Pregnancy in Wilson's disease: Management and outcome.

Wilson's disease (WD) is a rare inherited disorder of copper metabolism causing toxic hepatic and neural copper accumulation. Clinical symptoms vary widely, from asymptomatic disease to acute liver failure or chronic liver disease with or without neuropsychiatric symptoms. Continuation of specific medical treatment for WD is recommended during pregnancy, but reports of pregnancy outcomes in WD patients are sparse. In a retrospective, multicenter study, 282 pregnancies in 136 WD patients were reviewed. Age at disease onset, age at conception, and WD-specific treatments were recorded. Maternal complications during pregnancy, rate of spontaneous abortions, and birth defects were analyzed with respect to medical treatment during pregnancy. Worsening of liver function tests was evident during 16 of 282 (6%) pregnancies and occurred in undiagnosed patients as well as in those under medical treatment. Liver test abnormalities resolved in all cases after delivery. Aggravation of neurological symptoms during pregnancy was rare (1%), but tended to persist after delivery. The overall spontaneous abortion rate in the study cohort was 73 of 282 (26%). Patients with an established diagnosis of WD receiving medical treatment experienced significantly fewer spontaneous abortions than patients with undiagnosed WD (odds ratio, 2.853 [95% confidence interval, 1.634-4.982]). Birth defects occurred in 7 of 209 (3%) live births. CONCLUSION: Pregnancy in WD patients on anticopper therapy is safe. The spontaneous abortion rate in treated patients was lower than that in therapy-naïve patients. Although the teratogenic potential of copper chelators is a concern, the rate of birth defects in our cohort was low. Treatment for WD should be maintained during pregnancy, and patients should be monitored closely for hepatic and neurological symptoms. (Hepatology 2018;67:1261-1269).

High seroprevalence of anti-Hepatitis E antibodies in Austrian patients with autoimmune hepatitis.

BACKGROUND & AIMS: Increasing numbers of autochthonous hepatitis E virus infections have been reported in Europe. Chronic infections have been shown in immune-compromised patients after solid organ transplantation. Hepatitis E virus might be a possible trigger for autoimmune hepatitis and might cause disease flares or relapses in the further course of disease. Aim of this study was to investigate the presence of hepatitis E virus antibodies and hepatitis E virus RNA, and to analyse their impact on immunosuppressive treatment in patients with autoimmune hepatitis. METHODS: Sera from 92 autoimmune hepatitis patients (73/79.3% female, age: 42.2 ± 16.3 years [mean ± SD]) were tested. Patients were scored according to the simplified and revised scoring systems of the International Autoimmune Hepatitis Group. The prevalence of anti- hepatitis E virus antibodies (Beijing Wantai Biological Pharmacy Enterprises Co., Ltd, Beijing, China) and hepatitis E virus RNA was determined. RESULTS: 19/20.7% autoimmune hepatitis patients tested positive for hepatitis E virus-IgG, which was higher than in previous reports of healthy Austrian individuals (12.4%, P = 0.031); hepatitis E virus RNA was not detectable in any patient. Anti-hepatitis E virus positive patients were older (49.5 ± 9.5 vs 40.4 ± 17.2 years [mean ± SD], P = 0.033) but did not differ in laboratory findings at diagnosis (AST: 14.6 [1.3-70.6] vs 9.5 [0.7-62.7] × ULN [median/range]; P = 0.387, alanine aminotransferase: 18.3 [1.6-62.7] vs. 12.9 [0.8-62.6] × ULN; P = 0.511; IgG: 1.4 [1.0-2.5] vs 1.3 [0.6-3.8] g/dL × ULN; P = 0.278) nor in alanine aminotransferase levels after six months (0.7 [0.5-2.4] vs 1.0 U/L × ULN [0.1-22.4]; P = 0.077). CONCLUSIONS: No chronic hepatitis E virus infection was observed in our cohort of autoimmune hepatitis patients. Anti- hepatitis E virus-IgG positive patients were older and the seroprevalence was nearly twice as high as reported previously in healthy Austrian individuals, suggesting that hepatitis E virus-infection might act as trigger for the development of autoimmune hepatitis.

Long-term follow-up of ribavirin-free DAA-based treatment in HCV recurrence after orthotopic liver transplantation.

