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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Yazan Daaboul, Serge Korjian


The discovery of the hepatitis C virus was made based on early findings of patients with signs and symptoms of viral hepatitis lacking positive serologies for hepatitis A or B. These patients were originally described in 1974-5 as having "non-A, non-B viral hepatitis" (NANBH). It was not until 1989 that hepatitis C virus (HCV) was truly discovered when Qui-Lim Choo and colleagues successfully isolated the first cDNA clone 5-1-1 derived from the NANBH genome. The first interferon-alpha (INF-a) to treat HCV was developed in 1986 and approved in 1991. Approximately 10-15 years later, global efforts to reduce the burden of HCV were launched; worldwide campaigns were led by the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC).

Discovery of Non-A, Non-B Viral Hepatitis

In the early 1960s, scientists only differentiated between hepatitis A, an acute infection of short incubation period transmitted via the fecal-oral route, and hepatitis B, a potentially chronic infection of long incubation period transmitted via blood exposure. Consequently, the discovery of hepatitis C only occurred with the availability of diagnostic assays in the early 1970s.[1][2][3] In 1974-5, the works of Alfred Prince, Stephen Feinstone, and Harvey Alter led to the new discovery that was termed "non-A, non-B viral hepatitis" (NANBH) when serological markers for hepatitis A and B were both absent in patients with signs and symptoms of viral hepatitis.[1][2][4] Shortly after, studies scrutinizing the new discovery revealed that most patients with NANBH had been exposed to blood transfusions[5][6] and hepatic cirrhosis ensued in as many as 20% of these patients.[7]

With no techniques available with which to isolate the virus, the infective potential and mode of transmission of NANBH were later confirmed in 1978 when chimpanzees were infected with the virus following injection of human blood from patients confirmed to have the disease.[8][9][10] Experiments using chimpanzee models contributed to the discovery of various NANBH variants and agents, and allowed scientists to study the pathological aspects of hepatic injury in these infections.[11][12][13]

Discovery of Hepatitis C Virus

The attempt to discover the first NANBH antibodies persisted for several years. Although the virus was originally described in the early 1970s, the identification of NANBH-specific antibodies did not occur until 1985 by Yohko Shimizu and colleagues.[14] In 1989, the full isolation of a cDNA clone 5-1-1 derived from NANBH genome was finally successful. Qui-Lim Choo and colleagues were able to construct a random-primed complementary DNA (cDNA) from plasma containing an NANBH agent, showing that the virus is a positive-stranded RNA molecule composed of of 10,000 nucleotides.[15] With the isolation of the new agent, hepatitis C virus (HCV) was discovered and the term replaced NANBH for the first time in 1989.[15] In the early 1990s, HCV was then classified into 6 major genotypes and several subtypes.[16] Due to similarity with other RNA viruses, it was considered a type member of the genus Hepacivirus within the family Flavividae.[16][17][18]

Sequelae Following HCV Discovery

Following its discovery, blood tests were available by 1990 to detect the presence of HCV in blood products, to determine chronicity, and to reveal its association with such cancers as hepatocellular carcinoma and non-Hodgkin's lymphoma.[19][20][18] Worldwide efforts to prevent the transmission of HCV have been somewhat successful in reducing the global burden of HCV.[18]

Global Awareness Campaigns

In 2007, the World Health Organization (WHO) declared July 28 "World Hepatitis Day" and the Centers for Disease Control and Prevention (CDC) launched its national "Know More Hepatitis" campaign on July 28, 2011 to educate individuals born between 1945-1965 about HCV and launched its "Hepatitis Testing Day" on May 19, 2012.

Use of First Antiviral Drug for HCV

Even before the identification of the virus in 1989, the first effort to develop interferon-alpha (IFN-a) treatment against HCV was initiated in 1986 by Jay Houston Hoofnagle and colleagues.[21] The drug was finally approved by the Food and Drug Administration (FDA) for HCV treatment in 1991 at a dose of 3 million units subcutaneously three times weekly for 6 months. Ribavirin was first used to treat HCV in 1997; the drug demonstrated a decrease in aminotransferase levels and a good safety profile, despite its lack of antiviral activity as monotherapy.[22] The FDA approved the use of combination therapy of interferon alpha and ribavirin in 1998. Finally, pegylated interferon, which has a higher concentration and longer half life than interferon, was approved for use in 2001. Newer HCV protease inhibitors, such as telepravir, were developed in 2007.


