Direct-acting antivirals failed to reduce the incidence of hepatocellular carcinoma occurrence in hepatitis C virus associated cirrhosis: A real-world study

BACKGROUND Direct-acting antivirals(DAAs)revolutionized the treatment of chronic hepatitis C virus(HCV)-associated disease achieving high rates of sustained virological response(SVR).However,whether DAAs can reduce the occurrence of hepatocellular carcinoma(HCC)in patients with HCV-associated cirrhosis who are at high risk have not been concluded.AIM To investigate the effect of DAAs on the occurrence of HCC in patients with HCVassociated cirrhosis after achieving SVR.METHODS Of 427 inpatients with HCV-associated cirrhosis were enrolled in Tianjin Second People's Hospital from January 2014 to April 2020.118 patients weren’t received antiviral treatment with any reasons named non-antiviral treatment group,and 236 patients obtained from the 309 DAAs treatment patients according to the propensity score matching named DAAs treatment group.Demographic information and laboratory data were collected from baseline and the following up.Kaplan-Meier curve and Log-Rank test were used to compare the incidence and cumulative incidence of HCC between the two groups.Cox proportional risk regression was used to re-evaluate the risk factors for HCC.RESULTS HCC incidence was 4.68/100PY(95%CI,3.09-6.81)in the DAAs treatment group,while it was 3.00/100PY(95%CI,1.50-5.37)in the non-antiviral treatment group,and the relative risk was 1.82(95%CI,0.93-3.53,P>0.05).The incidence of HCC at 12,24,36 and 48 months was 3.39%,6.36%,8.47%and 10.17%in the DAAs treatment group,and it was 0%,0%,3.39%and 9.32%in the non-antiviral treatment group,respectively.Age>58[hazard ratio(HR)=1.089;95%CI,1.033-1.147;P=0.002]and liver stiffness measurement>27.85 kPa(HR=1.043;95%CI,1.022-1.065;P=0.000)were risk factors for HCC in all patients(n=427),and DAAs treatment didn’t show protective efficacy.CONCLUSION DAAs treatment seems failed to reduce the incidence of HCC occurrence in HCV-associated cirrhosis in 48 months,and even increased the incidence of HCC in 36 months.

Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-nave patients

AIM: To determine whether adding vitamin D, a potent immunomodulator, improves the hepatitis C virus (HCV) response to antiviral therapy. METHODS: Seventy-two consecutive patients with chronic HCV genotype 1 were randomized into two groups: the treatment group (n = 36, 50% male, mean age 47 ± 11 years) received Peg-α-2b interferon (1.5 μg/kg per week) plus ribavirin (1000-1200 mg/d) together with vitamin D3 (2000 IU/d, target serum level > 32 ng/mL), and the control group (n = 36, 60% male, mean age 49 ± 7 years) received identical therapy without vitamin D. HCV-RNA was assessed by realtime polymerase chain reaction (sensitivity, 10 IU/mL). The sustained virologic response (SVR) was defined as undetectable HCV-RNA at 24 wk post-treatment. RESULTS: Clinical characteristics were similar in both groups. The treatment group had a higher mean bodymass index (27 ± 4 kg/m2 vs 24 ± 3 kg/m2, P < 0.01), viral load (50% vs 42%, P < 0.01), and fibrosis score (> F2: 42% vs 19%, P < 0.001) than the controls. At week 4, 16 (44%) treated patients and 6 (17%) controls were HCV-RNA negative (P < 0.001). At week 12, 34 (94%) treated patients and 17 (48%) controls were HCV-RNA negative (P < 0.001). At 24 wk post-treatment (SVR), 31 (86%) treated patients and 15 (42%) controls were HCV-RNA negative (P < 0.001). Viral load, advanced fibrosis and vitamin D supplementation were strongly and independently associated with SVR (multivariate analysis). Adverse events were mild and typical of Peg-α-2b/ribavirin. CONCLUSION: Adding vitamin D to conventional Peg-α-2b/ribavirin therapy for treatment-na■ve patients with chronic HCV genotype 1 infection significantly improves the viral response.

