NATAP - DDW Liver Conference, San Diego, May 21-24 - Report 1
IL-10 for HCV: an experimental immune modulator in development
Sunday evening at the DDW Symposium, Bruce Bacon, MD, talked about the development and experimental use of IL-10. He said IL-10 appears to have important antifibrotic properties in patients with chronic HCV infection who had failed to respond to interferon/ribavirin. These comments were in part based on a report in a recent issue of Gastroenterology, described below. Bacon went on to say that in this pilot study Nelson and coworkers found significant improvement in fibrosis scores in a group of patients receiving IL-10. It is unknown whether this improvement is due to anti-inflammatiry properties of IL-10 or as a direct antifibrotic effect. IL-10 is being developed bt Schering Plough, and is being tested in several study centers. The use of IL-10 may have utility for individuals who previously were unable to achieve a sustained virologic response with standard HCV therapy. An improvement in ALT and fibrosis from IL-10 use may improve subsequent response to IFN+RBV. Since IL-10 is an immune modulator its affect in people coinfected with HCV and HIV is unknown. It may or may not have undesirable affects on people with coinfection so experimentation without proper research is not recommended. The use of any immune modulator may have undesired affects in HCV/HIV coinfection and needs research before clinical may.
In the March 10 2000 issue of Gastroenterology, David Nelson et al reported on a small pilot study of 1L-10. Here is a brief summary of their report. Interleukin (IL)-10 is a cytokine that down-regulates the proinflammatory response and has a modulatory effect on hepatic fibrogenesis. The aim of this study was to determine the effect of IL-10 on hepatic injury in patients with chronic hepatitis C. Twenty-four patients with chronic hepatitis C who had not previously responded to interferon-based therapy were enrolled in a randomized, double-blinded 2-dose trial in which they received either 4 or 8 µg/kg IL-10 subcutaneously daily for 90 days. Liver biopsies were performed before and
at the end of therapy. IL-10 was well tolerated with 22 patients completing the study. Serum ALT levels normalized in 19 of 22 patients by the end of therapy and weresustained in 5 of 22. Hepatic inflammation decreased in 19 of 22 patients, with 11 having a decrease by 2. Fibrosis decreased in 14 of 22 patients (mean change, 3.6-2.6; P= 0.001). There was no change in serum HCV RNA levels. IL-10 therapy was associated with changes in serological markers, suggesting a reduction of immune response and fibrogenesis. The degree of regression of liver fibrosis and histological improvement observed after only 12 weeks of IL-10 in this pilot study is similar to that previously reported in treatment-naive patients with chronic hepatitis C who responded to 48 weeks of IFN-based therapy.
Safety analysis was performed on all 24 patients who received study medication. rIL-10
was well tolerated with minimal side effects. The most frequent clinical adverse events during treatment with rIL-10 were headache, dry mouth, and insomnia. These were not dose limiting in any patient. Mild anemia occurred during the first 4 weeks of therapy in most subjects with an average decrease in hemoglobin level of 2.2 ± 0.3 g/dL. Hemoglobin levels stabilized without dose reduction and returned to baseline after completion oftreatment. The platelet count decreased slightly during therapy (by 14,000/dL; P = NS), and there was no effect on neutrophil counts. Anecdotally, most patients reported improvement in arthralgias, myalgias, fatigue, and disturbed sleep patterns during treatment, but these symptoms returned when the drug administration was stopped. Of 12 patients receiving higher dose of 8 ug/ml daily subcutaneously, 9 experienced headaches, 3 dry mouth/thirst, 2 sleep disturbances, 1 abdominal pain/nausea, 2 rash, 1 anxiety.
The authors concluded, importantly, this study selected refractory patients with chronic hepatitis C who had not responded to one or several courses of treatment with interferon alone or in combination with ribavirin. The degree of regression of liver fibrosis and histological improvement observed after only 12 weeks of IL-10 in this pilot study is similar to that previously reported in treatment-naive patients with chronic hepatitis C who responded to 48 weeks of IFN-based therapy. Here is the link to the more detailed report on the NATAP web site:
http://www.natap.org/april_2000/interleukin_10_treatment_reduces_4300.html
IL-10 HEPATIC DEFICIT IN HEPATITIS C VIRUS (HCV) INFECTION (abstract at DDW 2000)
Sebastien Dharancy, Emmanuelle Leteurtre, Luc Gambiez, Valerie Canva, Francois Rene Pruvot, Jean Claude Paris, Pierre Desreumaux, Gastroenterologie et hepatologie, Lille, France; Anatomo-pathologie, Lille, France; Chirurgie Adult Ouest, Lille, France.
