The New Treatment of Hepatitis C. Illustrate your essay with specific examples.

5.1 Interferon treatment:

All current treatment protocols for HCV are based on the use of interferon alpha (IFN-α), first developed in 1986 and administered either by intramuscular or subcutaneous injection (Feld et al., 2005; Stremmel et al., 1989). IFN-α is an endogenous glycoprotein normally secreted in response to viral infections. When administered therapeutically IFN-α is thought to function by binding to IFN cell-surface-receptors resulting in their dimerisation and activation of Janus-activated kinase 1 (Jak1) and tyrosine kinase 2 (Tyk2) (Gale, 2003). Jak1 and Tyk2 then phosphorylate and activate signal transducer and activator of transcription proteins 1 and 2 (STAT1 and STAT2). The STAT1/2 complex then translocates to the nucleus to combine with IFN-regulatory factor 9 (IRF-9) and initiate transcription of genes with antiviral activity, as well as those involved in apoptosis, protein degradation and lipid metabolism. These include the gene for protein kinase R which may suppress viral protein synthesis by inhibiting eukaryotic initiation factor 2 (Feld et al., 2005). This results in increased target cell killing by lymphocytes and inhibition of virus replication in infected cells, reducing HCV RNA levels in serum and liver to resolve the infection (Feld et al., 2005).
Several interferons are currently approved for the treatment of chronic HCV infections including; IFN-α 2a (produced by Hoffmann-La Roche), IFN α -2b (produced by Schering-Plough) and interferon alfacon-1 (produced by Intermune). These are usually administered for between six months to two years. After its initial trials, IFN-α monotherapy was adopted as the standard treatment recommendation for HCV, but is relatively ineffective, indeed treatment with IFN-α for 12months only resulted in a successful response in 16-20% of cases (Feld et al., 2005).

5.2 Interferon and Ribavirin treatment:

The efficacy of IFN-α treatment was increased by the coadministration of the broad-spectrum antiviral synthetic nucleoside ribavirin (1-b-D-ribofuranosyl-1,2,4-triazole-3-carboxyamide) (McHutchison et al., 1998). Ribavirin has been shown to upregulate IFN stimulated genes and increase the interaction of STAT1 with DNA, possibly potentiating the actions of IFN (Zhang et al., 2003). This combination treatment increased the sustained response rate to 35-40% and was approved for use in December 1998 (Feld et al., 2005). Results from three double-blind, placebo-controlled trials supporting this were published in 1998 (McHutchison et al., 1998; Poynard et al., 1998; Reichard et al., 1998). However, 10-25% of patients relapse even when treated with this combination, and though retreatment in these cases can result in a SVR, this usually requires a longer course of drugs and a high drug dose. One third of patients treated with IFN-α and ribavirin show no response to treatment and never become HCV RNA negative (Feld et al., 2005).
HCV treatment was further improved by the use of pegylated IFN-α, where a molecule of poly(ethylene glycol), known as PEG is attached to IFN-α. This increases the active half-life of the IFN-α, increasing its virological activity so that more constant blood levels are achieved with less frequent administration (Feld et al., 2005; Lindsay et al., 2001; Manns et al., 2001). There are two preparations of peginterferon alpha now available: peginterferon alpha-2b (known as Peg-Intron; produced by Schering-Plough) and peginterferon alpha-2a (known as Pegasys; produced by Hoffmann-La Roche). Based on these studies the currently recommended therapy for chronic hepatitis C is a 24-48 week course of pegylated interferon and ribavirin which achieves a SVR in 50% of patients. Figure 1 illustrates the increasing sustained virological response that has been achieved by developing HCV treatments, first by the combination of ribavirin with IFN-α (Study A, black bar), the addition of a PEG moiety onto IFN-α (studies B and C, black bars) and finally the current most potent combinations of pegylated IFN-α with ribavirin (studies D and E, black bars):
Study A (McHutchison et al., 1998): Comparison of interferon α -2b with ribavirin (black) versus interferon α -2b alone (grey), both for 48 weeks .Study B (Lindsay et al., 2001)): pegylated interferon α -2b (black) versus interferon α -2b (grey). Study C (Zeuzem et al., 2000) : pegylated interferon α -2a (black) versus interferon α -2a (grey). Study D (Manns et al., 2001): pegylated interferon α -2b with ribavirin (black) versus interferon α -2b with ribavirin (grey). Study E (Fried et al., 2002): pegylated interferon α -2a with ribavirin (black) versus interferon α -2b with ribavirin (grey).
Adapted from Di Bisceglie et al 2002
Responsiveness to treatment is dependent upon the age, weight and gender of the patient as well as the genotype of the virus (Kemmer et al., 2007; Montalbano et al., 2008). Evidence suggests that a sustained response is only achieved in approximately 45% of genotype 1 cases, which represent 70% of all cases in the US, whilst 76-80% of genotype 2 and 3 cases show a sustained response to combination therapy (2002b; Di Bisceglie et al., 2002). In addition, IFN-α can produce side effects such as fatigue, flu-like symptoms, nausea and depression (Laguno et al., 2004), while ribavirin can affect fetal development, and exacerbate anaemia, heart and kidney disease (Ferm et al., 1978; Kilham et al., 1977). Furthermore, those who do not respond to the current treatments can further damage their liver as the current regimes available for HCV eradication can accelerate hepatic dysfunction (Di Bisceglie et al., 2002).