  1. 1.0 1.1 Prince AM, Brotman B, Grady GF, Kuhns WJ, Hazzi C, Levine RW; et al. (1974). "Long-incubation post-transfusion hepatitis without serological evidence of exposure to hepatitis-B virus". Lancet. 2 (7875): 241–6. PMID 4136143.
  2. 2.0 2.1 Feinstone SM, Kapikian AZ, Purcell RH, Alter HJ, Holland PV (1975). "Transfusion-associated hepatitis not due to viral hepatitis type A or B." N Engl J Med. 292 (15): 767–70. doi:10.1056/NEJM197504102921502. PMID 163436.
  3. Seeff LB, Zimmerman HJ, Wright EC, Finkelstein JD, Garcia-Pont P, Greenlee HB; et al. (1977). "A randomized, double blind controlled trial of the efficacy of immune serum globulin for the prevention of post-transfusion hepatitis. A Veterans Administration cooperative study". Gastroenterology. 72 (1): 111–21. PMID 318578.
  4. Alter HJ, Holland PV, Morrow AG, Purcell RH, Feinstone SM, Moritsugu Y (1975). "Clinical and serological analysis of transfusion-associated hepatitis". Lancet. 2 (7940): 838–41. PMID 53329.
  5. Berman M, Alter HJ, Ishak KG, Purcell RH, Jones EA (1979). "The chronic sequelae of non-A, non-B hepatitis". Ann Intern Med. 91 (1): 1–6. PMID 464417.
  6. Aach RD, Szmuness W, Mosley JW, Hollinger FB, Kahn RA, Stevens CE; et al. (1981). "Serum alanine aminotransferase of donors in relation to the risk of non-A,non-B hepatitis in recipients: the transfusion-transmitted viruses study". N Engl J Med. 304 (17): 989–94. doi:10.1056/NEJM198104233041701. PMID 6782484.
  7. Hoofnagle JH, Alter HJ (1985). "Chronic non-A, non-B hepatitis". Prog Clin Biol Res. 182: 63–9. PMID 3929263.
  8. Alter HJ, Purcell RH, Holland PV, Popper H (1978). "Transmissible agent in non-A, non-B hepatitis". Lancet. 1 (8062): 459–63. PMID 76017.
  9. Tabor E, Gerety RJ, Drucker JA, Seeff LB, Hoofnagle JH, Jackson DR; et al. (1978). "Transmission of non-A, non-B hepatitis from man to chimpanzee". Lancet. 1 (8062): 463–6. PMID 76018.
  10. Hollinger FB, Gitnick GL, Aach RD, Szmuness W, Mosley JW, Stevens CE; et al. (1978). "Non-A, non-B hepatitis transmission in chimpanzees: a project of the transfusion-transmitted viruses study group". Intervirology. 10 (1): 60–8. PMID 632054.
  11. Shimizu YK, Feinstone SM, Purcell RH, Alter HJ, London WT (1979). "Non-A, non-B hepatitis: ultrastructural evidence for two agents in experimentally infected chimpanzees". Science. 205 (4402): 197–200. PMID 451589.
  12. Hollinger FB, Mosley JW, Szmuness W, Aach RD, Peters RL, Stevens C (1980). "Transfusion-transmitted viruses study: experimental evidence for two non-A, non-B, hepatitis agents". J Infect Dis. 142 (3): 400–7. PMID 6255037.
  13. Trépo C, Vitvitski L, Hantz O (1981). "Non-A, Non-B hepatitis virus: identification of a core antigen-antibody system that cross reacts with hepatitis B core antigen and antibody". J Med Virol. 8 (1): 31–47. PMID 6795310.
  14. Shimizu YK, Oomura M, Abe K, Uno M, Yamada E, Ono Y; et al. (1985). "Production of antibody associated with non-A, non-B hepatitis in a chimpanzee lymphoblastoid cell line established by in vitro transformation with Epstein-Barr virus". Proc Natl Acad Sci U S A. 82 (7): 2138–42. PMC 397508. PMID 2984683.
  15. 15.0 15.1 Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M (1989). "Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome". Science. 244 (4902): 359–62. PMID 2523562.
  16. 16.0 16.1 Simmonds P, Holmes EC, Cha TA, Chan SW, McOmish F, Irvine B; et al. (1993). "Classification of hepatitis C virus into six major genotypes and a series of subtypes by phylogenetic analysis of the NS-5 region". J Gen Virol. 74 ( Pt 11): 2391–9. PMID 8245854.
  17. Bukh J, Miller RH, Purcell RH (1995). "Genetic heterogeneity of hepatitis C virus: quasispecies and genotypes". Semin Liver Dis. 15 (1): 41–63. doi:10.1055/s-2007-1007262. PMID 7597443.
  18. 18.0 18.1 18.2 Houghton M (2009). "Discovery of the hepatitis C virus". Liver Int. 29 Suppl 1: 82–8. doi:10.1111/j.1478-3231.2008.01925.x. PMID 19207970.
  19. Colombo M, Kuo G, Choo QL, Donato MF, Del Ninno E, Tommasini MA; et al. (1989). "Prevalence of antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma". Lancet. 2 (8670): 1006–8. PMID 2572740.
  20. Craxì A, Laffi G, Zignego AL (2008). "Hepatitis C virus (HCV) infection: a systemic disease". Mol Aspects Med. 29 (1–2): 85–95. doi:10.1016/j.mam.2007.09.017. PMID 18177700.
  21. Hoofnagle JH, Mullen KD, Jones DB, Rustgi V, Di Bisceglie A, Peters M; et al. (1986). "Treatment of chronic non-A,non-B hepatitis with recombinant human alpha interferon. A preliminary report". N Engl J Med. 315 (25): 1575–8. doi:10.1056/NEJM198612183152503. PMID 3097544.
  22. Bodenheimer HC, Lindsay KL, Davis GL, Lewis JH, Thung SN, Seeff LB (1997). "Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: a multicenter trial". Hepatology. 26 (2): 473–7. doi:10.1002/hep.510260231. PMID 9252161.

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