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Although the potential role of inanimate surfaces in SARS-CoV-2 transmission has yet to be adequately assessed, it is still routine practice to apply deep and expensive environmental disinfection protocols. The aim of this study was to verify the presence of viable virus on different surfaces exposed to droplets released by coughing in SARS-CoV-2 RNA positive patients. Patients admitted to hospital with a positive SARS-CoV-2 real-time (RT)-PCR swab were asked to cough on steel, cardboard, plastic and their hands. Surfaces were tested at baseline (T 0) and at different timepoints thereafter using swabs dipped in medium, and quickly seeded on VERO E6 cells that were checked every other day for cytopathic effect (CPE). Laboratory-propagated SARS-CoV-2 strains were examined at the same time points and on identical materials. Ten RNA-positive patients were enrolled into the study. The median cycle threshold value was 20.7 (range 13–28.3). Nasopharyngeal swabs from 3 of the patients yielded viable virus 2–10 days post-inoculation. However, in none of the patients was it possible to isolate viable SARS-CoV-2 from sputum under identical experimental conditions. A CPE was instead already visible using laboratory-propagated SARS-CoV-2 strains at 20′, 60′, 180′ while an effect at 24 h required a 6-day incubation. The evidence emerging from this real-life study suggests that droplets delivered by SARS-CoV-2 infected patients on common inanimate surfaces did not contain viable virus. In contrast, and in line with several laboratory-based experiments, in vitro adapted viruses could survive and grow on the same fomites. [ABSTRACT FROM AUTHOR]

Direct acting antiviral agents (DAAs) have revolutionized the landscape of chronic hepatitis C (CHC) enabling treatment of all those infected. It remains to be determined how the characteristics of those receiving treatment are changing. We retrospectively analysed all the patients with CHC who received treatment with DAAs in a large referral centre since 01/01/2015. We stratified their demographic, clinical and virological characteristics at baseline and the sustained virological response (SVR) rates according to the year of treatment. In the study were included 2565 patients. During the study period, the yearly proportion of men and cirrhotic patients decreased (p <0.001) whereas mean age increased from 59.8 to 62.2 years old (p =0.04). An increasing trend was observed in the foreign-born patients from 4.3% to 7.9%, without reaching statistical significance. The prevalence of comorbidities had also increased during the study period (p <0.001). Instead, the yearly number of experienced patients decreased significantly (p <0.001) as well as the mean MELD score of cirrhotic patients from 9 to 7.6 (p <0.001). SVR rates increased significantly, from 93.4% in 2015 to 97.1% in 2018 (P <0.05). The population of patients with CHC receiving DAAs is becoming older and with more comorbidities. Nevertheless, this did not impact SVR rates. [ABSTRACT FROM AUTHOR]

Background and Aims: Obesity has been suggested as a possible risk factor for a more severe course of COVID-19; however, conclusive evidence is lacking and few studies have investigated the role of BMI as a risk factor for admission to intensive care unit (ICU) and mortality. We retrospectively analyzed a COVID-19 cohort recruited during the first 40 days of the epidemic in Italy. We examined the association between obesity and 30-day mortality, admission to ICU, mortality and length of hospital stay in patients with COVID-19.Methods and Results: Demographic, clinical and outcome data were retrospectively analyzed in 331 patients with COVID-19 admitted to hospital between 21 February and 31 March 2020. The predictive effect of obesity on mortality was assessed using a Cox proportional-hazard regression model, its effect on ICU admission and mortality in the ICU using logistic regressions, and its effect on length of hospital stay using a linear regression. Seventy-four of 331 patients had a BMI ≥30 kg/m2. Among obese patients, 21 (28.4%) required admission in ICU and 25 died (33.8%). After controlling for sex, age, comorbidities and clinical data, obesity was not significantly associated with mortality, mortality in ICU and length of hospital stay. The effect of obesity on ICU admission remained significant after controlling for sex, age, interstitial lung disease, heart disease and serum C-reactive protein.Conclusions: Obese patients with COVID-19 were more likely to be admitted to ICU than non-obese patients. However, there were no significant differences in mortality between the two groups. [ABSTRACT FROM AUTHOR]

