Changes in Liver Stiffness and Markers of Liver Synthesis and Portal Hypertension Following Hepatitis C Virus Eradication in Cirrhotic Individuals

SIMPLE SUMMARY: Liver cirrhosis is a dynamic process that may display improvements when the etiological factor is removed. In this retrospective study of HCV-cured cirrhotic patients, we evaluated changes in liver synthesis, surrogate markers of portal hypertension as well as liver stiffness before starting the antiviral treatment and following successful viral eradication. ABSTRACT: The advent of direct antiviral agents (DAAs) has radically changed the natural history of hepatitis C virus (HCV) chronic liver disease. Even patients with cirrhosis may display improvements in liver function or features of portal hypertension following viral eradication. The aim of this study was to assess whether a HCV cure would lead to improvements in cirrhotic patients using simple, readily available tools in clinical practice, together with liver stiffness (LS) measurement. This is a retrospective study of cirrhotic patients with cured HCV infection, with or without previous decompensation. Clinical and biochemical parameters as well as LS measurements were collected before antiviral treatment with DAAs and after 6 months following sustained virological response. Hepatic synthesis was assessed by serum albumin levels. Portal hypertension was indirectly assessed by platelet count. Liver function was determined by the CHILD score. A total of 373 cirrhotic patients with successful HCV eradication were retrospectively included. After 6 months of follow-up, a significantly higher proportion of patients showed improved liver function, shifting from the CHILD B/C to CHILD A group, (71.4%, p < 0.001). Similarly, LS improved from a median of 19.3 kPa (14.7–27) at the baseline vs. a median of 11.6 (7.7–16.8 kPa) at follow-up (p < 0.001). The proportion of patients who showed improved hepatic synthesis was 66.0%, which was statistically different when compared to that of patients who had a worsened condition (0.3%) (p < 0.001). Moreover, when classifying the cohort according to the RESIST-HCV score, we found that a significant proportion of patients shifted into the “low risk” group following DAA treatment (52% baseline vs. 45.6% at follow-up, p = 0.004). Even in the decompensated patients, LS improved from 1.6 to 2-fold from the baseline. Antiviral treatment is effective in improving indirect signs of hepatic synthesis and portal hypertension. Similarly, the LS values displayed significant improvements, even in decompensated patients

Factors Influencing the Intracellular Concentrations of the Sofosbuvir Metabolite GS-331007 (in PBMCs) at 30 Days of Therapy

Sofosbuvir (SOF) is an HCV NS5B polymerase inhibitor, and GS-331007 is its major metabolite. The aim of this study was to investigate whether clinical and pharmacological factors could influence GS-331007 intracellular (IC) concentrations in peripheral blood mononuclear cells (PBMCs) associated with a sustained virological response in patients treated with SOF and ribavirin (RBV). Drug levels were analyzed using liquid chromatography at different days of therapy, whereas variants in genes encoding transporters and nuclear factors were investigated using real-time PCR. This study enrolled 245 patients treated with SOF; 245 samples were analyzed for pharmacogenetics and 50 were analyzed for IC pharmacokinetics. The GS-331007 IC concentration at 30 days was associated with its plasma concentration determinate at 30, 60 and 90 days of SOF-therapy and with daclatasvir concentrations at 7 days of therapy. No genetic polymorphism affected IC exposure. In linear multivariate analysis, ledipasvir treatment, baseline albumin and estimated glomerular filtration rate were significant predictors of IC exposure. This study presents data on an IC evaluation in a cohort of patients treated with SOF, also considering pharmacogenetics. These results could be useful for regions where SOF–RBV treatment is considered the standard of care; moreover, they could further deepen the knowledge of IC exposure for similar drugs in the future

Long-Term Hepatocellular Carcinoma Development and Predictive Ability of Non-Invasive Scoring Systems in Patients with HCV-Related Cirrhosis Treated with Direct-Acting Antivirals

Patients with hepatitis C virus (HCV)-related cirrhosis treated with direct-acting antivirals (DAA) are still at risk of developing hepatocellular carcinoma (HCC). We investigated the accuracy of non-invasive scoring systems (NSS) for the prediction of de novo HCC development in patients treated with DAA on long-term follow-up (FU). We analyzed data from 575 consecutive patients with cirrhosis and no history of HCC who achieved a sustained virologic response (SVR) to DAA therapy. NSS (i.e., Forns index, APRI, FIB-4, ALBI, and aMAP) were calculated at 3 months after the end of therapy. Performance for de novo HCC prediction was evaluated in terms of area under the curve (AUC) and Harrell&rsquo;s C-index. During a median FU of 44.9 (27.8&ndash;58.6) months, 57 (9.9%) patients developed de novo HCC. All five NSS were associated with the risk of de novo HCC. At multivariate analysis, only the ALBI score resulted in being significantly and independently associated with de novo HCC development (adjusted hazard ratio = 4.91, 95% CI 2.91&ndash;8.28, p &lt; 0.001). ALBI showed the highest diagnostic accuracy for the detection of de novo HCC at 1-, 3-, and 5-years of FU, with AUC values of 0.81 (95% CI 0.78&ndash;0.85), 0.71 (95% CI 0.66&ndash;0.75), and 0.68 (95% CI 0.59&ndash;0.76), respectively. Consistently, the best predictive performance assessed by Harrell&rsquo;s C-statistic was observed for ALBI (C-index = 0.70, 95% CI 0.62&ndash;0.77). ALBI score may represent a valuable and inexpensive tool for risk stratification and the personalization of an HCC surveillance strategy for patients with cirrhosis and previous history of HCV infection treated with DAA