6.1 Inhibitors of viral replication

In an attempt to increase the synergistic effect of pegylated interferon plus ribavirin, researchers have recently been testing the nucleoside polymerase inhibitor R1626, which has previously been shown to inhibit replication of the HCV in vitro. In two recent phase two short trials up to 74% of individuals additionally taking R1626 had undetectable levels of HCV RNA after 2-4 weeks, compared to 5% of individuals taking the standard IFN-ribavirin combination therapy (Pockros et al., 2008; Roberts et al., 2008). However both these trials used low numbers of HCV infected individuals, and follow up studies determining whether the levels of HCV RNA remain undetectable in the blood are ongoing. Therefore the long-term efficacy of these recent trials remains to be determined.
A viral protein called p7 is another potential novel therapeutic target (Griffin et al., 2008). This protein is a virus-coded ion channel and has been shown to function in HCV replication in chimpanzees. p7 had been thought to be a potential therapeutic target, however there was significant variability between p7 inhibition and efficacy against infection. Research revealed that different HCV genotypes show genetic variability in p7 and that this correlates with the sensitivity of HCV to p7 inhibitors (Griffin et al., 2008).
Therefore genotype specific p7 inhibitors may be suitable therapies for chronic HCV infection (Griffin et al., 2008). A further potential therapeutic target in HCV is a cellular peptidyl-prolyl cis-trans isomerase (PPIase), known as cyclophilin B (CyPB) (Rice et al., 2005). This protein is critical for the efficient replication of the hepatitis C virus genome as evidenced by the reduction in HCV replication mediated by RNA mediated interference against it (Rice et al., 2005).

6.2 Prevention of viral binding

Another method of eliminating HCV infection is by preventing or reducing the ability of the virus to bind to and thereby infect host cells. This can be achieved by antibodies to prevent binding or inhibition of the host receptor which mediated the interaction with HCV. On human cells the CD81 surface protein has been identified as a potential receptor for HCV, acting by binding to a glycoprotein known as E2 on the exterior of HCV (Cao et al., 2007). Antibodies have been developed via phage display which bind to CD81, thereby competing with the viral E8 glycoprotein and may act as an antiviral by preventing HCV cell attachment (Cao et al., 2007).

6.3 Inhibitors of viral release

In order to reduce HCV infectivity, the endoplasmic reticulum glucosidase I inhibitor Celgosivir is currently being characterised. This is a potent inhibitor of a host enzyme that is hijacked by HCV to aid viral assembly and release. Initial results from a recent clinical trial suggest that Celgosivir can reduce HCV RNA, suggesting with further characterisation it may prove a novel therapy (Durantel et al., 2007).

6.4 New interferons:

Several research groups are attempting to increase the efficacy of the current treatment by the use of novel interferons. One such interferon is consensus interferon (cIFN), which contains the most common amino acid sequences from a variety of natural interferons. Initial trials suggest that cIFN in combination with ribavirin can treat patients who showed no response to the standard pegylated IFN and ribavirin treatment (Leevy, 2008). Indeed, in a recent study in 2008, of 137 patients who had not responded to standard treatments, 37% showed undetectable HCV RNA when treated with cIFN and ribavirin (Leevy, 2008). A second novel interferon under investigation is Albuferon, a protein fusion of IFNα and human serum albumin, which has a longer active half life (Chemmanur- et al., 2006). A comparison of albuferon and ribavirin with pegIFN and ribavirin found similar responses between the two treatments, but those using the albuferon treatment were scored with a higher quality of life (2003; Masci et al., 2003; Sung et al., 2003).

6.5 Hepatitis C virus vaccines

Though vaccines exist for hepatitis A and B, there are as yet no prophylactic vaccines available for HCV. A number of potential vaccines are under development including a synthetic E1 vaccine, which is directed against an HCV surface glycoprotein (Lorent et al., 2008). Initial clinical trials have suggested that this vaccine did not reduce the level of HCV RNA in individuals but did slow the liver damage observed in non-responders to standard therapy, suggesting that this warrants further characterisation (Leroux-Roels et al., 2005; Nevens et al., 2003). Another vaccine currently under investigation is the synthetic peptide vaccine IC41 (Firbas et al., 2006). In a clinical trial IC41 could increase IFN producing T-cells, particularly in non-responders to standard therapy, but could not significantly reduce the level of HCV RNA (Klade et al., 2008). Current research in this area aims to optimize the dose of these vaccines and assess whether they can potentiate the benefits observed with combination therapies (Klade et al., 2008).
Though new strategies for the treatment of HCV show significant promise for the future, it should also be noted that in those responsive to combination therapies, 99% of patients had no detectable virus up to a decade later (Adamek et al., 2007; Lau et al., 1998). Thus the current combination therapy represents a cure for the 50% of HCV infected individuals who respond.