB exhibiting a suboptimal response to ETV and may prevent further viral resistance and reduce renal and bone toxicity.

Hepatitis C virus treatment with glecaprevir and pibrentasvir in patients co-prescribed carbamazepine:Three case reports

BACKGROUND Highly effective and well-tolerated direct-acting antiviral(DAA)therapies have revolutionised the management of hepatitis C virus(HCV);however,niche populations face treatment barriers.DAAs co-prescribed with several firstgeneration anti-epileptic drugs(AEDs)are contraindicated due to drug-drug interactions.A common example is carbamazepine whereby steady-state carbamazepine reduces the maximum concentration and area under the curve of velpatasvir,glecaprevir and pibrentasvir due to potent cytochrome P450(CYP)3A4 induction.Carbamazepine also induces P-glycoprotein which reduces glecaprevir and pibrentasvir’s area under curve to infinite time.Sofosbuvirvelpatasvir and glecaprevir-pibrentasvir are contraindicated in patients who are co-prescribed carbamazepine due to the risk of reduced DAA therapeutic effect and consequently,virological treatment failure.This presents a challenge for patients in whom carbamazepine substitution is medically unfeasible,impractical or unacceptable.However,the properties of current generation DAA therapies,including high-potency non-structural protein 5A inhibitory effect,may be sufficient to overcome reduced bioavailability arising from carbamazepine related CYP 3A4 and P-glycoprotein induction.CASE SUMMARY We present a case series of three patients with non-cirrhotic,treatment-naïve,genotype 1a,1b,and 3a HCV who were treated with a 12 wk course of glecaprevir-pibrentasvir,while co-prescribed carbamazepine for seizure disorders.Glecaprevir-pibrentasvir combination therapy was chosen due to its potent in vitro activity and low barrier to pan-genotypic resistance associated variants.DAA therapy was dose-separated from carbamazepine to maximise time to peak concentration,and taken with meals to improve absorption.Sustained virological response at 12 wk was achieved in each patient with no adverse outcomes.CONCLUSION DAA therapies,including glecaprevir-pibrentasvir,warrant consideration as a therapeutic agent in people with HCV who are co-prescribed carbamazepine,particularly if AED substitution is not feasible.

Partial virological response to three different nucleotide analogues in naive patients with chronic hepatitis B

BACKGROUND： The definition of partial virological response （PVR） was proposed because of its clinical relevance. PVR relates to subsequent therapeutic failure which results in the modification of the regimen. Whether this rationale can be applied to all nucleotide analogues （NA） is not clear. This study was undertaken to analyze PVR influence on therapeutic outcomes during lamivudine, entecavir or tenofovir mono- therapy in NA-naive patients with chronic hepatitis B in routine clinical practice. METHODS： We retrospectively analyzed 150 NA-naive patients with chronic hepatitis B. These subjects received lamivudine, entecavir or tenofovir monotherapy between February 2001 and July2013. RESULTS： Sixty-nine patients were treated with lamivudine, 35 with entecavir, and 46 with tenofovir. The median therapeutic duration was 19.5 （6-147） months. PVR rates at 24 weeks were similar among three NAs （lamivudine 33.3%, entecavir 35.0%, tenofovir 32.4%, P--0.981）. For all three NAs, patients with a higher baseline viral load or HBeAg-positive status had a higher serum viral positive rate tested by polymerase chain reaction at week 24 and 48. Cumulative probability of virological breakthrough （VBR） for patients treated with lamivudine was 67% at 5 years, and PVR at 24 weeks was the independent risk factor for VBR （HR： 3.09; 95% CI： 1.09-8.74; P=0.034）; also lamivudine treated patients older than 50 years seemed to have a tendency for VBR （HR： 2.80; 95% CI： 0.99-8.18; P=0.052）. A majority of entecavir and tenofovir partial responders achieved and maintained virological response with prolonged monotherapy, except one entecavir treated patient who experienced VBR due to resistance mutations.CONCLUSIONS： Management strategy for lamivudine treatment should include adaptation of regimen according to PVR as an on-treatment response parameter due to its relation with unacceptably high VBR probability. Similar conclusion should not be directly related to entecavir or tenofovir treatment.

