| Abstract|| |
Hepatitis B Virus (HBV) infection is a significant global public health problem. Treatment options that have evolved rapidly over the last two decades have proven to be effective, but clear recommendations regarding the choice of first-line therapy are lacking. With the emergence of pegylated interferon (PEG IFN), conventional interferon has been relegated into the background and has a very limited role in the treatment of chronic Hepatitis B. Pegylated interferon α2a / 2b treatment has been documented to successfully achieve normalization of alanine aminotransferase (ALT) and viral suppression in nearly half of the patients. However, HBsAg loss can be achieved only rarely. Combination therapy, comprising of pegylated interferon plus nucleos(t)ide analogs theoretically appear attractive because of the synergistic anti-viral and immunomodulatory actions, but the available present literature does not provide sufficient evidence to recommend the combination therapy. Patient selection is important for tailoring the therapy for patients with chronic hepatitis B. Pegylated interferon seems suitable for young patients with raised ALTs, moderately high viral load, and having Genotype A / B; the advantage being finite duration of therapy and no risk of emergence of drug resistance.
Keywords: Chronic hepatitis B, genotype, hepatitis B virus, interferon, nucleos(t)ide analogs, pegylated interferon, treatment.
|How to cite this article:|
Sood A, Midha V. Interferon for HBV infection: Plain or Pegylated? Alone or in combination? Concurrent or sequential?. Hep B Annual 2011;8:71-83
| Introduction|| |
Hepatitis B virus (HBV) infection is a significant global public health problem. An estimated 400 million people worldwide have chronic HBV infection and more than 500,000 people die every year due to complications of HBV-related chronic liver disease. Despite the widespread availability of a safe and effective vaccine to prevent HBV infection, newly diagnosed infections remain common. Hence, effective treatment of chronic hepatitis B is of vital importance. The primary treatment endpoint used to define the optimal activity of any antiviral drug is a sustained decrease in serum HBV DNA to undetectable levels and various multiple secondary treatment endpoints include decreasing or normalizing serum ALT, loss or seroconversion of hepatitis B e antigen (HBeAg), loss or seroconversion of hepatitis B surface antigen (HBsAg), and perhaps, an improvement in the liver histology. Correspondingly, the ultimate goal of hepatitis B treatment is to prevent decompensated cirrhosis and hepatocellular carcinoma. 
As of today, the treatment landscape of chronic hepatitis B (CHB) has evolved rapidly over the years. Current guidelines for the management of chronic hepatitis B recognize two formulations of Peg IFN (Peginterferon α 2a / b) along with five nucleos(t)ide for its treatment, namely, lamivudine, telbivudine, adefovir, entecavir, and tenofovir.  All these treatment modalities have proven to be effective, but clear recommendations regarding the first-line therapy are lacking. This article will focus on the role of interferon in the management of chronic hepatitis B.
Mechanisms of action : Interferons (IFN) are naturally occurring cytokines with immunomodulatory, antiproliferative, and antiviral activity. Multiple naturally occurring forms of IFN exist, including IFN-alfa, produced by lymphocytes. The effects of IFN-alfa are predominantly immunomodulatory, with a limited direct antiviral effect on HBV. IFN-alfa binds to its cellular receptor and activates the secondary messengers, resulting in the production of multiple proteins that are important for the defense of the cell against viruses. The immunomodulatory effects of IFN-alfa include enhancement of antigen presentation to the immune system, activation of natural killer (NK) cells and other immune cells, and increased production of cytokines. Antiviral effects include degradation of viral mRNA, inhibition of viral protein synthesis, and prevention of infection of cells. 
| Interferon in chronic hepatitis B: plain or pegylated|| |
Interferons were first recognized in 1957, for their ability to interfere with viral activity. Modification of IFN through the attachment of a polyethylene glycol (PEG) molecule has led to improved pharmacokinetic and pharmacodynamic properties and has largely replaced conventional IFN. PEG-IFN is administered once weekly, resulting in a relatively continuous drug exposure during the dosing interval. Two types of PEG-IFN have been developed; a small linear 12-kDa PEG, linked to IFN alfa-2b (PEG-IFN alfa-2b) and a large branched 40-kDa PEG linked to IFN alfa 2a (PEG-IFN alfa-2a). PEG-IFN alfa-2a is registered for the treatment of both HBeAg-positive and HBeAg-negative CHB as a 48-week course, in a dosage of 180 µg administered subcutaneously once a week. PEG-IFN alfa-2b has only been registered for the treatment of CHB in countries with a high prevalence of HBV infection.
