Reinforced interferon alpha-2b and ribavirin is more effective than standard combination therapy in the retreatment of chronic hepatitis C previously nonresponsive to interferon: a randomized trial.

Interferon-alpha (IFN) monotherapy results in sustained virological clearance in a minority of patients with chronic hepatitis C. The aim of this study was to assess the effect of a reinforced regimen combining ribavirin and high-dose IFN for 48 weeks compared with a nonreinforced regimen combining a standard IFN regimen and ribavirin for 24 weeks in nonresponders with chronic hepatitis C. A total of 231 patients with chronic hepatitis C and previous nonresponse to IFN monotherapy were randomized. The reinforced group (n = 114) received IFN-2b 6 million units (MU) thrice weekly (TIW) and ribavirin for 48 weeks, and the nonreinforced group (n = 117) received IFN-2b 3 MU TIW and ribavirin for 24 weeks. The main outcome measure was a sustained virological response, defined as negative serum hepatitis C virus (HCV)-RNA 24 weeks following the end of treatment. This endpoint was determined in 98 patients of the reinforced group and 105 patients of the nonreinforced group. At the end of follow-up, a sustained virological response was observed in 29 of the 98 patients (29.6%) in the reinforced group vs 16 of the 105 patients (15.2%) in the nonreinforced group (P = 0.014). In multivariate analysis, factors associated with a sustained virological response were treated with a reinforced regimen [odds ratio (OR) 2.9; P = 0.06] and genotype 2 or 3 (OR 8.8; P < 0.0002). A total of 160 patients had paired biopsies before and after treatment. Histological activity improvement was observed in 32 of 80 patients (40%) and fibrosis worsening in 26 of 80 patients (33%) in the reinforced group vs 13 of 80 (16%) and 19 of 80 (24%) in the nonreinforced group (P = 0.30 and 0.20, respectively). Hence in nonresponders, a high-dose 48-week regimen of IFN and ribavirin combination was more effective than a regimen with interferon at lower dose and ribavirin for 24 weeks only.

Prognostic value of the soluble interleukin-2 receptor in chronic hepatitis C treated with interferon-alfa. Multicenter GER-CYT 04 Group.

BACKGROUND/AIMS: High serum levels of the soluble interleukin 2 receptor (sIL-2R) have been reported in patients with chronic hepatitis C. The aims of this study were to determine the evolution of sIL-2R considered as an indicator of activation of T cells in patients with hepatitis C virus (HCV) treated with IFN-alpha and to correlate sIL-2R serum levels with parameters reflecting ongoing liver disease and with outcome of interferon treatment. METHODS: In a case-control study, we studied patients enrolled in a multicenter randomized clinical trial which had demonstrated the benefit of a reinforced regimen of interferon alpha. Each of the 26 sustained virological responders (SVR) was paired for treatment regimen with two non-responders (NR). RESULTS: Prior to treatment, higher levels of sIL-2R were found in the sera of 78 patients compared with healthy controls (3791+/-210 pg/ml versus 956+/-88 pg/ml (p<0.001)). In the 78 patients after 4 weeks of treatment, the levels of sIL-2R were higher than pretreatment levels (4308+/-206 pg/ml (p<0.01)). In the NR, levels of sIL-2R increased significantly after 4 weeks of treatment compared with pretreatment levels (p<0.01), and levels of sIL-2R at week 72 were not significantly different from those at pretreatment. Conversely, in the SVR, levels of sIL-2R at week 4 did not significantly increase compared to pretreatment values, and thereafter gradually decreased. At week 72, levels of sIL-2R were significantly lower than before treatment (p<0.001). The difference between levels of sIL-2R at week 4 and before initiation of treatment (delta s IL-2R) was smaller in the SVR than in the NR (142+/-219 pg/ml versus 704+/-107 pg/ml (p<0.02). The disappearance of HCV RNA from the serum at week 4 showed a sensitivity of 92% (95% confidence interval 86-98) and a specificity of 60% (95% confidence interval 49-71), delta sIL-2R had a sensitivity of 42% (95% confidence interval 31-53) and a specificity of 81% (95% confidence interval 79-90) for the prediction of a sustained virological response 6 months after stopping treatment. The disappearance of HCV RNA from serum at week 4 and delta sIL-2R were independent and early predictive factors for a sustained virological response 6 months after stopping treatment. CONCLUSIONS: At week 4, delta sIL-2R may be a more specific parameter than the disappearance of HCV RNA for assessing total, and hence more sustained, elimination of HCV infection 6 months after stopping treatment.