M2BPGi for assessing liver fibrosis in patients with hepatitis C treated with direct-acting antivirals

BACKGROUND Assessing liver fibrosis is important for predicting the efficacy of direct-acting antivirals(DAAs)and patient prognosis.Non-invasive techniques to assess liver fibrosis are becoming important.Recently,serum Mac-2 binding protein glycosylation isomer(M2BPGi)was identified as a non-invasive marker of liver fibrosis.AIM To investigate the diagnostic accuracy of M2BPGi in assessing liver fibrosis in patients with chronic hepatitis C(CHC)treated with DAAs.METHODS From December 2017 to August 2018,80 treatment-naive adult patients with CHC who were eligible for DAAs therapy were consecutively enrolled in this observational cohort study.For 12 weeks,65 patients were treated with sofosbuvir/daclatasvir,and 15 patients were treated with sofosbuvir/daclatasvir and a weight-based dose of ribavirin at knowledge and technology association for hepatitis C management clinic,Cairo,Egypt.We measured serum M2BPGi levels,PAPAS index,fibrosis-4(FIB-4)score and liver stiffness measurements(LSM)at baseline and 12 weeks after the end of treatment.Serum M2BPGi levels were measured using enzyme-linked immunosorbent assay.RESULTS All patients achieved sustained virologic response(SVR12)(100%).Serum M2BPGi levels,LSM,FIB-4 score and PAPAS index decreased significantly at SVR12(P<0.05).Serum M2BPGi levels correlated positively with LSM at baseline and SVR12(P<0.001).At baseline,compared with the FIB-4 score and PAPAS index,M2BPGi was the best marker to distinguish patients with grade F4 fibrosis(AUC=0.801,P<0.001),patients with grade F2 from grade F0-1 fibrosis(AUC=0.713,P=0.012),patients with grade F3-4 from grade F0-2 fibrosis(AUC=0.730,P<0.001),and patients with grade F2-4 from grade F0-1 fibrosis(AUC=0.763,P<0.001).At SVR12,M2BPGi had the greatest AUCs for differentiating patients with grade F4 fibrosis(AUC=0.844,P<0.001),patients with grade F3 from grade F0-2 fibrosis(AUC=0.893,P=0.002),patients with grade F3-4 from grade F0-2 fibrosis(AUC=0.891,P<0.001),and patients with grade F2-4 from grade F0-1 fibrosis(AUC=0.750,P<0.001).CONCLUSION M2BPGi is a reliable marker for the non-invasive assessment and prediction of liver fibrosis regression in patients with CHC who achieved an SVR with DAAs therapy.

Hepatocellular carcinoma risk after viral response in hepatitis C virus-advanced fibrosis: Who to screen and for how long?

Hepatitis C virus(HCV)chronic infection is associated with fibrosis progression,end-stage liver complications and HCC.Not surprisingly,HCV infection is a leading cause of liver-related morbidity and mortality worldwide.After sustained virological response(SVR),the risk of developing hepatocellular carcinoma is not completely eliminated in patients with established cirrhosis or with advanced fibrosis.Therefore,lifelong surveillance is currently recommended.This strategy is likely not universally cost-effective and harmless,considering that not all patients with advanced fibrosis have the same risk of developing HCC.Factors related to the severity of liver disease and its potential to improve after SVR,the molecular and epigenetic changes that occur during infection and other associated comorbidities might account for different risk levels and are likely essential for identifying patients who would benefit from screening programs after SVR.Efforts to develop predictive models and risk calculators,biomarkers and genetic panels and even deep learning models to estimate the individual risk of HCC have been made in the direct-acting antiviral agents era,when thousands of patients with advanced fibrosis and cirrhosis have reached SVR.These tools could help to identify patients with very low HCC risk in whom surveillance might not be justified.In this review,factors affecting the probability of HCC development after SVR,the benefits and risks of surveillance,suggested strategies to estimate individualized HCC risk and the current evidence to recommend lifelong surveillance are discussed.