Abstract: The statements produced by the consensus conference on infection in end-stage liver disease promoted by the Italian Association for the Study of the Liver, are here reported. The topics of epidemiology, risk factors, diagnosis, prophylaxis, and treatment of infections in patient with compensated and decompensated liver cirrhosis were reviewed by a scientific board of experts who proposed 26 statements that were graded according to level of evidence and strength of recommendation, and approved by an independent jury. Each topic was explored focusing on the more relevant clinical questions. By systematic literature search of available evidence, comparison and discussion of expert opinions, pertinent statements answering specific questions were presented and approved. Short comments were added to explain the basis for grading evidence particularly on case of controversial areas. [Copyright &y& Elsevier]

Hepatitis C virus (HCV) elicits T- and B-cell responses which are believed to play an important role in infection control. B cells have generally been neglected because they do not seem to significantly influence the course of HCV infection. In this review, B lymphocytes are viewed both as classical antibody producing cells, with the hypervariable region 1 being a biologically relevant target protein and as a model of virus–host interaction in lymphoproliferative disorders characteristic of persistent microbial infections. [Copyright &y& Elsevier]

Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. McHutchison JG, Dusheiko G, Shiffman ML, Rodriguez-Torres M, Sigal S, Bourliere M, Berg T, Gordon SC, Campbell FM, Theodore D, Blackman N, Jenkins J, Afdhal NH; TPL102357 Study Group. Background: Eltrombopag is a new, orally active thrombopoietin-receptor agonist that stimulates thrombopoiesis. We evaluated its ability to increase platelet counts and facilitate treatment for hepatitis C virus (HCV) infection in patients with thrombocytopenia associated with HCV-related cirrhosis. Methods: Seventy-four patients with HCV-related cirrhosis and platelet counts of 20,000 to less than 70,000 per cubic millimeter were randomly assigned to receive eltrombopag (30, 50, or 75mg daily) or placebo daily for 4 weeks. The primary end point was a platelet count of 100,000 per cubic millimeter or more at week 4. Peginterferon and ribavirin could then be initiated, with continuation of eltrombopag or placebo for 12 additional weeks. Results: At week 4, platelet counts were increased to 100,000 per cubic millimeter or more in a dose-dependent manner among patients for whom these data were available: in 0 of the 17 patients receiving placebo, in 9 of 12 (75%) receiving 30mg of eltrombopag, in 15 of 19 (79%) receiving 50mg of eltrombopag, and in 20 of 21 (95%) receiving 75mg of eltrombopag (P <0.001). Antiviral therapy was initiated in 49 patients (in 4 of 18 patients receiving placebo, 10 of 14 receiving 30mg of eltrombopag, 14 of 19 receiving 50mg of eltrombopag, and 21 of 23 receiving 75mg of eltrombopag) while the administration of eltrombopag or placebo was continued. Twelve weeks of antiviral therapy, with concurrent receipt of eltrombopag or placebo, was completed by 36%, 53%, and 65% of patients receiving 30mg, 50mg, and 75mg of eltrombopag, respectively, and by 6% of patients in the placebo group. The most common adverse event during the initial 4 weeks was headache; thereafter, the adverse events were those expected with interferon-based therapy. Conclusions: Eltrombopag therapy increases platelet counts in patients with thrombocytopenia due to HCV-related cirrhosis, thereby permitting the initiation of antiviral therapy. (ClinicalTrials.gov number, NCT00110799.) 2007 Massachusetts Medical Society. [Abstract reproduced by permission of N Engl J Med 2007;357:2227–2236] [Copyright &y& Elsevier]

