Categorical and quantitative data are expressed as n (%) and median (IQR), respectively. Groups were compared using the Chi-square test for categorical variables and the ANOVA test for continuous variables. ALT, alanine aminotransferase; cccDNA, covalently closed circular DNA; iHBV-DNA, intrahepatic HBV-DNA; iHBV-RNA, intrahepatic HBV-RNA; n.a., not applicable; ULN, upper limit of normal. *Analysis of median (IQR) values for HBcrAg, HBV-RNA, iHBV-RNA, and iHBV-RNA/cccDNA was performed only considering patients with positive results. † Data available for 18 patients. One patient in the HBsAg loss group had detectable iHBV-RNA

Ongoing hepatitis A outbreak in Barcelona affects primarily the MSM community and is phylogenetically linked to current hepatitis A outbreaks described in other European countries. As a result of the high admission rate, these outbreaks may impact the admission pattern of referral liver units. Control measures, for example vaccinations programs tailored to the MSM community, must be taken to control further spreading.

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Hepatitis E virus (HEV) and hepatitis A virus (HAV) are both secreted in feces. Despite HEV transmission in Europe is mainly zoonotic, person‐to‐person transmission has not been completely excluded. Men who have sex with men (MSM) constitute a high‐risk group for HAV mostly due to oral sex. We investigated the potential transmission of HEV during an acute hepatitis A (AHA) outbreak mainly affecting MSM. One hundred and two patients were diagnosed with AHA. Sixty‐nine (68%) self‐reported to be MSM, 75% of whom had high‐risk sexual behaviors and 46% had suffered previous sexually transmitted diseases. We collected serum from 85 (83%) patients during AHA. HEV‐IgG seroprevalence was not different among MSM (7%) compared with non‐MSM (8%) patients. Two patients had positive anti‐HEV‐IgM, but all samples tested negative for HEV‐RNA. These results suggest that HEV does not spread by sexual contact or person‐to‐person in our area.

Background & Aims Detailed hepatitis C virus (HCV) kinetics modelling is scarce in patients with advanced liver disease receiving direct‐acting antivirals (DAAs). Due to budget restrictions, patients and health systems would benefit from the shortest possible treatment course. We investigated whether modelling very early HCV kinetics in cirrhotic patients under DAAs therapy could be used to individualize care and reduce treatment duration to achieve cure. Methods We included 74 patients with HCV‐related cirrhosis who received interferon‐free treatments for 12‐24 weeks. HCV genotype, liver disease stage and treatment regimen were recorded. Viral load was determined prospectively at very frequent intervals until target not detected (TND, <15 IU/mL). A viral kinetic model was used to predict time to cure based on HCV clearance in extracellular body fluid (CL‐EF). Results Sixty‐eight patients (92%) achieved cure. Thirteen (18%) had MELD ≥15, 35 (47%) were Child‐Pugh (CTP) ≥7. Median time to reach TND was 2 weeks (IQR: 1‐4 weeks). Modelling indicated an average DAAs efficacy in blocking viral production of ε = 99.1%. HCV half‐life (t1/2) was significantly shorter in patients with CTP <7, LSM <21 kPa or MELD <15 (1.5 vs 2.5 hours; P = 0.0057). The overall median CL‐EF was 5.6 weeks (4.1‐7.8). A CTP >7 and a LSM ≥21 kPa were significantly (P = 0.016) associated with longer CL‐EF. Conclusions The study provides insights into HCV dynamics during DAAs therapy in patients with compensated and decompensated cirrhosis. Viral kinetics modelling suggests that treatment duration may be optimized in patients with compensated cirrhosis.

The emergence of resistance-associated substitutions (RASs) can compromise the high efficacy of direct-acting antivirals (DAAs). Little is known about RASs selection at very early time points during DAA treatment. Therefore, we analyzed the potential emergence of RASs immediately after therapy initiation. Samples of 71 patients treated with different DAAs were collected at baseline, during therapy (hours 4 and 8; days 1-7; weeks 2-4) or until target not detected. HCV-RNA levels were determined by qPCR, and RASs were detected by deep sequencing. Sixty-three (89%) patients achieved a sustained virological response (SVR), 7 (10%) relapsed, and 1 (1%) experienced a breakthrough. Almost all non-SVR (7/8, 88%) showed RASs either at baseline or relapse. High-frequency RASs detected at baseline (Y93H and L159F+C316N) remained detectable at early time points during therapy and reappeared as most prevalent substitutions at relapse. Conversely, emergent RASs at relapse (Q80R, D168E/V, R155K and L31V) were not observed during the first hours-days, before HCV-RNA became undetectable. HCV-RNA decay and genetic evolution of the quasispecies followed a similar pattern during the first hours of therapy in SVR and non-SVR patients. In conclusion, the absence of early RASs selection and the similar dynamics of HCV kinetics and quasispecies in SVR and non-SVR patients after therapy initiation suggest that RASs selection may occur at later stages in the remaining reservoir, where viral populations persist hidden at very low replication levels. Nevertheless, we cannot completely exclude very early selection, when RASs are present below the sensitivity limit of deep sequencing.