Host genetic variations are associated with virological response to interferon therapy of chronic HCV in Han Chinese patients

Previous studies have suggested that host genetic polymorphisms may affect virological response to pegylatedinterferon and ribavirin（PEG-IFN/ ribavirin） therapy in chronic HCV infection.IL28 B and MxA are the most intensively studied genes in Chinese Han population.The current research is to summarize published data and evaluate the overall association of meaningful SNPs in these two genes with virological response to interferon-based therapy.Literature search was performed in online database and a systematic review was conducted based on the search results.Meaningful single nucleotide polymorphisms（SNPs） were summarized and analyzed for odds ratio（OR） and 95%confidence intervals（95%CI）.Data manipulation and statistical analyses were performed by using STATA 12.0and Review Manager version 5.1.Eighteen papers were included for final data analysis.Three SNPs of IL28 B and two SNPs of MxA were found to be associated with higher sustained virological response（SVR） to interferon therapy.The ORs and 95%CIs of each variant were：IL28B rs8099917 TT（OR：4.35,95%CI：3.10-6.12）,IL28 B rs12979860CC（OR：5.37,95%CI：3.95-7.31）,IL28 B rs7248668 CC（OR：3.50,95%CI：2.30-5.35）,MxA rs2071430 GT（OR：2.03,95%CI：1.31-3.13）,and MxA rsl7000900 AC/AA（OR：1.82,95%CI：1.17-2.83）.The genotypes of IL28 B rs8099917,rsl2979860,rs7248668,MxA rs2071430,and MxA rs17000900 were strong SVR predictors for PEG-IFN/ribavirin-treated HCV patients in Han Chinese population.Our findings suggest that host genetic variations are associated with virological response to interferon therapy of chronic HCV in Han Chinese patients.

Long-term follow-up of HCV patients with sustained virological response after treatment with pegylated interferon plus ribavirin

Background:The progress of liver diseases may not stop after viral eradication.This study aimed to provide data on long-term prognosis of patients with hepatitis C virus(HCV)infection who underwent pegylated interferon plus ribavirin(PR)regimen and achieved a sustained virological response 24 weeks post-treatment(SVR24).Methods:Responders to the PR regimen in our hospital from January 2011 to June 2014 were enrolled and prospectively followed up.Baseline characteristics were profiled.The incidence of hepatocellular carcinoma(HCC),progression of liver disease(increase in liver stiffness or occurrence of decompensated complication),and HCV recurrence was all monitored.The accumulative and annualized incidence rates(AIRs)of these adverse events were analyzed,and the risk factors were also examined.Results:In total,151 patients reached a median follow-up time of 103 weeks.Among them,two had an incidence of HCC during the surveillance with AIR of 0.68%(95%CI:0.00-1.63%).Six patients showed progression of liver disease with AIR of 2.05%(95%CI:0.42%-3.68%).Three patients who had risky behaviors encountered HCV reinfection.The cirrhotic patients faced higher risk of poor prognosis than non-cirrhotic patients,including HCC and progression of liver disease(AIR:6.17%vs.1.42%,P=0.039).Conclusions:The incidence of HCC and progression of liver disease was evident in PR responders during the long-term follow-up period,but the risk level was low.Cirrhotic responders were more vulnerable to develop HCC post SVR24 compared with non-cirrhotic ones.HCV recurrence was rare in responders with SVR24 who had corrected their risky behaviors.

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

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

Immediate virological response predicts the success of shortterm peg-interferon monotherapy for chronic hepatitis C

AIM:To investigate the efficacy of short-term peginterferon(PEG-IFN)monotherapy for chronic hepatitis C patients who achieved an immediate virological response.METHODS:Defining an"immediate virological response(IVR)"as the loss of serum hepatitis C virus(HCV) RNA 7 d after the first administration of PEG-IFNα,we conducted a 12-wk course of PEG-IFNα2a monotherapy without the addition of ribavirin for 38 patients who had low pretreatment HCV RNA load and exhibited IVR.The patients included 21 men and 17 women,whose ages ranged from 22 to 77 years(mean±SD:52.0±17.8 years).There were 4 patients with HCV genotype 1b,23 patients with genotype 2a and 4 patients with genotype 2b.HCV genotype was not determined for the remaining 7 patients.Patients were categorized into a sustained virological response(SVR)group,if serum HCV RNA remained negative for 24 wk after the end of treatment,or into a relapse group.RESULTS:Based on the intention-to-treat analysis,35 patients(92.1%)achieved SVR.One patient(2.6%)relapsed with serum HCV RNA 12 wk after the end of treatment.Two patients(5.3%)withdrew from the study during the 24-wk follow-up period.With regard to the HCV RNA genotype,the SVR rates were 100%(4/4) for genotype 1b,95.7%(22/23)for genotype 2a and 100%(4/4)for genotype 2b.The SVR rate in 7 patients,whose HCV RNA genotypes were not determined,was 71.4%(5/7).CONCLUSION:Short-term PEG-IFNα2a monotherapy is highly effective for chronic hepatitis C patients who have low pretreatment HCV RNA load and exhibit IVR.

Gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acidenhanced magnetic resonance imaging for evaluating fibrosis regression in chronic hepatitis C patients after direct-acting antiviral

BACKGROUND Direct acting antiviral(DAA)therapy has enabled hepatitis C virus infection to become curable,while histological changes remain uncontained.Few valid noninvasive methods can be confirmed for use in surveillance.Gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid(Gd-EOB-DTPA)is a liver-specific magnetic resonance imaging(MRI)contrast,related to liver function in the hepatobiliary phase(HBP).Whether Gd-EOB-DTPA-enhanced MRI can be used in the diagnosis and follow up of hepatic fibrosis in patients with chronic hepatitis C(CHC)has not been investigated.AIM To investigate the diagnostic and follow-up values of Gd-EOB-DTPA-enhanced MRI for hepatic histology in patients with CHC.METHODS Patients with CHC were invited to undergo Gd-EOB-DTPA-enhanced MRI and liver biopsy before treatment,and those with paired qualified MRI and liver biopsy specimens were included.Transient elastography(TE)and blood tests were also arranged.Patients treated with DAAs who achieved 24-wk sustained virological response(SVR)underwent Gd-EOB-DTPA-enhanced MRI and liver biopsy again.The signal intensity(SI)of the liver and muscle were measured in the unenhanced phase(UEP)(SI_(UEP-liver),SI_(UEP-muscle))and HBP(SI_(HBP-liver),SI_(HBP-muscle))via MRI.The contrast enhancement index(CEI)was calculated as[(SI_(HBP-liver)/SI_(HBP-muscle))]/[(SI_(UEP-liver)/SI_(UEP-muscle))].Liver stiffness measurement(LSM)was confirmed with TE.Serologic markers,aspartate aminotransferase-to-platelet ratio index(APRI)and Fibrosis-4(FIB-4),were also calculated according to blood tests.The grade of inflammation and stage of fibrosis were evaluated with the modified histology activity index(mHAI)and Ishak fibrosis score,respectively.Fibrosis regression was defined as a≥1-point decrease in the Ishak fibrosis score.The correlation between the CEI and liver pathology was evaluated.The diagnostic and follow-up values of the CEI,LSM,and serologic markers were compared.RESULTS Thirty-nine patients with CHC were enrolled[average age,42.3±14.4 years;20/39(51.3%)male].Twenty-one enrolled patients had eligible paired Gd-EOB-DTPA-enhanced MRI and liver tissues after achieving SVR.The mHAI median significantly decreased after SVR[baseline 6.0(4.5-13.5)vs SVR 2.0(1.5-5.5),Z=3.322,P=0.017],but the median stage of fibrosis did not notably change(P>0.05).Sixty pairs of qualified MRI and liver tissue samples were available for use to analyze the relationship between the CEI and hepatic pathology.The CEI was negatively correlated with the mHAI(r=-0.56,P<0.001)and Ishak score(r=-0.69,P<0.001).Further stratified analysis showed that the value of the CEI decreased with the progression of the stage of fibrosis rather than with the grade of necroinflammation.For patients with Ishak score≥5,the areas under receiver operating characteristics curve of the CEI,LSM,APRI,and FIB-4 were approximately at baseline,0.87–0.93,and after achieving SVR,0.83–0.91.The CEI cut-off value was stable(baseline 1.58 and SVR 1.59),but those of the APRI(from 1.05 to 0.24),FIB-4(from 1.78 to 1.28),and LSM(from 10.8 kpa to 7.1 kpa)decreased dramatically.The APRI and FIB-4 cannot be used as diagnostic means for SVR in patients with Ishak score≥3(P>0.05).Seven patients achieved fibrosis regression after achieving SVR.In these patients,the CEI median increased(from 1.71 to 1.83,Z=-1.981,P=0.048)and those of the APRI(from 1.71 to 1.83,Z=-2.878,P=0.004)and LSM(from 6.6 to 4.8,Z=-2.366,P=0.018)decreased.However,in patients without fibrosis regression,the medians of the APRI,FIB-4,and LSM also changed significantly(P<0.05).CONCLUSION Gd-EOB-DTPA-enhanced MRI has good diagnostic value for staging fibrosis in patients with CHC.It can be used for fibrotic-change monitoring post SVR in patients with CHC treated with DAAs.

