Box 1 Indications and contraindications to therapy

Indications Elevated/normal ALT

Necro-inflammation and fibrosis on liver biopsy Hepatitis C virus RNA positive

Extrahepatic manifestations (renal disease, cryoglobulinemia, porphyria cutanea tarda) Patient preference

Contraindications Absolute

Severe uncontrolled depression Unstable cardiac disease Uncontrolled concomitant disease Pregnancy Hemolytic diseases

Renal disease; creatinine greater than 2 mg/dL

Seizure disorder

Relative

Active drug and alcohol use Moderate depression/situational suicidal ideation Decompensated liver disease Autoimmune diseases inflammation and fibrosis on liver biopsy are obvious candidates for treatment. At the National Institutes of Health (NIH) consensus conference in 2002, however, there was a strong movement toward expanding the number of potential treatment candidates to include people with controlled depressive illness, methadone users, and patients who had stopped using alcohol recently. The other controversial area is whether to treat patients with persistently normal ALT. In the era of interferon (IFN) monotherapy, several case series suggested that patients with normal ALT might experience ALT flares and have a reduced SVR rate if treated with IFN [7,8]. Larger studies with IFN and ribavirin (RBV), however, have shown that ALT flares are not common and that the SVR rate is similar in patients with normal ALT compared with those with elevated ALT [9,10]. The current recommendation is that treatment of patients with normal ALT be considered on an individual basis, and it is believed that these patients will respond equally well to IFN and RBV combination therapy.

There remain some absolute contraindications to treatment, and these are listed in Box 1. In particular, therapy should not be undertaken in patients with decompensated liver disease and with active manic depressive disease or recent suicidal ideation. RBV is contraindicated specifically in patients with hemolytic disease, unstable cardiac disease, renal disease with a creati-nine above 2.0 mg/dL, and in patients who are pregnant or contemplating pregnancy.

Historical perspective

The efficacy of alpha interferon for treatment of HCV first was recognized when Hoofnagle et al published their preliminary findings in 1986 when HCV was known as non-A, non-B hepatitis [11]. They treated 10 patients with chronic non-A, non-B hepatitis with varying doses (0.5 to 5 million U) up to 12 months. The aminotransferases levels improved in 8 of 10 patients and in 3 patients who had follow-up biopsies done after 1 year of therapy showing marked improvement in liver histology. Several subsequent studies, including a large, multi-center, randomized clinical trial in the United States by Davis et al confirmed the initial finding that long-term IFN therapy improved liver function tests and liver histology [12]. The US Food and Drug Administration (FDA) approved alpha interferon monotherapy for the treatment of chronic HCV infection in 1993. In 1997, The NIH released the consensus statement recommending alpha interferon monotherapy at a dose of 3 million U three times weekly for 48 weeks as the standard of care for patients with chronic HCV infection. There are three IFNs approved for monotherapy in the United States, including IFN alfa 2b, IFN alfa 2a, and consensus IFN (CIFN). Multiple clinical trials of IFN monotherapy have been published using different doses and schedules, and overall there have been no major clinical differences in SVR between the different IFNs. Overall, the rates of SVR have been limited to 6% to 16%.

The optimal duration of treatment is 48 weeks for IFN monotherapy. In view of this relatively low response rate, higher doses, longer duration, induction doses, and dose escalation have been tried to increase SVR, but none of these variations has been shown prospectively to significantly increase response.

Combination therapy of interferon with ribavirin

A major advance occurred when IFN was combined with RBV in the pivotal studies of McHutchison et al [13], and SVR was increased from 13% to 38%. RBV is a nucleoside analog that putatively acts by means of inhibition of RNA-dependent RNA polymerase, depletion of intracellular guanosine triphosphate pools, and by altering Th1 and Th2 cytokine balance in the liver. Initial studies of RBV monotherapy in HCV resulted in biochemical but not histological response [14-16]. Two large randomized controlled clinical trials comparing IFN/RBV combination therapy with IFN monother-apy in HCV infection demonstrated a significant improvement in SVR for combination therapy (Fig. 1) [13,17]. Combination IFN/RBV therapy became the standard of care for naive patients, with a 24-week course of

IFN 24 IFN 48wks IFN/RBV IFN/RBV

wks 24wks 48wks

Fig. 1. SVR rates according to genotype for nai've patients receiving IFN alfa-2b versus combination IFN alfa-2b plus 1000/1200 mg ribavirin daily. In genotype non-1 patients, 24 weeks of combination IFN/RBV was equivalent to 48 weeks with a 62% SVR. For genotype 1 patients, SVR was 29% with 48 weeks of combination therapy (P less than 0.008 compared with IFN monotherapy for 48 weeks). (Data from McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 1998;339(21):1485-92; Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. Randomised trial of interferon alfa-2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alfa-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 1998; 352(9138):1426-32.)

