Mechanisms of Action

IFN was discovered as a substance that protects cells from viral infection. Two types of IFNs exist. Type I IFNs include IFN α (IFN-α), IFN β (IFN-β), and IFN ω (IFN-ω), whereas type II IFN includes only IFN γ (IFN-γ). There are at least 18 distinct genes encoding human IFN-α. Recently, 3 IFN-like cytokines in the interleukin (IL) 10 family designated as IL 28A, 28B, and 29 had been reported and termed IFN λ (IFN-λ). IFN-λ is similar to IFN-α and shares the same intracellular activation pathways. The recent discovery of IL-28B polymorphism as a genetic marker associated with spontaneous clearance of hepatitis C virus in patients with acute hepatitis C, as well as a sustained virological response (SVR) after pegylated IFN (PEG-IFN) and ribavirin treatment in patients with chronic hepatitis C, highlight the importance of IFN in immune recovery from viral hepatitis.

All type I IFNs bind to the same cell surface receptor (IFNAR1/2), although they differ in affinities. Type I IFNs have antiviral, antiproliferative, and immunomodulatory activities. IFN plays a role in adaptive as well as innate immune responses ( Fig. 2 ). IFN-α stimulates activity of T cells, natural killer cells, monocytes, macrophages, and dendritic cells. IFN-α also has antiviral activity. It induces IFN-stimulated genes (ISGs) resulting in a non–virus-specific antiviral state within the cell. This process begins with circulating IFN-α binding to IFN receptors, leading to activation of Janus-activated kinase 1 (Jak1) and tyrosine kinase 2 (Tyk2). The activated kinases phosphorylate the signal transducer and activator of transcription proteins 1 and 2 (STAT1 and STAT2). The activated STAT complex is translocated to the cell nucleus, where it combines with IFN-regulatory factor 9 (IRF-9), and this complex in turn binds to IFN-stimulated response element on cellular DNA, leading to expression of multiple ISGs. IFN-α also affects the translation of viral proteins via the protein kinase R (PKR) gene, which blocks viral protein synthesis through inhibition of eukaryotic initiation factor 2 (eIF2). IFN-α can reduce viral RNA stability through 2′,5′-oligoadenylate synthetase (2′5′OAS) and trafficking or activity of viral polymerase via induction of Mx proteins.

Mechanisms of action of IFN. IFNs bind to cell surface receptors leading to activation of the Jak-STAT pathway. The activated complex is translocated to the cell nucleus, stimulating the expression of multiple ISGs. IFNs decrease the translation of viral protein synthesis by RNA degradation and induction of Mx proteins. eIF2, eukaryotic initiation factor; IFNAR, Interferon alpha/beta receptor; IRF, Interferon regulatory factor; ISG, IFN-stimulated gene; Jak, Janus kinase; Mx, Mx protein; OASE 2-5 A, 2′, 5′-oligoadenylate synthetase; RNAse, ribonuclease; STAT, signal transducer and activator of transcription; Tyk2, tyrosine kinase 2; PKR, dsRNA-dependent protein kinase.

IFN-β has similar activities to IFN-α. IFN-λ acts on the same target genes as the type I IFNs as well as increasing the antiviral activity of subsaturating doses of IFN-α. IFN-γ has a more marked immunoregulatory effect but less potent antiviral activity compared with IFN-α.

