Evaluation of portal hypertension and varices by acoustic radiation force impulse imaging of the liver compared to transient elastography and AST to platelet ratio index.

BACKGROUND: Acoustic radiation force impulse imaging (ARFI) is a new method of liver stiffness measurement (LSM). The aim was to compare ARFI, transient elastography (TE) and AST to platelet ratio index (APRI) for the noninvasive diagnosis of clinically significant portal hypertension (CSPH, hepatic venous pressure gradient; HVPG ≥ 10 mmHg) and esophageal varices (EV). MATERIALS AND METHODS: LSM via ARFI and TE was performed in 88 consecutive patients with cirrhosis prior to HVPG measurement. The mean liver stiffness for ARFI was calculated out of 5 measurements for each lobe. RESULTS: LSM by TE and ARFI was not successful in 22 (25%) patients and 1 (1 %) patient, respectively, due to ascites or obesity. Both TE (r = 0.765; p < 0.001) and ARFI (r = 0.646; p < 0.001) correlated significantly with HVPG. At the optimal cut-off (16.8 kPa), TE (area under the curve, AUC 0.870) yielded a sensitivity and specificity of 89.7% and 75%, respectively, for predicting CSPH. At the optimal cut-off (2.58 m/s), the sensitivity and specificity for ARFI (AUC 0.855) were 71.4% and 87.5%, respectively. Using an APRI (AUC 0.838), the sensitivity and specificity were 69% and 87.5%, respectively. The AUC for the diagnosis of EV was 0.802 for TE (cut-off: 27.9 kPa), 0.743 for ARFI (cut-off: 2.74 m/s), and 0.805 for APRI (cut-off: 1.90). CONCLUSION: ARFI shows a higher applicability particularly in obese and ascitic patients. All three investigated methods show a high diagnostic accuracy for CSPH. Notably, APRI performed not significantly different compared to ARFI for the diagnosis of CSPH.

Revisiting predictors of virologic response to PEGIFN + RBV therapy in HIV-/HCV-coinfected patients: the role of metabolic factors and elevated GGT levels.

Evaluation of metabolic factors and elevated γ-glutamyltransferase (GGT) levels as independent predictors of treatment failure in a thoroughly documented cohort of HIV-/HCV-coinfected patients (HIV/HCV). Sixty-four HIV/HCV patients treated with pegylated interferon-α-2a plus ribavirin (PEGIFN + RBV) at the Medical University of Vienna within a prospective trial were included in this study. In addition, 124 patients with HIV/HCV from the AIFA-HIV and AHIVCOS cohorts were included as a validation cohort. Advanced liver fibrosis, GGT elevation, insulin resistance (IR) and low CD4+ nadir were defined as METAVIR F3/F4, GGT levels >1.5× sex-specific upper limit of normal, homoeostasis model assessment of insulin resistance >2 and CD4+ nadir <350 cells/µL, respectively. HCV-genotype 1/4 (OR26.3; P = 0.006), advanced liver fibrosis (OR20.2; P = 0.009), interleukin 28B rs12979860 non-C/C SNP (OR8.27; P = 0.02) and GGT elevation (OR7.97; P = 0.012) were independent predictors of treatment failure, while both IR (OR3.51; P = 0.106) and low CD4 + nadir (OR2.64; P = 0.263) were not independently associated with treatment failure. A statistically significant correlation between GGT elevation and prior alcohol abuse (r = 0.259; P = 0.039), liver steatosis (r = 0.301; P = 0.034) and low-density lipoprotein-cholesterol (r = -0.256; P = 0.041) was observed. The importance of GGT elevation as an independent predictor of treatment failure was confirmed in a validation cohort (OR2.76; P = 0.026). While GGT elevation emerged as an independent predictor of treatment failure in both the derivation and the validation cohort, no independent associations between metabolic factors and treatment failure were observed. Thus, our findings suggest that GGT elevation is an independent predictor of treatment failure in HIV/HCV that can easily be incorporated into predictive algorithms.

Viral determinants predicting hepatitis B surface antigen (HBsAg) seroclearance in HIV-/HBV-coinfected patients.

