Pegylated interferon for treatment of chronic hepatitis B virus infection

INTRODUCTION — Chronic hepatitis B virus (HBV) infection is a serious liver disorder that can result in cirrhosis, liver failure, and hepatocellular carcinoma. It remains a major global health problem affecting an estimated 316 million persons of whom roughly 550,000 die annually from HBV-related liver disease [1].

Interferons (IFN) have antiviral, antiproliferative, and immunomodulatory effects. Although standard IFN was initially used, it has been replaced by pegylated interferon (PegIFN).

This topic will review the use of IFN-alfa for the treatment of adults with chronic HBV. Topic reviews that provide a more general overview of the treatment of HBV in adults and children are found elsewhere. (See "Hepatitis B virus: Overview of management" and "Management of hepatitis B virus infection in children and adolescents".)

MECHANISM OF ACTION — Although interferon (IFN) has been used as treatment for chronic hepatitis B virus (HBV) infection for 40 years, its exact mechanisms of action are still unclear. IFN is thought to induce specific genes that interfere with several steps in the HBV lifecycle, including: virus entry; uncoating of the virion; transcription of viral DNA into RNA; translation of viral RNA into proteins; and assembly of nucleocapsids [2]. It may also augment cell-mediated immunity, thereby promoting clearance of HBV-infected hepatocytes. Increasing data suggest that NK cells may play an important role in IFN-mediated immune clearance of HBV [3-6]. (See "Characteristics of the hepatitis B virus and pathogenesis of infection", section on 'Replication cycle' and "Characteristics of the hepatitis B virus and pathogenesis of infection", section on 'Pathogenesis of infection'.)

IFN's effect on HBV transcription appears to be partly mediated by epigenetic modifications of the HBV covalently closed circular DNA (cccDNA) minichromosome [7,8]. In addition, IFN can induce degradation of cccDNA by induction of APOBEC3s (DNA editing enzymes) that can degrade foreign, but not host, DNAs and accelerate decay of HBV nucleocapsids [9,10]. These findings may explain why IFN treatment results in a higher rate of hepatitis B e antigen and hepatitis B surface antigen loss, and a more durable response compared with nucleos(t)ide analogue treatment. (See 'Virologic response' below and 'Studies of interferon therapy' below.)

GOALS OF THERAPY

Virologic response — A positive response to interferon (IFN) is characterized by suppression of hepatitis B virus (HBV) DNA and loss of hepatitis B e antigen (HBeAg) (in patients who were initially HBeAg-positive). This is followed by loss of hepatitis B surface antigen (HBsAg) in some patients during the course of follow-up [11-16]. Assessment of off-treatment response is important with IFN treatment, since loss of HBeAg and HBsAg, and seroconversion to hepatitis B e antibody and hepatitis B surface antibody may be delayed. (See 'Monitoring' below.)

Most responders are able to maintain their virologic response after cessation of treatment during follow-up of 5 to 10 years, unless they become immunocompromised [11,17-19]. As examples:

●One of the largest reports with long-term follow-up focused on 165 patients with HBeAg-positive chronic HBV who were treated with IFN between 1978 and 2002 [20]. Response to treatment was defined as HBeAg loss within 12 months after the end of therapy. Patients were followed for a median of 8.8 years. Fifty-four patients (33 percent) responded. Relapse occurred in only seven of the responders (13 percent). Loss of HBsAg during long-term follow-up was observed in 52 percent of responders, compared with only 9 percent of nonresponders.

●Another report focused on 266 patients treated with PegIFN with or without lamivudine, of whom 37 percent lost HBeAg during treatment [14]. Of 172 patients with follow-up data, 81 percent of those who lost HBeAg within 24 weeks of completing a 48-week course of treatment continued to be HBeAg-negative up to three years after cessation of treatment. Loss of HBsAg was achieved in 30 percent of patients who lost HBeAg (58 percent of those with genotype A and only 6 percent with non-A genotypes).