BACKGROUND & AIMS: Excellent efficacy and safety profile of second-generation DAA combinations improved treatment of chronic hepatitis C (HCV) as well as in HCV recurrence after orthotopic liver transplantation (OLT). The need of ribavirin addition is under debate as anaemia and decreased renal function are prevalent in transplant cohorts. The aim of this study was thus to assess safety and long-term efficacy of RBV-free DAA combinations in HCV-recurrent patients after OLT. PATIENTS & METHODS: A total of 62 OLT recipients (male: 50%/81%; age: 60.7 ± 8.5 years [mean ± SD]; GT - 1: 48, GT - 3: 9, GT - 4: 5; cirrhosis: 34%/55% [7%/21% decompensated], fibrosing cholestatic hepatitis: 1%/2%) received RBV-free treatment with second-generation DAA combinations: sofosbuvir (SOF)/daclatasvir (DCV): 42%/68%, SOF/simeprevir (SMV): 10%/16%, SOF/ledipasvir (LDV): 6%/10% and PrOD: 4%/7%. RESULTS: Data of at least 96 weeks of FUP after treatment cessation (mean: 120; up to 167 weeks) were analysed. All patients showed on-treatment response. By intention-to-treat (ITT) analysis, SVR12 was 97% (60/62, GT-1a: 11/11 [100%]; 1b: 33/34 [97%]; 1g: 1/1 [100%]; subtype not specified: 2/2 [100%]; GT3a: 9/9 [100%]; GT4: 4/5 [80%]) compared to SVR96 of 89% (55/62). No late relapses occurred. In total, 16 severe adverse events occurred, including two newly diagnosed carcinoma (lung cancer, hepatocellular carcinoma). Six patients died; one at treatment week 24 (HCV-RNA undetectable) and five during treatment-free FUP and after achieving SVR (SVR4: N = 1, SVR12: N = 3, after SVR96: N = 1 respectively). Reasons for death were: multi-organ failure (N = 4), impaired graft function (N = 1) and unknown (N = 1). CONCLUSION: RBV-free DAA combinations for the treatment of HCV recurrence after OLT are highly efficacious and well tolerated. Our long-term data show that viral eradication is durable but not necessarily translated into beneficial long-term clinical outcome.

Follow-up of sustained virological responders with hepatitis C and advanced liver disease after interferon/ribavirin-free treatment.

BACKGROUND: The introduction of direct-acting antivirals (DAA) has increased sustained virological response (SVR) rates in patients with advanced liver disease and chronic hepatitis C(CHC)infection. At present, data on clinical outcome and long-term durability of viral eradication after successful DAA therapy are scarce. AIM: To evaluate the long-term success of viral eradication in patients with advanced fibrosis or cirrhosis treated with DAAs. METHODS: Five hundred and fifty-one patients with advanced fibrosis (n = 158) or cirrhosis (CPS-A:317,CPS-B/C:76) and SVR after interferon and ribavirin-free DAA therapy treated between October 2013 and April 2016 were studied with a median follow-up of 65.6 (13.0-155.3) weeks. Only patients without hepatocellular carcinoma (HCC) at baseline and without liver transplantation were included. RESULTS: Twelve patients (2.2%) died during follow-up: the mortality rate was 0.6% in F3, 2.2% in CPS-A and 5.3% in CPS-B/C patients (P = .08). During follow-up 36 patients with cirrhosis (9.1%) developed a liver related event, including 16 with de-novo HCC (4.1%). Seven patients were transplanted at a median of 9.7 (range 3.8-21.7) months after EOT. History of decompensation was significantly associated with liver related events during follow-up (HR 7.9; 95% CI 2.7-22.6; P < .001), and with mortality (HR 5.5; 95% CI 1.5-20.2, P = .01). CONCLUSIONS: Eradication of HCV by DAA therapy was durable irrespective of the DAA combination used. Most of the cured patients had an excellent long-term clinical prognosis. Nevertheless, the risk of new occurrence of HCC remains worrisome and thus regular surveillance is obligatory even after clinical stabilization and improvement of the patient.

Sustained virologic response to interferon-free therapies ameliorates HCV-induced portal hypertension.

