Hepatitis C Virus (HCV):

Originally one source of NANBH (~90%?), hepatitis C virus (HCV) was first definitively identified by molecular cloning of the virus genome in 1989 (Choo et al, Science 244: 359-62, 1989). The virus cannot be cultured in vitro & this has hampered investigations. The HCV genome consists of a positive-sense RNA molecule approximately 9.5kb in length:

Hepatitis C genome diagram

In terms of genome organization, HCV is a member of the Flaviviridae and has now been placed in a new monotypic genus in this family. The genome contains a single long open reading frame which encodes a polyprotein of about 3000 amino acids. There is a non-coding region (NCR) of 324-341 nucleotides at the 5' end & a 3' NCR of variable length including a poly(U) tract. The 5' NCR contains an IRES apparently similar in function (but not structure) to that of picornaviruses.

The nucleotide sequence of HCV is highly variable, the most divergent isolates sharing only 60% nucleotide sequence homology. Isolates from all over the world have now been grouped into 6 main types, each with several subtypes, based on sequence data (Simmonds et al, Hepatology 21: 570-83, 1995). Types 1-3 account for almost all infections in Europe, type 4 is prevalent in Egypt & Zaire, type 5 in South Africa & type 6 in Hong Kong. It is not yet clear whether immunity to one type prevents subsequent infection with another, but there is some evidence that various genome types differ in their biological properties.

HCV infection occurs in approximately 0.1% of the UK population (inferred from the level of infection seen in UK blood donors), although rates of infection in other parts of the world are much higher. Since autumn 1991 the BTS has screened all donated blood for HCV. Several diagnostic tests have been developed, serological (used for screening blood donations) - using recombinant antigens, and molecular (PCR - being used to determine the extent of virus variation).

The parenteral route of infection seems to be most prevalent, with high rates of infection seen in intravenous drug abusers, haemophiliacs and recipients of unscreened blood transfusions. The possibility of sexual transmission cannot be eliminated, but if it occurs, the risk seems to be very low. Vertical transmission of HCV in utero & perinatally has also been reported, but again, appears to be rare.

Pathogenesis:

In the majority of cases HCV infection gives rise to an acute illness; 80% of such cases develop into chronic hepatitis. Almost all patients develop a vigorous antibody and cell-mediated immune response which fails to clear the infection but may contribute towards liver damage. Most flavivirus infections are cytopathic, but this has not been directly tested in the case of HCV since the virus cannot be cultured.
Spontaneous resolution of chronic liver disease is very rare (<2%) and patients with chronic disease are at risk of developing hepatocellular carcinoma (HCC). AS with HBV, chronic HCV infection is a major risk factor for HCC (30% of UK HCC patients?). Time from HCV transmission to development of cancer ranges from 10 to 50 years (median 30 years). There is a strong association between chronic HCV infection, cirrhosis, and hepatocarcinogenesis (Haydon et al Gut 40: 128-132, 1997). The duration from the onset of acute hepatitis until the time of diagnosis of cirrhosis of the liver and of HCC is about 20 and 30 years, respectively. The acute phase lasts from the onset of disease until 2-3 years thereafter, and the silent phase which follows lasts for 10-15 years. Since so little is known about the biology of HCV, it is presently unclear how this RNA virus establishes a persistent infection.

Therapy:

Recurrent HCV infection occurs in >90% infected liver transplant recipients, although not all patients develop subsequent liver disease. At the present time, the only therapy with any demonstrated efficacy against HCV-induced liver disease involves the use of alpha-IFN, but this approach is not entirely successful. Even in the best trials reported, only 40-50% of chronic suffers respond and 50% of these individuals relapse when treatment is stopped and there is evidence that alpha-IFN treatment is much less effective against some HCV genotypes than others. The development of vaccines, although proceeding, has been slowed by the extreme antigenic variability of the virus. Even when available, vaccines will not alleviate the problems faced by millions of chronic HCV carriers worldwide. No conventional drugs active against HCV infection (i.e. other than IFN) have yet been developed.

IFN therapy is expensive due to the high cost of recombinant human interferons, the large doses & lengthy course of administration necessary to achieve maximum response rates in recipients. Typical therapeutic regimes may be 3 million units IFN administered by injection three times a week for six months. However, recent studies suggest that 3-6 million units IFN three times a week for one year or even longer may be necessary to achieve maximum response rates (Chemello et al. Hepatology 22: 700-706, 1995; Hakozaki et al. Am.J.Gastroenterol., 90: 1246-1249, 1995). The cost of the treatment effectively rations the number of patients able to receive this therapy. There are data from early studies which suggest that sustained response rates are enhanced if ribavirin, a broad spectrum antiviral agent, is administered in combination with IFN.
Read: Terrault, N.A. "Treatment of chronic hepatitis B and chronic hepatitis C" Rev.Med.Virol. 6:215-228 (1996).

Most antibodies to HCV do not play a major role in clearance of infection, although neutralising antibodies do exist. However, these tend to be strain-specific & are ineffective against emerging strains, allowing infection to persist. Formidable obstacles remain to be overcome before a generally useful HCV vaccine is available. Thus there is clearly a desperate need for effective antiviral therapy to complement future vaccination programmes when these become available and to mitigate the effects of long-term HCV infection. However, our inability to propagate HCV in any tissue-culture system and due to the lack of any other animal model than the chimpanzee has confounded the development of antiviral compounds active against this agent.

HAV | HBV | HDV | HEV | GBV-C/HGV | TTV

© AJC 1998