Adaptive immune response during hepatitis C virus infection.

Hepatitis C virus (HCV) infection affects about 170 million people worldwide and it is a major cause of liver cirrhosis and hepatocellular carcinoma. HCV is a hepatotropic non-cytopathic virus able to persist in a great percentage of infected hosts due to its ability to escape from the immune control. Liver damage and disease progression during HCV infection are driven by both viral and host factors. Specifically, adaptive immune response carries out an essential task in controlling non-cytopathic viruses because of its ability to recognize infected cells and to destroy them by cytopathic mechanisms and to eliminate the virus by non-cytolytic machinery. HCV is able to impair this response by several means such as developing escape mutations in neutralizing antibodies and in T cell receptor viral epitope recognition sites and inducing HCV-specific cytotoxic T cell anergy and deletion. To impair HCV-specific T cell reactivity, HCV affects effector T cell regulation by modulating T helper and Treg response and by impairing the balance between positive and negative co-stimulatory molecules and between pro- and anti-apoptotic proteins. In this review, the role of adaptive immune response in controlling HCV infection and the HCV mechanisms to evade this response are reviewed.

HCV-specific CD8+ cell detection at week 12 of chronic hepatitis C treatment with PEG-interferon-α2b/ribavirin correlates with infection resolution.

Lower than 2-log viral-load (VL) decrease at week 12 (w12) of chronic hepatitis C (CHC) treatment with Peg-interferon/ribavirin has 100% negative predictive value (PV) of sustained virologic response (SVR), and this could be related with absence of HCV-specific cytotoxic T lymphocyte (CTL) response. In this study, percentage of cases with SVR, according to peripheral HCV-specific cytotoxic response at w12, was analysed (Group-1: detection(+), Group-2: detection(-)). SVR was higher in group-1 (93%) than in group-2 (47%) (p=0.003). An increase on HCV-specific CTL frequency between baseline and w12 and higher specific reactivity were observed in group-1 (p=0.011 and p=0.025). HCV-specific CTL detection at w12 correlated with level of VL decrease (p=0.016, r=0.389), and among HCV genotype-1 patients with either early or delayed virologic response (EDVR), 100% positive PV of SVR was observed. In summary, HCV-specific CTL detection at w12 of Peg-interferon/ribavirin treatment correlates with SVR and in EDVR genotype-1 cases predicts SVR.

Role of T cell death in maintaining immune tolerance during persistent viral hepatitis.

Virus-specific T cells play an important role in the resolution of hepatic infection. However, during chronic hepatitis infection these cells lack their effector functions and fail to control the virus. Hepatitis B virus and hepatitis C virus have developed several mechanisms to generate immune tolerance. One of these strategies is the depletion of virus-specific T cells by apoptosis. The immunotolerogenic liver has unique property to retain and activate naïve T cell to avoid the over reactivation of immune response against antigens which is exploited by hepatotropic viruses to persist. The deletion of the virus-specific T cells occurs by intrinsic (passive) apoptotic mechanism. The pro-apoptotic molecule Bcl-2 interacting mediator (Bim) has attracted increasing attention as a pivotal involvement in apoptosis, as a regulator of tissue homeostasis and an enhancer for the viral persistence. Here, we reviewed our current knowledge on the evidence showing critical role of Bim in viral-specific T cell death by apoptotic pathways and helps in the immune tolerance.

Bim-mediated apoptosis and PD-1/PD-L1 pathway impair reactivity of PD1(+)/CD127(-) HCV-specific CD8(+) cells targeting the virus in chronic hepatitis C virus infection.

PD-1 molecule promotes anergy and IL-7 receptor (CD127) induces an anti-apoptotic effect on T cells. Correlation between PD-1/CD127 phenotype and hepatitis C virus (HCV)-specific CD8(+) cell reactivity in resolved infection (RI) after treatment and persistent HCV-infection (PI) was analysed. Directly ex vivo, PD-1 and CD127 expression on HCV-specific CD8(+) cells displayed a positive and negative correlation, respectively with viraemia. Proliferation after stimulation on PD-1(-)/CD127(+) cells from RI cases was preserved, while it was impaired on PD-1(+)/CD127(-) cells from PI patients. PD1(+)/CD127(+) population was observed in PI, and these maintained expansion ability but they did not target the virus. Frequency of PI cases with HCV-specific CD8(+) cell proliferation increased after anti-PD-L1 and anti-apoptotic treatment. Bim expression on HCV-specific CD8(+) cells from PI patients was enhanced. In conclusion, during chronic HCV infection non-reactive HCV-specific CD8(+) cells targeting the virus are PD-1(+)/CD127(-)/Bim(+) and, blocking apoptosis and PD-1/PD-L1 pathway on them enhances in vitro reactivity.

Factors that modify therapy adherence in patients with inflammatory bowel disease.

