pp 1-15 | Cite as

From B to Non-B to C: The Hepatitis C Virus in Historical Perspective

  • Harvey J. AlterEmail author
Part of the Topics in Medicinal Chemistry book series


The discovery of HCV was an evolutionary process beginning with the serendipitous identification of the Australia antigen that later proved to be the surface protein of the hepatitis B virus (HBV) and the first marker for any human hepatitis virus. Studies of transfusion-associated hepatitis made it evident that most cases were unrelated to HBV. The later discovery of the hepatitis A virus (HAV) made it apparent that non-B cases were also non-A leading to the awkward terminology non-A, non-B hepatitis (NANBH). While NANBH was identified only by exclusion and had no specific serologic or molecular marker, using chimpanzee transmission studies, it was possible to show that the NANBH agent was small and enveloped and most consistent with being a flavivirus as it later proved to be. Clinical studies showed that NANBH could lead to cirrhosis, hepatocellular carcinoma, and liver-related fatality. The major breakthrough occurred in the late 1980s when the Chiron Corporation cloned the NANBH agent and renamed it the hepatitis C virus (HCV). Adding HCV serologic testing, and later molecular testing, to routine donor screening virtually eradicated TAH with current risk estimated to be one case in two million transfusions. More recently, direct-acting antiviral agents have been shown to result in sustained virologic responses, tantamount to cure, in 98% of treated subjects. The existing challenges are to identify currently unrecognized HCV carriers and to make treatment accessible to all.


Australia antigen HBV HCV Hepatitis B virus Hepatitis C virus NANBH NANBV Non-A Non-B hepatitis Posttransfusion hepatitis Transfusion-associated hepatitis 


Compliance with Ethical Standards

Ethical Statement: All patient studies described herein were performed under NIH IRB approved protocols with appropriate informed consent.

Chimpanzee studies were approved by the animal use committees of the Southwest Foundation for Biomedical Research, San Antonio Texas or the NIH, Intramural program.