Most studies of IFN in hepatitis B have focused on IFN-α. IFN-α has less-potent antiviral activity compared with oral nucleos(t)ide analogues that directly inhibit HBV replication. Clinical trials comparing IFN with lamivudine have consistently shown a smaller decrease in serum HBV DNA in the IFN-treated patients. Viral kinetic studies confirmed that the phase I decline of HBV DNA, which reflects the direct antiviral effect on virus production, was less steep in patients receiving IFN compared with those receiving lamivudine, with a mean HBV half-life of 1.6 (±1.1) days versus 9.5 (±3) hours, respectively. IFN also has immunomodulatory effects. Flares in aminotransferases have been observed in 25% to 40% of patients during IFN treatment. Flares followed by a decrease in serum HBV DNA levels have been termed host-induced flares and are believed to reflect immune-mediated lysis of infected hepatocytes. In one study, host-induced flares were observed in 24 of 67 (36%) patients who were hepatitis B e antigen (HBeAg) positive and receiving PEG-IFN. Patients with host-induced flares had a higher rate of HBeAg loss: 58% compared with 20% in patients who did not have a host-induced flare. Viral kinetic studies have shown that the second- (with PEG-IFN monotherapy) or third-phase (with PEG-IFN and lamivudine combination or lamivudine alone) viral decline reflects clearance of infected hepatocytes. These studies also suggest that PEG-IFN-α cleared infected cells to a greater extent than lamivudine, possibly reflecting its immunomodulatory activity, which is believed to be important in eliminating infected hepatocytes that harbor cccDNA.

Pharmacokinetics

Initial studies used IFN prepared from leukocytes or lymphoblastoid cell lines. IFNs used nowadays are manufactured using recombinant technology and PEG-IFN has superseded standard IFN.

Early studies on standard IFN and lymphoblastoid IFN involved a wide range of doses administered intravenously or as subcutaneous (SC) or intramuscular injections daily, every other day, or 3 times a week. The bioavailabilities of SC IFN-α2a and IFN-α2b are high, comparable to intravenous formulation. The mean terminal elimination half-life (t1/2β) of IFN-α2a and IFN-α2b following SC injection is 3.5 and 2.9 hours, respectively, but the duration of the biologic effects is likely much longer. One study found that dosing on alternate days, or 3 times a week, was as effective in suppressing HBV DNA as daily dosing but an insensitive assay was used to determine this dose-response effect.

PEG-IFN involves the conjugation of a polyethylene glycol molecule to IFN. Pegylation increases the molecular weight, thereby decreasing renal clearance and increasing the elimination half-life. PEG-IFN α-2a is conjugated with a single 40-kDa branched PEG moiety that consists of 2 monomethoxy PEG chains. PEG-IFN-α2b is conjugated with a linear 12-kDa PEG molecule.

PEG-IFN-α2a has a mean t1/2 of 77 hours after a single dose. At steady state, the ratio of serum peak to trough concentrations of PEG-IFN-α2a is about 1.5:2.0, indicating that serum concentrations of the drug are sustained during the 1-week dosing interval. The elimination half-life of PEG-IFN-α2b is 40 hours at week 1 and 58 hours at week 4. Previous studies showed that a significant proportion of chronic hepatitis C patients receiving PEG-IFN-α2b had a trough concentration less than the limits of detection by day 7 during once-weekly dosing. Viral kinetic studies have also observed viral rebounds by day 3. These data suggest that the optimal dosing interval of PEG-IFN-α2b should be shorter than 7 days.

PEG-IFN-α2a has a restricted volume of distribution, being distributed predominantly in the intravascular compartment, whereas PEG-IFN-α2b is distributed widely throughout the body fluids and tissues. The volume of distribution of PEG-IFN-α2b is dependent on the patient’s body weight; therefore, weight-based dosing is recommended. By contrast, PEG-IFN-α2a is administered as a fixed dose.

PEG-IFN-α2a is primarily metabolized by the liver and the metabolic products are subsequently excreted by the kidney, whereas PEG-IFN-α2b is metabolized and cleared by the kidney. Compared with standard IFN-α, renal clearance of PEG-IFN-α2a and PEG-IFN-α2b is reduced more than 100-fold and tenfold, respectively. There is a 25% to 45% reduction in clearance of PEG-IFN-α2a in patients undergoing chronic hemodialysis and a dose reduction from 180 μg/wk to 135 μg/wk is recommended for these patients. Maximum plasma concentration of PEG-IFN-α2b is increased by 90%, and half-life by up to 40% in patients with creatinine clearance (CrCl) less than 30 mL/min compared with those with normal renal function. It is recommended that the dose of PEG-IFN-α2b be reduced by 25% and 50% in patients with CrCl of 30 to 50 mL/min and less than 30 mL/min including those undergoing hemodialysis, respectively.