BACKGROUND & AIMS: We aimed to investigate the impact of sustained virologic response (SVR) to interferon (IFN)-free therapies on portal hypertension in patients with paired hepatic venous pressure gradient (HVPG) measurements. METHODS: One hundred and four patients with portal hypertension (HVPG ⩾6mmHg) who underwent HVPG and liver stiffness measurement before IFN-free therapy (baseline [BL]) were retrospectively studied. Among 100 patients who achieved SVR, 60 patients underwent HVPG and transient elastography (TE) after antiviral therapy (follow-up [FU]). RESULTS: SVR to IFN-free therapies significantly decreased HVPG across all BL HVPG strata: 6-9mmHg (BL: 7.37±0.28 vs. FU: 5.11±0.38mmHg; -2.26±0.42mmHg; p<0.001), 10-15mmHg (BL: 12.2±0.4 vs. FU: 8.91±0.62mmHg; -3.29±0.59mmHg; p<0.001) and ⩾16mmHg (BL: 19.4±0.73 vs. FU: 17.1±1.21mmHg; -2.3±0.89mmHg; p=0.018). In the subgroup of patients with BL HVPG of 6-9mmHg, HVPG normalized (<6mmHg) in 63% (12/19) of patients, while no patient progressed to ⩾10mmHg. Among patients with BL HVPG ⩾10mmHg, a clinically relevant HVPG decrease ⩾10% was observed in 63% (26/41); 24% (10/41) had a FU HVPG <10mmHg. Patients with Child-Pugh stage B were less likely to have a HVPG decrease (hazard ratio [HR]: 0.103; 95% confidence interval [CI]: 0.02-0.514; p=0.006), when compared to Child-Pugh A patients. In the subgroup of patients with BL CSPH, the relative change in liver stiffness (per %; HR: 0.972; 95% CI: 0.945-0.999; p=0.044) was a predictor of a HVPG decrease ⩾10%. The area under the receiver operating characteristic curve for the diagnosis of FU CSPH by FU liver stiffness was 0.931 (95% CI: 0.865-0.997). CONCLUSIONS: SVR to IFN-free therapies might ameliorate portal hypertension across all BL HVPG strata. However, changes in HVPG seemed to be more heterogeneous among patients with BL HVPG of ⩾16mmHg and a HVPG decrease was less likely in patients with more advanced liver dysfunction. TE might be useful for the non-invasive evaluation of portal hypertension after SVR. LAY SUMMARY: We investigated the impact of curing hepatitis C using novel interferon-free treatments on portal hypertension, which drives the development of liver-related complications and mortality. Cure of hepatitis C decreased portal pressure, but a decrease was less likely among patients with more pronounced hepatic dysfunction. Transient elastography, which is commonly used for the non-invasive staging of liver disease, might identify patients without clinically significant portal hypertension after successful treatment.

DAA-based antiviral treatment of patients with chronic hepatitis C in the pre- and postkidney transplantation setting.

DAA-based regimens for chronic hepatitis C infection encourage treatment of "difficult-to-treat" cohorts. This study investigated efficacy and safety of DAA-based regimens in HCV patients on dialysis or postkidney or liver/kidney transplantation. Twenty-five patients treated with DAA combinations were evaluated: 10 were on dialysis (eight: hemodialysis, two: peritoneal dialysis), eight were kidney transplant recipients, and seven were liver/kidney transplant recipients. Except for one patient treated with daclatasvir ([DCV]/60 mg/QD)/simeprevir ([SMV]/150 mg/QD), the others received sofosbuvir-based regimens ([SOF];400 mg/QD) combined with SMV:eight, DCV:13 or either ledipasvir ([LDV]90 mg/QD), ribavirin ([RBV];weight based) or pegylated interferon/RBV. HCV-RNA was determined by Abbott RealTime (LLOQ]:12 IU/ml) or Roche AmpliPrep/COBAS TaqMan assay (LLOQ:15 IU/ml); treatment response evaluated every 4 weeks, at the end of treatment, and 4 and 12 weeks thereafter. Twenty-four (96%) patients achieved SVR 12/24 (ITT-analysis). Mean treatment duration was 15.1 ± 5.1 weeks (±SD), and two patients terminated prematurely - both reached SVR12. Six patients were hospitalized due to complications of underlying disease. One patient achieved SVR24 but was re-infected (week 27). Kidney function remained stable; serum creatinine increased in only one patient - SOF was reduced to 400 mg/48 h. Treatment with DAA combinations in renally impaired HCV patients is highly effective and well tolerated. These findings call for further controlled trials and data from real-life cohorts.

Interferon-free antiviral treatment of chronic hepatitis C in the transplant setting.

Interferon-based regimens with first-generation protease inhibitors have a limited efficacy and an unfavorable safety profile. Combination therapies with two or more second-generation direct-acting antivirals plus/minus ribavirin revolutionized treatment strategies in patients chronically infected with hepatitis C virus. In this rapidly evolving era, patients in the transplant setting benefit from interferon-free treatment regimens. Scientific societies can barely keep up with this development, making it necessary to update the clinical guidelines by the American and European Associations for the Study of Liver Diseases within short periods. This review presents and discusses the currently available data of the use of interferon-free treatment in the setting of liver transplantation. However, costs, different reimbursement strategies, and health-care options cannot be answered by guidelines and recommendations from scientific societies. Further investigator-initiated trials are needed to individualize treatment concepts.

Long-term outcomes of patients with Wilson disease in a large Austrian cohort.