  1. 1.
    Bar-Gal GK, Kim MJ, Klein A et al (2012) Tracing hepatitis B to the 16th century in a Korean mummy. Hepatology 56:1671–1680Google Scholar
  2. 2.
    Lurman A (1885) Eine Icterusepidemie. Berl Klin Wochenschr 22:2023Google Scholar
  3. 3.
    Editorial (1942) Jaundice following yellow fever immunization. JAMA 119:1110Google Scholar
  4. 4.
    Seeff LB, Beebe GW, Hoofnagle JH (1987) A serological follow-up of the 1942 epidemic of post-vaccination hepatitis in the United States Army. N Engl J Med 316:965–970Google Scholar
  5. 5.
    Paul JR, Havens WP, Sabin AB et al (1945) Transmission experiments in serum jaundice and infectious hepatitis. JAMA 128:911–915Google Scholar
  6. 6.
    Barker LF, Shulman NR, Murray R et al (1970) Transmission of serum hepatitis. JAMA 211:1509–1512Google Scholar
  7. 7.
    Krugman S, Giles JP, Hammonds J (1967) Infectious hepatitis: evidence for two distinctive clinical, epidemiological and immunological types of infection. JAMA 200:365Google Scholar
  8. 8.
    Krugman S, Giles JP, Hammond J (1971) Viral hepatitis, type B (MS-2 strain): studies on active immunization. JAMA 217:41–45Google Scholar
  9. 9.
    Blumberg BS, Alter HJ, Visnich S (1965) A “new” antigen in leukemia sera. JAMA 191:541–546Google Scholar
  10. 10.
    Blumberg BS, Gerstley BJS, Hungerford DA et al (1967) A serum antigen (Australia antigen) in Down’s syndrome, leukemia and hepatitis. Ann Intern Med 66:924–931Google Scholar
  11. 11.
    Sutnick AI, London WT, Bayer M et al (1968) Anicteric hepatitis associated with Australia antigen; occurrence in patients with Down’s syndrome. JAMA 205:670–674Google Scholar
  12. 12.
    Prince AM (1968) An antigen detected in the blood during the incubation period of serum hepatitis. Proc Natl Acad Sci 60:814–821Google Scholar
  13. 13.
    Bayer ME, Blumberg BS, Werner B (1968) Particles associated with Australia antigen in the sera of patients with leukemia, Down’s syndrome and hepatitis. Nature 218:1057–1059Google Scholar
  14. 14.
    Gerin JL, Purcell RH, Hoggan MD et al (1969) Biophysical properties of Australia antigen. J Virol 4:763–768Google Scholar
  15. 15.
    Dane OS, Cameron CH, Briggs M (1970) Virus-like particles in serum of patients with Australia antigen-associated hepatitis. Lancet 1:695–698Google Scholar
  16. 16.
    Okochi K, Murakami S (1968) Observations on Australia antigen in Japanese. Vox Sang 15:374–385Google Scholar
  17. 17.
    Gocke DJ, Greenberg HB, Kavey NB (1970) Correlation of Australia antigen with posttransfusion hepatitis. JAMA 212:877–879Google Scholar
  18. 18.
    Gocke DJ, Kavey NB (1969) Hepatitis antigen: correlation with disease and infectivity of blood donors. Lancet 2:1055–1059Google Scholar
  19. 19.
    Szmuness W, Stevens CE, Harley EJ et al (1980) Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high risk population in the United States. N Engl J Med 303:833–841Google Scholar
  20. 20.
    Beasley RP, Hwang L-Y, Lee GC-Y et al (1983) Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B immune globulin and hepatitis B vaccine. Lancet 2:1099–1102Google Scholar
  21. 21.
    Beasley RP, Hwang L-Y, Lin C-C et al (1981) Hepatocellular carcinoma and hepatitis B virus: a prospective study of 22,707 men in Taiwan. Lancet 2i:1006–1008Google Scholar
  22. 22.
    Kew MC, Rossouw E, Hodkinson J et al (1983) Hepatitis B virus status of southern African Blacks with hepatocellular carcinoma: comparison between rural and urban patients. Hepatology 3:65–68Google Scholar
  23. 23.
    Walsh JH, Purcell RH, Morrow AG et al (1970) Posttransfusion hepatitis after open-heart operations: incidence after the administration of blood from commercial and volunteer donor populations. JAMA 211:261–265Google Scholar
  24. 24.
    Allen JG (1970) Commercially obtained blood and serum hepatitis. Surg Gynecol Obstet 131:277–281Google Scholar
  25. 25.
    Alter HJ, Holland PV, Purcell RH et al (1972) Postransfusion hepatitis after exclusion of the commercial and hepatitis B antigen positive donor. Ann Intern Med 77:691–699Google Scholar
  26. 26.
    Feinstone SM, Kapikian AZ, Purcell RH (1973) Hepatitis A: detection by immune electron microscopy of a virus-like antigen associated with acute illness. Science 182:1026–1028Google Scholar
  27. 27.
    Feinstone SM, Kapikian AZ, Purcell RH et al (1975) Transfusion-associated hepatitis not due to viral hepatitis type A or B. N Engl J Med 292:767–770Google Scholar