Reinforced regimen of interferon alfa-2a reduces the incidence of cirrhosis in patients with chronic hepatitis C: a multicentre randomised trial. Multicentre GER-CYT-04 Group.

BACKGROUND/AIMS: Our aim was to assess and compare the long-term effect of interferon at standard (6 months) and reinforced dose and duration regimens in chronic hepatitis C. METHODS: A multicentre institutional trial included 244 previously untreated patients with chronic hepatitis C, without cirrhosis, who were randomly allocated to either standard (3 MU thrice a week for 24 weeks; n=120) or reinforced (6 MU daily for 12 days, 6 MU thrice a week for 22 weeks, 3 MU thrice a week for 24 weeks; n=124) regimens. The main endpoint was sustained ALT response at 72 weeks (18 months); secondary end-points were virological (branched DNA and PCR) and histological responses (incidence of cirrhosis) at month 18. RESULTS: Sustained ALT response was observed in five patients (4%, 95% confidence interval 0-8%) in the standard group and in 21 patients (18%, 95% confidence interval 11-25%), from the reinforced group (p=0.002), in agreement with virological response in 21 (81%) patients. Cirrhosis at month 18 was observed in ten (10%) patients in the standard group and one (1%) in the reinforced group (p=0.004). CONCLUSIONS: The standard regimen of interferon, in chronic hepatitis C, confers a minimal sustained response rate at 18 months and may not prevent the occurrence of cirrhosis. Reinforced regimens allow sustained response to be reached in a limited number of patients and reduce the risk of cirrhosis during 18 months of follow-up.

Sequential study of serum glycoprotein fucosylation in acute hepatitis.

BACKGROUND: alpha-Fetoprotein is a useful diagnostic marker in hepatocellular carcinoma, during which its serum level increases and its glycan structure is hyperfucosylated. Normally-expressed glycoproteins (alpha 1-antitrypsin and transferrin) are also hyperfucosylated in hepatocellular carcinoma. alpha-fetoprotein serum levels are also increased in conditions associated with hepatic regeneration, such as acute hepatitis. We conducted a longitudinal study of the alpha 1-6 fucosylation pattern of serum alpha-fetoprotein in ten patients with acute hepatitis and compared it to that of transferrin and alpha 1-antitrypsin. METHODS: Protein levels were measured by using immunochemical assays. Crossed affinoimmunoelectrophoresis in the presence of Lens culinaris agglutinin was performed for each protein, and the fucosylation index, corresponding to the agglutinin reactive fraction, was determined. The results were compared to those in 25 healthy donors and five newborns. RESULTS: alpha-Fetoprotein was hyperfucosylated and remained stable throughout the course of the disease. In contrast, serum transferrin and alpha 1-antitrypsin gradually became hyperfucosylated during the course of acute hepatitis. The transferrin and alpha 1-antitrypsin fucosylation indexes correlated with each other, but not with the alpha-fetoprotein fucosylation index. No correlation was found between alpha-fetoprotein, alpha 1-antitrypsin and transferrin fucosylation indexes and the corresponding glycoprotein serum levels. CONCLUSIONS: Hyperfucosylation of alpha-fetoprotein is not specific to hepatocellular carcinoma. Increased alpha 1-6 fucosylation should not be considered solely as a tumour marker, but might also reflect cell proliferation. The study of alpha 1-6 hyperfucosylation process of normally-expressed glycoproteins awaits further investigation, to test its usefulness as a new marker of liver regeneration during the follow-up of acute hepatitis.