Chronic hepatitis C virus (HCV) infection affects 71 million people worldwide. The availability of highly efficient direct-acting antivirals has revolutionized the treatment landscape with over 95% cure rates. The WHO has launched a global programme to achieve rather ambitious HCV elimination targets for 2030. This article aims to provide a critical overview of the current HCV elimination programmes in Europe highlighting the elements that should be implemented to achieve elimination and those that are already in place to promote this process. Review of the recently published literature and opinion of experts in the field. Elimination of hepatitis C as a public health threat appears to be a difficult task, which should be subdivided into smaller targets, the so-called micro-elimination goals, to increase chances of success. Macro-elimination strategies based on mass-screening are difficult to implement. Evidence supporting the efficacy of micro-elimination comes from key populations, such as people who inject drugs. HCV elimination is proceeding at different speeds in Europe. Some countries are on target with the WHO's objectives whereas others lack economic support and political advocacy, and have insufficient infrastructures to achieve this. The absence of an effective prophylactic vaccine is hampering the process and should be overcome. Elimination of hepatitis C worldwide appears plausible, but in several countries probably not within the time frame suggested by the WHO. In the absence of vaccination, universal access to HCV treatment would act as a 'therapeutic' option to reduce transmission, especially in high-risk populations. [ABSTRACT FROM AUTHOR]

Background & Aims: The phenotypic and functional characteristics of natural killer (NK) cells in chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are incompletely defined and largely controversial. Methods: We studied NK cell receptor expression, cytotoxic activity, and cytokine production in peripheral blood mononuclear cells from 35 patients with chronic hepatitis C, 22 with chronic hepatitis B, and 30 healthy controls. Results: Patients with chronic HBV infection had an increased proportion of NKG2C+ NK cells with normal inhibitory receptor expression and a lower proportion of activated NK cells compared with HCV+ patients, which was associated with normal or reduced cytolytic activity and markedly dysfunctional tumor necrosis factor-α and interferon-γ production. Patients with chronic HCV infection showed a predominantly activating phenotype, featuring a decreased percentage of cells expressing the inhibitory receptor KIR3DL1 and a concomitant increase in the proportion of NKG2D+ NK cells. Expression of the CD69 early activation antigen on NK cells positively correlated with serum alanine aminotransferase and HCV RNA values, suggesting participation of virus-induced effector NK cells in liver necroinflammation. Phenotypic changes in HCV+ patients were associated with enhanced cytokine-induced cytolytic activity and increased usage of natural cytotoxicity and NKG2D receptor pathways, accompanied by defective cytokine production, although to a lesser extent than patients with chronic HBV infection. Conclusions: These findings provide evidence for a functional dichotomy in patients with chronic HBV and HCV infections, featuring conserved or enhanced cytolytic activity and dysfunctional cytokine production, which may contribute to virus persistence. [Copyright &y& Elsevier]

• New immunological treatments have changed the management of several cancers. • The impact of these treatments on the infection risk has not been ascertained yet. • Studies and trials on immune checkpoint inhibitors, chimeric antigen receptor T cells, and bispecific T-cell engagers report several infections. • Respiratory tract, urinary tract, and device-related infections are dominant. Immunological treatments (immune checkpoint inhibitors [ICIs], chimeric antigen receptor T [CAR-T] cells, bispecific T-cell engagers [BiTEs]) have deeply changed the treatment of several cancers. However, the impact of these treatments on the risk of developing infections has not been completely ascertained yet. We reviewed all the registration studies of currently approved ICIs, CAR-T cells, and BiTEs to collect all the reported infections. For each drug, we have generated a report with the infections occurring in at least 10% of the patients enrolled. The most frequently reported infections involving patients treated with ICIs involved the respiratory tract, including nasopharyngitis, upper respiratory tract infections, and pneumonia and the urinary tract. Those treated with CAR-T cells frequently reported the incidence of unspecified infections and infestations, bacterial infections, and viral infections. In patients treated with BiTEs, nasopharyngitis, pneumonia, and device-related infections were the most frequently reported conditions. A wide range of infections are reported in registration studies and clinical trials of ICIs, CAR-T cells, and BiTEs. [ABSTRACT FROM AUTHOR]