The aim of this retrospective study was the identification of clinically useful viral determinants for the prediction of hepatitis B surface antigen (HBsAg) seroclearance and sustained virological response in hepatitis B virus/human immunodeficiency virus (HBV-/HIV)-coinfected patients receiving HBV-active combined antiretroviral therapy (cART). Quantification of HBsAg, HBeAg and HBV DNA before and after initiation of HBV-active cART in a cohort of 59 HIV-/HBV-coinfected patients was performed. Calculations of receiver operating characteristics (ROC) and Kaplan-Meier analysis were used for the identification of predictors of HBsAg seroclearance for HBeAg-positive [HBeAg(+); n = 36] and HBeAg-negative [HBeAg(-);n = 23] patients. HBeAg(+) patients with an HBsAg on-treatment decline ≥ 1 log IU/mL per year achieved higher HBsAg loss rates (P = 0.0294), whereas the quantification of HBeAg had no predictive value for HBsAg seroclearance. Among HBeAg(-) patients, a pretreatment baseline cut-off level of HBsAg ≤ 100 IU/mL was highly predictive for HBsAg seroclearance. No significant influence of the HBV genotype on HBsAg seroclearance was observed among the entire cohort. Quantitative determination of HBsAg provides a clinically useful viral parameter for the prediction of HBsAg seroclearance both in HBeAg(+) and HBeAg(-) HIV-/HBV-coinfected patients receiving HBV-active cART.

Five-year on-treatment efficacy of lamivudine-, tenofovir- and tenofovir + emtricitabine-based HAART in HBV-HIV-coinfected patients.

Data on the efficacy of lamivudine (LAM)-, tenofovir (TDF)- and emtricitabine (FTC)-based antiretroviral therapy (HAART) in HBV-HIV coinfection are limited. We completed a retrospective analysis of HBV-HIV-coinfected patients treated at the Medical University of Vienna. One-hundred and ten coinfected patients were included, with 57% being initially HBV e-Antigen (HBeAg) positive. Baseline HBV load was significantly higher in HBeAg+ than in HBeAg- patients (5962 ± 3663 vs 20 ± 19 × 10(6) IU/mL; P < 0.0001). Over a median observation period of 83 month (range: 26-183), 87% received HAART and 91% showed a suppression of HBV replication. After 5 years of continuous treatment, HBeAg seroconversion was achieved in 21% of LAM-, 50% of TDF- (P = 0.042 vs LAM) and in 57% of TDF + FTC (P = 0.008 vs LAM)-treated patients, respectively. HBsAg loss after 5 years was found in 8% (LAM), 25% (TDF; P = 0.085 vs LAM) and 29% (TDF + FTC; P = 0.037 vs LAM) of HBeAg+ patients. In HBeAg- patients, HBsAg loss was achieved in 11% (LAM), 27% (TDF; P = 0.263 vs LAM) and 36% (TDF + FTC; P = 0.05 vs LAM), respectively. Pretreatment CD4+ counts did not influence rates of HBeAg seroconversion and of HBsAg loss. Patients with HBsAg loss had lower baseline HBV-DNA levels and higher AST/ALT levels than patients without HBsAg loss. Transient HAART-related hepatotoxicity was found in 32% (Grade I: 21%; II:7%; III:2%; IV:0%). Most HBV-HIV-coinfected patients achieve complete suppression of HBV replication despite high baseline viremia. TDF-based HAART leads to high rates of HBeAg seroconversion and HBsAg loss after 5 years of continuous exposure. One-third of HBV-HIV-coinfected patients may experience transient HAART-related hepatotoxicity.

The risk of infections in HIV-HCV coinfected patients during antiviral therapy with pegIFN+RBV.