●A third study included a total of 315 patients with HBeAg-negative HBV who were followed for three years after treatment with PegIFN (with or without lamivudine) or with lamivudine alone for 48 weeks [16]. Three years after treatment, the proportion of patients with normal serum alanine aminotransferase (ALT) levels was significantly higher in patients treated with PegIFN (31 versus 18 percent). Similarly, more patients treated with PegIFN achieved HBV DNA levels of ≤10,000 copies/mL (approximately 2000 international units/mL) (28 versus 15 percent) and HBsAg loss (9 versus 0 percent). This study found that approximately 25 percent of HBeAg-negative patients treated with PegIFN for 48 weeks had a durable response when virologic response was defined as HBV DNA ≤10,000 copies/mL (approximately 2000 international units/mL) and approximately 14 percent had a durable response when virologic response was defined as HBV DNA ≤400 copies/mL (approximately 80 international units/mL).

●In a study that examined long-term durability of IFN-induced HBsAg loss in 238 patients followed for a median of 160 weeks after treatment cessation, cumulative relapse (reappearance of HBsAg and/or HBV DNA on at least two occasions four to eight weeks apart), ranged from 0.84 percent at 26 weeks to 9.66 percent 597 weeks after treatment cessation [21].

Disappearance of HBV DNA in serum, as determined by polymerase chain reaction (PCR) assay, occurs in 50 to 100 percent of patients who clear both HBeAg and HBsAg. This usually occurs at the time the patient becomes HBsAg-negative; disappearance of HBV DNA is seldom achieved in patients who clear HBeAg but remain HBsAg-positive [11]. Although IFN is associated with a higher rate of HBsAg loss compared with nucleos(t)ide analogues, loss of HBsAg occurs in only 5 to 10 percent of patients who receive PegIFN when assessed 24 weeks after completing a one-year course [2]. In addition, it is rarely observed in Asian patients and those infected with non-A genotypes [19,22].

Patients treated with combination therapy of PegIFN and lamivudine are significantly more likely to achieve a virologic response (eg, HBV DNA suppression, HBeAg seroconversion, and HBsAg loss) compared with those treated with lamivudine monotherapy, but responses are similar to those treated with PegIFN monotherapy [23-25]. More detailed descriptions of the trials evaluating the efficacy of IFN are found below. (See 'Pegylated interferon with or without lamivudine' below.)

Clinical response — A sustained viral response, particularly in those who clear both HBeAg and HBsAg, is almost invariably accompanied by normalization of ALT, a decrease in necroinflammatory activity, and overtime a decrease in fibrosis as well [26]. However, residual damage, as manifested by portal inflammation and fibrosis, may still be present [20,27].

Available data from long-term follow-up studies suggest there is a decreased incidence of HCC, and improved overall survival and survival free of hepatic decompensation among patients who received IFN [12,15,28-30]. However, data are scant, since in most studies the duration of follow-up was short. In addition, these benefits were mainly observed in patients who achieved a sustained response [12,15,17,20,28,31,32].

The benefits of IFN on HCC have also been demonstrated by several meta-analyses [33-36]. In one analysis, the relative risk of HCC among those treated with interferon compared with those who were untreated was 0.59 (95% CI 0.43-0.81) [34]. Meta-analysis of studies including IFN-containing regimens found a 30 to40 percent reduction in HCC risk compared to untreated patients [33,34].

WHOM TO TREAT — The decision to initiate antiviral therapy for the treatment of chronic hepatitis B virus infection (HBV) is primarily based upon the presence or absence of cirrhosis, the alanine aminotransferase (ALT) level, and the HBV DNA level (table 1). A detailed discussion of the indications for antiviral therapy is found elsewhere.

Selection of patients — For individuals who require treatment of chronic HBV infection, PegIFN should be considered as an option for treatment-naïve, immunocompetent patients. Contraindications to IFN are discussed below. (See 'Contraindications' below.)

