The Complement System and C1q in Chronic Hepatitis C Virus Infection and Mixed Cryoglobulinemia

Only 15 to 20 percent of patients with chronic hepatitis C have a sustained virologic response to interferon therapy. We compared the efficacy and safety of recombinant interferon alfa-2b alone with those of a combination of interferon alfa-2b and ribavirin for the initial treatment of patients with chronic hepatitis C. We randomly assigned 912 patients with chronic hepatitis C to receive standard-dose interferon alfa-2b alone or in combination with ribavirin (1000 or 1200 mg orally per day, depending on body weight) for 24 or 48 weeks. Efficacy was assessed by measurements of serum hepatitis C virus (HCV) RNA and serum aminotransferases and by liver biopsy. The rate of sustained virologic response (defined as an undetectable serum HCV RNA level 24 weeks after treatment was completed) was higher among patients who received combination therapy for either 24 weeks (70 of 228 patients, 31 percent) or 48 weeks (87 of 228 patients, 38 percent) than among patients who received interferon alone for either 24 weeks (13 of 231 patients, 6 percent) or 48 weeks (29 of 225 patients, 13 percent) (P<0.001 for the comparison of interferon alone with both 24 weeks and 48 weeks of combination treatment). Among patients with HCV genotype 1 infection, the best response occurred in those who were treated for 48 weeks with interferon and ribavirin. Histologic improvement was more common in patients who were treated with combination therapy for either 24 weeks (57 percent) or 48 weeks (61 percent) than in those who were treated with interferon alone for either 24 weeks (44 percent) or 48 weeks (41 percent). The drug doses had to be reduced and treatment discontinued more often in patients who were treated with combination therapy. In patients with chronic hepatitis C, initial therapy with interferon and ribavirin was more effective than treatment with interferon alone.

The complement system consists of a tightly regulated network of proteins that play an important role in host defense and inflammation. Complement activation results in opsonization of pathogens and their removal by phagocytes, as well as cell lysis. Inappropriate complement activation and complement deficiencies are the underlying cause of the pathophysiology of many diseases such as systemic lupus erythematosus and asthma. This review represents an overview of the complement system in an effort to understand the beneficial as well as harmful roles it plays during inflammatory responses.

Although new activation and regulatory mechanisms are still being identified, the basic architecture of the complement system has been known for decades. Two major roles of complement are to control certain bacterial infections and to promote clearance of apoptotic cells. In addition, although inappropriate complement activation has long been proposed to cause tissue damage in human inflammatory and autoimmune diseases, whether this is indeed true has been uncertain. However, recent studies in humans, especially those using newly available biological therapeutics, have now clearly demonstrated the pathophysiologic importance of the complement system in several rare diseases. Beyond these conditions, recent genetic studies have strongly supported an injurious role for complement in a wide array of human inflammatory, degenerative, and autoimmune diseases. This review includes an overview of complement activation, regulatory, and effector mechanisms. It then focuses on new understandings gained from genetic studies, ex vivo analyses, therapeutic trials, and animal models as well as on new research opportunities.