Treatment of Chronic HCV Infection with IFNa

Chronic HCV infection is curable, and cure is the goal of antiviral therapy. Successful treatment is characterized by a sustained virological response (SVR), defined by undetectable HCV RNA in a sensitive assay (detection limit < 50 international units (IU)/ml) 6 months after the end of therapy. Recent large-scale follow-up studies have shown no relapse or recurrence after 4-6 years in more than 99% of patients who have an SVR (McHutchison et al. 2006; Swain et al. 2007).

The choice of IFN-a as a potential treatment for chronic hepatitis C in 1986 was empirical (Hoofnagle et al. 1986). At this time, the causative agent of chronic "nonA, non-B" hepatitis had not yet been identified, and there was no way of evaluating HCV replication or, thus, the antiviral activity of a drug. In the first cohort of 10 patients with chronic non-A, non-B hepatitis treated with IFN-a, a significant decline in alanine aminotransferase (ALT) levels was observed in 8 patients, and liver histology had improved at the end of therapy in the three patients who were biopsied (Hoofnagle et al. 1986). Ten years later, 5 of the 10 patients were free of infection (Lau et al. 1998).

5.1.1 Standard IFN-a and Pegylated IFN-a Monotherapy

The first National Institutes of Health (NIH) Consensus Development Conference on Management of Hepatitis C, held in 1997 (1997), recommended that standard

IFN-a be used at the same dose for 48 weeks for the treatment of chronic hepatitis C. However, the SVR rates were still only 12-20% with this treatment schedule (Di Bisceglie and Hoofnagle 2002; Lindsay et al. 2001). The development of pegylated IFN-a was found to ensure sustained drug exposure. Pegylated IFN-a2a is administered at a fixed dose of 180 ^g/week, whereas pegylated IFN-a2b is administered at a weight-adjusted dose of 1.5 ^g/kg/week. Both pegylated IFNs have been reported to yield a twofold higher SVR rate than the corresponding standard IFN-a when administered alone for 48 weeks

5.1.2 IFN-a-Ribavirin Combination Therapy

Ribavirin is a guanosine analogue with a broad spectrum of activity against DNA and RNA viruses (Sidwell et al. 1972). Ribavirin modestly and transiently inhibits HCV replication in vivo (Pawlotsky et al. 2004), but it efficiently prevents relapses during IFN-ribavirin combination therapy (Bronowicki et al. 2006). The underlying mechanisms are unknown. In the first trial of standard IFN-a and ribavirin combination therapy, HCV was eradicated in 40% of patients who received the combination, but in none of those on IFN-a monotherapy (Brillanti et al. 1994). Further randomized controlled trials (McHutchison et al. 1998; Poynard et al. 1998) led to the approval of the standard IFN-a-ribavirin combination as the standard treatment for chronic hepatitis C, before the development of pegylated IFNs (1999).

Ribavirin is administered at a dose of 0.8-1.2 g/day, depending on body weight and the HCV genotype (2002). Higher doses may be necessary for heavy patients. The addition of ribavirin increased the SVR rate to 41% and 43%, respectively, compared to 16% and 19% with standard IFN-a2a and IFN-a2b monotherapy (McHutchison et al. 1998; Poynard et al. 1998). In the three main registration trials (randomized controlled studies involving patients without cirrhosis), pegylated IFN-a plus ribavirin gave global SVR rates of 54-56%, compared to 18-39% with pegylated IFN-a monotherapy (Fried et al. 2002; Hadziyannis et al. 2004; Manns et al. 2001). The SVR rates ranged from 76% to 84% in patients with HCV genotype 2 or 3 infection and from 42% to 52% in patients with HCV genotype 1 infection. Little information is available on patients with other genotypes, but the SVR rates in patients with HCV genotype 4 infection appear to be close to those in patients with genotype 1 infection. Pretreatment variables that correlated with sustained viral eradication included HCV genotypes 2 and 3, lower baseline viral load, lower body weight, younger age, and milder hepatic fibrosis (Fried et al. 2002; Hadziyannis et al. 2004; Manns et al. 2001). In pivotal trials approximately 10% of patients discontinued therapy because of adverse events, and dose reductions were required in about 30% of cases (Fried et al. 2002; Hadziyannis et al. 2004; Manns et al. 2001). Neutropenia and thrombocytopenia were frequently associated with IFN-a administration, and hemolytic anemia was the most frequent adverse effect of ribavirin administration (Fried et al. 2002; Hadziyannis et al. 2004; Manns et al. 2001). Ribavirin-associated anemia can be severe and demand discontinuation or dose reduction.