PegIFN may be most suitable for patients who desire a finite duration of treatment (eg, young adults and women planning to conceive in the future), particularly if they are HBeAg-positive and are infected with HBV genotype A, and if a week 12 stop rule will be applied. However, interferon has been associated with more side effects compared with nucleos(t)ide analogues. Thus, the decision to use PegIFN or a nucleos(t)ide analogue as primary therapy should be made after careful discussion with the patient. (See 'Predictors of response' below and 'Response to treatment' below and 'Adverse reactions' below and "Hepatitis B virus: Overview of management", section on 'Choice of initial agent'.)

Predictors of response — In general, antiviral therapy for HBV is most likely to benefit patients with active liver disease (elevated serum ALT concentration or chronic hepatitis on liver biopsy) and HBV DNA levels >20,000 international units/mL for hepatitis B e antigen (HBeAg)-positive patients and >2000 international units/mL for HBeAg-negative patients (table 1). (See "Hepatitis B virus: Overview of management".)

In addition, a number of other factors have been found to predict response with PegIFN [23,37-47]. For patients who are HBeAg positive, predictive factors include:

●Genotype A; this genotype is associated with a higher rate of HBeAg seroconversion and HBsAg clearance than genotypes B, C, or D

●Viral load <2 x 10⁸ international units/mL

●Pretreatment serum ALT level >2 times the upper limit of normal

●Rapid decline in HBsAg level during the first 12 to 24 weeks of treatment

An illustrative study of the predictive value of pretreatment factors included a total of 721 patients who received PegIFN in two previous trials [23,38,41]. The likelihood of sustained HBeAg loss (defined as undetectable HBeAg and HBV DNA levels <2000 international units/mL six months after stopping treatment) could be predicted by pretreatment levels of HBV DNA and ALT and the HBV genotype [41]. The likelihood of response varied across these predictors, ranging from as high as 54 percent in patients with genotype A, an ALT ≥2 times the upper limit of normal, and an HBV DNA <9 log copies/mL (<2 x 10⁸ international units/mL), to as low as 7 percent in patients with HBV genotype D, an ALT level ≤2 times the upper limit of normal, and an HBV DNA of ≥9 log copies/mL. The predictive accuracy of these observations requires additional validation.

One study reported long-term follow-up of 267 HBeAg-positive patients treated with standard or PegIFN followed for a median of 11.5 years [48]. The 5- and 10-year cumulative incidence of HBsAg loss were 14 and 32 percent, respectively. Baseline factors associated with a higher rate of HBsAg loss were male sex, White race, genotype A, age ≥40 years, and cirrhosis. Both HBeAg loss and HBsAg loss were associated with improvement in clinical outcomes. Data in similar untreated patients are not available for comparison.

Predictors of response to PegIFN in HBeAg-negative patients have been described but have not been confirmed:

●One study found that a marked elevation in serum ALT (>10 times the upper limit of normal or more than 300 U/L) levels during therapy was predictive of a normal ALT and histologic improvement six months after stopping PegIFN therapy [24].

●Polymorphisms of IL28B have been shown to be strong predictors of response to PegIFN in patients with chronic hepatitis C. The favorable variant rs12979860 (C versus T) in the IL28B region was shown to be associated with a higher rate of sustained response to PegIFN in a study of HBeAg-negative chronic HBV [49], but the predictive value of IL28B in hepatitis B studies is inconsistent.

In contrast, studies suggest that IFN is not effective for the following groups:

●HBeAg+, HBV DNA+, with normal serum ALT – IFN treatment is not warranted in these patients since the response rate is less than 10 percent [50-53]. This profile is frequently seen in Asian patients, particularly in children who were infected perinatally.

Although an initial study suggested that Asian patients who were HBeAg+ and HBV DNA+ responded poorly to IFN treatment [51], a subsequent trial found that Chinese adults with elevated serum ALT levels responded to IFN at a similar rate as White patients (39 percent) [52].

●HBeAg-, HBV DNA undetectable or low (<2000 international units/mL), with normal ALT levels – These inactive carriers do not require treatment unless there is evidence of cirrhosis since virus replication is low and liver inflammation is inactive. These patients should be monitored to make sure they are in the inactive state as patients with HBeAg-negative chronic hepatitis may also have intermittently undetectable HBV DNA and normal ALT.

