Changes in ultrastructure of hepatocytes and liver test results before,during, and after treatment with interferon-β in patients with HBeAg-positive chronic active hepatitis

We studied the histological and ultrastructural changes in the liver and alterations in the liver test results before, during, and after treatment with human interferon- from five patients with hepatitis B e antigen-positive chronic active hepatitis. A daily dose of 3×10⁶ to 6×10⁶ units of interferon- was given intravenously for four weeks. The total index of periportal and portal inflammation, intralobular degeneration, and focal necrosis before treatment was decreased significantly six months after treatment (P<0.05). Ultrastructurally, the structure of endoplasmic reticulum was irregularly shaped or fragmentally decreased during treatment, but these disappeared six or 12 months after treatment. Glycogen particles diminished greatly during treatment. The alanine aminotransferase concentrations in these patients increased during treatment. Serum albumin and cholinesterase levels decreased significantly at the fourth week of treatment (P<0.01) and at the third day (P<0.01) to the second week (P<0.05) of treatment, respectively. These results suggest that interferon- injures endoplasmic reticulum and glycogen areas and damages the cholinesterase activity in the early stage of treatment and protein synthesis in patients with hepatitis B e antigen-positive chronic active hepatitis.     

Circulating levels of interleukin-6, vascular endothelial growth factor, YKL-40, matrix metalloproteinase-3, and total aggrecan in spondyloarthritis patients during 3 years of treatment with TNFα inhibitors

The objectives of the study were to investigate short and long-term changes and relations to treatment response of plasma interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), YKL-40, matrix metalloproteinase-3 (MMP-3), and total aggrecan in patients with spondyloarthritis (SpA) treated with tumor necrosis factor-alpha (TNFα) inhibitors and to compare with levels in healthy subjects. Biomarkers were measured in an observational cohort of 49 SpA patients (ankylosing spondylitis, n = 32, and psoriatic arthritis, n = 17) initiating TNFα inhibitor therapy (infliximab, n = 38; etanercept, n = 8; and adalimumab, n = 3) and compared with levels in healthy subjects. Clinical parameters and biomarkers were measured at baseline, weeks 2, 6, and every 6–12 weeks for up to 3 years. Patients with co-morbidities (n = 4), missing baseline samples (n = 3), and adverse events (n = 5) were excluded. Patients with SpA had compared with healthy subjects elevated IL-6 (median 8.5 ng/l (range, 0.98–64) vs. 1.3 (0.33–26)), VEGF (105 ng/l (22–752) vs. 45 (12–351)), YKL-40 (74 μg/l (14–572) vs. 43 (20–184)), and MMP-3 (43 μg/l (9.1–401) vs. 16 (2.5–47), p ≤ 0.001), whereas total aggrecan was lower (662 μg/l (223–2,219) vs. 816 (399–2,190),p ≤ 0.001). Two weeks after first treatment, all biomarker levels changed towards normal levels (p ≤ 0.03) in clinical responders (n = 24), and persistent reductions over 3 years were found in IL-6, VEGF, YKL-40, and MMP-3. Only MMP-3 decreased (p ≤ 0.02) in non-responders (n = 13). The study demonstrated changes of plasma IL-6, VEGF, YKL-40, MMP-3, and total aggrecan and a potential value for monitoring disease activity and treatment response in SpA patients. Larger prospective studies are required to clarify clinical utility of these biomarkers.     

High ability to predict the treatment outcome of peginterferon and ribavirin combination therapy based on the reduction in HCV RNA levels at 4?weeks after starting therapy and amino acid substitutions in the hepatitis C virus in patients infected with HCV genotype 1b

Background

The ability to predict the outcome of peginterferon (PEG-IFN) and ribavirin combination therapy based on the reduction in hepatitis C virus (HCV) RNA levels at 4?weeks after starting the therapy and amino acid substitutions in HCV was to be confirmed.

Methods

We measured the reduction in HCV RNA levels at 4?weeks after starting the combination therapy, as well as examining amino acid substitutions at residue 70 in the HCV core and within the interferon sensitivity-determining region (ISDR) of HCV non-structural protein 5A (NS5A), for 101 patients infected with HCV genotype 1b. The ability of these factors to predict a sustained virologic response (SVR) was analyzed.

Results

When a 3 log₁₀ reduction in HCV RNA levels at 4?weeks after starting therapy was set as the cut-off value, an SVR was achieved in 37 of the 46 patients (80.4%) with a ??3 log₁₀ decrease and in 4 of the 55 patients (7.3%) with a <3 log₁₀ decrease. All 4 patients who achieved an SVR despite a <3 log₁₀ reduction in HCV RNA levels at 4?weeks had an arginine at residue 70 in the HCV core and a non-wild-type sequence for the ISDR of HCV NS5A.

Conclusion

A ??3 log₁₀ reduction in HCV RNA levels at 4?weeks after starting therapy indicates that a patient has a high likelihood of achieving an SVR as a final outcome. Additional information on the amino acid substitutions at residue 70 in the HCV core and within NS5A-ISDR will further increase the ability to predict a clinical response.