Recovery, persistence, and sequelae in hepatitis C virus infection: A perspective on long-term outcome

Hepatitis C has emerged in recent years as the most common basis for liver disease in the United States, having infected an estimated 3.9 million peop le in this country and an estimated 170 million worldwide. Currently, it is the predominant reason for undergoing liver transplantation. The disease i t causes is characterized by silent onset in most infected individuals, a h igh rate of viral persistence, and the potential for development of ever-wo rsening chronic liver disease, ranging from chronic hepatitis to cirrhosis and occasionally to hepatocellular carcinoma. Such progression, when it occ urs, is also most commonly a silent process that may take 20-40, and occasi onally even more, years to reach its endpoint. Because of these characteris tics, it has been exceedingly difficult to accurately assess the natural hi story. Efforts to accomplish this have consisted of retrospective, prospect ive, and cohort studies. The most concerning data have derived from the ret rospective study approach, generally performed at tertiary referral centers . Because these centers commonly attract persons with existing chronic live r disease, they have tended to describe a high rate of progression to cirrh osis and cancer This "referral bias" is avoided in the prospective and coho rt study approach, and data derived from these studies indicate a lower rat e of progression and a correspondingly higher rate of either recovery or mi nimal liver disease. In this review, we briefly describe potential mechanis ms of viral persistence; present detailed information on outcomes that have derived from retrospective, prospective, and cohort studies, involving bot h adults and children; examine the data regarding progression of fibrosis a nd of progression to hepatocellular carcinoma; consider cofactors that migh t enhance liver disease progression; and report the emerging data that sugg est that spontaneous viral clearance may be higher than is currently believ ed. We conclude with the view that severe, life-threatening, progressive li ver disease clearly occurs in a sizable minority (perhaps 30%) of chronical ly infected persons but speculate that fibrosis progression is neither line ar or inevitable and hence that most hepatitis C virus carriers will have e ither a stable nonprogressive course or such indolent progression that they will die from an unrelated disease before the severe sequelae of hepatitis C become manifest or will have a sustained "curative" response to therapy. Although this view provides reasonable hope to the hepatitis C virus-infec ted individual, it does not deny the enormous burden this infection present s as the result of its high prevalence and global distribution. The sheer m agnitude of the infected population will result in a large number with seve re life-threatening liver disease even if the proportion of inferred indivi duals that develop progressive disease is relatively small.