Pre-treatment prediction of response to peginterferon plus ribavirin in chronic hepatitis C genotype 3

AIM: To evaluate pre-treatment factors associated with sustained virological response(SVR) in patients with hepatitis C virus(HCV) genotype 3 treated with peginterferon and ribavirin(RBV). METHODS: We retrospectively analyzed treatment naive, mono-infected HCV genotype 3 patients treated with peginterferon and RBV. Exclusion criteria included presence of other liver disease, alcohol consumption and African American or Asian ethnicity. The variables collected and compared between patients who achieved an SVR and patients who did not were as follows: gender, age, fibrosis stage, diabetes, body mass index,steatosis, INFL3 polymorphism, pre-treatment HCVRNA, type of peginterferon, RBV dose and adherence. RESULTS: A total of 107 patients treated between June, 2004 and March, 2013 were included. Mean treatment duration was 25.1(± 1.8) wk. Overall, 58%(62/107) of the patients achieved an SVR and 42%(45/107) did not. In the multivariate logistic regression analysis, pre-treatment HCV-RNA ≥ 600000 UI/m L(OR = 0.375, 95%CI: 0.153-0.919, P = 0.032) and advanced fibrosis(OR = 0.278, 95%CI: 0.113-0.684,P = 0.005) were significantly associated with low SVR rates. In patients with pre-treatment HCV-RNA ≥600000 UI/m L and advanced fibrosis, the probability of achieving an SVR was 29%(95%CI: 13.1-45.2).In patients with pre-treatment HCV-RNA < 600000UI/m L and mild to moderate fibrosis, the probability of achieving an SVR was 81%(95%CI: 68.8-93.4).CONCLUSION: In patients with HCV genotype 3infections the presence of advance fibrosis and high pre-treatment viral load might be associated with poor response to peginterferon plus RBV. These patients could benefit the most from new direct antiviral agentsbased regimes.

Direct-acting antivirals for chronic hepatitis C treatment: The experience of two tertiary university centers in Brazil

BACKGROUND Hepatitis C virus(HCV)treatment has undergone major changes in recent years.Previous interferon-based therapies have been replaced by oral direct-acting antivirals(DAA)regimens,with high sustained virologic response(SVR)rates,and a lower incidence of adverse events(AEs).AIM To evaluate the efficacy and safety of DAAs for HCV treatment in subjects from two tertiary university centers in Brazil.METHODS This is a multicenter retrospective cohort study of 532 patients with chronic hepatitis C(CHC),undergoing treatment with interferon-free regimens from November 2015 to November 2019.The therapeutic regimen was defined by the current Brazilian guidelines for HCV management at the time of treatment.Demographic,anthropometric,clinical,and laboratory variables were evaluated.SVRs were assessed at 12 to 24 wk after therapy by intention-to-treat(ITT),and modified ITT(m-ITT)analysis.AEs and serious adverse events(SAEs)were registered.In the statistical analysis,a P value of<0.05 was considered significant.RESULTS The mean age was 56.88 years,with 415(78.5%)being HCV genotype 1,followed by genotype 3(20.1%).Moreover,306(57.5%)subjects had cirrhosis,and a third of them had decompensated cirrhosis.Sofosbuvir(SOF)plus daclatasvir±ribavirin was the most frequently used treatment(66.9%),followed by SOF plus simeprevir(21.2%).The overall ITT SVR was 92.6%(493/532),while the m-ITT SVR was 96.8%(493/509).Variables associated with treatment failure via ITT evaluation were hepatic encephalopathy(OR:4.320;95%CI:1.920-9.721,P=0.0004),presence of esophageal varices(OR:2.381;95%CI:1.137-4.988,P=0.0215),previous portal hypertensive bleeding(OR:2.756;95%CI:1.173-6.471,P=0.02),higher model for end-stage liver disease scores(OR:1.143,95%CI:1.060–1.233,P=0.0005),lower serum albumin levels(OR:0.528,95%CI:0.322-0.867,P=0.0115),higher serum creatinine(OR:1.117,95%CI:1.056-1.312,P=0.0033),and international normalized ratio(INR)levels(OR:5.542,95%CI:2.023-15.182,P=0.0009).AEs were reported in 41.1%(211/514)of patients,and SAEs in 3.7%.The female gender,higher body mass index,esophageal varices,higher INR values,and longer treatment duration were independently associated with AE occurrence.CONCLUSION Treatment with oral DAAs attains a high SVR rate,with fewer SAEs in a real-life cohort of subjects with CHC,from two tertiary university centers in Brazil.