IFN 24 IFN 48wks IFN/RBV IFN/RBV

wks 24wks 48wks

Fig. 1. SVR rates according to genotype for nai've patients receiving IFN alfa-2b versus combination IFN alfa-2b plus 1000/1200 mg ribavirin daily. In genotype non-1 patients, 24 weeks of combination IFN/RBV was equivalent to 48 weeks with a 62% SVR. For genotype 1 patients, SVR was 29% with 48 weeks of combination therapy (P less than 0.008 compared with IFN monotherapy for 48 weeks). (Data from McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 1998;339(21):1485-92; Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. Randomised trial of interferon alfa-2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alfa-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 1998; 352(9138):1426-32.)

treatment for genotyped 2 and 3 patients and a 48-week course for genotype 1 patients.

Pegylated alfa interferon monotherapy

Pegylation is a process by which a polyethylene glycol molecule is attached to a protein or drug to decrease renal clearance and increase bioavailability and efficacy. The renal clearance and short half-life of alfa interferons necessitated their administration three times a week and made them an excellent target molecule for pegylation. A critical concept with pegylation of biologically active proteins is the need to achieve a balance between increasing the half-life while maintaining biological activity. Increasing the size of the pegylated component can decrease renal clearance but also reduces the biological activity of the IFN component. There are two forms of peginter-ferons that have been approved by the FDA for use in chronic HCV; PEG-IFN 2a (Pegasys) IFN and PEG-IFN 2b (PEG-INTRON). PEG-IFN 2a has a 40kDa branched chain PEG attached to IFN alfa 2a, and PEG-IFN 2b has a 12kDa straight chain PEG attached to IFN alfa 2b. Both PEG-IFNs retain reduced but effective biological activity while having a favorable pharmacological profile that allows for once weekly administration. These PEG-IFNs have replaced IFN as the preferred form of IFN for use in treatment of HCV infection.

Clinical trials have confirmed a twofold increase in efficacy of PEG-IFNs compared with standard IFN in HCV treatment-naive patients (Table 1). Zeuzem et al showed that in the SVR was 39% in patients treated with PEG-IFN 2a at a dose of 180 mg for 48 weeks compared with 19% in patients taking standard interferon 2a at a dose of 6 mU three times weekly for 12 weeks then 3 mU three times weekly for 36 weeks [18]. In this trial, 62% of the subjects had genotype 1 HCV, and 7% had cirrhosis. In their multivariate analysis, use of PEG-IFN 2a, younger age, smaller body surface area, absence of cirrhosis or bridging fibrosis, a lower HCV RNA level, and a nongenotype 1 infection were associated with higher SVR. Subsequent studies using PEG-IFN 2a have shown a somewhat reduced SVR of 29%.

The results are similar in a study from Lindsay et al comparing there doses of PEG-IFN 2b (0.5, 1.0 and 1.5 mg/kg per week) with standard IFN alfa 2b at 3 mU three times weekly for 48 weeks [19]. The SVR was only 12% with standard IFN but 18%, 25%, and 23%, respectively with escalating doses of PEG-IFN 2b. In this study, two pretreatment variables were associated with higher SVR when a multivariate analysis was performed: nongenotype 1 and HCV RNA less than 2 million copies/mL.

In a difficult-to-treat population of naive patients with advanced fibrosis, defined as bridging fibrosis or cirrhosis, PEG-IFN 2a again demonstrated superior SVR compared with IFN alfa 2a. Heathcote et al randomized 271 patients with cirrhosis or bridging fibrosis into one of three groups: standard IFN alpha-2a at a dose of 3 mU three times weekly; PEG-IFN

Table 1

Randomized controlled trials of peginterferon monotherapy

Study Zeuzem et al, 2000 Heathcote et al, 2000 Lindsay et al, 2001

Type of IFN

IFN a-2a

PegIFN a-2a

IFN a-2a

PegIFN a-2a

PegIFN a-2a

IFN a-2b

PegIFN a-2b

PegIFN a-2b

PegIFN a-2b

Dose and

6 mU for

180 mg for

3 mU for

90 mg for

180 mg for

3 mU for

0.5 mg/kg/wk

1.0 mg/kg/wk

1.5 mg/kg/wk

duration

12 weeks, then 3 mU for 36 weeks

48 weeks

48 weeks

48 weeks

48 weeks

48 weeks

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