Background: Chronic hepatitis C virus (HCV) infection impairs natural killer (NK) cell phenotype and function. Whether restoration of NK cells occurs after successful interferon (IFN)-free therapies remains a controversial issue. Aim: To analyze how HCV-related liver cirrhosis impacts changes in NK cells prior and post-IFN-free therapies. Methods: NK cell analysis by multicolor flow cytometry was performed in HCV-infected patients with (n = 17) and without (n = 14) cirrhosis at baseline, week 4 during therapy, and weeks 12 and 48 after the end of therapy (FU12 and FU48, respectively). Non-HCV cirrhotic patients (n = 12) and healthy individuals (n = 12) served as controls. Results: At baseline, HCV cirrhotic patients presented an altered distribution of NK subsets (CD56 dim and CD56 bright) with higher expression of NKp46, HLA-DR, NKp30, KIR2DL2/L3, NKG2A, and CD85j receptors compared to healthy controls. All frequencies normalized by FU48, except for CD85j + cells. Likewise, substantial alterations were detected in NK cell function assessed by (i) signal transducer and activator of transcription 1 (STAT1) and phosphorylated levels of STAT1 and STAT4, (ii) degranulation (CD107a), (iii) cytotoxicity [tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)], and (iv) cytokine production [IFN-γ and tumor necrosis factor-α (TNF-α)]. Of note, NK cell function at FU48 remained partially impaired. In contrast, non-cirrhotics showed normal baseline frequencies of HLA-DR-, NKG2A-, and CD85j-expressing NK cells. Importantly, altered baseline frequencies of NK cell subsets and NKp46 + CD56 dim cells, as well as NK cell function, were rapidly and completely restored. Conclusions: NK cell phenotype alterations persist after HCV eradication in cirrhotic patients, while their function is only partially restored, compromising immune restoration and immunosurveillance.

Chronic hepatitis C virus (HCV) infection impairs HCV CD8 + T-cell responses, while it could influence immune responses towards unrelated viruses/vaccines (e.g. cytomegalovirus, CMV, and influenza, Flu). The aim of our study was to delineate whether restoration of these virus-specific CD8 + T cells occurs after direct-acting antiviral (DAA) therapies and particularly in patients with cirrhosis. We performed longitudinal analysis (baseline, week 4, follow-up [FU] 12 and FU48) of virus-specific CD8 + T cells by multicolour flow cytometry in HCV-cirrhotic patients undergoing DAA therapy (n = 26) after in vitro expansion with immunodominant HCV, CMV and Flu epitopes restricted by HLA-A*02. HCV noncirrhotic patients (n = 9) and healthy individuals (n = 10) served as controls. We found that the proliferative capacity of HCVspecific CD8 + T cells increased from baseline up to FU48 in a significant proportion of cirrhotic and noncirrhotic patients. Nevertheless, these cells remained poor cytokine producers in both patient groups, regardless of the down-regulation of inhibitory co-regulatory receptors in HCV-cirrhotic patients at FU48. Likewise, high expression levels of these exhaustion markers were detected in CMV-/Flu-specific CD8 + T cells in HCV-cirrhotic patients at all time points, albeit without affecting their proliferative capacity or cytokine production. We conclude that DAA therapies induce restoration of the proliferative capacity of HCV-specific CD8 + T cells. However, these cells remain phenotypically and functionally impaired. Contrarily, the 'exhausted' phenotype in CMV-/Flu-specific CD8 + T cells in HCV-cirrhotic patients did not associate with their functions. Larger studier with longer follow-up may elucidate whether this complex interplay influences the outcome of cirrhotic patients. | 1409 PERPIÑÁN Et al.