Hepatitis C virus burden:Treating and educating people without prejudice

Hepatitis C virus(HCV)infection has a worldwide incidence of 1.1%.In Italy,60%of people who inject drugs(PWIDs)and are receiving assistance for substance use disorder are infected with HCV.However,this subset of patients has extremely limited access to care due to multiple factors,including alcohol abuse,psychological comorbidities,and homeless status.AIM To describe the impact of our HCV-dedicated service for substance use disorder(SSUD)service on PWIDs receiving anti-HCV therapy.METHODS A dedicated,multidisciplinary team was set up at the SSUD of Trento in October 2020 to provide antiviral treatment to HCV RiboNucleic Acid-positive patients with an active or previous history of substance abuse.The treatment was followed by a health education program.Patients were treated with Direct-Acting Antivirals(DAAs).Data were retrospectively analyzed to assess the efficacy of our dedicated program in terms of therapy completion,HCV eradication,and compliance(primary endpoint).The rate of HCV reinfection and DAA-related toxicity were also assessed(secondary endpoints).RESULTS A total of 40 patients were enrolled in the study:28(70.0%)were treated with Sofosbuvir/Velpatasvir,while 12(30.0%)received Glecaprevir/Pibrentasvir.At the time of inclusion in the study,36 patients were receiving opioid agonist maintenance therapy,whilst another 4 had just finished the treatment.37.5%had a history of alcoholism and 42.5%received concomitant psychiatric treatment.All 40 patients(100.0%)completed the therapy cycle and 92.5%of patients adhered to the program.All patients tested negative for viral load at the end of the treatment.There were no significant drug interactions with common psychiatric treatments and no side effects were observed.The sustained virological response was achieved in 92.5%of cases with good tolerability,although two patients discontinued treatment temporarily.After HCV eradication,one patient died from an overdose,another from complications of cirrhosis,and one reinfection occurred.CONCLUSION Very high adherence to therapy and good tolerability was observed in our series of HCV patients treated at the SSUD,regardless of the substance abuse condition.Further validation in a larger population is required.

The Predictive Value of On-treatment Virological Response for Sustained Virological Response in Patients with Chronic Hepatitis C Receiving a Personalized Treatment Program

To investigate the effects of individualised treatment with peginterferon alpha-2a(40 kD)plus ribavirin in Chinese patients with CHC.Methods Total of 297 consecutive Chinese patients were enrolled,including 250 nave cases and 47 cases who were previously treated.Treatment duration was determined according to viral genotypes,prior treatment history and viral responses at week 4,12 and 24.Results Totally,235 patients(79.1%)completed treatment and 186(87.3%)achieved SVR.And 219 out of 289(75.8%)patients achieved HCV RNA negative at week 4(RVR)and 259 of 276(93.8%)at week 12.Among the 164 patients with RVR who completed follow-up,158(96.3%)achieved SVR.Patients with RVR had lower baseline viral loads than patients without RVR(P=0.034).The positive predictive value(PPV)of RVR for SVR was 90.7%(OR 2.10 vs.non-RVR,95%CI:0.50-8.7).Similar outcomes were observed among patients with HCV undetectable at week 12.Conclusions Viral suppression by week 4 is associated with a high rate of treatment success in treatment nave and experienced patients receiving individualized CHC therapy.