BACKGROUND & AIMS: Wilson disease is an autosomal recessive disorder that affects copper metabolism, leading to copper accumulation in liver, central nervous system, and kidneys. There are few data on long-term outcomes and survival from large cohorts; we studied these features in a well-characterized Austrian cohort of patients with Wilson disease. METHODS: We analyzed data from 229 patients diagnosed with Wilson disease from 1961 through 2013; 175 regularly attended a Wilson disease outpatient clinic and/or their physicians were contacted for information on disease and treatment status and outcomes. For 53 patients lost during the follow-up period, those that died and reasons for their death were identified from the Austrian death registry. RESULTS: The mean observation period was 14.8 ± 11.4 years (range, 0.5-52.0 years), resulting in 3116 patient-years. Of the patients, 61% presented with hepatic disease, 27% with neurologic symptoms, and 10% were diagnosed by family screening at presymptomatic stages. Patients with a hepatic presentation were diagnosed younger (21.2 ± 12.0 years) than patients with neurologic disease (28.8 ± 12.0; P < .001). In 2% of patients, neither symptoms nor onset of symptoms could be determined with certainty. Most patients stabilized (35%) or improved on chelation therapy (26% fully recovered, 24% improved), but 15% deteriorated; 8% required a liver transplant, and 7.4% died within the observation period (71% of deaths were related to Wilson disease). A lower proportion of patients with Wilson disease survived for 20 years (92%) than healthy Austrians (97%), adjusted for age and sex (P = .03). Cirrhosis at diagnosis was the best predictor of death (odds ratio, 6.8; 95% confidence interval, 1.5-31.03; P = .013) and need for a liver transplant (odds ratio, 07; 95% confidence interval, 0.016-0.307; P < .001). Only 84% of patients with cirrhosis survived 20 years after diagnosis (compared with healthy Austrians, P =.008). CONCLUSION: Overall, patients who receive adequate care for Wilson disease have a good long-term prognosis. However, cirrhosis increases the risk of death and liver disease. Early diagnosis, at a precirrhotic stage, might increase survival times and reduce the need for a liver transplant.

Role of FDFT1 polymorphism for fibrosis progression in patients with chronic hepatitis C.

BACKGROUND: In chronic hepatitis C (CHC), steatosis is associated with fibrosis and impaired response to antiviral therapy. Recently, a polymorphism of single nucleotide polymorphism SNP rs2645424 of farnesyl diphosphate farnesyl transferase 1 (FDFT1) was identified in NAFLD/NASH as a possible causal link to steatosis and fibrosis progression. SNP rs738409 in the adiponutrin gene (PNPLA3) is a well described factor for steatosis. This study evaluated the relation of these SNPs on steatosis, fibrosis and treatment response in CHC. METHODS: The SNPs rs738409478 and rs2645424 were determined by real-time PCR in 478 patients with CHC (m/f: 314/164; mean age: 44.9 ± 10.7; GT1: 387, GT4: 91) who completed treatment with peg-IFN-α-2a/ribavirin. All had a pretreatment liver biopsy. Steatosis and fibrosis were graded by board-certified pathologists according to Brunt and METAVIR respectively. RESULTS: The distribution of FDFT1 rs2645424 was GG: 186 (38.9%), AG: 222 (46.4%) and AA: 70 (14.6%) and of the rs738409 PNPLA3 allele: CC: 269 (56.3%), CG: 177 (37.0%) and GG: 32 (6.7%). Overall, FDTF1 polymorphism was not linked to the extent of steatosis or fibrosis. However, in patients without steatosis the AA genotype was associated with advanced fibrosis [AA: 8/20 (40.0%), AG: 6/70 (8.5%), GG: 9/57 (16.1%), P = 0.003]. In contrast, the minor PNPLA3 allele was associated with both steatosis and advanced fibrosis (P < 0.001). Both SNPs did not influence treatment response. CONCLUSION: The minor allele in FDFT1 was associated with advanced fibrosis in the non-steatotic but not in the steatotic subgroup. This may reflect different metabolic pathways in fibrosis progression for steatotic and non-steatotic patients with CHC.

Revisiting the predictors of a sustained virologic response in the era of direct-acting antiviral therapy for hepatitis C virus.

Several host (age, sex, race, fibrosis stage, interleukin 28B polymorphism) and viral factors (hepatitis C virus [HCV] genotype, viral load) allow estimating the response to interferon-based therapies (which includes first-generation protease inhibitors) before treatment. However, treatment should not be denied to any patient based on unfavorable factors alone. Metabolic conditions associated with poor response (diabetes, insulin resistance, obesity) and alcohol abuse can be influenced before starting treatment. "On-treatment" predictors of response allow treatment to be tailored to the individual need of the patient. Patients with undetectable HCV RNA after 4 weeks (rapid virologic response [RVR]) have the highest chance for cure (>85%) both by dual and triple therapy. For triple therapy, the decision to shorten treatment requires that the virus remains undetectable for an additional 8 (telaprevir) to 20 (boceprevir) weeks (extended RVR). Based on viral kinetics, an even earlier prediction after 2 weeks of treatment with direct acting antivirals appears feasible.

Effect of gender and ITPA polymorphisms on ribavirin-induced anemia in chronic hepatitis C patients.