Infection with HCV leads to chronic hepatitis in 70% of patients. Immunologic dysfunctions are implicated in the control of viral persistence and hepatic injury but their mechanisms remain unclear. IL-10 is a cytokine with immunomodulatory properties inhibiting the production of inflammatory cytokines and regulated virus-related lesions (1). Its hepatic production during HCV infection is unknown. Aim: To compare hepatic IL-10 mRNA concentrations in patients with chronic hepatitis C and controls. Methods: Sixteen non treated patients with chronic HCV infection (age 39y, 13M, 3F) and 8 healthy controls (age 59y, 4M, 4F) had liver biopsies. Hepatic IL-10 mRNA concentrations were quantified on the total liver sample by competitive PCR (number of IL-10 molecules/103 -actin molecules) and analyzed according to the intensity of hepatic inflammation and fibrosis (METAVIR score) and to the level of viral replication (number of copies/µl). Results: Concentrations of IL-10 mRNA were decreased in patients with chronic hepatitis C (282317) as compared to controls (482169)(p=0.01). No correlation between IL-10 mRNA levels and METAVIR scores or viral loads was found. Conclusion: Concentration of IL-10 was decreased in the liver of patients with chronic HCV infection. This deficit may be involved in hepatic lesions induced by HCV and may support the beneficial therapeutic effects of recombinant human IL-10 in patients with chronic HCV infection (2). 1 Nishio, et al. Circulation 1999;100:1102.; 2. McHutchinson, et al. Gastroenterology 1999;116:L284.
INTERLEUKIN-10, INTERLEUKIN-15, SOLUBLE TUMOR NECROSIS FACTOR- RECEPTORS AND TRANSFORMING GROWTH FACTOR- 1 IN HEPATITIS C VIRUS INFECTION: RELEVANCE TO PATHOGENESIS AND CLINICAL MANAGEMENT (abstract at DDW 2000
Sawsan A. Omran, Nora E. El-Bassiouni, Azza E. El Bassiony, Naglaa H. El-Sherif, Maha M. Akl, Abdel-Moneim T. Hussein, Theodore Bilharz Research Institute, Giza, Egypt; Military Med Acad, Cairo, Egypt.
Cytokines may be implicated in the pathogenesis of hepatitis C virus infection. In this study, the serum levels of IL-10, IL-15, soluble TNF- receptors, TNF-RI (p55) & -RII (p75) and TGF-1 were assessed in 42 patients with type C hepatitis, 13 asymptomatic carriers with persistently normal serum ALT values, 18 patients with chronic hepatitis (CH) and 11 patients with liver cirrhosis (LC) using enzyme immunoassays. Cytokine levels were compared with biochemical response (ALT) and histopathologic grade of liver disease. Serum IL-10, IL-15, TNF-Rs, and TGF-1 levels were significantly higher (p<0.05) in all diseased groups compared to uninfected controls (n= 15). The increase in the levels of IL-15, sTNF-RII and TGF-1 matched the severity of liver disease, the highest values (p<0.01) were encountered in patients with LC. A positive correlation was detected between serum levels of IL-15 and ALT values (r= 0.72, p<0.01) in patients with LC. Assessment of cytokine levels in 12 patients with CH during interferon- therapy (12 wks) revealed a significant decline in circulating IL-10 and IL-15 levels, which paralleled the decrease in serum ALT values. Further, both cytokines remained at low levels in patients with sustained responses. Therapy, however, did not affect serum levels of sTNF-Rs and TGF-1. These findings indicate that serum levels of IL-15 and TGF-1 correlated with the disease progress in chronic hepatitis C infection and may reflect the degree of liver disease necroinflammatory activity. Data may also suggest that modulation of T cell function and cytokine production may be one mechanism whereby IFN- therapy results in reduction of viral burden in hepatitis C infection.