Johannes Vermehren

Liver fibrosis in viral hepatitis: noninvasive assessment with acoustic radiation force impulse imaging versus transient elastography.

PURPOSE To compare, in a pilot study, acoustic radiation force impulse (ARFI) imaging technology integrated into a conventional ultrasonography (US) system with both transient elastography (TE) and serologic fibrosis marker testing for the noninvasive assessment of liver fibrosis. MATERIALS AND METHODS Informed consent was obtained from all subjects, and the local ethics committee approved the study. ARFI imaging involved the mechanical excitation of tissue with use of short-duration acoustic pulses to generate localized displacements in tissue. The displacements resulted in shear-wave propagation, which was tracked by using US correlation-based methods and recorded in meters per second. Eighty-six patients with chronic viral hepatitis underwent TE, ARFI imaging, and serum fibrosis marker testing. Results were compared with liver biopsy findings, which served as the reference standard. RESULTS ARFI imaging (rho = 0.71), TE (rho = 0.73), and serum fibrosis marker test (rho = 0.66) results correlated significantly with histologic fibrosis stage (P < .001). Median ARFI velocities ranged from 0.84 to 3.83 m/sec. Areas under the receiver operating characteristic curve for the accuracy of ARFI imaging, TE, and serum fibrosis marker testing were 0.82, 0.84, and 0.82, respectively, for the diagnosis of moderate fibrosis (histologic fibrosis stage, > or = 2) and 0.91, 0.91, and 0.82, respectively, for the diagnosis of cirrhosis. CONCLUSION ARFI imaging is a promising US-based method for assessing liver fibrosis in chronic viral hepatitis, with diagnostic accuracy comparable to that of TE in this preliminary study. SUPPLEMENTAL MATERIAL http://radiology.rsnajnls.org/cgi/content/full/252/2/595/DC1.

Treatment predictors of a sustained virologic response in hepatitis B and C

Treatment predictors are important tools for the management of therapy in patients with chronic hepatitis B and C virus (HBV, HCV) infection. In chronic hepatitis B, several pretreatment parameters have been identified for prediction of virologic response to interferon alfa-based antiviral therapies or treatment with polymerase inhibitors. In interferon alfa and pegylated interferon alfa-treated patients, low baseline HBV DNA concentrations, HBV genotype A (B), and high baseline ALT levels are significantly associated with treatment response. In patients treated with nucleos(t)ide analogues, low baseline HBV DNA but not viral genotype is positively associated with virologic response. During treatment the best predictor of response is HBV DNA kinetics. Early viral suppression is associated with favourable virologic response and reduced risk for subsequent resistance mutations. For the current standard treatment with pegylated interferon alfa and ribavirin in patients with chronic hepatitis C, infection with HCV genotypes 2 and 3, baseline viral load below 400,000-800,000 IU/ml, Asian and Caucasian ethnicity, younger age, low GGT levels, absence of advanced fibrosis/cirrhosis, and absence of steatosis in the liver have been identified as independent pretreatment predictors of a sustained virologic response. After initiation of treatment, initial viral decline with undetectable HCV-RNA at week 4 of therapy (RVR) is the best predictor of sustained virologic response independent of HCV genotype.

Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy

BACKGROUND & AIMS Vitamin D is an important immune modulator and preliminary data indicated an association between vitamin D deficiency and sustained virologic response (SVR) rates in hepatitis C virus (HCV) genotype 1 patients. We, therefore, performed a comprehensive analysis on the impact of vitamin D serum levels and of genetic polymorphisms with functional relevance within the vitamin D cascade on chronic hepatitis C and its treatment. METHODS Vitamin D serum levels, genetic polymorphisms within the vitamin D receptor and 1α-hydroxylase were determined in a cohort of 468 HCV genotype 1, 2, and 3 infected patients who were treated with interferon-alfa based regimens. RESULTS Chronic hepatitis C was associated with a high incidence of severe vitamin D deficiency compared to controls (25(OH)D(3)<10 ng/ml in 25% versus 12%, p<0.00001). 25(OH)D(3) deficiency correlated with SVR in HCV genotype 2 and 3 patients (50% and 81% SVR for patients with and without severe vitamin D deficiency, respectively, p<0.0001). In addition, the CYP27B1-1260 promoter polymorphism rs10877012 had substantial impact on 1,25-dihydroxyvitamin D serum levels (72, 61, and 60 pmol/ml for rs10877012 AA, AC, and CC, respectively, p=0.04) and on SVR rates in HCV genotype 1, 2, and 3 infected patients (77% and 65% versus 42% for rs10877012 AA, AC, and CC, respectively, p=0.02). CONCLUSIONS Chronic hepatitis C virus infection is associated with vitamin D deficiency. Reduced 25-hydroxyvitamin D levels and CYP27B1-1260 promoter polymorphism leading to reduced 1,25-dihydroxyvitamin D levels are associated with failure to achieve SVR in HCV genotype 1, 2, and 3 infected patients.