Many controlled studies of IFN in patients with chronic hepatitis B have been reported. In a meta-analysis including 15 randomized, controlled trials, published between 1986 and 1992, comparing interferon versus placebo in HBeAg-positive chronic hepatitis B, the superiority of IFN was shown for rates of undetectable HBV DNA, HBeAg loss, and HBsAg loss [Figure 1]. In these studies, using various regimes, the mean virological response rate was 37% versus 17%, the mean rate of HBeAg loss was 33% versus 12%, and the rate of hepatitis B surface antigen (HBsAg) loss was 8% versus 2% in the interferon-treated groups versus the placebo groups.  A dosage of 5 million units (MU) to 10 MU, three times per week, for four to six months, has shown good efficacy, with satisfactory tolerance in these studies. 
|Figure 1: Meta-analysis of interferon-alpha trials in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (Wong DKH et al., Ann Intern Med, 1993)|
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The discrepancies in the results of the various different studies in this meta-analysis were, in part, due to the different therapeutic regimens and the varying populations of patients included in these trials. A certain number of factors were predictive of poor response to IFN: low serum HBV DNA level, high serum ALT levels, and also, infection with HBV at birth or early in life (as often occurs in areas where HBV infection is hyperendemic, such as, Southeast Asia). 
A randomized, controlled study comparing PEG IFN alfa-2a with IFN alfa-2a was carried out in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B; the treatment duration and follow-up being 24 weeks. At the end of the follow-up, the treatment response, defined as the loss of HBeAg with a serum HBV DNA level below 500,000 copies / mL and normal ALT levels were observed in 19 to 28% of the patients receiving PEG IFN alfa-2a (at doses of 90 ug, 180 ug or 270 ug / week) and in 12% of the patients who received standard IFN-2a; the difference was not significant. However, when the three PEG IFN groups were pooled retrospectively, there was a significant difference as compared to the IFN group (24% vs. 12%; P = 0.036), especially among the difficult-to-treat patients, as those having high HBV DNA levels or low ALT levels [Figure 2]. This study strongly suggested that PEG IFN alfa-2a was more effective than standard IFN-2a for the treatment of chronic hepatitis B. The safety profile of PEG IFN was comparable to that of conventional IFN, with the same frequency of adverse events or laboratory abnormalities.  Therefore, conventional interferon had a very limited scope of use for chronic hepatitis B and was virtually replaced by PEG-IFN.
|Figure 2: Pegylated interferon (PEG IFN) alfa 2-a versus IFN alfa 2a in hepatitis B e antigen (HBeAg) positive chronic hepatitis B. (Cooksley G et al., J Viral Hepat, 2003)|
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| Interferon in chronic hepatitis B: alone or in combination?|| |
There have been three large muticenter trials of the Peginterferon therapy either alone or in combination with lamivudine, two in HBeAg-positive and one in HBeAg-negative chronic hepatitis B. Two of these studies used Peginterferon alfa-2a, while one used Peginterferon alfa-2b. The results of two of these pivotal trials for HBeAg-positive CHB are shown in [Table 1]. PEG-IFN monotherapy administered for one year has resulted in HBeAg seroconversion in about one-third of HBeAg-positive patients, after 24 to 26 weeks of treatment-free follow-up. Sustained viral suppression (serum HBV DNA < 100,000 to 200,000 copies / mL) has occurred in 27 to 32% of the patients. Serum HBV DNA has been suppressed below 400 copies / mL in 7 to 14% of the patients after six months of follow-up. In both studies, PEG-IFN monotherapy has been compared with PEG-IFN and lamivudine (LAM) combination therapy. ,
|Table 1: Rates of sustained virological and biochemical response to PEG-IFN in HBeAg-positive chronic hepatitis B |
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The ultimate surrogate end-point of therapy and loss of HBsAg with appearance of anti-HBs occurred in only 4-6% of the patients after one year of treatment and six months of post-treatment follow-up. In both these studies, the addition of lamivudine to PEG-IFN monotherapy did not increase the response rates, although on-treatment viral suppression was more vigorous in patients who received the combination therapy. A representative cohort of 172 patients treated with PEG-IFN alfa 2b, with or without lamivudine, in the aforementioned study were enrolled in a subsequent follow-up study and revisited after a mean of three years. HBeAg seroconversion was sustained in 70%, and 11% of the patients were HbsAg-negative at the end of the follow-up. 