OBJECTIVES: Antiviral treatment with pegIFN/RBV decreases ANC and CD4+ cell count. An association between neutropenia, a low CD4+ cell count and infections has not been demonstrated so far in HIV-HCV coinfected patients. METHODS: The incidence, type, and severity of infections were recorded in 85 HIV-HCV coinfected and 164 monoinfected patients receiving pegIFN/RBV for 48 weeks. ANC and CD4+ cell count were assessed every 4 weeks during therapy. RESULTS: The incidence of infections was significantly higher in HIV-HCV than HCV-Mono (38% vs. 15%; p = 0.001). Types of infections: pneumonia (n = 16/n = 24), bacteraemia/sepsis (n = 5/n = 2), skin infections (n = 15/n = 12), urinary tract infections (n = 4/n = 1), OIs (n = 10/n = 1). The incidence of neutropenia grade 1, 2 3 or 4 was similar in HIV-HCV and HCV-Mono, respectively. The incidence of infections was not associated with neutropenia (HCV-Mono: p = 0.584; HIV-HCV: p = 0.23) or with CD4+ cell counts <200/µL (HIV-HCV: p = 0.29). OIs occurred more often in HIV-HCV patients with CD4+ cell count <200/µL (p = 0.024). CONCLUSIONS: Up to 38% and 15% of HIV-HCV coinfected and HCV-monoinfected patients develop infections during pegIFN+RBV therapy but without any correlation to neutropenia. Antibacterial prophylaxis/treatment should be considered early in HIV-HCV coinfected patients developing CD4+ cell counts <200/µL during antiviral therapy as these patients have an increased risk of OIs.

Non-selective ß-blockers improve the correlation of liver stiffness and portal pressure in advanced cirrhosis.

BACKGROUND: Liver stiffness (LS) correlates with portal pressure (hepatic venous pressure gradient, HVPG). However, the dynamic components of portal hypertension (PHT) in advanced cirrhosis may not be adequately assessed by TE. The influence of treatment with non-selective ß-blockers (NSBB) on the correlation of HVPG and LS has not been investigated. METHODS: One hundred and twenty-two patients with esophageal varices were included. LS, hemodynamic parameters, and HVPG were recorded at baseline (BL) and after 6 weeks of treatment with NSBB (FU). The correlation of LS and HVPG was compared to control patients with HVPG ≤ 12 mmHg. RESULTS: Patients with higher Child-Pugh stages (A:88/B:25/C:9) had higher levels of liver stiffness (47.4 ± 16.5 vs. 70.3 ± 7.9 vs. 73.7 ± 2.1 kPa) and HVPG (21 ± 5 vs. 26 ± 5 vs. 26 ± 4 mmHg). The correlation of LS and HVPG was stronger in controls with HVPG ≤ 12 mmHg (R = 0.951; P < 0.0001) than in patients with HVPG > 12 mmHg (R = 0.538; P = 0.0004). The association of HVPG with LS became stronger under treatment with NSBB, which finally restored the linear correlation of HVPG and LS (R = 0.930; P < 0.0001). Forty-three percent (53/122) of patients were hemodynamic responders to NSBB. The improvement in the correlation of LS and HVPG under NSBB was mainly noted in hemodynamic responders (R = 0.864), but not in nonresponders (R = 0.535), whereas changes in LS, heart rate, and MAP were similar in responders and nonresponders. CONCLUSIONS: Targeting the hyperdynamic circulation and the increased splanchnic blood inflow by treatment with NSBB unmasks the linear (mechanical) correlation of HVPG and LS in patients with HVPG > 12 mmHg. Measurement of LS by TE is not a feasible method to assess the dynamic components of PHT.

Value of hepatic venous pressure gradient measurement before liver resection for hepatocellular carcinoma.

BACKGROUND: Portal hypertension associated with liver cirrhosis increases the risk of postoperative complications after liver resection for hepatocellular carcinoma (HCC). This study assessed the role of preoperative hepatic venous pressure gradient (HVPG) assessment in identifying portal hypertension. METHODS: All patients who underwent liver resection for HCC between January 2000 and December 2009 at the Department of General Surgery, Medical University Vienna, were analysed retrospectively. HVPG was assessed prospectively in a subset of patients before liver resection. The influence of this assessment on postoperative complications was investigated. RESULTS: A total of 132 patients were enrolled, of whom 39 underwent HVPG measurement. Mean(s.d.) HVPG was 6·4(3·0) and 4·3(1·4) mmHg in patients with and without postoperative complications respectively (P = 0·028). Complication rates differed significantly at a cut-off HVPG value of 5 mmHg: 11 of 21 patients with a gradient of 1-5 mmHg developed complications versus 12 of 14 patients with a higher value (P = 0·045). HVPG exceeding 5 mmHg was associated with worse liver fibrosis (P = 0·004), higher rates of postoperative liver dysfunction (5 of 13 versus 1 of 18; P = 0·022) and ascites (7 of 14 versus 3 of 21; P = 0·022), and a longer hospital stay (median (range) 11 (7-26) versus 8 (4-20) days; P = 0·034). Overall postoperative morbidity did not differ between patients who had preoperative HVPG assessment and those who did not (P = 0·142). CONCLUSION: Preoperative HVPG assessment predicted liver fibrosis and postoperative complications.