Acoustic radiation force impulse-imaging and transient elastography for non-invasive assessment of liver fibrosis and steatosis in NAFLD

BACKGROUND Transient elastography (TE) and acoustic radiation force impulse (ARFI)-imaging have shown promising results for the staging of liver fibrosis. AIM The aim of the present study was to compare ARFI of the left and right liver lobe with TE using the standard and obese probes for the diagnosis of liver fibrosis in NAFL/NASH. In addition, liver steatosis is evaluated using the novel controlled attenuation parameter (CAP). METHODS Sixty-one patients with NAFLD/NASH were included in the study. All patients received TE with both probes, ARFI of both liver lobes and CAP. The results were compared with liver histology. RESULTS 57 patients were included in the final analysis. The diagnostic accuracy for TE measurements with the M-and XL-probe and for ARFI of the right and left liver lobe was 0.73, 0.84, 0.71 and 0.60 for the diagnosis of severe fibrosis, and 0.93, 0.93, 0.74 and 0.90 for the diagnosis of cirrhosis, respectively. No significant difference of results was observed between TE and ARFI in the subgroup of patients with reliable TE-measurement when taking into account the best results of both methods. However, while a significant correlation could be found for TE with histological liver fibrosis, the correlation of ARFI with liver fibrosis was not statistically significant. A significant correlation was found for CAP with histological steatosis (r=0.49, p<0.001). CONCLUSIONS No significant difference in diagnostic accuracy for the non-invasive assessment of liver fibrosis was found for transient elastography and ARFI. Nevertheless TE significantly correlated with liver fibrosis while ARFI did not. CAP enables the non-invasive assessment of steatosis.

Analysis of long-term persistence of resistance mutations within the hepatitis C virus NS3 protease after treatment with telaprevir or boceprevir

BACKGROUND Telaprevir and boceprevir are highly selective hepatitis C virus (HCV) NS3/4A proteaseinhibitors in phase 3 development. Viral breakthrough during mono- and triple-therapies with PEG-interferon and ribavirin and relapse is associated with resistance. OBJECTIVES Potential persistence of resistance mutations during long-term follow-up should be analyzed. STUDY DESIGN Clonal sequence analysis of the NS3-protease gene was performed at long-term follow-up in HCV genotyp-1 infected patients who received telaprevir or boceprevir within phase-1b studies for comparison with resistant variants present directly after the end-of-treatment. RESULTS After a median follow-up of 4.2 years in 28 of 82 patients HCV-RNA was still detectable. Resistance variants were detected in two of 14 telaprevir- and in four of 14 boceprevir-treated patients. For telaprevir patients two low-level (V36M, V36A) and one high-level (A156T) mutation associated with resistance were detected at low frequencies (4-9% of the clones). In five boceprevir-treated patients four low level mutations (V36A, T54A/S, V55A) were observed at low frequencies (1-10%) while in one patient additionally a combined variant (T54S+R155K) was detected at 94%. Presence of resistant variants at long-term follow-up was not predictable by variants detected at the end-of-treatment. In one patient a V55A variant which was dominant already at baseline was still detectable at long-term follow-up. CONCLUSIONS In the majority of patients after short-term treatment with telaprevir or boceprevir wild-type NS3-protease isolates are detectable by clonal sequencing at long-term follow-up. Detectable resistance mutations in single patients are not predictable by initial frequencies of variants.

Multi-center evaluation of the Abbott RealTime HCV Assay for monitoring patients undergoing antiviral therapy for chronic hepatitis C

BACKGROUND Hepatitis C virus (HCV) RNA monitoring during antiviral therapy is essential for early prediction of treatment success and failure to peginterferon alfa/ribavirin (PEG-IFN/RBV) therapy. OBJECTIVES In this multi-center study we assessed the clinical utility of the Abbott RealTime HCV assay for monitoring patients undergoing antiviral therapy for chronic infection with HCV genotypes (GT) 1-3. STUDY DESIGN We analyzed serum from 361 patients with chronic hepatitis C who had been treated with PEG-IFN/RBV. The predictive value of rapid virologic response (RVR), partial (≥2log(10) decline) and complete (HCV-RNA undetectable) early virologic response (pEVR/cEVR) based on RealTime HCV for achieving sustained virologic response was evaluated. In addition, the utility of RealTime HCV to tailor treatment duration according to individual virologic responses was studied in a subset of 136 GT 1 patients and compared to the reference tests, Versant HCV Quantitative 3.0 (bDNA) and Qualitative (TMA) assay. RESULTS At week 4 of therapy, patients with RVR had a 100% and 93.5% probability to achieve an SVR in GT 1 and GT 2/3 patients, respectively. At week 12, patients who did not achieve a pEVR had a 97.2% and 100% probability of not achieving an SVR. In addition, assignment of GT 1 patients to abbreviated or extended treatment durations based on low baseline HCV-RNA (<800,000IU/mL) and RVR or pEVR was highly concordant between RealTime HCV and bDNA/TMA assays (97.8% and 91.9%, respectively). CONCLUSIONS The RealTime HCV assay is suitable for monitoring virologic response to PEG-INF/RBV therapy and tailoring treatment duration accordingly.