Successful antiviral therapy is associated with a decrease of serum prohepcidin in chronic hepatitis C

AIM: To assess serum concentrations of prohepcidin in chronic hepatitis C individuals and evaluate their associations with disease activity and efficacy of pegylated interferon (PEG-IFN)/ribavirin (RBV) therapy. METHODS: Prohepcidin was measured in sera of 53 chronic hepatitis C patients. Concentrations of prohepcidin and other iron metabolism markers were analyzed at 9 time points before, during and after the end of antiviral therapy. RESULTS: In hepatitis C virus (HCV) genotype 1-infected individuals, a gradual decrease of prohepcidin during antiviral therapy was observed in responders (88.8 ± 14.7 ng/mL before therapy vs 60.6 ± 0.3 ng/mL in the 48th wk, P = 0.04). In contrast, no decrease was observed in non-responders. A similar association was observed in HCV genotype 3a individuals, with a statistically significant decline in serum prohepcidin only in the responder group (99.5 ± 5.2 ng/mL at baseline vs 72.7 ± 6.1 ng/mL in the 24th wk, P = 0.01). Moreover, HCVRNA at week 12 of therapy was positively correlated with baseline (R = 0.63, P < 0.005) and week 12 (R = 0.60, P = 0.01) serum prohepcidin concentrations in HCV genotype 1 infection. CONCLUSION: Successful PEG-IFN/RBV therapy results in a decline of serum prohepcidin concentration in chronic hepatitis C, which may suggest a direct effect of HCV on iron metabolism at the prohormonal level of hepcidin.

Impact of IL28B gene polymorphisms rs8099917 and rs12980275 on response to pegylated interferon-α/ribavirin therapy in chronic hepatitis C genotype 4 patients

Host genetic factors may predict the outcome and treatment response in hepatitis C virus（HCV）infection.One of these factors is the single nucleotide polymorphisms of the interleukin 28B（IL28B）gene.We sought to evaluate the outcome of pegylated interferon and ribavirin therapy in association with IL-28B rs8099917 and rsl2980275 in patients infected with HCV genotype 4.A total of 180 patients with chronic hepatitis C were selected from Egyptians who have received combined therapy with pegylated interferon and ribavirin for 6 months and their response was evaluated after follow-up at 0,6,12,24 and 48 weeks from the beginning of the therapy.Blood samples were collected from responders and non-responders.Genomic DNA was extracted from whole blood and genotyping was carried out by polymerase chain reaction and restriction fragment length polymorphism（PCR-RFLP）.Our results showed that TT genotype of rs8099917 was associated with higher sustained viral response（SVR）rates and G allele represented a risk factor for failure of response（OR=3.7,CI=1.8：7.64）while rs12980275 was not significantly associated with SVR in genotype 4 Egyptian patients.The determination of 1L-28B SNPs may be useful in enhancing correct prediction of SVR achievement in treating this group of genotype 4 patients.

Eight-week ledipasvir/sofosbuvir in non-cirrhotic, treatment-na?ve hepatitis C genotype-1 patients with hepatitis C virus-RNA < 6 million: Single center, real world effectiveness and safety

