Natural Killer Cell Characteristics in Patients With Chronic Hepatitis B Virus (HBV) Infection Are Associated With HBV Surface Antigen Clearance After Combination Treatment With Pegylated Interferon Alfa-2a and Adefovir

The role of natural killer (NK) cells in the process of hepatitis B virus (HBV) surface antigen (HBsAg) clearance and whether their phenotype is related to treatment outcome in patients with chronic hepatitis B are currently unknown. Patients with chronic hepatitis B (HBV DNA load, >17 000 IU/mL) were treated with pegylated interferon alfa-2a and adefovir for 48 weeks. NK cell phenotype and function were analyzed in 7 responders (defined as individuals with HBsAg clearance by week 72; 3 HBV e antigen [HBeAg]-positive and 4 HBeAg-negative), 7 matched nonresponders, and 7 healthy controls. Subsequently, 34 baseline samples from HBeAg-positive patients with chronic hepatitis B were analyzed. During treatment, the percentage and absolute number of CD56(bright) NK cells increased significantly, whereas the percentage and absolute number of CD56(dim) NK cells decreased. At baseline, responders had a significantly lower expression of chemokine receptor CX3CR1 on CD56(bright) NK cells and inhibitory receptor NKG2A on CD56(dim) NK cells, compared with nonresponders. In addition, responders had higher CD56(bright) TRAIL expression and interferon γ production at end of treatment. These baseline differences were not found in HBeAg-positive patients who had HBeAg seroconversion without HBsAg clearance. Combination therapy significantly influences NK cell phenotype and function. Differences between patients with chronic hepatitis B with HBsAg clearance and nonresponders suggest that NK cells play a role in the clearance of HBsAg during interferon-based combination therap

Factor XIII Val34Leu mutation accelerates the development of fibrosis in patients with chronic hepatitis B and C

Aim: There is considerable variation in liver fibrosis stage and progression to cirrhosis among patients with chronic hepatitis B (CHB) or C (CHC). Coagulation pathway activity due to genetic variations could influence the rate of fibrosis. We investigated thrombotic risk factors and their association with the extent and progression of fibrosis in CHB or CHC patients. Methods: In total, 194 patients with CHB (n = 88) or CHC (n = 106) were included. Data on demographic and laboratory findings were collected. Liver biopsies were evaluated according to the Ishak classification system. Fibrosis progression rate (FPR), defined as ratio of fibrosis score to duration of infection, was determined for 131 patients. Prevalence of factor V Leiden, prothrombin G20210A, plasminogen activator inhibitor type-1 (PAI-1) 4G/5G and factor XIIIA Val34Leu mutations was evaluated. Results: Heterozygosity for factor V Leiden, prothrombin G20210A, PAI-1 4G/5G and factor XIIIA Val34Leu mutations was present in 3.1%, 2.1%, 49% and 28% of the patients, respectively. Factor XIII Val34Leu mutation was a risk for enhanced FPR (odds ratio 4.7; P = 0.01). In patients with both factor XIII Val34Leu and PAI-1 4G/5G mutations the risk of an accelerated FPR was further increased (odds ratio 5.0; P = 0.02). Mutations of the other thrombotic genes were not significantly associated with fibrosis stage and FPR. Conclusion: Our data show that factor XIII Val34Leu mutation alone or in combination with PAI-1 4G/5G mutation is a risk factor for an increased rate of liver fibrosis development in patients with CHB or CH

HBsAg loss in patients treated with peginterferon alfa-2a and adefovir is associated with SLC16A9 gene variation and lower plasma carnitine levels

Achievement of HBsAg loss remains the hallmark of chronic hepatitis B treatment. In order to identify host factors contributing to treatment-induced HBsAg loss, we performed a genome-wide screen of single nucleotide polymorphisms (SNPs) and studied its immunological consequence. Chronic hepatitis B patients (40 HBeAg-positive and 44 HBeAg-negative) treated with peginterferon alfa-2a and adefovir were genotyped for 999,091 SNPs, which were associated with HBsAg loss at week 96 (n = 9). Plasma carnitine levels were measured by tandem-mass spectrometry, and the effect of carnitine on the proliferative capacity of hepatitis B virus (HBV)-specific and non-specific CD8 T cells was studied in vitro. One polymorphism, rs12356193 located in the SLC16A9 gene, was genome-wide significantly associated with HBsAg loss at week 96 (p = 1.84 × 10(-8)). The previously reported association of rs12356193 with lower carnitine levels was confirmed in our cohort, and baseline carnitine levels were lower in patients with HBsAg loss compared to patients with HBsAg persistence (p = 0.02). Furthermore, we demonstrated that carnitine suppressed HBV-specific CD8 T cell proliferation. In chronic hepatitis B patients treated with peginterferon and adefovir, we identified strong associations of SLC16A9 gene variation and carnitine levels with HBsAg loss. Our results further suggest that a lower baseline plasma carnitine level increases the proliferative capacity of CD8 T cells, making patients more susceptible to the immunological effect of this treatment. These novel findings may provide new insight into factors involved in treatment-induced HBsAg loss, and play a role in the prediction of treatment outcom