The HCV story evolved from prospective studies of transfusion-associated hepatitis (TAH) conducted at NIH in the late 1960’s and 70’s. Prior to 1970, when there were no donor screening tests for hepatitis viruses, the incidence of TAH in open heart surgery patients was approximately 30%. This high rate was predicated on the large volume transfused, the use of paid donor sources and the detection of anicteric cases by transaminase elevations. In 1970, the adoption of an all-volunteer donor supply and introduction of first generation HBV donor screening resulted in a marked reduction in TAH to about 10%. In 1973, retrospective testing of stored samples showed that only 25% of cases were HBV related. In 1975, HAV was discovered and all non-B cases were tested. None were due to HAV, giving rise to the designation non-A, non-B hepatitis (NANBH). Next, NANB was transmitted to chimps proving blood transmission and supporting a viral etiology. Further in-vitro studies using pedigreed samples and the chimp model showed that the virus was lipid-enveloped and 40-60 nm in diameter, consistent with it being an alpha or flavivirus, as it later proved to be. Patient follow-up showed that while NANBH was generally mild, it led to cirrhosis in 20% and liver-related mortality. Despite, considerable inferential knowledge of viral structure and important clinical data on severity, methods of viral detection were elusive until Houghton and colleagues cloned the NANB agent in 1989 and renamed the agent HCV. Chiron developed an antibody assay and retrospective testing of the NIH cohort showed that virtually all cases of NANBH were HCV-related. A first generation anti-HCV assay for donor screening was introduced in 1990 and improved in 1992. By 1997, our prospective study showed the virtual eradication of TAH, though by mathematical modeling the current risk is calculated to be 1:2,000,000 transfusions.
The hallmark of HCV infection is viral persistence. Treatment of chronic HCV using interferon (IFN) alone was minimally effective, but adding ribavirin to pegylated IFN improved virologic response rates to near 70%. The big treatment breakthrough came with the development of direct acting antivirals (DAAs) targeted to HCV polymerase, replication complex and protease proteins. Current sustained virologic response rates, tantamount to cure, after 8-12 weeks of oral DAAs, approximate 98%. Hence, in 40 years we have come from an unrecognized disease, to full definition of the agent to curative treatments. What remains is to identify the mass of chronically infected persons worldwide and to make these miracle drugs accessible and affordable. |