Atypical autoantigen targets of perinuclear antineutrophil cytoplasm antibodies (P-ANCA): specificity and clinical associations.

Atypical antineutrophil cytoplasm antibodies (A-ANCA) are defined here as ANCA detected by IIF and not directed against the predominant ANCA antigens, proteinase 3 (PR3) and myeloperoxidase (MPO). A-ANCA are found in a variety of clinical conditions, namely rheumatoid arthritis, inflammatory bowel diseases, chronic hepatic diseases and several infections including HIV infection. They are directed against a variety of still ill-defined neutrophil antigens and most frequently yield a perinuclear pattern (P-ANCA) of binding by indirect immunofluorescence on ethanol fixed neutrophils. This paper reviews the literature on A-ANCA and our recent data suggesting that, among others, cathepsin G is one of the predominant antigen targets of A-ANCA. From a clinical point of view, the distinction between MPO-ANCA and A-ANCA is not possible by indirect immunofluorescence (IIF). The determination of ANCA antigens by specific ELISA is therefore necessary to differentiate P-ANCA with MPO specificity from those with undefined specificity. This is of importance because the clinical value of MPO-ANCA is clearly established while the presence of A-ANCA is difficult to interpret given their occurrence in a large variety of clinical conditions.

US-guided percutaneous liver biopsy with plugging of the needle track: a prospective study in 72 high-risk patients.

The efficiency, accuracy, and safety of ultrasound-guided liver biopsy with plugging of the needle track were prospectively assessed in 72 patients at high risk for hemorrhage. Seventy-eight biopsy procedures were performed in 72 consecutive patients prospectively classified into four different groups on the basis of coagulation parameters. Sixty-two patients (86%) had severe or moderately severe coagulation disorders. Fifty-four biopsy procedures were performed in 50 patients with diffuse liver disease, and 24 were performed in 24 patients with focal liver lesions. The biopsy track was embolized with gelatin particles and thrombin. Biopsy specimens adequate for histologic diagnosis were obtained in 69 of the 72 patients (96%). In focal lesions, accuracy and sensitivity in the diagnosis of malignancy were 75% and 89%, respectively. Two serious bleeding complications (2.8%) were encountered in two of the patients with major coagulation disorders. Liver biopsy with plugging of the needle track is a practical technique and is a feasible alternative to the transjugular approach. Respective indications for both methods depend on the severity of coagulation disorders and the presence of focal lesions.

Detection of serum HBV-DNA by polymerase chain reaction (PCR) in patients before reactivation of chronic hepatitis B.

Reactivation of chronic hepatitis B is characterized by the reappearance of HBV-DNA in serum. The purpose of the study was to determine whether, before reactivation, HBV-DNA would be detectable in serum, using a sensitive procedure of detection, namely polymerase chain reaction (PCR). We studied 17 patients with chronic hepatitis B who experienced an episode of reactivation, defined by the reappearance of HBV-DNA in serum. None of these 17 sera had HBV-DNA demonstrable by dot-blot hybridization nor liquid hybridization in sera collected before reactivation. Using PCR, HBV-DNA was detected, before reactivation, in 13 of the 17 episodes of reactivation tested with Southern-blot and hybridization. HBV-DNA was not detectable with PCR in the serum of four patients who subsequently experienced an episode of reactivation. In conclusion, our results show low level HBV replication before reactivation in most, but not all, HBs-positive, HBV-DNA-negative patients. This suggests that reactivation may occur even in patients with no HBV-DNA demonstrable in serum with PCR prior to reactivation.

Retroperitoneal fibrosis after surgery for aortic aneurysm in a patient with periarteritis nodosa: successful treatment with corticosteroids.

A 54-year-old man with hepatitis B virus-related periarteritis nodosa developed retroperitoneal fibrosis with bilateral hydronephrosis 2.5 months after placement of an aortobifemoral prosthesis for abdominal aortic aneurysm. Retroperitoneal fibrosis disappeared after treatment with corticosteroids. This observation is interesting in the light of the hypothesis that retroperitoneal fibrosis is caused by vasculitis.