5.1.3 Optimized Pegylated IFN-a-Ribavirin Combination Therapy

Pegylated IFN-a-ribavirin combination therapy can be improved by increasing the dose of pegylated IFN-a and/or ribavirin in selected patients and by tailoring the length of treatment to the virological response.

Elevated Doses

The optimal dose of ribavirin is still uncertain. The approved dose is 0.8 g/day for patients infected with HCV genotypes 2 and 3, and 1.0-1.2 g/day in patients (weighting less and more than 75 kg, respectively) infected with HCV genotypes 1, 4, 5, and 6. However, several studies have suggested that higher serum ribavirin concentrations are associated with higher SVR rates (Jen et al. 2000, 2002; Lindahl et al. 2005). In patients infected with HCV genotype 1, the probability of an SVR increases with the AUC of ribavirin concentrations (Snoeck et al. 2006). In addition, the proportion of patients achieving an SVR is higher with a standard weight-based dose of ribavirin than with a low dose (Jensen et al. 2006). Although adverse effects are more frequent and more serious, the use of high ribavirin doses (average 2.5 g/day) to treat patients with high-viral-load HCV genotype 1 infection is feasible and leads to an SVR in 9 out of 10 patients (Lindahl et al. 2005). The use of higher ribavirin doses is offset by the potential increase in drug-related toxicity (principally hemolytic anemia), especially at doses above 15mg/kg. Epoetin (or darbepoetin, an epoetin prodrug) can be used to reduce the incidence and severity of anemia. However, neither the FDA nor the EMEA has approved the use of these drugs in the treatment of chronic hepatitis C, and the cost-effectiveness of this approach has been questioned (McHutchison et al. 2007b). In patients with HCV genotype 2 or 3 infection, the SVR rate is not strongly influenced by the dose of ribavirin, and 0.8 g/day is probably sufficient to maximize the chances of achieving an SVR (Fried et al. 2002; Hadziyannis et al. 2004; Manns et al. 2001). Whether lower doses of ribavirin could be sufficient to achieve the same SVR rates is currently under investigation.

In a so-called difficult-to-treat patient population (HCV RNA > 800,000 IU/ml and body weight > 85 kg), raising the doses of both pegylated IFN-a and ribavirin significantly increased the SVR rate (Fried et al. 2006). In another study, weight-based ribavirin administration up to 1.4 g/day was more effective than a fixed dose of 0.8 g/day in patients infected with HCV genotype 1 (Jacobson et al. 2005). In a small number of cirrhotic patients infected with HCV genotype 1 who had not responded to a previous course of pegylated IFN-a and ribavirin, 180 |g of pegylated IFN-a2a every 5 days, combined with ribavirin, induced an SVR in several cases (Hezode et al. 2006). Ongoing trials are assessing more frequent administration and higher weekly doses of pegylated IFN-a, and higher doses of ribavirin, in nonresponder and difficult-to-treat patients. Patients receiving such reinforced therapy must be carefully monitored for toxicity, and the merits and drawbacks of growth factor administration should be considered.

Tailoring the Treatment Duration to the Virological Response

Current guidelines state that the length of treatment should be tailored to the HCV genotype (Pawlotsky 2006). Patients infected with HCV genotypes 1, 4, 5, and 6 should be treated for 48 weeks (with 1.0-1.2 g/day ribavirin), whereas patients infected with HCV genotypes 2 and 3 should be treated for 24 weeks only (with 0.8 g/day ribavirin) (2002; Hadziyannis et al. 2004). Treatment must be stopped at week 12 in genotype 1-infected patients who do not have a 2-log drop in their HCV RNA level. Rapid virologic responses (RVR) are defined by an HCV RNA level below 50 IU/ml at week 4 of therapy. Several recent reports suggest that patients with an RVR could qualify for shorter treatment, which would improve adherence and reduce the cost of therapy. Conversely, extending treatment duration beyond 48 weeks may achieve an SVR in patients infected with HCV genotype 1 who have a slow vi-rologic response, defined as an HCV RNA decline of more than 2 log IU/ml but a value above 50 IU/ml at week 12. For more detailed information, see the chapter by Zeuzem, this volume.