Contrast-Enhanced Ultrasound for the differentiation of benign and malignant focal liver lesions: a meta-analysis

International guidelines of Ultrasound recommend the performance of contrast‐enhanced ultrasound (CEUS) as the first method of choice after conventional ultrasound for the diagnostic work‐up of focal liver lesions. However, these recommendations are based on the results of multiple single studies and only few large multicentre studies.

Comparison of acoustic radiation force impulse imaging with transient elastography for the detection of complications in patients with cirrhosis

Acoustic radiation force impulse (ARFI) imaging is a new non‐invasive, ultrasound‐based method for the evaluation of liver fibrosis and cirrhosis.

Intraductal endoscopic radiofrequency ablation for the treatment of hilar non-resectable malignant bile duct obstruction

AIM To evaluate the safety and technical success of endoscopic radiofrequency ablation (RFA) for palliative treatment of malignant hilar bile duct obstruction. METHODS In this study, a recently CE and FDA-approved endoscopic RFA catheter was first tested in an ex vivo pig liver model to study the effect of electrosurgical variables on the extent of the area of induced necrosis. Subsequently, a retrospective analysis was conducted of all patients treated with endoscopic RFA for malignant biliary obstruction at our center between February 2012 and April 2013. All patients received an additional plastic stent implantation into the biliary tree following RFA. RESULTS In the pig model, ablation time of 60-90 seconds using the bipolar soft coagulation mode at 8-10 watts with an effect of 8 was found to be the most feasible setting. Twelve patients (5 females, 7 males; mean age, 70 years) underwent 19 endoscopic RFA (range, 1-5) sessions. Deployment of RFA was successful in all patients. Systemic chemotherapy was administered in four patients. We observed biliary bleeding 4-6 wk after the intervention in three cases and two of these patients died: in one patient, spontaneous hemobilia occurred, whereas bleeding started during stent extraction in the other. In the third patient, bleeding was stopped by insertion of a non-covered self-expanding metal stent. Another three patients developed cholangitis during follow-up. Seven patients died during follow-up and median survival was 6.4 mo (95%CI: 0.05-12.7) from the time of the first RFA. CONCLUSION Endoscopic RFA is an easy to perform and technically highly successful procedure. However, hemobilia possibly associated with RFA occurred in three of our patients. Therefore, larger prospective studies are needed to further evaluate the safety and efficacy of this promising new method.

Second-Generation Cobas AmpliPrep/Cobas TaqMan HCV Quantitative Test for Viral Load Monitoring: a Novel Dual-Probe Assay Design

ABSTRACT Hepatitis C virus (HCV) RNA viral load (VL) monitoring is a well-established diagnostic tool for the management of chronic hepatitis C patients. HCV RNA VL results are used to make treatment decisions with the goal of therapy to achieve an undetectable VL result. Therefore, a sensitive assay with high specificity in detecting and accurately quantifying HCV RNA across genotypes is critical. Additionally, a lower sample volume requirement is desirable for the laboratory and the patient. This study evaluated the performance characteristics of a second-generation real-time PCR assay, the Cobas AmpliPrep/Cobas TaqMan HCV quantitative test, version 2.0 (CAP/CTM HCV test, v2.0), designed with a novel dual-probe approach and an optimized automated extraction and amplification procedure. The new assay demonstrated a limit of detection and lower limit of quantification of 15 IU/ml across all HCV genotypes and was linear from 15 to 100,000,000 IU/ml with high accuracy (<0.2-log10 difference) and precision (standard deviation of 0.04 to 0.22 log10). A specificity of 100% was demonstrated with 600 HCV-seronegative specimens without cross-reactivity or interference. Correlation to the Cobas AmpliPrep/Cobas TaqMan HCV test (version 1) was good (n = 412 genotype 1 to 6 samples, R 2 = 0.88; R 2 = 0.94 without 105 genotype 4 samples). Paired plasma and serum samples showed similar performance (n = 25, R 2 = 0.99). The sample input volume was reduced from 1 to 0.65 ml in the second version. The CAP/CTM HCV test, v2.0, demonstrated excellent performance and sensitivity across all HCV genotypes with a smaller sample volume. The new HCV RNA VL assay has performance characteristics that make it suitable for use with currently available direct-acting antiviral agents.