Intensification with pegylated interferon during treatment with tenofovir in HIV-hepatitis B virus co-infected patients.

In hepatitis B "e" antigen (HBeAg) positive patients with hepatitis B virus (HBV) mono-infection, intensification of nucleos(t)ide analogue treatment with pegylated interferon (PegIFN) could help induce higher HBeAg seroclearance rates. Our aim was to determine the long-term effect of adding PegIFN to tenofovir (TDF)-containing antiretroviral therapy on seroclearance in HBeAg-positive patients co-infected with the human immunodeficiency virus (HIV) and HBV. In this prospective matched cohort study, 46 patients with 1-year PegIFN intensification during TDF-containing antiretroviral therapy (TDF+PegIFN) were matched 1:1 to controls undergoing TDF without PegIFN (TDF) using a time-dependent propensity score based on age, CD4+ count and liver cirrhosis status. Kinetics of HBeAg quantification (qHBeAg) and hepatitis B surface antigen quantification (qHBsAg) were estimated using mixed-effect linear regression and time to HBeAg seroclearance or HBsAg seroclearance was modelled using proportional hazards regression. At baseline, previous TDF exposure was a median 39.8 months (IQR=21.4-59.4) and median qHBeAg and qHBsAg levels were 6.9 PEIU/mL and 3.72 log10 IU/mL, respectively (P>.5 between groups). Median follow-up was 33.4 months (IQR=19.0-36.3). During intensification, faster average declines of qHBeAg (-0.066 vs -0.027 PEIU/mL/month, P=.001) and qHBsAg (-0.049 vs -0.026 log10 IU/mL/month, P=.09) were observed in patients undergoing TDF+PegIFN vs TDF, respectively. After intensification, qHBeAg and qHBsAg decline was no different between groups (P=.7 and P=.9, respectively). Overall, no differences were observed in HBeAg seroclearance (TDF+PegIFN=13.2 vs TDF=12.6/100 person·years, P=.5) or HBsAg seroclearance rates (TDF+PegIFN=1.8 vs TDF=1.3/100 person·years, P=.7). In conclusion, PegIFN intensification in HBeAg-positive co-infected patients did not lead to increased rates of HBeAg or HBsAg clearance, despite faster declines of antigen levels while on PegIFN.

Discordance between biochemical markers of liver activity and fibrosis (Actitest-Fibrotest) and liver biopsy in patients with chronic hepatitis C.

INTRODUCTION: The purpose of this clinical trial was to determine in routine practice and in comparison with liver biopsy the limitations of two blood tests, Actitest and Fibrotest, for the evaluation of hepatic activity and fibrosis in patients with chronic hepatitis C. METHODS: Routine blood tests, Actitest and Fibrotest, and liver biopsy were performed in 96 patients with chronic hepatitis C attending routine outpatient clinics. Receiver operating characteristics (ROC) curves were used to assess the diagnostic value of the biochemical tests in comparison with the METAVIR classification. RESULTS: The study population was predominantly male (63.5%) with a mean age of 48 years; 83.3% of the patients had genotype 1 hepatitis C virus infection. Treatment status was naive (62.5%), nonresponders (17.7%), relapsers (7.3%), or unknown (12.5%). The comparison of F0-F2 versus F3-F4 estimated the negative predictive value at 92% and the positive predictive value at 52% for a cut-off of 0.455. Discrepancies in activity score were more frequently due to a higher score of the biochemical test compared to biopsy (18 cases out of 19). Discrepancies for fibrosis were observed in 18 patients with a higher score for biochemical test in eight and a higher score for liver biopsy in 10 cases. A significant increase of gamma-glutamyl-transferase (GGT) (p=0.0001) and alanine aminotransferase (ALT) (p<0.0001) was observed in case of biochemical test overestimation of activity, and a significant increase of alpha2-macroglobulin (p=0.006) and GGT (p=0.018) in case of biochemical test overestimation of fibrosis. CONCLUSION: This prospective study confirms the good diagnostic value of biochemical tests for necrotico-inflammatory activity and fibrosis as compared with the histological analysis of liver biopsy. Clinicians must interpret Actitest and Fibrotest results with caution in patients with a significant elevation of ALT, and/or GGT and/or alpha2-macroglobulin which could overestimate hepatic injury.

