Efecto "in vitro" de los corticoides sobre la replicación del virus C. Efecto "in vivo" de los corticoides a dosis bajas y prolongadas sobre la hepatopatía crónica por virus C

Zusammenfassung

There are multiple clinical entities which need long-term, low-dose oral corticosteroids. The prevalence of hepatitis C virus (HCV) infection in general population is high and, therefore, it is not infrequent to use corticosteroids with or without azathioprine in HCV-infected patients for different diseases which sometimes are associated to the virus itself. However, there is no information enough to consider corticosteroids as beneficial or harmful drugs on natural history of chronic hepatitis C. The aims of this study were: 1) to study the in vitro effect of prednisone and azathioprine on HCV replication in a subgenomic replicon; 2) to evaluate the effect in vivo (variation in AST, ALT, HCV RNA and liver fibrosis) of low-dose corticosteroids for prolonged time with or without azathioprine in patients with chronic hepatitis C receiving this therapy for other reasons. Material and Methods: Aim 1: subgenomic replicon Ava.5 and human hepatoma cell line Huh.7 were used. Huh.7 cells harbouring a subgenomic HCV replicon system were cultured with different doses of prednisone, azathioprine and ribavirin plus interferon-α. We measured HCV RNA by reverse transcriptase PCR. β-actin mRNA was quantified and used as an endogenous reference. Aim 2: retrospective-prospective observational study of 28 patients with chronic hepatitis C treated with corticosteroids at low-doses (≤30mg/day) with or without azathioprine for more than 6 months. AST, ALT, HCV RNA and liver fibrosis were determined, and results were compared with a control group of nontreated chronic hepatitis C patients. Results: Aim 1: prednisone did not produce any effect on HCV replication while ribavirin plus interferon-α inhibited HCV replication. Azathioprine led to cell death. Aim 2: mean age was 47.2±10.4 years. 42.9% were male. Mean dose of prednisone was 9.1±4.9 mg/day (range: 2.5 – 30mg/day). Mean treatment time was 76.3±79.6 months (range: 7.4 – 349.4 months). 35.7% received concomitant azathioprine. Transaminases decreased significantly only within the first three months of treatment (AST from 93.7±99.6 to 55.2±42.9 UI/ml, p=0.006; ALT from 135.1±149.1 to 82.8±77 UI/ml, p=0.002), with non-significant changes thereafter. Corticosteroids led to a non-significant increase in HCV RNA, and a non-significant increase in fibrosis: from 2.11 to 2.25 (p=0.42) - mean follow-up 123.6±88 months (range: 22.3 – 329.1 months), as compared to non-treated subjects: from 1.77 to 2.02 (p = 0.007) - mean follow-up 21.6±7.9 months (range: 12.2 – 41.6 months). When fibrosis progression was adjusted considering the time between examinations in years, progression was also lower in treated cases (0.054±0.25 units versus 0.196±0.6 units, p=0.26). Conclusion: Corticosteroids in vitro did not affect HCV replication. Corticosteroid in vivo caused a significant initial decrease in transaminases, non-significant changes in HCV RNA, and a trend to a slower fibrosis progression in comparison to a control group. Therefore, orticosteroids did not accelerate progression of chronic hepatitis C.