Background/Aims: Hepatitis C virus (HCV) is a known risk factor for hepatocellular carcinoma (HCC), but whether the risk varies among patients infected with different HCV genotypes is still controversial. We performed a meta-analysis to clarify whether the genotype 1b is associated with a higher risk of HCC than other genotypes. Methods: We identified 57 relevant papers through a literature search to December 2007 but, since age could represent a major confounder, we focused the meta-analysis on the 21 studies presenting age-adjusted risk estimates for HCV genotype 1b vs. other genotypes. We used random-effects models with the DerSimonian–Laird method and assessed heterogeneity between studies and publication bias. Results: Patients infected with HCV genotype 1b have almost double the risk to develop HCC than those infected with other genotypes (Relative Risk (95% Confidence Intervals)=1.78(1.36–2.32)). The pooled risk estimate was somewhat lower when we restricted the analysis to the eight studies conducted in patients with liver cirrhosis (1.60;1.07–2.39) or considering the 36 studies presenting only crude data (1.63;1.30–2.06). In seven studies excluding patients with liver cirrhosis, the RR (95% CI) increased to 2.46(1.69–3.59). Conclusions: This meta-analysis suggests that HCV genotype 1b plays an important role in HCC development, especially in patients with early stage liver disease. [Copyright &y& Elsevier]

Background & Aims Natural killer (NK) cells play an important role in the pathogenesis of hepatitis C virus (HCV) infection. We have previously shown that culture-derived HCV (HCVcc) enhance tumor necrosis-factor-related apoptosis-inducing ligand (TRAIL) expression on healthy NK cells, but not on those from patients infected with HCV, which was likely dependent on accessory cells. Here we sought to elucidate the mechanisms involved in altered TRAIL upregulation in this setting. Methods Peripheral blood mononuclear cells (PBMC) from controls and patients infected with HCV were exposed to HCVcc. Cell depletions were performed to identify cells responsible for NK cell activation. Flow cytometry and ELISA were used to identify the cytokines involved in the NK activation process. Results In patients infected with HCV, soluble factors secreted by control PBMC restored the ability of NK cells to express TRAIL. Of note, CD14+ cell depletion had identical effects upon virus exposure and promoted increased degranulation. Moreover, increased concentrations of interleukin (IL)-18 binding protein a (IL-18BPa) and IL-36 receptor antagonist (IL-36RA) were observed after PBMC exposure to HCVcc in patients with HCV. HCVcc-induced NK cell TRAIL expression was inhibited by IL-18BPa and IL-36RA in control subjects. There were statistically significant correlations between IL-18BPa and indices of liver inflammation and fibrosis, supporting a role for this protein in the pathogenesis of chronic HCV infection. Conclusions During chronic HCV infection, monocytes play a key role in negative regulation of NK cell activation, predominantly via secretion of inhibitors of IL-18 and IL-36. Lay summary Coordination and collaboration between immune cells are essential to fight pathogens. Herein we show that during HCV infection monocytes secrete IL-18 and IL-36 inhibitory proteins, reducing NK cell activation, and consequently inhibiting their ability to express TRAIL and kill target cells. [ABSTRACT FROM AUTHOR]

