HLA-C and KIR combined genotype as new response marker for HBeAg-positive chronic hepatitis B patients treated with interferon-based combination therapy.

Current treatment for chronic hepatitis B infection (CHB) consists of interferon-based therapy. However, for unknown reasons, a large proportion of patients with CHB do not respond to this treatment. Hence, there is a pressing need to establish response markers to select patients who will benefit from therapy and to spare potential nonresponders from unnecessary side effects of antiviral therapy. Here, we assessed whether HLA-C and KIR genotypes were associated with treatment outcome for CHB. Twelve SNPs in or near the HLA-C gene were genotyped in 86 CHB patients (41 HBeAg positive; 45 HBeAg negative) treated with peginterferon alfa-2a + adefovir. Genotyping of killer immunoglobin-like receptors (KIRs) was performed by SSP-PCR. One SNP in HLA-C (rs2308557) was significantly associated with combined response in HBeAg-positive CHB patients (P = 0.003). This SNP is linked to the HLA-C group C1 or C2 classification, which controls KIR binding. The combination of KIR2DL1 with its ligand HLA-C2 was observed significantly more often in HBeAg-positive patients with a combined response (13/14) than in nonresponders (11/27, P = 0.001). Patients with the KIR2DL1/C2 genotype had significantly higher baseline ALT levels (136 vs 50 U/L, P = 0.002) than patients without this combination. Furthermore, KIR2DL1-C2 predicted response independent of HBV genotype and ALT at baseline. HLA-C and KIR genotype is strongly associated with response in HBeAg-positive CHB patients treated with interferon-based therapy. In combination with other known response markers, HLA-C/KIR genotype could enable the selection of patients more likely to respond to interferon-based therapy.

Intestinal carriage of Staphylococcus aureus: how does its frequency compare with that of nasal carriage and what is its clinical impact?

The bacterial species Staphylococcus aureus, including its methicillin-resistant variant (MRSA), finds its primary ecological niche in the human nose, but is also able to colonize the intestines and the perineal region. Intestinal carriage has not been widely investigated despite its potential clinical impact. This review summarizes literature on the topic and sketches the current state of affairs from a microbiological and infectious diseases' perspective. Major findings are that the average reported detection rate of intestinal carriage in healthy individuals and patients is 20% for S. aureus and 9% for MRSA, which is approximately half of that for nasal carriage. Nasal carriage seems to predispose to intestinal carriage, but sole intestinal carriage occurs relatively frequently and is observed in 1 out of 3 intestinal carriers, which provides a rationale to include intestinal screening for surveillance or in outbreak settings. Colonization of the intestinal tract with S. aureus at a young age occurs at a high frequency and may affect the host's immune system. The frequency of intestinal carriage is generally underestimated and may significantly contribute to bacterial dissemination and subsequent risk of infections. Whether intestinal rather than nasal S. aureus carriage is a primary predictor for infections is still ill-defined.

Intrahepatic IP-10 mRNA and plasma IP-10 levels as response marker for HBeAg-positive chronic hepatitis B patients treated with peginterferon and adefovir.

INTRODUCTION: Interferon-y-inducible protein-10 (IP-10), also called CXCL10, is produced by different types of cells such as monocytes, neutrophils and hepatocytes. IP-10 functions as an inflammatory cytokine, which after binding to its receptor CXCR3, expressed on T-lymphocytes, leads to immune activation. We aimed to establish if IP-10 expression in liver tissue and in plasma of chronic hepatitis B (CHB) patients correlated with each other and further to investigate if IP-10 levels before and during therapy with peginterferon and adefovir could predict treatment outcome in CHB patients. PATIENTS AND METHODS: A total of 86 CHB patients (41 HBeAg-positive and 45 HBeAg-negative) received combination therapy of peginterferon and adefovir for 48 weeks. Combined Response (CR) (HBeAg-negativity, HBV-DNA ≤ 2000 IU/mL, ALT normalization) and non-response (NR) were assessed at Week 72. Plasma IP-10 levels were measured at baseline and during treatment at Day 3 (D3) and Week 1 (W1). Pre-treatment liver biopsies from 40 of 86 patients were obtained and stored in liquid nitrogen for the analysis of intrahepatic IP-10 mRNA expression. RESULTS: CR was achieved in 14/41 HBeAg-positive and 17/45 HBeAg-negative patients. Mean baseline plasma IP-10 levels were significantly higher in HBeAg-positive patients with CR than NR (3.20 vs 3.00 log pg/mL p = 0.03); but not in HBeAg-negative patients. Baseline IP-10 levels correlated with ALT-levels in HBeAg-positive and -negative patients (both p < 0.001), and with a decline of HBsAg-levels of ≥0.5 log IU/mL at Week 12 in HBeAg-positive patients (p = 0.001). Plasma IP-10 levels were associated with intrahepatic IP-10 mRNA expression, however, more strongly in HBeAg-positive (R = 0.79, p < 0.001) than in HBeAg-negative patients (R = 0.53, p = 0.011). IP-10 levels only correlated with HAI-scores in HBeAg-positive patients (R = 0.40 p = 0.025). Mean plasma IP-10 levels of both HBeAg-positive and -negative patients increased significantly at D3 compared to baseline (+0.30 log pg/mL p = 0.003), to then decline subsequently at W1 to a level still significantly higher than baseline (+0.14 log pg/mL p < 0.001). The increase of IP-10 was significantly higher in HBeAg-positive patients with NR than in those with CR (+0.35 versus +0.11 log pg/mL p = 0.003). CONCLUSIONS: Baseline plasma IP-10 levels and IP-10 mRNA expression in the liver are correlated with each other, suggesting that plasma IP-10 reflects intrahepatic immune activation. Higher IP-10 levels at baseline seem to be associated with CR in HBeAg-positive patients treated with peginterferon and adefovir, but not in HBeAg-negative patients.

Upregulation of CXCR3 expression on CD8+ T cells due to the pervasive influence of chronic hepatitis B and C virus infection.

Chronic systemic 'latent' viral infections such as Cytomegalovirus infection (CMV) are known to leave a fingerprint in the total T-cell population. We investigated whether chronic infections with a 'persistent' viremia, such as chronic hepatitis B and C (CHB, CHC), characterized by local organ-specific inflammation, also impact the total peripheral T-cell population or other virus specific T-cells that do not target hepatitis viruses. No phenotypic or functional differences were found between CD8(+) T-cells or CMV- or Epstein-Barr virus specific T-cells in viral hepatitis and healthy controls (HC). However, expression of chemokine-receptor CXCR3 was significantly higher on total peripheral CD8(+) T-cells of CHB or CHC patients compared to HC (p<0.005) which may reflect the pervasive influence of a persistent viral infection, even when restricted to the liver. In CHB higher CXCR3 expression was associated with positive HBeAg-status and correlated with the percentage of HBsAg expressing hepatocytes found in liver biopsies, both pointing to a relation between CXCR3 expression and disease activity. In fact chemokine-receptors such as CXCR3 are important for T-cell recruitment to the liver and chemokine-ligands specific for CXCR3 are upregulated in chronic hepatitis. Modulating chemokine(receptor) expression could be a potential target for future therapy to optimize the anti-viral immunologic environment in the liver.