BACKGROUND & AIMS: Single nucleotide polymorphisms (SNPs) in the inosine triphosphate pyrophosphatase (ITPA) gene protect patients from ribavirin induced anemia. To investigate other possible protective cofactors, gender differences were analyzed in patients with HCV genotype 1. METHODS: Hemoglobin levels at baseline (Hb0) and the decline after 4 weeks of treatment (HbΔ4) were analyzed in 308 chronic hepatitis C patients participating in 5 Austrian trials (n=308, age 43.9 ± 11.1, male:185, female:123, BMI 25.3 ± 3.9, no cirrhosis: n=259, liver cirrhosis: n=49). All patients were treated with 180 µg peginterferon-alpha 2a and ribavirin [1000-1200 mg/d; females: mean (95% CI) 15.8 mg/kg (15.4-16.2); males 14.3 (14.1-14.5); p<0.001]. The SNPs rs6051702, rs1127354, rs7270101 and IL28B rs12979860 were analyzed by the StepOnePlus Real time PCR System. RESULTS: 188 were major alleles homozygotes; 95 (30.8%) carried the minor allele (C) of rs6051702, 47 (15.3%) of rs1127354 (A), and 69 (22.4%) of rs7270101 (C). The overall Hb0 was 14.8 g/dl (14.6-14.9) [mean (95%CI); females 13.7 (13.5-13.9); males 15.5; 15.3-15.6; p<0.001]. The overall HbΔ4 was greater in major allele homozygotes [2.8 g/dl (2.6-3.0)] than in minor allele carriers [1.6 (1.4-1.9); p<0.001]. Irrespective of the ITPA genotypes HbΔ4 was smaller in female [2.0 (1.7-2.2)] than in male patients [2.6 (2.4-2.8); p<0.001] and among females in premenopausal [1.5 (1.3-1.8)] than in postmenopausal patients [2.7 (2.3-3.1); p<0.001]. CONCLUSIONS: Irrespective of the protective effect of ITPA mutations, premenopausal females less likely develop ribavirin induced anemia.

A diagnostic score for the prediction of spontaneous resolution of acute hepatitis C virus infection.

BACKGROUND & AIMS: IL28B polymorphisms, jaundice, decline in HCV-RNA, IP-10, and gender have been proposed to be indicative of spontaneous clearance of acute hepatitis C virus infection. The aim of this study was to define a score enabling the discrimination of patients with spontaneous clearance of HCV from those with development of viral persistence and need for early antiviral treatment. METHODS: 136 patients (74 male; 35 ± 15 years) were analyzed. From variables predictive of spontaneous clearance, calculated by univariate analysis, three scores were built. Analogous cut-offs were evaluated by computing area under the receiver operating characteristic curves. Candidate variables and cut-offs were: (I) presence of IL28B C/C (p=0.027), (II) age (p=0.031; cut-off: 35 years), (III) peak-bilirubin (p=0.018; cut-off: 6 mg/dl), (IV) HCV-RNA decline within 4 weeks (p<0.001;cut-off: >2.5 log), (V) serum IP-10 (p=0.003; cut-off: 546 pg/ml), (VI) presence of CD4(+) Th1 cells (p=0.024). Each variable was allocated to 0 or 1 point, an HCV-RNA decline of ≥ 1 log 10 but <2.5 log 10 to 1 point, a decline of ≥ 2.5 log 10 to 2 points. Three scores were evaluated (Score 1: I-IV; Score 2: I-V; Score 3: I-VI). RESULTS: A cut-off of ≥ 3 points out of 5 in Score 1 (AUROC: 0.82; DeLong 95% CI: 0.76-0.93) predicted spontaneous clearance with a sensitivity of 71% (95% CI: 0.53-0.86) and specificity of 87% (95% CI: 0.73-0.95). PPV and NPV were 79% and 82%. Corresponding findings for Score 2 including IP-10 (AUROC: 0.93; DeLong 95% CI: 0.86-0.93) at a cut-off of ≥ 4 were: sensitivity 81%, specificity 95% (PPV: 100%; NPV: 77%). A cut-off of ≥ 5 in Score 3 (AUROC: 0.98; DeLong 95% CI: 0.95-1.0) predicted spontaneous resolution with a sensitivity of 75% and specificity of 100% (PPV: 100%; NPV: 88%). CONCLUSIONS: The scores enable a reliable discrimination between AHC-patients with high potential for spontaneous clearance from candidates for early therapeutic intervention due to marginal chance of spontaneous resolution.

Serum level of IP-10 increases predictive value of IL28B polymorphisms for spontaneous clearance of acute HCV infection.