  28. 28.
    Alter HJ, Purcell RH, Holland PV et al (1978) Transmissible agent in “non-A, non-B” hepatitis. Lancet 1:459–463Google Scholar
  29. 29.
    Tabor E, Gerety RJ, Drucker JA et al (1978) Transmission on non-A, non-B hepatitis from man to chimpanzee. Lancet 1:463–466Google Scholar
  30. 30.
    Feinstone JM, Mihalik KB, Kamimura J et al (1983) Inactivation of hepatitis B virus and non-A, non-B virus by chloroform. Infect Immun 4:816–821Google Scholar
  31. 31.
    He L-F, Alling DW, Popkin TJ et al (1987) Determining the size of non-A, non-B hepatitis virus by filtration. J Infect Dis 156:636–640Google Scholar
  32. 32.
    Berman MD, Alter HJ, Ishak KG et al (1979) The chronic sequelae of non-A, non-B hepatitis. Ann Intern Med 91:1–6Google Scholar
  33. 33.
    Rakela J, Redeker AG (1979) Chronic liver disease after acute non-A, non-B viral hepatitis. Gastroenetrology 77:1200–1202Google Scholar
  34. 34.
    Realdi G, Alberti A, Ruggi M et al (1982) Long-term follow-up of acute and chronic non-A, non-B post-transfusion hepatitis: evidence of progression to liver cirrhosis. Gut 23:270–275Google Scholar
  35. 35.
    Ghany MG, Kleiner DE, Alter HJ et al (2003) Progression of fibrosis in chronic hepatitis C. Gastroenterology 124:97–104Google Scholar
  36. 36.
    Choo Q-L, Kuo G, Weiner AJ et al (1989) Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:359–362Google Scholar
  37. 37.
    Bradley DW, Cook EH, Maynard JE et al (1979) Experimental infection of chimpanzees with antihemophilic (factor VIII) materials: recovery of virus like particles associated with non-A, non-B hepatitis. J Med Virol 3:253–269Google Scholar
  38. 38.
    Bradley DW, McCaustland KA, Cook EH et al (1985) Post-transfusion non-A, non-B hepatitis in chimpanzees: physicochemical evidence that the tubular forming agent is a small enveloped virus. Gastroeneterology 88:773–779Google Scholar
  39. 39.
    Kuo G, Choo Q, Alter HJ et al (1989) An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 244:362–364Google Scholar
  40. 40.
    Alter HJ, Purcell RH, Shih JW et al (1989) Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis. New Engl J Med 321:1494–1500Google Scholar
  41. 41.
    Alter HJ, Houghton M (2000) Hepatitis C virus and eliminating post-transfusion hepatitis. Nat Med 6:1082–1086Google Scholar
  42. 42.
    Alter HJ, Purcell RH, Holland PV et al (1981) The relationship of donor transaminase (ALT) to recipient hepatitis: impact on blood transfusion services. JAMA 246:630–634Google Scholar
  43. 43.
    Aach RD, Szmuness W, Mosley JW (1981) Serum alanine amino transferase of donors in relation to the risk of non-A, non-B hepatitis in recipients: the transfusion-transmitted viruses study. N Engl J Med 304:989–994Google Scholar
  44. 44.
    Stevens CE, Aach RD, Hollinger FB (1984) Hepatitis B virus antibody in blood donors and the occurrence of non-A, non-B hepatitis in transfusion recipients; an analysis of the transfusion-transmitted virus study. Ann Intern Med 101:733–738Google Scholar
  45. 45.
    Koziol DE, Holland PV, Alling DW et al (1986) Antibody to hepatitis B Core antigen as a paradoxical marker for non-A, non-B hepatitis agents in donated blood. Ann Intern Med 104:488–495Google Scholar
  46. 46.
    Dodd RY, Notari EP, Stramer SL (2002) Current prevalence and incidence of infectious disease markers and estimated window period risk in the American Rd cross blood donor population. Transfusion 42:975–979Google Scholar
  47. 47.
    Feld JJ, Jacobson IM, Hezode C et al (2015) Sofosbuvir and velpatasvir for HCV genotype 1,2,4, 5 and 6 infection. N Engl J Med 373:2599–2607Google Scholar
  48. 48.
    Casado JL, Esteban MA, Banon S (2015) Fibrosis regression explains differences in outcome in HIV-HCV coinfected patients with cirrhosis after sustained virologic response. Dig Dis Sci 60:3473–3481Google Scholar
  49. 49.
    Morgan RL, Baack B, Smith BD et al (2013) Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med 158:329–337Google Scholar
  50. 50.
    Kattakuzhy S, Gross C, Emmanuel B et al (2017) Expansion of treatment for hepatitis C virus infection by task shifting to community-based nonspecialist providers: a nonrandomized clinical trial. Ann Intern Med 167:311–318Google Scholar

Copyright information

© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019

Authors and Affiliations

  1. 1.National Institutes of HealthBethesdaUSA

Personalised recommendations