Contraindications — IFN should not be used in patients with the following comorbid conditions given the potential for adverse reactions (see 'Adverse reactions' below):

●Decompensated cirrhosis because there is a high risk of serious infections and hepatic failure [54,55]. IFN treatment appears to be safe and effective for patients who have cirrhosis but no clinical or biochemical evidence of decompensation or signs of portal hypertension. However, caution must still be exercised, as decompensation can occur in patients who develop ALT flares during treatment.

●A history of suicidal tendency or active psychiatric illness.

●Autoimmune illness.

●Severe leukopenia or thrombocytopenia.

●Concurrent severe systemic (eg, cardiopulmonary) disorders.

In addition, IFN should not be used in women who are pregnant given concerns for pregnancy loss [56]. Thus, women of childbearing potential should have pregnancy tests throughout the course of treatment (table 2). (See "Hepatitis B and pregnancy", section on 'Safety of antiviral agents in pregnancy'.)

TREATMENT REGIMEN — PegIFN-alfa 2a should be given at a dose of 180 mcg once weekly for 48 weeks. The approach to treatment is described in the figure (algorithm 1). PegIFN has replaced standard IFN. The attachment of polyethylene glycol to standard IFN (pegylation) reduces its rate of absorption following subcutaneous injection as well as its renal and cellular clearance and immunogenicity. These effects enhance the half-life of PegIFN, allowing it to be dosed once a week.

Alternative regimens to enhance the efficacy of PegIFN are being evaluated. These include combining PegIFN with nucleos(t)ide analogues [57-61], extending the duration of treatment in hepatitis B e antigen (HBeAg)-negative patients [38], and adding PegIFN or switching to PegIFN after hepatitis B virus (HBV) DNA has been suppressed with nucleos(t)ide analogues. Although studies suggest some benefit, there is insufficient evidence to incorporate these approaches into routine care. More detailed descriptions of these studies are found below. (See 'Pegylated interferon with or without lamivudine' below and 'Combination with other nucleos(t)ide analogues' below.)

MONITORING — Patients receiving interferon (IFN) therapy should be assessed for evidence of toxicity, as well as for virologic, serologic, and biochemical response both during treatment and after therapy has been completed [62]. We monitor patients at weeks 4, 12, 24, 36, and 48 during treatment, and weeks 12, 24, and 48 post treatment (table 2).

Response to treatment — Several endpoints are used to assess the efficacy of hepatitis B treatment (table 3).

●Hepatic panel – A hepatic panel should be obtained at baseline and all assessment visits (table 2). Because alanine aminotransferase (ALT) flares are common during IFN treatment, the biochemical response to treatment is generally assessed using data obtained 6 and 12 months after completion of IFN treatment.

●HBV DNA – We check the hepatitis B virus (HBV) DNA at baseline, at week 12, and then at all other assessment visits.

●HBeAg and anti-HBe – For hepatitis B e antigen (HBeAg)-positive patients, we check HBeAg and hepatitis B e antibody (anti-HBe) at baseline, week 24 and 48 on treatment, and then every 12 to 24 weeks until 48 weeks post treatment.

●HBsAg – Hepatitis B surface antigen (HBsAg) should be measured in patients who were HBsAg-positive, and have undergone HBeAg seroconversion, and in HBeAg-negative patients with an undetectable HBV DNA. For such patients we monitor the HBsAg at baseline, at week 48, and then again at weeks 24 and 48 weeks post treatment.

If quantitative HBsAg testing is available, this should be measured at 12 weeks, since on-treatment declines in the HBsAg level at 12 weeks are associated with a favorable response. Studies have found that a lack of, or an insufficient decline in, HBsAg level after 12 weeks of PegIFN is associated with a high negative predictive value (>95 percent) of off-treatment response [39,63-72]. This has prompted suggestions to use a week 12 HBsAg response as a stop rule to avoid futile treatment and to minimize cost and adverse events [73].

However, there is no unified stop rule that can be applied to all HBV genotypes, and the proposed stop rules have not been validated in prospective studies.

