Table of Contents  

Alter: Hepatitis C virus – from Hippocrates to cure

A half-millennium transpired between the first recognition of ‘serum’ hepatitis and the development of the first assay to reliably detect the hepatitis B virus (HBV). It was the serendipitous discovery of the Australia antigen1 that set the path forward to the eventual eradication of post-transfusion hepatitis (PTH) in the developed world. The critical steps in this pathway were:

  1. the recognition that the Australia antigen represents the envelope protein of the hepatitis B virus (HBsAg);

  2. the establishment of prospective studies which demonstrated that the primary risk factor for PTH was the use of paid donor blood;

  3. the finding in these same prospective studies that HBV accounted for only 25% of PTH and, by inference, that there must exist a non-B agent responsible for most PTH;2

  4. the discovery of hepatitis A virus (HAV) and the clear demonstration that HAV did not account for any cases of non-B PTH, leading to the recognition of non-A, non-B hepatitis (NANBH);3

  5. the histological demonstration that NANBH could evolve to cirrhosis, hepatocellular carcinoma (HCC) and liver-related fatality;4

  6. the cloning of hepatitis C virus (HCV)5 and demonstration that it accounted for virtually all cases of NANBH;

  7. the development of sensitive serological and molecular assays, and their implementation in blood donor screening;

  8. the virtual eradication of PTH in countries that combined sensitive HBV and HCV donor screening;6

  9. the development of direct-acting antivirals which can now cure > 90% of HCV carriers and reliably prevent cirrhosis and most cases of HCV-related HCC.7

Prior to recent curative therapies, the disease burden of HCV infection was accelerating, with a threefold increase in HCV-related HCC observed between the late 1970s and the late 1990s. Simultaneously, HCV emerged as the leading cause of end-stage liver disease and the leading indication for liver transplantation in the USA. Up to the turn of this century, there was little indication that this accelerating trend would abate because interferon-based therapies were, at most, 50% effective. However, the new century then ushered in the advent of HCV-specific designer drugs, termed ‘direct-acting antivirals (DAAs)’.7

The first of these DAAs were targeted to the viral protease (NS3), and when added to standard interferon therapy increased the sustained virological response (SVR) rate, tantamount to cure, to 70%. However, this increased efficacy was accompanied by increased side-effects, increased complexity of administration, decreased compliance and significantly increased cost. To circumvent the use of interferon, DAAs were directed to other genomic regions, particularly the NS5B polymerase and then the NS5A replication complex. Combined polymerase and replicase complex inhibitors provided well-tolerated, interferon-free oral regimens, with SVR rates > 90%. At least two companies have combined the NS5A/NS5B inhibitors into a single pill to be taken once daily for only 8–12 weeks.

Most recently, a second-generation DAA has been licensed in the USA that is pan-genotypic and has been shown to induce SVR in 98% of patients;7 toxicity is minimal and adherence very high. It has already been shown that an SVR can halt the progression to cirrhosis and diminish the incidence of HCC. If such drugs could be universally distributed at a low cost, it is conceivable that HCV infection could be eradicated, even in the absence of a vaccine. However, dissemination of these ‘miracle’ drugs has been severely limited by high cost and currently we are at a stand-off between corporate profits and maximum cures. Even at their high costs, DAAs have been calculated to be cost-effective, but neither third party payers nor governments have been willing to absorb the large upfront costs for the long-term savings. The HCV field would greatly benefit by the human immunodeficiency virus treatment model. Indeed, in the long run, HCV treatment would be less costly because of the short duration of therapy required for cure.

In summary, the last 50 years have seen:

  1. the discovery of HBV;

  2. the discovery of HAV;

  3. the recognition of non-A, non-B hepatitis and then cloning of HCV;

  4. the discovery of the delta agent and hepatitis E virus;

  5. the development of vaccines for hepatitis A, B and E;

  6. the virtual eradication of transfusion-associated hepatitis in countries resourced to perform serological and molecular virus screening of blood donors;

  7. curative treatments for HCV and highly effective treatments to suppress HBV replication;

  8. curative therapies for small liver cancers;

  9. liver transplantation for end-stage liver disease with high 5-year survival rates.

Hippocrates would be proud of these accomplishments.

References

1. 

Blumberg BS, Alter HJ, Visnich SA. A ‘new’ antigen in leukemia sera. JAMA 1965; 191:541–6. http://dx.doi.org/10.1001/jama.1965.03080070025007

2. 

Alter HJ, Holland PV, Purcell RH, et al. Posttransfusion hepatitis after exclusion of the commercial and hepatitis B antigen positive donor. Ann Int Med 1972; 77:691–6. http://dx.doi.org/10.7326/0003-4819-77-5-691

3. 

Feinstone SM, Kapikian AZ, Purcell RH, Alter HJ, Holland PV. Transfusion-associated hepatitis not due to viral hepatitis type A or B. New Engl J Med 1975; 292:767–70. http://dx.doi.org/10.1056/NEJM197504102921502

4. 

Berman MD, Alter HJ, Ishak KG, Purcell RH, Jones EA. The chronic sequelae of non-A, non-B hepatitis. Ann Int Med 1979; 91:1–6. http://dx.doi.org/10.7326/0003-4819-91-1-1

5. 

Kuo G, Choo Q, Alter HJ, et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989; 244:362–4. http://dx.doi.org/10.1126/science.2496467

6. 

Alter HJ, Houghton M. Hepatitis C virus and eliminating post-transfusion hepatitis. Nature Med 2000; 6:1082–6. http://dx.doi.org/ 10.1038/80394

7. 

Feld JJ, Jacobson IM, Hezode C, et al. Sofosbuvir and velpatisvir for HCV genotype 1, 2, 4, 5, and 6 infection. New Engl J Med 2015; 73:2599–607. http://dx.doi.org/10.1056/NEJMoa1512610




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