BACKGROUND & AIMS: Single nucleotide polymorphisms (SNPs) in IL28B and serum levels of interferon γ inducible protein 10 (IP-10) predict outcomes of antiviral therapy in patients with chronic hepatitis C. We associated IL28B SNPs rs12979860 and rs8099917, along with serum levels of IP-10, with outcomes of patients with acute hepatitis C (AHC). METHODS: We studied 120 patients with AHC (64 male; 37 ± 16 years old) and 96 healthy individuals (controls). The IL28B SNPs rs12979860 and rs8099917 were detected using real-time polymerase chain reaction; serum concentrations of IP-10 were measured by enzyme-linked immunosorbent assays of 62 patients with AHC. RESULTS: Hepatitis C virus was cleared spontaneously from 59 patients (49.2%). The IL28B rs12979860 C/C genotype was more frequent among patients with AHC than controls (62.5% vs 39.6%; P < .001) and among patients with spontaneous clearance than those without (74.6% vs 51.7%; P = .02) (positive predictive value, 60.3%). Patients with IL28B rs12979860 C/C more frequently developed jaundice (53.2% vs 27.6%; P = .022) than carriers of the T allele. The median level of IP-10 was lower among patients with AHC and spontaneous clearance (764 [113-2470] pg/mL) than those without spontaneous clearance (1481 [141-4412] pg/mL; P = .006). Based on receiver operating characteristic analysis, 540 pg/mL IP-10 was set as the cutoff for patients most likely to have spontaneous clearance (positive predictive value, 71.4%; negative predictive value, 65.9%). Including data on IP-10 levels increased the ability of the IL28B rs12979860 C/C to identify patients most likely to have spontaneous clearance (83% of those who had an IP-10 level <540 pg/mL and 32% who had an IP-10 level >540 pg/mL) (P < .01). CONCLUSIONS: The combination of serum level of IP-10 and SNPs in IL28B can identify patients with AHC who are most likely to undergo spontaneous clearance and those in need of early antiviral therapy.

Treatment of chronic hepatitis C genotype 1 patients at an academic center in Europe involved in prospective, controlled trials: is there a selection bias?

UNLABELLED: Pegylated interferon-alpha2/ribavirin (peg-IFN/RBV) is the standard of care (SOC) for patients with chronic hepatitis C (CHC) infection. Currently, direct-acting antiviral agents (DAAs) are evaluated in clinical trials. The aim of this study was to compare baseline characteristics and sustained virologic response (SVR) rates in patients included in clinical trials to those receiving SOC. Medical records of all 503 treatment-naïve patients with CHC, genotype (GT) 1, referred over a 4-year period (January 2006-December 2009) were reviewed. Only 310 of 503 (62%) patients received antiviral therapy, 141 were enrolled in randomized, controlled trials ("study patients"; 101 in DAA studies), and 169 received SOC. At baseline, viral load and platelet count were higher and bilirubin was lower in study patients than in SOC patients. History of psychiatric disorders was more common in SOC patients (43 [25%] versus study patients with 18 [13%]; P < 0.01). Liver biopsy was obtained in 98% of study patients, but only in 59% of SOC patients. Twenty-nine (21%) and 40 (40%) study and SOC patients, respectively, had advanced fibrosis (F3/4; P = 0.001). By intent-to-treat analysis, SVR rates were higher in DAAs (64%; 95% confidence interval [CI]: 53.4-74.4) than in SOC patients (46%; 95% CI: 37.9-53.7; P < 0.01), but not different when calculated on a treated-per-protocol (TPP) basis. Interleukin (IL)28B GT was equally distributed in both cohorts. By chance, more patients treated with IFN/RBV had rs12979860 C/C-GT (up to 44%) than DAA-treated patients. If analyzed according to the IL28B polymorphism, TPP SVR rates did not reach statistically significant differences among study and SOC patients. CONCLUSIONS: Baseline characteristics slightly favored study patients, but IL28B GT and treatment adherence were the most important factors determining outcome. Thus, the applicability of the results of controlled studies has to be tested in a "real-world" setting.

Association of the IL28B genotype with insulin resistance in patients with chronic hepatitis C.