Best therapy for the easiest to treat hepatitis C virus genotype 1binfected patients

BACKGROUND The revolution in treatment of patients with chronic hepatitis C virus(HCV)infection dates back to the introduction of direct-acting antivirals(DAAs).The increase in efficacy was most pronounced in patients infected with genotype(GT)1b,as this was the most poorly responsive population to treatment during the interferon era.AIM To identify the most effective interferon-free therapy for GT1b-infected patients and to determine positive and negative predictors of virological response.METHODS This real-world retrospective analysis included patients chronically infected with GT1b HCV whose data were obtained from the multicenter observational EpiTer-2 database.Treatment effectiveness was evaluated for each therapeutic regimen as the percentage of sustained virological responses(SVR).Assessment of the safety was based on the evaluation of the course of therapy,the occurrence of adverse events including serious ones,deaths during treatment and in the post 12-wk follow-up period.RESULTS The studied population consisted of 11385 patients with a mean age of 53±14.8 years and a female predominance(53.4%).The majority of them were treatment-naïve(74.6%)and patients with cirrhosis accounted for 24.3%.Of the DAA regimens used,76.9%were GT-specific with ombitasvir/paritaprevir/ritonavir+dasabuvir±ribavirin being the most used option(32.4%).A total of 10903 patients responded to treatment resulting in a 98.1%in the per-protocol analysis after excluding 273 patients without SVR data.The effectiveness of all regimens exceeded 90%and the highest SVR of 98.9%was achieved in patients treated with a combination of glecaprevir/pibrentasvir.Logistic regression analyses showed that the virologic response was independently associated with female sex[odds ratio(OR)=1.67],absence of decompensated cirrhosis at baseline(OR=2.42)and higher baseline platelets(OR=1.004 per 1000/μL increase),while the presence of human immunodeficiency virus(HIV)coinfection significantly decreased the odds of response(OR=0.39).About 95%-100%of patients completed therapy irrespective of the drug regimen.At least one adverse effect occurred in 10.9%-36.3%and most of them were mild.No treatment related deaths have been reported.CONCLUSION We documented very high effectiveness and a good safety profile across all DAA regimens.Positive predictors of SVR were female sex,absence of decompensated cirrhosis at baseline and higher platelet count while HIV coinfection reduced the effectiveness.

Factors influencing the failure of interferon-free therapy for chronic hepatitis C:Data from the Polish EpiTer-2 cohort study

BACKGROUND The introduction of direct-acting antiviral drugs into clinical practice has revolutionized the treatment of chronic hepatitis C,making it highly effective and safe for patients.However,few researchers have analyzed the factors causing therapy failure in some patients.AIM To analyze factors influencing the failure of direct antiviral drugs in the large,multicenter EpiTer-2 cohort in a real-world setting.METHODS The study cohort consisted of patients with chronic hepatitis C treated at 22 Polish centers from 2016-2020.Data collected from the online EpiTer-2 database included the following:hepatitis C virus(HCV)genotype,stage of fibrosis,hematology and liver function parameters,Child-Turcotte-Pugh and Model for End-stage Liver Disease scores,prior antiviral therapy,concomitant diseases,and drugs used in relation to hepatitis B virus(HBV)and/or human immunodeficiency virus(HIV)coinfections.Adverse events observed during the treatment and follow-up period were reported.Both standard and machine learning methods were used for statistical analysis.RESULTS During analysis,12614 patients with chronic hepatitis C were registered,of which 11938(mean age:52 years)had available sustained virologic response(SVR)data[11629(97%)achieved SVR and 309(3%)did not].Most patients(78.1%)were infected with HCV genotype 1b.Liver cirrhosis was diagnosed in 2974 patients,while advanced fibrosis(F3)was diagnosed in 1717 patients.We included patients with features of hepatic failure at baseline[ascites in 142(1.2%)and encephalopathy in 68(0.6%)patients].The most important host factors negatively influencing treatment efficacy were liver cirrhosis,clinical and laboratory features of liver failure,history of hepatocellular carcinoma,and higher body mass index.Among viral factors,genotype 3 and viral load also exerted an influence on treatment efficacy.Classical statistical analysis revealed that treatment ineffectiveness seemed to be influenced by the male sex,which was not confirmed by the multivariate analysis using the machine learning algorithm(random forest).Coinfection with HBV(including patients with on-treatment reactivation of HBV infection)or HIV,extrahepatic manifestations,and renal failure did not significantly affect the treatment efficacy.CONCLUSION In patients with advanced liver disease,individualized therapy(testing for resistance-associated variants and response-guided treatment)should be considered to maximize the chance of achieving SVR.