5.2 Treatment of Acute HCV Infection with IFN-a

HCV infection is rarely diagnosed in the acute phase, as most acutely infected individuals are asymptomatic. Between 50% and 90% of patients develop chronic infection, however, and this warrants early therapy. After occupational exposure with a known date, treatment should not be started before the acute episode characterized by alanine aminotransferase elevation, but it should always be started within 24 weeks after the onset of symptoms. The optimal treatment schedule for acute hepatitis C is controversial. Pegylated IFN-a monotherapy at the standard dose for 24 weeks yielded SVR rates close to 100% in symptomatic patients referred to tertiary care centers (De Rosa et al. 2006; Jaeckel et al. 2001; Santantonio et al. 2005; Wiegand et al. 2006). Shorter therapy may be envisaged (Calleri et al. 2007). Combination with ribavirin is recommended if a first course of pegylated IFN-a monother-apy fails to eradicate the infection. Viral elimination appears to be independent of the HCV genotype and the HCV RNA level (Calleri et al. 2007; De Rosa et al. 2006; Jaeckel et al. 2001).

5.3 Future Perspectives of IFN-Based HCV Therapy 5.3.1 Other IFNs

Several studies have tested IFN-ß for chronic hepatitis C, achieving response rates similar to those obtained with IFN-a and with similar or fewer adverse effects (Barbaro et al. 1999; Castro et al. 1997; Habersetzer et al. 2000; Montalto et al.

1998; Villa et al. 1996). Recent reports from Japan suggest that daily IFN-p administration is highly effective in patients with low or moderate HCV RNA levels (Horiike and Onji 2003; Shiratori et al. 2000). Twice-daily administration of IFN-p as induction therapy has also been reported to be effective (Kim et al. 2005; Naka-jima et al. 2003). It is unlikely, however, that IFN-p will be used in routine clinical practice unless it is pegylated or otherwise modified, and until specific clinical trials are done.

IFN-œ (Intarcia Therapeutics, Emeryville, California) has been reported to be well tolerated and safe, in patients infected with various HCV genotypes, at doses of 15-120 |g three times weekly for 12 weeks, with dose-dependent virological and biochemical responses (Plauth et al. 2002). At a dose of 25 |g daily, IFN-œ induced a 2-log HCV RNA decline at week 12 in two-thirds of 74 patients infected with HCV genotype 1 (Gorbakov et al. 2005). In a recent trial, SVR was achieved in 6% and 36% of patients receiving the same dose of IFN-œ without and with ribavirin, respectively (Novozhenov et al. 2007). A new trial of IFN-œ, delivered continuously by an implantable device, will start soon.

IFN-y has potent activity against HCV in the subgenomic replicon system (Dash et al. 2005; Frese et al. 2002; Lanford et al. 2003). Synergistic immunomodulatory effects of IFN-y1b and IFN-a have been reported (Wang et al. 2006). However, a pilot study of IFN-y at a dose of 100-400 |g three times per week showed no antiviral efficacy in patients infected with HCV genotype 1 who had not responded to standard therapy or who had relapsed (Soza et al. 2005).

IFN-A1 exhibits dose- and time-dependent inhibition of HCV replication in various models, independently of type I and II IFN receptors and induced pathways (Marcello et al. 2006). A pegylated form of IFN-A, will soon enter clinical evaluation.

5.3.2 New IFN-a Molecules

Alb-IFN-a2b has been reported to induce a dose-dependent antiviral response in previously untreated patients and in nonresponders to the pegylated IFN-a and rib-avirin combination (Bain et al. 2006; Balan et al. 2006). The results of a phase II trial in untreated genotype 1-infected patients were recently reported: the SVR rates were not significantly different among four groups of patients receiving either the standard pegylated IFN-a2a and ribavirin combination or alb-IFN-a2b at doses of 900 |g every two weeks, 1,200 |g every 2 weeks and 1,200 |g every 4 weeks (Zeuzem et al. 2007). End-of-treatment responses to alb-IFN-a2b administered every 2 or 4 weeks in combination with ribavirin are similarly frequent in patients infected with HCV genotypes 2 and 3 (Bain et al. 2007). Higher doses of alb-IFN-a2b given every 4 weeks are currently under investigation, and the product will soon enter phase III clinical evaluation.

Consensus IFN-a has been used in various populations of HCV-infected patients but the published results are variable. Consensus IFN-a gave a higher response rate than the combination of standard IFN-a and ribavirin in patients who relapsed after standard IFN-a monotherapy (Miglioresi et al. 2003). In patients in whom the standard IFN-a-ribavirin combination failed, an SVR rate of approximately 30% was obtained with consensus IFN-a (Bocher et al. 2006). In contrast, an SVR was achieved in only 8% of patients who did not respond to standard IFN-a2b plus ribavirin (Moskovitz et al. 2003). Recently, a direct comparison of consensus IFN-a-ribavirin and pegylated IFN-a-ribavirin showed similar SVR rates of 37% and 41%, respectively, in previously untreated patients infected with HCV genotype 1 (Sjogren et al. 2007). Nevertheless, there is no clear evidence that consensus IFN-a is superior to other IFNs when given at equivalent doses. The future of consensus IFN-a will depend on the development of a pegylated or otherwise pharmacologically modified form.