Adverse reactions — Adverse events associated with IFN therapy can be severe and may require dose reduction or discontinuation of treatment. The major side effects of IFN include an initial flu-like syndrome, which occurs in approximately 90 percent of patients [2]. Other side effects include fatigue, anorexia and nausea, diarrhea, weight loss, hair loss, emotional lability and depression, bone marrow suppression, and induction of autoantibodies, which can result in thyroid abnormalities in up to 30 percent of patients, or enhancement of autoimmune diseases [74,75].

In addition to clinical assessment, we obtain the following laboratory tests to assess adverse events:

●Complete blood count with differential at all assessment visits (table 2).

●Thyroid stimulating hormone at baseline, weeks 12, 24, and 48 on treatment, and week 12 post treatment.

Hepatitis flares — IFN therapy is associated with flares (at least twofold increase over baseline) in serum ALT concentrations in 30 to 50 percent of patients [76]. This response is thought to reflect immune-mediated lysis of infected hepatocytes and may be considered an indicator of a favorable response. (See "Characteristics of the hepatitis B virus and pathogenesis of infection".)

To monitor for flares, we obtain a hepatic panel at baseline and all assessment visits (table 2). In general, IFN should be continued in patients with hepatitis flares. However, treatment may need to be discontinued or IFN dose reduced if the flare is severe and accompanied by symptoms or an increase in the serum bilirubin concentration, addition of nucleos(t)ide analogues may ameliorate these severe flares though supporting evidence is lacking.

In one study, the pattern of HBV DNA surrounding the flare was highly predictive of the likelihood of achieving loss of HBeAg. In this trial that compared PegIFN alfa-2b with or without lamivudine in HBeAg-positive patients, 67 patients (25 percent) experienced a total of 75 hepatitis flares with approximately similar rates in the combination and monotherapy groups [77]. There was no significant difference in the rates of HBeAg loss among those with and without a flare. However, flares that occurred after an increase in HBV DNA levels (referred to as "virus-induced" flares because they probably reflect increased expression of viral antigens) were not associated with HBeAg loss. In contrast, flares that were followed by a decrease in HBV DNA titers (referred to as "host-induced" flares because they likely reflect immune mediated lysis of infected hepatocytes) were significantly associated with HBeAg loss (58 percent compared with 20 percent for virus-induced flares). Loss of HBsAg was observed only in patients with a host-induced flare.

TREATMENT OF NONRESPONDERS — The optimal treatment of patients who do not respond to a course of interferon include observation or treatment with a nucleos(t)ide analogue. A second course of interferon (IFN) is generally not recommended. For those who are treated with a nucleos(t)ide analogue, entecavir and tenofovir are preferred. Existing studies indicate that these patients respond just as well as those who are IFN-naïve. (See "Hepatitis B virus: Overview of management".)

STUDIES OF INTERFERON THERAPY — Multiple studies have evaluated the efficacy of interferon (IFN) therapy for treatment of chronic HBV. The initial studies used standard interferon-alfa; however, this agent is no longer available for clinical use.

Standard interferon — The use of standard interferon-alfa is effective in improving virologic outcomes in patients with chronic hepatitis B virus infection (HBV). However, for those who are hepatitis B e antigen (HBeAg) negative, relapse is common after cessation of treatment. Several studies in IFN-naïve or IFN-experienced patients have compared the combination of standard IFN and lamivudine with IFN or lamivudine monotherapy.

●HBeAg-positive – Multiple studies have evaluated the efficacy of standard IFN in HBeAg-positive chronic HBV [78]. The following benefits were found in a meta-analysis of studies comparing treatment with standard IFN for three to six months with placebo (with all estimates reported after 6 to 12 months of post-treatment follow-up) [78]. Although standard IFN is no longer used, data from these early studies provide evidence of a beneficial effect of IFN compared with no treatment.

•More frequent loss of viral replication markers (HBeAg) – 33 versus 12 percent with placebo

•More frequent loss of HBV DNA (by hybridization assay) – 37 versus 17 percent

•More frequent loss of hepatitis B surface antigen (HBsAg) – 7.8 versus 1.8 percent

•The treated patients were also much more likely to seroconvert to hepatitis B e antibody and to show normalization in alanine aminotransferase (ALT) levels.