[Value of high-dose interferon-alpha in chronic viral hepatitis C patients non-responder to a 1st treatment. Pilot study prospective and randomized trial]. / Intérêt de l'interféron alpha à forte dose chez les malades atteints d'une hépatite virale chronique C non répondeurs à un premier traitement. Etude pilote prospective et randomisée.

OBJECTIVES: The aim of this study was to evaluate the efficacy of two different doses of alpha interferon (IFN) for retreatment in chronic hepatitis C patients who were non responders to initial treatment by IFN at a dose of 3 MIU TIW for 6 months. METHODS: This open, pilot, prospective, randomized and bicentric study included patients with biopsy-proven chronic hepatitis C. Non response was defined as serum ALT levels > 2 upper limit of normal for the entire first treatment period, HCV RNA positivity by PCR at the end of the first treatment period, and the persistence of histologically-proven chronic active hepatitis after the first treatment period. Patients were randomized into two groups: group I received IFN alpha 2b 10 MIU TIW for 2 months, then 6 MIU TIW for 4 months, group 2 received IFN alpha 2b 6 MIU TIW for 6 months. RESULTS: Twenty three patients (17 male, 6 female, mean age: 38.7 +/- 9.1 years) were included: 14 were randomized in group 1 and 9 in group 2. Both groups were similar for the main clinical, biochemical, and histological variables. At the end of retreatment, 2 patients (14.2%) had biochemical and virological response in group 1 and 4 in group 2 (44.4%) (non significant). Only one biochemical and virological sustained response was observed in group 2 (11.1%) (non significant). There was no difference between the groups for complete and sustained response. An overall statistical significant improvement of Knodell score was observed (7.8 +/- 3.8 vs 9.6 +/- 3.2, P < 0.02) in the 18 patients who had a second biopsy 6 months after the end of therapy, while the Knodell score did not change at the end of the first treatment period. This improvement was statistically significant in group 2 (5.4 +/- 3.0 vs 9.2 +/- 9.5 before treatment, P < 0.02) and concerned intralobular necrosis (P < 0.05). The Metavir index did not change. The number of side-effects was similar in both groups. CONCLUSIONS: These results suggest that histological improvement may be obtained after IFN retreatment in some patients who are non-responders to the first treatment, despite an absence of biochemical and/or virological response.

Role of anti-interferon antibodies in breakthrough occurrence during alpha 2a and 2b therapy in patients with chronic hepatitis C.

BACKGROUND/AIMS: Alpha interferon induces aminotransferase normalization in about 50% of patients with chronic viral hepatitis C. However, some patients who initially respond experience a relapse during the treatment period (breakthrough phenomenon). The aim of this study was to evaluate the prevalence of breakthrough and its relationship with the emergence of neutralizing anti-interferon antibodies. METHODS: We studied 172 patients with histologically proven chronic hepatitis C, treated with interferon alpha 2a or 2b 3 mega units three times a week for 6 months. For each patient, HCV RNA level (polymerase chain reaction and bDNA) and anti-interferon antibodies dosage were determined during therapy. RESULTS: Among 84 patients with initial response, 13 (15.5%) experienced breakthrough. The kinetics of alanine aminotransferase and HCV RNA levels were strongly correlated, suggesting that breakthrough is not due to a random alanine aminotransferase fluctuation during treatment, but to the reappearance of viral replication. Neutralizing anti-interferon antibodies emergence was observed in 38.5% in patients with breakthrough, as compared to 9.0% and 2.8% of non-responder and complete-responder patients, respectively (p<0.0005). By multivariate analysis, the only factor predictive of breakthrough was the emergence of neutralizing anti-interferon antibodies 3 months after the onset of therapy. CONCLUSION: Our results suggest that the emergence of neutralizing anti-interferon antibodies during treatment may explain breakthrough in about one third of cases. Other causes may also be responsible for this phenomenon and they remain to be determined.