Background & Aims The Fc receptor family for immunoglobulin (Ig)G type III (FcγRIII, CD16) is an activating receptor on natural killer (NK) cells and an essential mediator of antibody-dependent cellular cytotoxicity (ADCC). There is only limited information on its role during chronic hepatitis C virus (HCV) infection. We studied CD16 expression in relation to NK cell functional activity in HCV-infected patients and sought mechanistic insights into virus-induced modulation. Methods NK cell CD16 expression and activation status were evaluated ex vivo by flow cytometry in HCV-infected patients and healthy controls (HC) as well as in vitro after co-culture with HCV-infected HuH7.5 cells. Rituximab-mediated ADCC was assessed in HC and HCV-infected patients using Daudi cells as a target. The role of metzincins in CD16 down-modulation was assessed using specific inhibitory molecules and by evaluating intracellular mRNA levels. Results HCV-infected patients exhibited increased frequencies of ex vivo activated NK cells and a concomitantly decreased NK CD16 expression, which resulted in impaired ADCC activity. Moreover, exposure of NK cells to culture-derived HCV recapitulated the ex vivo findings of decreased CD16 expression and increased NK cell activation. Importantly, blockade of metzincin-mediated shedding activity, including selective a disintegrin and metalloproteinase 17 (ADAM-17) inhibition, restored NK CD16 expression. Successful treatment with direct-acting antivirals partially improved NK ADCC function despite delayed CD16 reconstitution. Conclusion Chronic HCV infection induces NK cell activation resulting in ADAM-17-dependent CD16 shedding and consequent impaired ADCC function. Altered ADCC may contribute to failure to eradicate HCV-infected hepatocytes. Lay summary We show here that hepatitis C virus (HCV) activates natural killer (NK) lymphocytes which, as a consequence, loose their Fc receptor for IgG (CD16), an essential molecule for antibody binding. We show that this occurs through the action of enzymes named metzincins, resulting in altered NK-mediated antibody-dependent killing (ADCC) of target cells. This mechanism may contribute to HCV persistence and may represent a general phenomenon whereby some viruses can escape host’s immune responses. [ABSTRACT FROM AUTHOR]

Toll-like receptor 7 (TLR7) is a ssRNA receptor that activates dendritic cells and macrophages upon ssRNA binding; however, little is known of its role in CD4 + T cells. We show here that hepatitis C virus (HCV) induces a dose dependent inhibition of cytokine production and expression of activation markers in CD4 T cells, which were restored by a TLR7-specific antagonist. These findings indicate that HCV induces CD4 T cell impairment via TLR7 which may contribute to failure of virus eradication, casting doubts on the use of TLR7 agonists to boost innate immunity in chronic RNA virus infections. [ABSTRACT FROM AUTHOR]

Objective To evaluate whether rituximab at a low dose of 250 mg/m 2 × 2 may be as effective as at higher dosages, most commonly 375 mg/m 2 × 4, used in previous studies on the treatment of patients with refractory mixed cryoglobulinemia (MC) vasculitis associated with hepatitis C virus (HCV) infection. Methods We conducted a phase 2, single-arm two-stage trial (EUDRACT n. 2008-000086-38) of low-dose rituximab in 52 patients with HCV-associated MC who were ineligible/intolerant or non-responder to antiviral therapy. The primary outcomes were response of vasculitis evaluated by the Birmingham Vasculitis Activity Score (BVAS) at months 3, 6 and 12, rate of relapses and time to relapse, and rate of adverse events. Our data were compared with those reported in 19 published studies selected among 291 reviewed in a literature search. Results The cumulative response rate (complete and partial) at month 3 was 81% in our patients, and 86% in 208 patients from studies using high-dose rituximab. The relapse rate and median time to relapse were, respectively, 41% and 6 months in our study, and 32% and 7 months in high-dose studies. Treatment-related adverse events were 11.5% in our study and 19.9% in high-dose studies. None of these differences was statistically significant. Conclusion Rituximab at a low dosage of 250 mg/m 2 × 2 is as effective as at higher dosages for treating MC vasculitis. This low-dose regimen may improve the cost/benefit profile of rituximab therapy for MC. [ABSTRACT FROM AUTHOR]