●HBeAg-negative – Treatment with standard IFN in patients who are HBeAg-, HBV DNA+, with elevated serum ALT (many of whom are infected with a precore variant) has been associated with a decrease in serum HBV DNA and ALT levels, but relapse is common after cessation of treatment [79,80]. A longer course of therapy (24 months) appeared to be more effective in inducing a sustained response [31,81]. (See 'Treatment regimen' above.)

Pegylated interferon with or without lamivudine — Pegylated interferon (PegIFN) has replaced standard interferon because it is associated with higher rates of response and requires less frequent dosing [47,82]. (See 'Treatment regimen' above.)

Approval of PegIFN alfa-2a was based upon two studies in patients with HBeAg-positive and HBeAg-negative chronic HBV where PegIFN was compared with lamivudine or combination therapy with PegIFN plus lamivudine [23,24]. In the trials described in this section, PegIFN and lamivudine were started simultaneously in the combination therapy group. Overall, these studies did not show a benefit of combination therapy compared with PegIFN monotherapy in inducing off-treatment virologic response or loss of HBeAg and HBsAg. However, combination therapy did decrease the emergence of lamivudine-resistant HBV compared with lamivudine monotherapy. Similar findings were found in trials evaluating PegIFN-alfa-2b.

●HBeAg-positive

•In the licensing trial for PegIFN alfa-2a, 814 patients with HBV DNA >500,000 copies/mL (approximately 100,000 international units/mL) and ALT 1 to 10 times the upper limit of normal were randomly assigned to PegIFN alfa-2a (180 mcg once weekly) alone, or in combination with lamivudine (100 mg daily), or to lamivudine monotherapy [23]. Patients were treated for 48 weeks and assessed after 24 weeks of follow-up.

At week 72, all endpoints were significantly more likely to be reached in the two groups receiving PegIFN alfa-2a compared with the group that received lamivudine monotherapy. Endpoints for the PegIFN groups (monotherapy and combination therapy) compared with the group that received lamivudine monotherapy were as follows: HBeAg seroconversion in 32 and 27 versus 19 percent; HBV DNA <100,000 copies/mL (approximately 20,000 international units/mL) in 32 and 34 versus 22 percent; HBeAg loss in 34 and 28 versus 21 percent; and ALT normalization in 41 and 39 versus 28 percent. Eight patients in each of the two groups who received PegIFN, but none in the lamivudine monotherapy group, lost HBsAg.

Serious adverse events occurred in 4 percent, 6 percent, and 2 percent of patients and in the groups that received PegIFN monotherapy, combination therapy, and lamivudine monotherapy, respectively. Among those who received lamivudine monotherapy, two patients developed liver failure after cessation of treatment, and at week 48, lamivudine-resistant mutations were detected in 27 percent (compared with 4 percent in the combination therapy group).

•The dose and duration of PegIFN alfa-2a were supported in a trial that compared 90 versus 180 mcg weekly doses of PegIFN alfa-2a given for 24 or 48 weeks [63]. The study included 544 patients (mostly Asians with genotypes B or C) randomly assigned to one of four treatment arms. HBeAg seroconversion rate was highest in the 48-week 180 mcg group (36 percent) compared with 26 percent for the 48-week 90 mcg group, 23 percent in the 24-week 180 mcg group, and 14 percent in the 24-week 90 mcg group. The 24-week duration of treatment was significantly inferior to the 48-week duration, and the 90 mcg dose was significantly inferior to the 180 mcg dose. It is unclear if these results apply to patients with adult-acquired infection or genotype A infection.