AIM To evaluate sustained viral response(SVR) of 8-wk ledipasvir/sofosbuvir therapy among non-cirrhotic, genotype-1 hepatitis C virus(HCV) patients with RNA < 6 million IU/m L.METHODS We performed a retrospective cohort study to examine SVR rates, predictors of treatment failure and safety analysis of 8-wk ledipasvir/sofosbuvir(LDV/SOF) therapy among non-cirrhotic, genotype 1 HCV patients with viral load < 6 million IU/m L. Primary outcome was an achievement of SVR at 12 wk after treatment. Secondary outcomes were identifying predictors of treatment failure and adverse events during treatment.RESULTS Total 736 patients: 55% males, 51% Caucasians and 65% were genotype 1a. Non-cirrhotic state of 53% was determined by clinical judgment(imaging, AST, platelet count) and 47% had documented liver fibrosis testing(biopsy, vibration-controlled transient elastography, serum biomarkers). Overall SVR12 was 96%. No difference in SVR12 was seen between patients whose non-cirrhotic state was determined by clinical judgment and patients who had fibrosis testing. Age groups, gender, ethnicity and genotype 1 subtype did not predict SVR. Non-cirrhotic state determined by clinical judgment based on simple, non-invasive tests were not associated with lower SVR [OR = 1.02, 95%CI: 0.48-2.17, P = 0.962]. The AUROC for hepatitis C RNA viral load was 0.734(P < 0.001, 95%CI: 0.66-0.82). HCV RNA 2.2 million IU/m L was identified as the cutoff value with sensitivity 73% and specificity 64%. HCV RNA < 2.2 million IU/m L was associated with significantly higher SVR 98% with OR = 0.22(95%CI: 0.1-0.49, P < 0.001) compared to SVR 92% in HCV RNA ≥ 2.2 million IU/m L. No death or morbidities were reported.CONCLUSION Our outcomes validate safety and effectiveness of 8-wk LDV/SOF therapy in non-cirrhotic, untreated HCV genotype 1 patients with HCV RNA < 6 million IU/m L.

Response rates to direct antiviral agents among hepatitis C virus infected patients who develop hepatocellular carcinoma following direct antiviral agents treatment

Aim:Patients with chronic hepatitis C virus(HCV)infection who develop hepatocellular carcinoma(HCC)soon after treatment with direct antiviral agents(DAA)may have been harboring hitherto hidden tumors.If this were true,they should have a lower sustained viral response(SVR)rate,since active HCC hampers DAA efficacy.We aimed to verify this hypothesis.Methods:We included all patients who attended an HCV clinic,provided that they:(1)had no previous history of HCC;(2)had received at least one DAA dose;and(3)had been followed-up clinically and ultrasonographically for at least six months after concluding DAA.Results:The study population included n=789 patients(55%males,median age 62 years).A median of 9.3 months(8.8-11.9)after concluding DAA,n=19(2.4%)patients were discovered to harbor HCC.In comparison to all others,patients with HCC were more commonly male(84%vs.54%,P=0.009),obese(47%vs.17%,P=0.002),and cirrhotic(95%vs.35%,P<0.001)and had less commonly achieved an SVR(68%vs.98%,P<0.001).Moreover,they had a trend for being less commonly treatment na?ve(58%vs.67%,P=0.051).Based on multivariate analysis, ;the independent predictors of HCC were male sex(P=0.031),cirrhosis(P=0.004),obesity(P=0.006),and failure to achieve an SVR(P<0.001).Conclusion:Lack of achieving SVR is a strong independent predictor of development of HCC early after treatment of hepatitis C with DAA.Treatment failure should further alert clinicians to the possibility of this dreadful complication.

A randomized trial of a 4- vs 12-week daily interferon dose regimen combined with ribavirin in treatment of patients with chronic hepatitis C

BACKGROUND: Standard combination-therapy of ribavi- rin with alternate day interferon (IFN) in patients with chronic hepatitis C ( CHC) has been reported to achieve 30%-55% sustained viral response. Early reduction of viral load by daily dosage of IFN could enhance viral clearance. However, the duration of daily dosage protocol and the likely side-effects have not been well studied. We compared the efficacy and safety of a 4- vs 12-week daily IFN dosage in patients with CHC. METHODS: Fifty-nine, histologically proven CHC patients having ALT levels >1.5 ×ULN were divided randomly into 2 groups, group I was given IFN 3 MIU daily for 4 weeks, followed by tiw up to 12 months and group was given IFN 3 MIU daily for 12 weeks, followed by tiw up to 12 months. Ribavirin was given in a dose of 800-1200 mg/d for 12 months. RESULTS: Fifty-two of the 59 patients (group group completed the study. The pretreatment vari- ables and the prevalence of HCV genotype 1 were compara- ble between the groups. Nine patients (29%) in group and 6 (25%) in group had stage 3, 4 fibrosis. At the end of 4, 12, 24 and 52 weeks, HCV RNA negativity was ob- served in 27%, 54%, 65% and 71% in group I and 38%, 54%, 71% and 75% in group respectively (P =ns). Four of the eight (50%) patients with genotype 1 and 30 (69.8%) of 43 patients with genotype non-1 responded to therapy (P =ns). Sustained viral response was achieved in 61% and 71% in groups respectively. None of the variables predicted non-response precisely. No serious adverse effects were observed and they were comparable between the two groups. CONCLUSION: Daily IFN dosage with ribavirin is safe and can achieve response in up to 65% patients. Since the effica- cy of a 4-week daily dosage of IFN is comparable to a 12- week schedule, we recommend the former regimen.