BACKGROUND & AIMS: Insulin resistance, fibrosis and steatosis are established predictors of response to peg-interferon/ribavirin therapy in chronic hepatitis C (CHC). Several host genetic polymorphisms (IL28B, PNPLA3) modify treatment-outcome, the degree of steatosis or fibrosis. The aim of our study was to evaluate the role of these polymorphisms on insulin resistance (IR) in treatment-naïve patients with chronic hepatitis C. METHODS: Two hundred and two non-diabetic CHC patients (GT1: 181, GT4: 21; m = 126, f = 76) undergoing liver biopsy in two tertiary academic centers were studied. The SNPs rs12979860 (IL28B) and rs738409 (PNPLA3) were investigated by RT-PCR. HOMA-IR, BMI, stage of fibrosis, extent of steatosis, and genetic data were analyzed. RESULTS: Insulin resistance (HOMA-IR ≥ 3.0) was associated with rs12979860 genotype, presence of advanced fibrosis, and higher BMI. HOMA-IR in CC and in TC/TT was 2.08 ± 1.61 (mean ± SD) and 2.94 ± 2.89 (p=0.041), respectively. HOMA-IR was higher in advanced than in mild fibrosis (F3-4: 3.92 ± 3.15; F0-2: 2.38 ± 2.38; p=0.004). The percentage of steatotic hepatocytes was higher in patients with advanced fibrosis (21.3 ± 21.5 vs. 9.1 ± 14.2; p<0.001), HOMA-IR ≥ 3.0 (17.7 ± 17.8 vs. 8.8 ± 15.4%; p<0.001), and BMI > 25.0 kg/m(2) (14.7 ± 17.0 vs. 9.1 ± 16.1; p<0.001). The rs738409 GG genotype was associated with advanced fibrosis and steatosis, but not with HOMA-IR. Multivariable logistic regression identified advanced fibrosis (OR: 2.820, 95% CI: 1.344-5.917; p = 0.006) and the IL28B genotype non-CC (OR: 3.000, 1.348-6.676; p = 0.007) as independent risk factors for insulin resistance. CONCLUSIONS: Insulin resistance is more common in carriers of the T allele of SNP rs12979860 than in CC homozygotes and may partly explain the poor outcome of peginterferon/ribavirin therapy in these patients.

Early virologic response and IL28B polymorphisms in patients with chronic hepatitis C genotype 3 treated with peginterferon alfa-2a and ribavirin.

BACKGROUND & AIMS: Polymorphisms of the IL28B gene (rs12979860 and rs8099917) are associated with high sustained virological response (SVR) rates in HCV genotype 1 patients. This study analyzes the impact of these IL28B polymorphisms on early treatment response (weeks 2 and 4) and SVR in HCV genotype 3 patients. METHODS: rs12979860 and rs8099917 were analyzed by the Step-OnePlus Real-time PCR system in 71 out of 72 Caucasian HCV genotype 3 patients participating, at our center, in a randomized study comparing 400mg with 800 mg ribavirin/day. HCV RNA was determined at weeks 2 and 4 of 180 µg/week peginterferon alfa-2a/ribavirin treatment. Sixty-nine patients completed the treatment and follow-up. RESULTS: rs12979860 genotyping revealed that 27 (37.5%) patients had C/C, 39 (54.2%) T/C, and 5 (6.9%) T/T. Thirteen patients (18.1%) became HCV RNA negative at week 2 and an additional 30 (41.7%) at week 4 (rapid virologic response; RVR); thus a total of 43 had a RVR (C/C: 77.8%; T/C or T/T: 50.0%). Irrespective of the ribavirin dose, the viral load decline was larger than in those with the T allele (T/C or T/T) (week 2: 4.46; [0.36-6.02] median; [range] vs. 3.50; [0.14-5.62]; log IU HCV-RNA/ml; p<0.001; week 4: 4.97; [1.21-6.20] vs. 4.49; [1.16-6.23]; p=0.003). Despite the faster initial viral response in C/C carriers, SVR rates were not different compared to T-allele carriers. Results of the SNP in the rs8099917 region were similar. CONCLUSIONS: IL28B polymorphisms modulate early virologic response to peginterferon/ribavirin treatment. In contrast to HCV genotype 1 patients, no effect on SVR rates was observed in genotype 3 patients. The clinical relevance of an earlier viral decline in C/C patients needs to be determined.

Impact of IL28B genotype on the early and sustained virologic response in treatment-naïve patients with chronic hepatitis C.

BACKGROUND & AIMS: Single nucleotide polymorphisms (SNPs) in the gene that encodes interleukin (IL)-28B predict response of patients with chronic hepatitis C to antiviral therapy. We investigated the roles of polymorphisms rs12979860 and rs8099917 on the early virologic response of treatment-naïve patients. METHODS: SNPs were identified by real-time polymerase chain reaction analysis of samples from 682 patients (genotype [GT]1=372, GT2/3=208, GT4=102) who were treated with 180 µg pegylated interferon-α2a and 400 or 800 mg (GT2/3, depending on the protocol) or 1000-1200 mg (GT1/4) ribavirin/day. The duration of treatment was 24 (GT2/3) or 24-72 weeks (GT1/4). RESULTS: Patients with C/C also had higher rates of rapid virologic response (RVR) (GT1, 38.3% vs 11.6%; GT4, 76.5% vs 23.5%; both P<.001) and sustained virologic responses (SVRs) (GT1, 79.1% vs 43.2%; GT4, 85.3% vs 44.1%; both P<.001). In patients with GT2/3, the RVR was more frequent in carriers of C/C (75.3% vs 52.6%, P<.01), but SVR rates were similar between those with C/C and T (80.5% vs 74.4%, P=.31). Results for rs8099917 were comparable. The positive predictive value of rs12979860 C/C for SVR was higher than that of rs8099917 T/T (80.5% vs 71.6%). Overall, RVR was the best predictor of SVR. In patients who did not have GT1, IL28B polymorphisms did not affect the SVR if RVR data were included in the multivariate analysis. CONCLUSIONS: An early virologic response to pegylated interferon and ribavirin is more likely among carriers of rs12979860 C/C and rs8099917 T/T, which might underlie their high rates of SVR. Determination of the IL28B genotype and whether patients have an RVR might be used in future studies of patients with hepatitis C virus genotype 1 or 4.