•The use of PegIFN alfa-2b was evaluated in a trial that included 266 patients who were randomly assigned to receive PegIFN alfa-2b with lamivudine (100 mg daily) or placebo for 52 weeks [38]. The PegIFN dose was 100 mcg weekly for the first 32 weeks and 50 mcg weekly from week 32 to 52. At week 78, the proportion of patients achieving HBeAg loss was similar in the monotherapy and combination therapy groups (36 versus 35 percent). The response rates were also similar with regards to suppression of HBV DNA and changes in serum aminotransferase levels. However, HBeAg loss occurred more commonly in patients infected with HBV genotype A (47 percent) or B (44 percent) than those infected with genotype C (28 percent) or D (25 percent), and in those with host-induced hepatitis flares during treatment.

Long-term follow-up of 172 (65 percent) patients at a mean of 3.0±0.8 years after completion of the initial trial found that 37 percent had lost HBeAg and 11 percent had lost HBsAg [14]. Among the initial responders, 81 percent had sustained HBeAg loss and 30 percent had HBsAg loss.

•In another trial, 100 Chinese patients were randomly assigned to either PegIFN-alfa-2b (1.5 mcg/kg per week, maximum 100 mcg) for 32 weeks plus lamivudine (100 mg daily) for 52 weeks or lamivudine monotherapy for 52 weeks [25]. The rate of sustained response (defined as HBeAg seroconversion and HBV DNA level <500,000 copies/mL [approximately 100,000 international units/mL] at least 24 weeks after the end of treatment) was significantly higher in the combination therapy group (36 versus 14 percent). There were no significant differences in the proportion of patients with normalization of serum ALT or histologic improvement. Lamivudine-resistant mutations were detected more often in the monotherapy group compared with the combination therapy group (40 versus 21 percent). A follow-up report found that the overall rate of HBeAg seroconversion increased to 60 percent by year 5 post treatment, and two patients had lost HBsAg [19].

●HBeAg-negative

•The licensing trial for HBeAg-negative patients included a total of 537 patients who were randomly assigned to receive PegIFN alfa-2a (180 mcg weekly) plus placebo or lamivudine (100 mg daily), or lamivudine monotherapy for 48 weeks [80]. Approximately two-thirds of patients were Asian, and 22 to 31 percent had bridging fibrosis or cirrhosis. After 24 weeks of follow-up, the percentage of patients with normalization of serum ALT levels or HBV DNA levels below 20,000 copies/mL (approximately 4000 international units/mL) was significantly higher in those who received PegIFN monotherapy or combination therapy compared with lamivudine monotherapy. Rates of sustained suppression of HBV DNA to below 400 copies/mL (approximately 80 int. units/mL) were also significantly higher in the PegIFN monotherapy or combination therapy groups compared with lamivudine monotherapy (19 and 20 versus 7 percent, respectively). Loss of HBsAg occurred in seven patients in the PegIFN monotherapy group and five in the combination therapy group compared with none in the lamivudine group.

A subsequent report described outcomes of patients with follow-up for up to three years post-treatment [25]. The proportion of patients with a normal ALT was significantly higher with PegIFN monotherapy or combination therapy with lamivudine compared with lamivudine alone (31 and 31 versus 18 percent, respectively). HBV DNA levels ≤10,000 copies/mL (approximately 2000 international units/mL) were also more likely in those who received PegIFN monotherapy or combination therapy compared with lamivudine monotherapy (28 and 25 versus 15 percent, respectively). HBsAg loss occurred in 8 percent in each of the two groups that received PegIFN but none in the lamivudine monotherapy group.

These data indicate that 25 to 30 percent of patients with HBeAg-negative chronic HBV had sustained biochemical/clinical remission after a one-year course of PegIFN. However, only 59 percent of patients entered the long-term follow-up study. Intention to treat analysis, including all patients in the original trial, showed that ALT normalization was observed in only 20 percent of patients who received PegIFN monotherapy, 20 percent of those who received combination therapy, and with 8 percent of those who received lamivudine. Similarly, HBV DNA levels ≤10,000 copies/mL (approximately 2000 international units/mL) were observed in 18 and 16 versus 7 percent of these groups, respectively.