Prevalence and significance of anticardiolipin, anti-beta2 glycoprotein I and anti-prothrombin antibodies in chronic hepatitis C.

Antiphospholipid antibodies have been demonstrated in chronic hepatitis C, but their clinical and pathogenetic significance remains elusive. We prospectively studied 115 patients (85 men, mean age 36.9 years) with chronic hepatitis C without cirrhosis and treated by alpha-interferon (alpha-IFN). Antiphospholipid determinations comprised anticardiolipin (ACA), anti-beta2-glycoprotein I and anti-prothrombin antibodies of the IgG and IgM classes. At entry, 24 patients (21%) were found to possess low to moderate ACA levels (18 IgG, two IgM and four both isotypes) compared with only 4/115 age- and sex-matched control subjects (3.5% P=0.001). ACA positivity rate increased to 31% (P=0.01) after a 6-month course of alpha-IFN treatment. In contrast, the prevalence of anti-beta2-glycoprotein I and anti-prothrombin antibodies was not significantly different from controls at either time point. The presence of ACA correlated with that of antinuclear antibodies (P=0.0002), but was not associated with parameters such as histological activity, viral burden and response to alpha-IFN, nor with a history of thrombosis or pregnancy loss. However, a non-significant trend of higher incidence of mild thrombocytopenia among ACA-positive patients was observed. We conclude that low-titre ACA positivity is a common finding in patients with chronic hepatitis C, especially following alpha-IFN treatment, but does not select a category with different clinical features. These data are in keeping with the absence of associated anti-beta2GPI and anti-prothrombin antibodies, and do not support a role for HCV infection in the pathogenesis of the antiphospholipid syndrome.

Tenoxicam, a non-steroid anti-inflammatory drug, is unable to increase the response rate in patients with chronic hepatitis C treated by alpha interferon.

The purpose of this study is to compare a combination of interferon (IFN)-alpha2a (Roferon) + Tenoxicam with IFN-alpha2a alone in the treatment of chronic hepatitis C. This prospective, randomized double-blind study included 149 patients, all of whom were diagnosed with active chronic hepatitis C but non-cirrhotic (ALT > or = 1.5 upper limit of normal, anti-hepatitis C virus (HCV) positive by enzyme-linked immunosorbant assay2 and RIBA3). The patients were randomized in two groups, as follows: G1 (n = 76): IFNalpha2a 3 million units times per week during 6 months + placebo; and G2 (n = 73): IFNalpha2a 3 million units three times per week + Tenoxicam (20 mg/day) during 6 months. Alanine aminotransferase (ALT) and HCV RNA were determined before and at months 6 and 12 of treatment. 2'5' oligoadenylate synthetase activity (2'5' AS) was dosed in mononuclear cells before and at 3-month treatment intervals in 28 patients. Liver biopsy was performed before and 6 months after the end of therapy. Parameters were similar before therapy for both groups. Biochemical and virological responses were similar for both groups at month 6 (49.3% vs. 42.9% and 43.3% vs. 38.3%, respectively) and month 12 (28.3% vs. 23.8% and 17.2% vs. 17.5%, respectively). HCV RNA level significantly decreased in both groups at month 6, with no difference whatever the therapy; however, the HCV RNA level returned to initial values at month 12 and was the only significant prognostic factor of a sustained response. No peak of 2'5' AS activity was observed during treatment in patients with dual therapy. A histological improvement was also noted in both groups without difference, regardless of therapy. The percentage of adverse events was identical for both groups. Paracetamol intake, assessed in 80 patients, was 49.1 g per 6 months in the G1 group and 22.5 g per 6 months in the G2 group (not significant). In conclusion, the non-steroid anti-inflammatory drug, Tenoxicam, does not increase IFNalpha efficacy in the treatment of chronic hepatitis C. This combination is well tolerated and partially lowers Paracetamol intake, but not preexisting alpha-IFN adverse events.