PEG-IFN treatment has been less extensively studied in HBeAg-negative patients. In one trial, the patients were randomized to receive peg-IFN alfa-2a alone, lamivudine alone, or the combination, for 48 weeks of therapy. The patients were subsequently followed up for 24 weeks. The primary end-point was suppression of HBV DNA levels to below 20,000 copies / mL and normalization of ALT. The response rate was 36% for the PEG-IFN monotherapy group, both at the end of treatment and after 24 weeks of follow-up. After 24 weeks of follow-up, 38% of the patients treated with PEG-IFN had HBV DNA levels 10,000 copies / mL (the level below which the inactive carrier state is defined, and 4% of the HBeAg-negative patients had cleared HBsAg). For lamivudine, the response rates were 69% at the end of therapy and 23% after 24 weeks of follow-up. Addition of lamivudine to PEG-IFN increased the probability of an end-of-therapy response, but this difference was not sustained post treatment. Results of long-term follow-up studies showed that the off-treatment sustainability of response to PEG-IFN was lower in the HBeAg-negative compared to the HBeAg-positive disease. Three years after discontinuation of PEG-IFN alfa-2a therapy, a sustained virological response (HBV DNA < 10,000 copies / mL, six months after treatment discontinuation) proved to be durable in 43% of the initial responders. The rate of HBsAg loss increased to 9%,  [Figure 3].
|Figure 3: (A, B) Pegylated interferon (PEG IFN) alfa-2a in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. In this randomized, controlled trial, the rates of response 24 weeks after therapy (normal ALT level and serum HBV DNA < 20,000 copies / mL) were higher in the two groups that received PEG IFN alfa-2a (with or without lamivudine) than in the group that received lamivudine. There was no difference in response rates between the group that received PEG IFN alfa-2a alone and the group that received the PEG IFN alfa-2a plus lamivudine. (Marcellin P et al., NEJM, 2004)|
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The combination therapy theoretically offers advantages based on a combination of immunomodulatory and antiviral effects, synergistic antiviral effects, and a higher barrier toward resistance. Several studies have assessed whether the addition of first generation nucleos(t)ide analogs to PEG-IFN therapy improves the treatment outcomes. Irrespective of the HBeAg status, the addition of LAM to PEG-IFN has resulted in a higher degree of on-treatment viral suppression, but a similar sustained off-treatment response, compared to PEG-IFN alone. The PEG-IFN alfa-2b and adefovir (ADV) combination therapy has resulted in rates of HBeAg loss and seroconversion, similar to those found in individuals treated with PEG-IFN alone or in combination with LAM. Furthermore, no differences in sustained virological and biochemical response rates have been observed between HBeAg-negative patients treated with PEG-IFN alfa-2a monotherapy and PEG-IFN and the ADV combination therapy. Another study has reported that combining PEG-IFN alfa-2a with the immunomodulatory agent ribavirin (RBV) does not lead to higher response rates for the treatment of HBeAg-negative patients, when compared with the PEG-IFN monotherapy. 
Overall, there is insufficient evidence to suggest the use of a combination of lamivudine or nucleos(t)ide analogs with interferon in patients with chronic hepatitis B.
| Interferon in chronic Hepatitis B: concurrent or sequential?|| |
As majority of patients do not experience a sustained response after one year of PEG-IFN therapy; investigators have attempted to increase the response rates using alternative administration strategies.
As lower baseline HBV DNA levels are associated with a higher probability of response, it has been hypothesized that lowering HBV DNA levels with nucleos(t)ide analogs before commencing PEG-IFN therapy can increase the response rates. So far, results of studies attempting to test this hypothesis have been conflicting and definitive data from adequately powered trials are still awaited.