Concomitant highly active antiretroviral therapy leads to smaller decline and faster recovery of CD4+ cell counts during and after pegylated interferon plus ribavirin therapy in HIV-hepatitis C virus coinfected patients.

INTRODUCTION: The impact of highly active antiretroviral therapy (HAART) on CD4+ cell course during treatment with pegylated interferon plus ribavirin (PegIFN-RBV) in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is unknown. METHODS: We determined CD4(+) cell count in 94 HIV-HCV coinfected patients undergoing treatment with pegylated interferon plus RBV at baseline, treatment weeks 4-48 (W4-W48), and months 1, 3, and 6 of follow-up. Of the 94 patients, 70 underwent concomitant HAART (group A) and 24 did not (group B). RESULTS: Group A showed smaller CD4(+) cell decreases from W24-W48 (P = .027) and greater CD4(+) cell increases after cessation of pegylated interferon plus ribavirin therapy (P = .002) than group B showed. CONCLUSIONS: Concomitant HAART leads to smaller decreases and faster recovery of CD4(+) cells during and after pegylated interferon plus RBV therapy.

Successful HCV eradication and inhibition of HIV replication by intravenous silibinin in an HIV-HCV coinfected patient.

INTRODUCTION: The efficacy of antiviral therapy with pegylated interferon (PEGIFN) plus ribavirin (RBV) in patients with HIV and hepatitis C virus (HCV) coinfection is limited. Intravenous silibinin (ivSIL), a milk thistle extract with proven antiviral effects represents a novel therapeutic strategy for virological nonresponders. METHODS: We report a case of an HIV-HCV coinfected patient, who has not responded to a prior course of PEGIFN-α2a (180 µg/week/s.c.) and RBV (1000 mg/day/p.o.). Testing for IL-28ß small nucleotid polymorphism revealed the nonfavourable genotype T/T. Antiretroviral therapy was not prescribed because the patients presented with well-preserved CD4+ cell counts and low HIV-RNA levels. She received retreatment with ivSIL for two weeks followed by PEGIFN/RBV combination therapy starting at week 1. RESULTS: After 2 weeks of ivSIL therapy both HCV-RNA and HIV-RNA become undetectable. On ivSIL monotherapy we noticed a trend towards an increase of CD4+ cell counts and a decrease of HIV-RNA. After 16 weeks PEGIFN+RBV was discontinued due to patients wish because of adverse events. HCV-RNA was still negative 24 weeks after cessation of therapy, while HIV-RNA returned to baseline levels. CONCLUSION: ivSIL may represent a potential treatment option for retreatment of HIV-HCV coinfected patients nonresponding to PEGIFN+RBV combination therapy. Further investigations on the possible beneficial effects of ivSIL on CD4+ cell counts and HIV-RNA levels are necessary.

Germline recruitment in mice: a genetic program for epigenetic reprogramming.

Germ cells provide an enduring link between generations and therefore must possess the fundamental ability of reprogramming their genome to generate a totipotent state. We wish to understand the molecular basis of the unique properties of the mammalian germ line. Recently we identified Blimp1, a potent transcriptional repressor of a histone methyltransferase subfamily, as a critical determinant of the germ cell lineage in mice. Surprisingly, Blimp1 expression marks the origin of the germ line in proximal epiblast cells in pregastrulation embryos, substantially earlier than previously thought. Furthermore, we showed that established primordial germ cells undergo extensive erasure of genome-wide histone H3 lysine 9 dimethylation (H3K9me2) and DNA methylation, two major repressive epigenetic modifications, and instead acquire high levels of H3-K27 trimethylation (H3K27me3) in their migration period. We suggest that germline specification is a genetic system for the orderly reprogramming of the cells' epigenome toward a totipotent state, with reacquisition of totipotency-associated transcription factors and continued Blimp1 expression preventing their reversion to an explicit pluripotent state or somatic differentiation.