Distinctive magnetic resonance imaging findings of hepatocellular carcinoma after hepatitis C virus eradication with direct-acting antivirals

Aim:The aim of the present study was to evaluate the characteristics of the magnetic resonance imaging features of hepatocellular carcinoma(HCC)that developed early after the eradication of hepatitis C virus(HCV)by direct-acting antiviral(DAA)treatment.Methods:This study included 26 patients who achieved sustained viral response with DAA and developed HCC thereafter within one year(DAA-SVR HCC).The radiologic characteristics of these patients were evaluated by contrast-enhanced magnetic resonance imaging,including diffusion-weighted imaging(DWI)and T2-weighted imaging(T2WI).For comparison,80 HCC patients with positive HCV RNA(HCV-positive HCC)were included.Among 42 patients where tumor biopsy was available,histological grade and radiologic findings were compared.Results:The rates of high intensity on DWI and T2WI were significantly higher in DAA-SVR HCC compared to HCV-positive HCC(DWI:100%vs.67.5%,P<0.001T2WI:92.6%vs.67.5%,P=0.01).HCC with high intensity on DWI or T2WI was more likely to have moderately or poorly differentiated HCC compared to well-differentiated HCC(DWI:69.7%vs.30.3%,P=0.02;T2WI:66.7%vs.27.3%,P=0.03).Conclusion:High intensity on DWI and hyperintensity on T2WI were distinctive features of HCC that developed within one year after the end of DAA treatment.

Effectiveness of Ledipasvir/Sofosbuvir with / without Ribavarin in Liver Transplant Recipients with Hepatitis C

Background and Aims:Recurrent infection of hepatitis C virus (HCV) in liver transplant (LT) recipients is universal and associated with significant morbidity and mortality.Methods:We retrospectively evaluated the safety and efficacy of ledipasvir/sofosbuvir with and without ribavirin in LT recipients with recurrent genotype 1 hepatitis C.Results:Eighty-five LT recipients were treated for recurrent HCV with ledipasvir/sofosbuvirwith and without ribavirin for 12 or 24 weeks.The mean (± standard deviation [SD]) time from LT to treatment initiation was 68 (±71) months.The mean (± SD) age of the cohort was 63 (±8.6) years old.Most recipients were male (70%).Baseline alanine transaminase,total bilirubin,and HCV ribonucleic acid (RNA) values (± SD) were 76.8 (±126)mg/dL,0.8 (±1.3) U/L,and 8,010,421.9 (±12,420,985)IU/mL,respectively.Five of 43 recipients who were treated with ribavirin required drug cessation due to side effects,with 4 of those being anemia complications.No recipient discontinued the ledipasvir/sofosbuvir.Eighty-one percent of recipients had undetectable viral levels at 4 weeks after starting therapy,and all recipients had complete viral suppression at the end of therapy.The sustained viral response at 12 weeks after completion of therapy was 94%.Conclusion:Ledipasvir and sofosbuvir with and without ribavirin therapy is an effective and well-tolerated interferon-free treatment for recurrent HCV infection after LT.Anemia is not uncommon in LT recipients receiving ribavirin.