Characterization of a novel chemiluminescent enzyme immunoassay for the quantitation of antibodies to hepatitis B core antigen class IgG and correlation with intrahepatic HBV covalently-closed-circular DNA

Background and aims: Non-invasive biomarkers for the cure and the management of chronic hepatitis B (CHB) infection are an unmet need. Our aim was to characterize a novel HBV assay for the quantitation of anti-HBc IgG and to assess the correlation between serum anti-HBc IgG and intrahepatic HBV cccDNA, in comparison to quantitative hepatitis B surface antigen (qHBsAg) and hepatitis B core-related antigen (HBcrAg) in patients with CHB infection. Method: Serum samples and liver specimens were collected from 35 CHB patients (26M/9F; median age 52 [20-70] years; 25 chronic hepatitis and 10 cirrhosis). Intrahepatic HBV cccDNA was measured by digital-droplet PCR (Bio-Rad, USA) following total DNA digestion with plasmid safe ATP-dependent DNase. Serum qHBsAg and HBcrAg were measured by CLEIA on Lumipulse® G600 II analyzer (Fujirebio, Japan). qHBsAg limit of sensitivitywas 0.005 IU/ml. The lower limit of detection (LLoD) and the measurement range of HBcrAg were 2 Log U/ml and 3-7 Log U/ml, respectively. The WHO 1st International Standard for anti-HBc (NIBSC code 95/522) was used for the calibration of anti-HBc IgG assay (Lumipulse® G HBcAb-N, Fujirebio). Results: The newassay for anti-HBc IgG quantitation showed a linear dynamic range (R2 = 0.997, p &lt; 0.001); lower limit of detection (LLoD) and quantitation (LLoQ) were estimated at 0.5 IU/ml and 0.8 IU/ml, respectively. The coefficient of variation (CV) for repeatability was 3.1% whereas the CV for reproducibility was 4.0%. In liver specimens, mean HBV cccDNA levels were 3.11 ± 1.14 Log copies/105 cells; in serum samples, mean qHBsAg, HBcrAg and anti-HBc IgG values were 3.13 ± 1.31 Log IU/ml, 3.8 ± 1.9 Log U/ml and 3.68 ± 0.83 Log IU/ml, respectively. In 18/35 (51%) patients, HBcrAg was below the measurement limit of the assay (&lt;3 Log U/ml). HBV cccDNA correlated significantly with qHBsAg (r = 0.624, p &lt; 0.001), HBcrAg (r = 0.734, p &lt; 0.001) and anti-HBc IgG (r = 0.553, p &lt; 0.001). In patients with HBcrAg values &lt;3.0 Log U/ml, intrahepatic HBV cccDNA correlated significantly with anti-HBc IgG (r = 0.752, p &lt; 0.001) but not with qHBsAg (r = 0.384, p = 0.116). Conclusion: Anti-HBc IgG quantitation by CLEIA was a sensitive and accurate assay. Among the investigated biomarkers, HBcrAg was confirmed as reliable surrogate marker of intrahepatic HBV cccDNA. In patients with low HBcrAg levels (&lt;3.0 log), anti-HBc IgG quantitation by CLEIA may be proposed as alternative marker for intrahepatic HBV cccDNA measurement

ABCB11 and ABCB1 gene polymorphisms impact on telaprevir pharmacokinetic at one month of therapy

In 2011 direct-acting antivirals, including telaprevir, have been developed to achieve a better antiviral effect. It was reported that telaprevir is a substrate of P-glycoprotein (ABCB1) and cytochrome P450 3A4. The aim of this retrospective study was the evaluation of the influence of some single nucleotide polymorphisms (SNPs) of genes (ABCB1, SLC28A2/3, SLC29A1) involved in TLV and RBV transport and their correlation with plasma TLV drug exposure at 1 month of therapy. We also investigated the association of a SNP in ABCB11 gene, whose role in TLV transport was not yet shown. Twenty-nine HCV-1 patients treated with telaprevir, ribavirin and pegylated-interferon-\u3b1 were retrospectively analyzed; allelic discrimination was performed by real-time PCR. Telaprevir Ctrough levels were influenced by Metavir score (P=0.023), ABCB1 2677 G>T (P=0.006), ABCB1 1236 C>T (P=0.015) and ABCB11 1131 T>C (P=0.033) SNPs. Regarding ABCB1 3435 C>T, a not statistically significant trend in telaprevir plasma concentration was observed. Metavir score (P=0.002, OR -336; 95% CI -535;-138), ABCB1 2677 (P=0.020, OR 497; 95% CI 86; 910), ABCB11 1131 (P=0.002, OR 641; 95% CI 259;1023) and CNT2 -146 (P=0.006, OR -426; 95% CI -721;-132) were able to predict telaprevir plasma levels in the regression analysis. Other SNPs showed no association. This study reveals BSEP implication in telaprevir transport and confirms the involvement and influence of P-glycoprotein on telaprevir plasma levels. To date, no similar data concerning pharmacogenetics and pharmacokinetics were published, but further studies in different and bigger cohorts are needed