OBJECTIVES: Inflammatory bowel disease is associated with a high risk of deficient adherence to therapy. Our study was designed to analyze the adherence to treatment in a specialized inflammatory bowel disease clinic, and to study which factors could influence it. METHODS: 107 consecutive patients (64% Crohn's disease, 36% ulcerative colitis) filled up an anonymous survey with data on demography, disease, therapy and a self-applied adherence declaration. RESULTS: A 69% (95%CI: 60-77%) showed some type of non-adherence. A 66% (95 CI%: 57-75%) acknowledged some involuntary non-adherence: either forgetting to take their dose (63%) or being careless about having taken it (27%). A 16% (95 CI%: 9-22%) showed some voluntary non-adherence: interrupting the therapy when feeling better (13%) or when feeling worse (6%). A 25% forgot at least a dose a week in the last 12 months. Multivariate analysis identified as risk factors for a lower adherence the dosing in three or more takes a day (OR 3; 95%CI: 1.1-8.4; p=0.03) and feeling little informed about their disease (OR 4.9; 95%CI: 1.1-23.8; p=0.04). Immunomodulator therapy predicted better adherence (OR 0.29; 95%CI: 0.11-0.74; p=0.01). CONCLUSIONS: Adherence to therapy in inflammatory bowel disease patients is not satisfactory, and worse in patients treated with mesalazine. Optimizing the information on the disease and giving the medication in one or two daily doses could enhance therapeutic adherence.

Ectopic papilla of Vater in the pylorus.

The major papilla of Vater is usually located in the second portion of the duodenum, to the posterior medial wall. Sometimes the mouth of the biliary duct is located in other areas. Drainage of the common bile duct into the pylorus is extremely rare. A 73-year old man, with a history of duodenal ulcer, was admitted to hospital with the diagnosis of cholangitis. Dilatation of the extrahepatic biliary duct was observed by abdominal ultrasonography, and endoscopic retrograde cholangiopancreatography (ERCP) was performed. No area suggesting the presence of the papilla of Vater was found within the second duodenal portion. Finally the major papilla was located in the theoretical pyloric duct. Cholangiography was performed and choledocholithiasis was found in the biliary tree. The patient underwent dilatation of the papilla with a balloon tyre and removal of a 7 mm stone using a Dormia basket, which solved the problem without further complications. This anomaly increased the difficulty of performing therapeutic interventions during ERCP. This alteration in anatomy may increase the risk of complications during papillotomy, with a theoretically higher risk of perforation. Dilatation using a balloon was the chosen therapeutic technique both in our case and in the literature, due to its low rate of complications.

Pancreatitis aguda y lesiones ocupantes de espacio hepáticas en paciente trasplantado de médula ósea por mieloma múltiple / Acute pancreatitis and space-occupying hepatic lesions in a patient with bone marrow transplant due to multiple myeloma

Los pacientes con mieloma múltiple (MM) no tienen mayor incidencia de pancreatitis aguda ni diferente etiología de ésta que la población general. Sin embargo, pueden presentar pancreatitis aguda, o hiperamilasemia o hiperlipasemia aisladas, por causas que son poco habituales sin la presencia de la enfermedad hematológica. En los pacientes con MM, la afectación hepática aparece en el 30 al 50% de los casos. Fundamentalmente se produce como infiltración difusa de predominio sinusoidal, y la aparición en forma de nódulos es menos frecuente. Se presenta el caso de un paciente que recibió un trasplante de médula ósea por MM y que presentó un cuadro compatible clínica y analíticamente con pancreatitis aguda de etiología no filiada, durante el que se identificó la presencia de múltiples lesiones hepáticas ocupantes de espacio que se diagnosticaron mediante biopsia como recidiva extramedular de mieloma (AU)

Patients with multiple myeloma (MM) do not have a higher incidence of acute pancreatitis or pancreatitis of other etiologies than the general population. However, these patients may develop acute pancreatitis, or hyperamylasemia or isolated hyperlipasemia, due to etiologies that are highly infrequent in the absence of hematological disease. Liver involvement is found in 30 50% of patients with MM and mainly manifests as diffuse sinusoidal infiltration and less frequently in the form of nodules. We report the case of a patient who underwent bone marrow transplantation due to MM who showed clinical and laboratory findings compatible with acute pancreatitis of unknown origin, during which the presence of multiple space-occupying hepatic lesions was identified. Based on the results of biopsy, a diagnosis of extramedullary recurrence of MM was established (AU)

[Acute pancreatitis and space-occupying hepatic lesions in a patient with bone marrow transplant due to multiple myeloma]. / Pancreatitis aguda y lesiones ocupantes de espacio hepáticas en paciente trasplantado de médula ósea por mieloma múltiple.