Portal pressure predicts outcome and safety of antiviral therapy in cirrhotic patients with hepatitis C virus infection.

BACKGROUND & AIMS: There are limited data on the efficacy and safety of antiviral therapy in patients with hepatitis C virus (HCV)-related cirrhosis, particularly on the impact of portal hypertension. METHODS: We assessed hepatovenous pressure gradient (HVPG), liver stiffness (transient elastography), and interleukin (IL)-28B polymorphisms (rs12979860) in 90 cirrhotic patients with HCV infection (82% genotype 1 or 4) before antiviral therapy with pegylated interferon and ribavirin. Efficacy and safety were evaluated. RESULTS: Rates of sustained virologic response were significantly lower among patients with clinically significant portal hypertension (CSPH; HVPG ≥ 10 mm Hg; n = 50) than among patients without CSPH (HVPG <10 mm Hg; n = 40): 14% vs 51% (P = .0007). Seventy-nine percent and 83% of patients with CSPH and without CSPH, respectively, received more than 80% of planned dose (P = .647). The predictive value of HVPG (area under the curve [AUC], 0.743) was greater than that of liver stiffness (AUC, 0.647) or of baseline HCV RNA levels (AUC, 0.620). The IL-28B polymorphism was not associated significantly with a sustained virologic response. Multivariate analysis revealed that HVPG (odds ratio [OR], 14.3; P = .009), baseline HCV RNA levels (OR, 5.3; P = .019), and HCV genotype (OR, 6.5; P = .046) were independent risk factors for treatment failure. A trend toward higher incidence of anemia and neutropenia was observed for patients with CSPH. The incidence and grade of thrombocytopenia were significantly higher among patients with than without CSPH (94% vs 75%; P = .006). CONCLUSIONS: HVPG is an independent predictor of response to antiviral therapy, with better predictive value than liver stiffness, baseline HCV RNA levels, HCV genotype, or IL-28B polymorphism. The incidence and grade of thrombocytopenia during antiviral therapy are higher among patients with CSPH. In evaluating cirrhotic HCV patients for antiviral treatment, measurement of HVPG should be considered.

Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy.

BACKGROUND & AIMS: Oral Silibinin (SIL) is widely used for treatment of hepatitis C, but its efficacy is unclear. Substantially higher doses can be administered intravenously (IV). METHODS: Pedigreed nonresponders to full-dose pegylated (Peg)-interferon/ribavirin (PegIFN/RBV) were studied. First, 16 patients received 10 mg/kg/day SIL IV (Legalon Sil; Madaus, Köln, Germany) for 7 days. In a subsequent dose-finding study, 20 patients received 5, 10, 15, or 20 mg/kg/day SIL for 14 days. In both protocols, PegIFN alpha-2a/RBV were started on day 8. Viral load was determined daily. RESULTS: Unexpectedly, in the first study, HCV-RNA declined on IV SIL by 1.32 +/- 0.55 log (mean +/- SD), P < .001 but increased again in spite of PegIFN/RBV after the infusion period. The viral load decrease was dose dependent (log drop after 7 days SIL: 0.55 +/- 0.5 [5 mg/kg, n = 3], 1.41 +/- 0.59 [10 mg/kg, n = 19], 2.11 +/- 1.34 [15 mg/kg, n = 5], and 3.02 +/- 1.01 [20 mg/kg, n = 9]; P < .001), decreased further after 7 days combined SIL/PegIFN/RBV (1.63 +/- 0.78 [5 mg/kg, n = 3], 4.16 +/- 1.28 [10 mg/kg, n = 3], 3.69 +/- 1.29 [15 mg/kg, n = 5], and 4.85 +/- 0.89 [20 mg/kg, n = 9]; P < .001), and became undetectable in 7 patients on 15 or 20 mg/kg SIL, at week 12. Beside mild gastrointestinal symptoms, IV SIL monotherapy was well tolerated. CONCLUSIONS: IV SIL is well tolerated and shows a substantial antiviral effect against HCV in nonresponders.