Summary: The burden of infectious diseases both before and after liver transplantation is clearly attributable to the dysfunction of defensive mechanisms of the host, both as a result of cirrhosis, as well as the use of immunosuppressive agents. The present document represents the recommendations of an expert panel commended by the Italian Association for the Study of the Liver (AISF), on the prevention and management of infectious complications excluding hepatitis B, D, C, and HIV in the setting of liver transplantation. Due to a decreased response to vaccinations in cirrhosis as well as within the first six months after transplantation, the best timing for immunization is likely before transplant and early in the course of disease. Before transplantation, a vaccination panel including inactivated as well as live attenuated vaccines is recommended, while oral polio vaccine, Calmette-Guerin’s bacillus, and Smallpox are contraindicated, whereas after transplantation, live attenuated vaccines are contraindicated. Before transplant, screening protocols should be divided into different levels according to the likelihood of infection, in order to reduce costs for the National Health Service. Recommended preoperative and postoperative prophylaxis varies according to the pathologic agent to which it is directed (bacterial vs. viral vs. fungal). Timing after transplantation greatly determines the most likely agent involved in post-transplant infections, and specific high-risk categories of patients have been identified that warrant closer surveillance. Clearly, specifically targeted treatment protocols are needed upon diagnosis of infections in both the pre- as well as the post-transplant scenarios, not without considering local microbiology and resistance patterns. [Copyright &y& Elsevier]

Background & Aims: A substantial proportion of patients with chronic hepatitis C virus infection treated with pegylated interferon α/ribavirin fail to achieve sustained virological response (SVR). Since growing evidence suggests that innate immunity may influence treatment responses, we examined natural killer (NK) cell phenotypic and functional changes during standard antiviral therapy. Methods: Expression of several NK-cell regulatory molecules was evaluated by flow cytometry in 37 consecutive patients with chronic HCV infection at baseline and at different time points during and after discontinuation of treatment. Cytokine production was evaluated by intracellular staining. Cytolytic potential was assessed as degranulation and as antibody-dependent cytotoxicity. Results: Baseline frequencies of CD56dim NK cells and perforin content were significantly higher, whereas CD16 expression was lower in SVR vs. non-responder subjects. Analysis by linear regression for repeated measures during the first 12weeks showed significantly increased frequencies of activated (CD69+) NK cells in rapid virological responders (RVR) and identified a typical NK cell profile associated with SVR, featuring higher NK perforin content, lower CD16 expression, and higher proportion of CD56dim/CD16− cells. Moreover, SVR patients displayed higher natural and antibody-dependent NK cell cytotoxicity. IL28B rs12979860 CC homozygosis was significantly associated with SVR, independently of NK-cell phenotype and function. Conclusions: Different NK-cell phenotypic and functional features, in patients with chronic hepatitis C treated with standard therapy, were observed between non-responder vs. SVR patients, suggesting a potential role of NK cells in the response to treatment. [Copyright &y& Elsevier]

Abstract: Eradication of hepatitis C virus (HCV) by antiviral therapy is the treatment of choice for mixed cryoglobulinemia secondary to this infection, but many patients fail to achieve sustained viral responses and need second-line treatments. Several studies have demonstrated that the infusion of the anti-CD20 monoclonal antibody rituximab is highly effective for refractory mixed cryoglobulinemia, with a clinical response in approximately 80% of patients, although the relapse rate is high. Virtually all published studies employed a rituximab dosage of 375mg/m2 given four times, a schedule used for treating non-Hodgkin''s lymphomas. Based on a prior pilot study, we designed a phase II single-arm two-stage study (EUDRACT n. 2008-000086-38) to evaluate the efficacy of a lower dosage of rituximab, 250mg/m2 given twice, for refractory mixed cryoglobulinemia. We present here the preliminary results in the first 27 patients enrolled. The overall response rate in 24 evaluable patients was 79%, and the mean time to relapse was 6.5months, similar to the 6.7months reported in studies with high-dose rituximab. Side effects were comparable to those seen in patients treated with high-dose. Increase of HCV viral load, reported in some high-dose studies, was not observed in our patients. Low-dose rituximab may provide a more cost/effective and possibly safer alternative for treating refractory HCV-associated mixed cryoglobulinemia. [Copyright &y& Elsevier]

