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Interferon
Treatment options for patients with chronic HCV have evolved
from interferon (IFN) monotherapy to combination therapy with
IFN and ribavirin (RBV) to combination therapy with pegylated
interferon (PEG IFN) and RBV. When 24 to 48 weeks of combination
therapy with IFN and ribavirin was adopted as the standard of
care for HCV treatment, sustained virologic response (SVR) rates
rose from approximately 20% in monotherapy to approximately 40%
in combination therapy. Along with improvements in SVR, patients
experienced half the rate of relapse following combination
therapy compared with that observed with monotherapy (McHutchison
et al, 1998; Poynard et al, 1998).
Interferon alfa-2a and IFN alfa-2b comprise the primary IFNs available for treatment in the HCV-infected patient. Naturally occurring small protein molecules, endogenous alfa IFNs are produced and secreted by T cells and fibroblasts in response to viral-induced leukocytes. Specific cell surface membrane receptors bind IFN (endogenous and exogenous) proteins; the binding of IFN to the receptor produces a complex sequence of intracellular events, including the induction of enzymes (Figure 4).  Figure 4. Proposed Antiviral Effects of Interferon. The events that follow include:
(Drug Facts and Comparisons, 2001; Davis et al, 1999). Standard Interferon alfa/Ribavirin Combination Therapy
Ribavirin is an orally available guanosine nucleoside
analogue with limited antiviral activity against a broad
array of RNA and DNA viruses, prompting its
investigation in persons with chronic HCV infection.
Unfortunately, RBV monotherapy has no impact on HCV RNA,
and while significant decreases in serum alanine
aminotransferase (ALT) levels have been observed, these
were not sustained once therapy was discontinued (Di
Bisceglie et al, 1995). Nonetheless, RBV was studied in
combination with IFN alfa-2b in persons with chronic HCV
infection. In separate studies, McHutchison and
colleagues and Poynard and coworkers randomized patients
to receive IFN alfa-2b plus RBV or placebo for 24 or 48
weeks. The combination of IFN alfa-2b plus RBV resulted
in SVR rates of 41% in persons infected with HCV
genotype 1 and 67% in those infected with HCV genotypes
2 or 3, nearly 2-times greater than the SVR rate
observed in those receiving IFN alfa-2b plus placebo (McHutchison
et al, 1998; Poynard et al 1998). Combination therapy
with IFN alfa-2b and RBV 1000 mg (body weight
75 kg) or 1200 mg (body weight>75 kg) daily in 2 divided
doses was approved by the FDA in 1998, replacing IFN
alfa monotherapy as the standard of care for the
treatment of persons chronically-infected with HCV.Pegylated Interferon alfa Monotherapy
Interferon alfa is rapidly absorbed, has a high
volume of distribution, and is rapidly cleared
by the kidneys. Although initial clinical trials
employed a standard regimen of IFN alfa 3 MIU
thrice weekly, viral kinetic studies conducted
by Neumann and colleagues demonstrated the
greatest anti-HCV effect when IFN alfa was
administered at 10 MIU daily, suggesting that
IFN alfa was being delivered at doses that were
too low and given too infrequently (Neumann et
al, 1998). To address the inadequacies of
standard IFN, researchers examined the effect of
adding polyethylene glycol (PEG) to the IFN alfa
molecule. The addition of the nontoxic
water-soluble polymer (composed of repeating
methyl groups) to IFN increases the half-life of
the molecule, providing continuous exposure over
a 1-week period. In addition, PEG IFNs have
enhanced pharmacokinetic and dynamic properties,
including improved absorption and volume of
distribution and decreased renal clearance. More
importantly, in clinical trials, patients with
chronic hepatitis C who received PEG IFN alfa-2a
or alfa-2b achieved SVR rates that were nearly
2-fold greater than those observed among
patients receiving standard IFN alfa-2a or
alfa-2b (Lindsay, 2001; Zeuzem, 2001; Heathcote,
2001).
Pegylated Interferon alfa/Ribavirin Combination Therapy
Recently, randomized controlled trials
have demonstrated that the addition of
RBV to PEG IFN therapy is more effective
than either PEG IFN monotherapy or
standard IFN/RBV combination therapy,
leading to the FDA approval of PEG IFN
(12 kDa) alfa-2b/RBV combination
therapy. In addition, PEG IFN (40 kDa)
alfa-2a/RBV combination therapy
currently is under FDA review for
approval.