Patients with multiple myeloma (MM) do not have a higher incidence of acute pancreatitis or pancreatitis of other etiologies than the general population. However, these patients may develop acute pancreatitis, or hyperamylasemia or isolated hyperlipasemia, due to etiologies that are highly infrequent in the absence of hematological disease. Liver involvement is found in 30-50% of patients with MM and mainly manifests as diffuse sinusoidal infiltration and less frequently in the form of nodules. We report the case of a patient who underwent bone marrow transplantation due to MM who showed clinical and laboratory findings compatible with acute pancreatitis of unknown origin, during which the presence of multiple space-occupying hepatic lesions was identified. Based on the results of biopsy, a diagnosis of extramedullary recurrence of MM was established.

DNA-guided hepatitis B treatment, viral load is essential, but not sufficient.

Hepatitis B virus (HBV) infection is a global public health problem that concerns 350 million people worldwide. Individuals with chronic hepatitis B (CHB) are at increased risk of developing liver cirrhosis, hepatic de-compensation and hepatocellular carcinoma. To maintain undetectable viral load reduces chronic infection complications. There is no treatment that eradicates HBV infection. Current drugs are expensive, are associated with adverse events, and are of limited efficacy. Current guidelines try to standardize the clinical practice. Nevertheless, controversy remains about management of asymptomatic patients with CHB who are hepatitis B e antigen (HBeAg)-positive with normal alanine aminotransferase, and what is the cut-off value of viral load to distinguish HBeAg-negative CHB patients and inactive carriers. We discuss in detail why DNA level alone is not sufficient to begin treatment of CHB.

The role of CCR5/CXCR3 expressing CD8+ cells in liver damage and viral control during persistent hepatitis C virus infection.

BACKGROUND/AIMS: CXCR3 and CCR5 play a major role in recruiting cytotoxic T cells (Tc) and secreting secondary type 1 cytokines (Tc1) in the liver. HCV could impair their expression as a survival mechanism. The role of these chemokine receptors on CD8+ cells in chronic hepatitis C is analysed. METHODS: Serum, chemokines, peripheral blood and intrahepatic lymphocytes from chronic hepatitis C patients were studied. CXCR3/CCR5 expressing CD8+ cells were quantified by flow-cytometry. Serum chemokines concentration (CXCL10/CCL3) was measured by ELISA. Basal data were correlated with liver inflammation. Longitudinal data were obtained during treatment and correlated with virologic response. RESULTS: CCR5/CXCR3 expressing CD8+ cells were enriched in the liver and correlated with inflammation. Chronic HCV patients presented the same frequency of CCR5(high)/CXCR3(high) expressing CD8+ cells in peripheral blood as in healthy controls but higher serum concentration of CXCL10/CCL3. Treatment with PEG-interferon alpha-2b plus ribavirin increased CCR5(high)/CXCR3(high) expressing CD8+ cells frequency in peripheral blood and decreased CXCL10/CCL3 serum concentration. Increase in CXCR3(high) expressing CD8+ cells after 24 weeks of treatment was correlated with SVR. CONCLUSIONS: In chronic hepatitis C, anti-viral treatment induces an increase in CD8+ cells expressing chemokine receptors associated with Tc1 response and a reduction in their ligands. Achievement of viral control is associated with an increase in CXCR3(high) expressing CD8+ cells during treatment.

HCV clearance and treatment outcome in genotype 1 HCV-monoinfected, HIV-coinfected and liver transplanted patients on peg-IFN-alpha-2b/ribavirin.

BACKGROUND/AIMS: Differences in HCV-RNA clearance during therapy might explain the lower efficacy of peg-IFN/RBV in HIV/HCV-coinfection. There are limited data on HCV-RNA clearance and treatment outcomes in liver transplanted (LT) patients. METHODS: To assess the rates of SVR and baseline predictors of failure after 48 weeks of weight-adjusted peg-IFN-alpha-2b/RBV in 120 patients with HCV genotype 1: 61 HCV-monoinfected, 40 HIV-coinfected and 19 LT-patients. Viral clearance was evaluated in patients completing 24 weeks of therapy (n=112, 93%). RESULTS: SVR was significantly lower in HIV-coinfection than in HCV-monoinfection or LT (18 vs. 39 vs. 42%, P<0.02). By multivariate analysis, HIV-coinfection (OR 3.048, 95% CI 1.133-8.196; P=0.027), baseline HCV-RNA over 800,000 IU/ml (OR 2.800; 95% CI 1.121-6.993, P=0.027) and higher AST values (OR 1.009; 95% CI 1.001-1.018; P=0.028) were significantly associated to failure. Despite similar baseline HCV load (5.67 vs. 5.75 vs. 5.90 log10 IU/ml), HIV-coinfection showed significantly lower HCV-RNA decreases than HCV-monoinfection at weeks 4 (P=0.015), 12 (P=0.015) and 24 (P=0.0003), and than LT at weeks 12 (P=0.003) and 24 (P=0.023). 36/60 subjects (60%) reaching EVR by week 12 obtained SVR vs. 3/60 (5%) who did not. CONCLUSIONS: HIV-coinfection was independently associated to treatment failure, and led to a significantly slower HCV-RNA clearance.