5.3.3 Enhanced IFN-a-Based Therapy

The results of IFN-a-based therapy can theoretically be improved by using better-tolerated drugs that mimic the action of ribavirin and/or by using HCV inhibitors that, when combined, substantially reduce HCV replication. Since the mechanism of action of ribavirin is still unknown, no credible alternative approach is currently available. In contrast, many specific inhibitors of the HCV replication cycle are in preclinical development and several have reached clinical development (Pawlotsky et al. 2007). A number of them are being tested in combination with pegylated IFN-a, with or without ribavirin.

The NS3/4A serine proteinase inhibitors telaprevir (VX-950, Vertex Pharmaceuticals, Cambridge, Massachusetts) and boceprevir (SCH 503034, Schering-Plough Corporation, Kenilworth, New Jersey) have now advanced to phase II clinical trials. In a recent trial, HCV RNA became undetectable (below 10IU/ml) in all 12 patients receiving the triple combination of pegylated IFN-a2a, ribavirin, and telapre-vir for 28 days (Rodriguez-Torres et al. 2006). Preliminary results of the PROVE 1 phase II trial showed that, after 12 weeks of treatment with telaprevir plus both pegylated IFN-a and ribavirin, HCV RNA was undetectable (<10IU/ml) in significantly more genotype 1-infected treatment-naive patients than in the arm receiving only the dual combination of pegylated IFN-a and ribavirin, without telaprevir (70% and 39%, respectively). Telaprevir administration was associated with more frequent dermatological (especially rash and pruritus) and gastrointestinal side effects (McHutchison et al. 2007a). Telaprevir was withdrawn after 12 weeks in all the groups, and the patients will continue on pegylated IFN-a and ribavirin for various times. Other trials of the triple combination given for 12 or 24 weeks and a dual combination of pegylated IFN-a and telaprevir (without ribavirin) are undergoing in treatment-naive and nonresponder patients (PROVE 2 and PROVE 3).

In nonresponders to IFN-a-ribavirin, the antiviral effect of boceprevir appeared to be strictly additive to that of pegylated IFN-a2b (Sarrazin et al. 2007). In an ongoing phase II clinical trial, higher doses of boceprevir are being administered to treatment-naive patients, in combination with pegylated IFN-a and ribavirin.

Resistance is a problem when these drugs are administered alone and will need to be carefully monitored when they are used in combination with IFN-a and ribavirin.

Inhibitors of the RNA-dependent RNA polymerase belong to two categories: nucleoside/nucleotide inhibitors target the catalytic site of the enzyme, and non-nucleoside inhibitors target allosteric sites of the RdRp (Pawlotsky et al. 2007). Three RdRp inhibitors have been tested in clinical trials, including two nucleo-side inhibitors, valopicitabine (NM283, Idenix Pharmaceuticals, Cambridge, Massachusetts, and Novartis) and R1626 (Roche), and a non-nucleoside inhibitor, HCV-796 (ViroPharma, Exton, Pennsylvania, and Wyeth Pharmaceuticals, Madison, New Jersey) (Pawlotsky et al. 2007).

In a phase IIb trial involving 190 HCV genotype-1-infected treatment-refractory patients, valopicitabine had a dose-dependent additive effect to that of pegylated IFN-a2a (Afdhal et al. 2006). Frequent gastrointestinal side-effects have been reported and the development of valopicitabine has been halted. In a phase II trial in which HCV genotype 1- and non-1-infected patients received the combination of pegylated IFN-a2b and HCV-796 for 14 days, the HCV RNA level fell more than with pegylated IFN alone (3.3-3.5 log IU/ml in the combination groups and 1.6 log IU/ml in the pegylated IFN-a group), and no viral breakthroughs due to resistance selection occurred during the 14 days of administration (Villano et al. 2007). R1626, combined with pegylated IFN alpha and ribavirin, has recently progressed to phase II clinical development. Further studies are needed to establish the potential benefits and drawbacks of adding HCV replication cycle inhibitors to the pegylated IFN-a-ribavirin combination, the current standard of care.

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