PEG IFN alfa-2b plus RBV
Manns et al, 2001
In a randomized open-label international trial, Manns and colleagues (2001) studied 1530 patients with chronic HCV infection, randomly assigning them into one of three 48-week treatment groups:
Patients who received higher dose PEG IFN had a significantly higher SVR rate (54%) than the other 2 treatment groups, which were each 47% (P = .01). Genotype 1 patients demonstrated an SVR rate of 42% when treated with higher dose PEG IFN, vs SVR rates of 34% and 33% in the lower dose PEG IFN and standard IFN groups, respectively. Genotype 2 and 3 patients achieved SVR rates of approximately 80% in all 3 treatment groups (Figure 5).  Figure 5. Sustained Virologic Response by HCV Genotype. In addition, Manns and coworkers found that SVR was higher among patients who received more RBV per day, expressed as the number of milligrams per kilogram of body weight per day. In a subset analysis, they found that the SVR was higher among patients who received more than 10.6 mg/kg of RBV daily (~800 mg for a 70 kg person) (Figure 6).  Figure 6. Sustained Virologic Response by Treatment Regimen and Ribavirin Dose. The authors concluded that PEG (12 kDa) IFN alfa-2b 1.5 µg/kg per week and ribavirin given at doses >10.6 mg/kg per day for 48 weeks was more effective than standard IFN and ribavirin. PEG (40 kDa) IFN alfa-2a plus RBV4
Fried et al, 2001
Similarly, Fried and coworkers conducted a multicenter, partially blinded, randomized clinical trial for the treatment of chronic hepatitis C among persons who had not been treated previously. Patients were randomized into one of three 48-week treatment groups
The SVR rate was 56% in the PEG IFN alfa-2a plus RBV group, significantly higher than the 45% SVR observed in the IFN alfa-2b/RBV combination group and the 30% SVR observed in the PEG IFN alfa-2a monotherapy group (P = .001) (Figure 7).  Figure 7. Sustained Virologic Response by Treatment Regimen. Among patients infected with HCV genotype 1, the SVR rate was 46% in the PEG (40 kDa) IFN alfa-2a plus RBV group, which was significantly higher than the SVR observed in the standard IFN/RBV group (37%) and in the PEG (40 kDa) IFN alfa-2a/placebo group (21%). Similarly, among patients infected with HCV genotypes 2 and 3, SVR rates were highest in the PEG (40 kDa) IFN alfa-2a/RBV groups (Figure 8). Similar to the study by Manns and colleagues, Fried and coworkers concluded that PEG (40 kDa) IFN alfa-2a plus RBV was more effective than standard IFN/RBV for patients with HCV genotype 1. However, these studies left important questions unanswered regarding the appropriate duration of therapy in persons infected with HCV genotypes 2 or 3 and the most effective daily dose of RBV.  Figure 8. Sustained Virologic Response Rates by Treatment Regimen and HCV Genotype. To address these outstanding clinical issues, Hadziyannis and colleagues conducted a multicenter, double-blind, randomized, controlled clinical trial among persons chronically infected with hepatitis C who had not previously been treated. Study participants (N = 1284) were randomized to one of four treatment groups, which compared 2 dosing schemes of RBV (800 mg/day versus 1000-1200 mg/day) and 2 treatment durations (24 weeks vs 48 weeks). Randomization was stratified by HCV genotype, HCV RNA level (viral load), and geographic region.
Hadziyannis and colleagues reported that among persons infected with HCV genotype 1, the SVR rate was greatest among those treated with PEG (40 kDa) IFN alfa-2a/high dose RBV (1000-1200 mg) for 48 weeks, whereas among those with HCV genotype 2 or 3, shorter duration of therapy (24 weeks) and low dose RBV (800 mg/day) revealed comparable SVR rates to standard IFN/RBV therapy (Figure 9).  Figure 9. Sustained Viral Response Rates by HCV Genotype, Ribavirin Dose and Treatment Duration. However, longer duration of HCV therapy was associated with more adverse events, leading to higher rates of withdrawal from therapy (Figure 10).  Figure 10. Rate of Withdrawal From Therapy by Ribavirin Dose and Treatment Duration. In addition, the rate of RBV discontinuation for clinical adverse events and/or laboratory abnormalities was significantly higher among those treated for 48 weeks compared with 24 weeks (Figure 11).  Figure 11. Rate of RBV Discontinuation by Ribavirin Dose and Treatment Duration. Based on these data, it is recommended that persons infected with HCV genotype 1 be treated with PEG IFN plus higher dose RBV (1000-1200 mg/day) for 48 weeks, whereas those with HCV genotype 2 or 3 should be treated for 24 weeks. However, the higher rates of adverse effects and dose reduction and/or discontinuation of RBV observed among those treated for 48 weeks and among those receiving higher dose RBV clearly indicate the need for the development of strategies to reduce side effects, improve quality of life, and prevent the need for RBV dose reduction among patients treated with PEG IFN alfa/RBV. |
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