Background & Aims: Chronic microbial infections are frequently associated with B-cell activation and polyclonal proliferation, potentially leading to autoimmunity and lymphoproliferative disorders. We assessed B-cell phenotype and function in chronic hepatitis B (HBV) and chronic hepatitis C (HCV) virus infection. Methods: We studied 70 patients with chronic HCV infection, 34 with chronic HBV infection and 54 healthy controls. B-cell phenotype was assessed by flow cytometry using monoclonal antibodies specific for CD27, the CD69, CD71, and CD86 activation markers and the chemokine receptor CXCR3. Differentiation into immunoglobulin-producing cells (IPC) was analysed by ELISpot upon stimulation and with CD40 ligand±IL-10 as surrogate bystander T-cell help or CpG oligodeoxynucleotide±IL-2, as innate immunity signal. Proliferation was examined by flow cytometry using carboxyfluorescein diacetate succinimidyl ester (CFSE) after stimulation with CpG. Results: A significantly higher proportion of B cells from both HCV- and HBV-infected patients expressed activation markers compared with controls and a positive correlation was found between CXCR3+ B cells and HCV RNA values. Memory B cells from patients with chronic HCV and HBV infections showed enhanced differentiation into IPC compared with controls, although this was restricted to IgG and at a lower level in HCV-compared with HBV-infected patients. Moreover, patients’ activated B cells displayed significantly lower proliferative ability compared to healthy donors despite low expression of the FcRL4 exhaustion marker. Conclusions: B-cell activation, but not exhaustion, is common in chronic viral hepatitis. However, enhanced B-cell differentiation and deficient proliferative capacity were not associated with commitment to terminal differentiation. [ABSTRACT FROM AUTHOR]

Recently released clinical practice guidelines and consensus conference statements point to the importance of hepatitis B virus (HBV) genotyping in therapeutic algorithms for the treatment of chronic hepatitis B. This information usually comes from post hoc analyses of clinical trials which were not designed to study associations with the HBV genotype. We have performed a literature search through to April 2009 and have selected randomized clinical trials of currently approved anti-HBV drugs providing information on HBV genotypes and (i) baseline characteristics of study subjects, (ii) any response to antiviral therapy, (iii) interaction between HBV genotypes and the type of therapy. There were several intrinsic features and weaknesses in the majority of clinical trials conducted so far which make it difficult to reach firm conclusions about the role of HBV genotypes in response to antiviral therapy. Indeed, most trials were necessarily multicenter in order to reach a sufficient statistical power, but pooling together patients of different ethnicities may have revealed false-positive associations between response to antiviral therapy and HBV genotype. Moreover, endpoint definitions, especially for the composite ones, varied substantially among studies, leading to lack of homogeneity. Finally, possible interactions between the type of therapy and the HBV genotype were only seldom analysed. The present review highlights several caveats regarding current indications proposed by the major clinical practice guidelines and consensus conference statements published thus far and emphasise the need for further long term studies in the field. [Copyright &y& Elsevier]

Background/Aims: Graft re-infection invariably occurs after liver transplantation (OLT) for chronic hepatitis C and disease progression is unpredictable. We prospectively examined peripheral blood mononuclear cells (PBMC) subsets and natural killer (NK) cell receptors (NKRs) in patients with recurrent hepatitis C post-OLT. Methods: PBMC were obtained at baseline and at different time points after OLT. NKRs were identified using monoclonal antibodies by flow cytometry. Results: The proportions of NK, natural T (NT), total and γδ T cells were significantly reduced (p <0.01) 7 days post-transplant, probably as a result of graft repopulation. NKG2D+ NK cells were significantly higher compared with healthy controls (p <0.01), declined post-OLT and subsequently returned to baseline values. This, together with a progressive increase in the proportion of CD94/NKG2C+ NK cells over time (p ⩽0.01), appeared to be related to hepatitis C recurrence. There was a statistically significant correlation between expression of the natural cytotoxicity receptors (NCRs) and ALT (p <0.05), supporting the hypothesis that NK cells participate in the necroinflammatory process. Conclusions: The data are compatible with homing of immune cells to the liver allograft after surgery, most of which return to pre-OLT levels. HCV recurrence may cause variations in selected NKRs expression akin to other viral infections. [Copyright &y& Elsevier]