Sequential therapy with lamivudine 100 mg daily for four weeks followed by Peg IFN alfa 2a 1.0 µg / kg per week for a further 24 weeks compared with Peg IFN alfa 2b monotherapy for 24 weeks, in patients with HBeAg positive chronic HBV infection showed a significantly higher rate of HBV DNA undetectability (50% vs. 14.8%) and higher rates of HBeAg clearance (38.9% vs. 14.8%), six months post therapy.  Another trial assessing different combination regimens for PEG IFN and lamivudine showed that a simultaneous commencement of both tends to provide more profound viral suppression than staggered regimens, in the early phase of the treatment of HBeAg-positive CHB. 
Very few trials have used alternative administration strategies such as sequential therapies, aimed at lowering HBV DNA levels, with nucleos(t)ide analogs prior to interferon therapy. Hence, no definitive recommendation can be made.
In practice - Who to treat
The advantages and limitations of PEG-IFN and nucleos(t)ide analogs should be weighed for every individual patient. PEG-IFN offers a higher chance of a post-therapy-sustained response, but at a higher cost and with considerable side effects. Nucleos(t)ide analogs provide easy daily oral dosing and can maintain adequate viral suppression for prolonged periods, but post treatment, the sustained response can probably not be achieved in a majority of patients. Prolonging treatment with these agents may enhance the chances of HBeAg and HBsAg seroconversion, but pose the risk of viral resistance. Only patients who have a high baseline probability of response to PEG-IFN should be considered for this therapeutic regimen, because the potential benefits may offset the higher costs and side effects.  Non-eligible patients or non-responders to PEG-IFN should be treated with the most potent NA. [Table 2].
|Table 2: General recommendations for the use of PEG-IFN as first-line therapy for HBeAg-positive chronic hepatitis B |
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| Adverse events|| |
Treatment with PEG-IFN is associated with considerable side effects; the most frequently reported are a flu-like syndrome, headache, myalgia, fatigue, and local reactions at the injection site. These symptoms typically present early during therapy, whereas, neuropsychiatric side effects associated with PEG-IFN use, such as mood changes and irritability, without depression, tend to present in the later stages. Hepatitis flares have been reported to occur during PEG-IFN therapy. Especially host-induced flares with elevations in ALT and a decline in HBV DNA levels have been associated with a favorable outcome. PEG-IFN has mild myelosuppressive effects, but PEG-IFN-induced neutropenia and thrombocytopenia result in clinically significant symptoms, including bleeding and infections, in only a select group of patients.
| Predictors of response to ifn|| |
The prediction of response to PEG-IFN at baseline has been challenging and is aptly reflected in the absence of clear recommendations with regard to which patients should be considered as candidates for PEG-IFN therapy. Analysis of the two largest trials investigating the efficacy of PEG-IFN in HBeAg-positive chronic hepatitis B has shown that the response rates are higher in patients with HBV genotypes A and B compared to C and D, and in patients with lower baseline HBV DNA levels or higher baseline ALT levels. In addition to the HBV genotype, lower HBV DNA levels, and higher ALT levels, female sex, older age, and no prior treatment with IFN have also been recognized as significant predictors of response at the baseline. Similarly, baseline predictors of sustained virological response are less well-defined for HBeAg-negative chronic hepatitis B and include younger age, female sex, higher baseline ALT levels, lower baseline HBV DNA concentrations, and HBV genotype [Table 3].
Frequent assessments of HBV DNA levels during treatment are recommended. Nevertheless, prediction of the response based on viral decline during the first months of therapy has been difficulty, and hence, the focus has changed to other measures of viral replicative status, such as, HBeAg and HBsAg level quantification in the serum. 
| Summary|| |
Considerable advances have been made in the treatment of chronic hepatitis B over the past decade. With the availability of new and highly efficacious oral agents, the choice of first-line therapy has become increasingly complex. The importance of the appropriate selection of candidates for interferon therapy cannot be overemphasized. Nevertheless, between conventional versus pegylated interferon, the use of conventional IFN has been largely superseded by pegylated IFN, because of its improved administration schedule, better pharmacokinetics, and higher antiviral potency. In fact, conventional IFN has been dropped from treatment recommendations for chronic hepatitis B (CHB) management in favor of the pegylated form.
There is still insufficient evidence to recommend the combination therapy of nucleos(t)ide analogs with pegylated IFN, by expert panels, although only trials with lamivudine are available to date. No trial is available combining more efficacious nucleos(t)ide analogs with Peg-IFN. The concurrent / sequential use of nucleos(t)ide analogs still remains to be studied.
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Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]