Optimal Dose and Duration of PEG-IFN

A phase II dose-ranging study that involved mainly Asian patients with HBeAg-positive CHB receiving PEG-IFN-α2a 90 μg, 180 μg, or 270 μg once weekly compared with standard IFN-α2a 4.5 MIU 3 times a week for 24 weeks, demonstrated an HBeAg clearance rate at week 48 of 37%, 35%, 29%, and 25%, respectively. These data indicate that response to 90 μg and 180 μg of PEG-IFN-α2a was comparable with and superior to standard IFN-α2a. Phase III trials of PEG-IFN-α2a used 180-μg doses to conform to the dose approved for the treatment of hepatitis C and to ensure that all patients regardless of size received an adequate dose, and 48 weeks was chosen to synchronize with the comparator arm (lamivudine). The optimal dose and duration of PEG-IFN-α2a for HBeAg-positive chronic hepatitis is being evaluated in an ongoing study comparing 90- versus 180-μg doses and 24 versus 48 weeks treatment.

Dose-ranging studies in patients with CHB have not been performed for PEG-IFN-α2b. A phase II dose-ranging study of PEG-IFN-α2b in patients with chronic hepatitis C found that SVR rates were comparable in patients who received 1.0-μg/kg or 1.5-μg/kg doses and better than those who received 0.5-μg/kg doses. The similarity in SVR rates in patients with hepatitis C receiving 1.0-μg/kg and 1.5-μg/kg doses of PEG-IFN-α2b was confirmed in the IDEAL study. Clinical trials of PEG-IFN-α2b in CHB have used varying doses. In the 2 largest studies, doses of 100 μg/wk for 32 weeks followed by 50 μg/wk until week 52 were used in 1 study, whereas doses of 100 μg/wk for 32 weeks were used in the other study. Weight-based dosing was not used in studies of PEG-IFN-α2b in CHB.

A longer duration of standard IFN therapy, 24 versus 12 months, had previously been shown to result in a higher rate of sustained response in patients with HBeAg-negative chronic hepatitis. Studies are ongoing to determine whether a higher rate of sustained response can be achieved with a 24- versus 12-month course of PEG-IFN in patients with HBeAg-negative chronic hepatitis.

Clinical Efficacy of PEG-IFN

HBeAg-positive chronic hepatitis

Responses to PEG-IFN treatment with and without lamivudine are summarized in Table 1 . In the phase III trial comparing PEG-IFN-α2a monotherapy, combination of PEG-IFN-α2a and lamivudine, and lamivudine monotherapy, serum HBV DNA decreased by 4.5, 7.2, and 5.8 log ₁₀ copies/mL, respectively at the end of 48 weeks of treatment. HBeAg seroconversion occurred in 27%, 24%, and 20% of patients, respectively, at week 48, and in 32%, 27%, and 19% ( P = .02), respectively, 24 weeks after stopping treatment. Studies of PEG-IFN-α2b showed similar results. One study found that HBeAg seroconversion rates 26 weeks after stopping treatment were similar in patients who received PEG-IFN-α2b with or without lamivudine (29.2% and 28.6%, respectively), whereas another study showed that HBeAg seroconversion rates 24 weeks after stopping treatment were higher in patients who received a combination of PEG-IFN-α2b and lamivudine than in patients who received lamivudine monotherapy: 36% and 14%, respectively. These data showed that, although PEG-IFN has weaker antiviral activity compared with lamivudine, PEG-IFN with its immunomodulatory effect results in a higher rate of HBeAg seroconversion than lamivudine, and the difference is magnified during posttreatment follow-up. These studies also showed that addition of lamivudine to PEG-IFN did not increase the rate of HBeAg seroconversion, despite a greater decline in serum HBV DNA during treatment.

Table 1

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