•A second trial explored the benefits of extending the duration of PegIFN to 96 weeks [38]. In this trial, 128 patients with HBeAg-negative chronic HBV genotype D were randomly assigned to one of three treatment arms: PegIFN alfa-2a (180 mcg weekly) for 48 weeks, PegIFN alfa-2a (180 mcg weekly) for 48 weeks followed by 135 mcg weekly for an additional 48 weeks, or combination of PegIFN alfa-2a (180 mcg weekly) and lamivudine (100 mg/day) for 48 weeks followed by PegIFN alfa-2a (135 mg weekly) for 48 weeks. At 48-week post-treatment follow-up, a higher proportion of patients who received PegIFN monotherapy for 96 weeks achieved a virological response (HBV DNA <2000 international units/mL: 29 versus 12 percent) compared with those who received PegIFN for only for 48 weeks. Combination treatment was not associated with a higher virological response as compared with PegIFN alfa-2a alone, but only 13 patients in the combination treatment group completed follow-up. There were no significant differences in adverse events or discontinuation rates in the two groups that received PegIFN monotherapy. Nevertheless, given the higher costs, the clinical benefits of extended therapy with PegIFN alfa-2a need to be validated in larger studies.

●The efficacy of PegIFN in patients with lamivudine-resistant M204V/I mutations has not been well studied. In one study of 16 patients who received PegIFN, only two patients underwent HBeAg seroconversion and achieved sustained virologic suppression and ALT normalization [83]. However, in a randomized study, where HBeAg-positive patients with lamivudine resistance received lamivudine for 12 weeks in conjunction with either PegIFN for 48 weeks (n = 155) or adefovir for 72 weeks (n = 80), significantly more patients treated with PegIFN achieved HBeAg seroconversion six months after treatment (15 versus 4 percent) [84]

Combination with other nucleos(t)ide analogues — Different strategies of combining PegIFN and nucleos(t)ide analogues have been proposed. Most studies have adopted an approach that involves the simultaneous start of both PegIFN and nucleos(t)ide analogues to simplify the study design. However, others have adopted an add-on or sequential approach, where patients start a nucleos(t)ide analogue first and PegIFN is then added or nucleos(t)ide analogues are initiated and the patient is then switched to PegIFN; these approaches are based on the rationale that IFN may be more effective in patients with lower levels of viremia.

A meta-analysis of these different strategies included 33 studies of de novo combination therapy, 15 studies of add-on therapy, and 12 studies of switch therapy [85]. Compared with nucleos(t)ide analogue monotherapy, de novo combination therapy improved the probability of HBeAg loss (relative risk [RR]1.62, 95% CI 1.33-1.97) and HBsAg loss (RR 15.59, 95% CI 3.22-75.49), but rates of HBeAg loss and HBsAg loss were similar to that of IFN monotherapy. When IFN was added on to nucleos(t)ide analogue therapy or nucleos(t)ide analogue therapy was switched to IFN, there was also improved HBsAg loss compared with nucleos(t)ide analogue monotherapy (RR 4.52 [95% CI 1.95-10.47] and RR 12.15 [95% CI 3.99-37.01], respectively). By contrast, when IFN was switched to a nucleos(t)ide analogue, there was no improvement in HBsAg loss compared with nucleos(t)ide analogue monotherapy, although the rates of achieving undetectable HBV DNA and HBeAg loss were higher.

●PegIFN and entecavir

•In a randomized, open-label study, 218 treatment-naïve Chinese HBeAg-positive patients were randomized to receive 48 weeks of PegIFN alfa2a (180 mcg weekly) alone, or with 24 weeks of entecavir (0.5 mg daily) added prior to or after initiation of PegIFN [57]. HBeAg seroconversion assessed 24 weeks post-treatment was 31 percent in PegIFN monotherapy group, 25 percent in entecavir add-on group, and 26 percent in the entecavir pre-treatment group indicating a short course of entecavir administered in the manner designed in this study did not offer any additional benefit.

•In another randomized, open-label study, 175 HBeAg-positive patients receiving entecavir monotherapy (0.5 mg daily) were randomized to receive add-on PegIFN alfa2a (180 mcg weekly) from week 24 to 48 or to continue entecavir monotherapy [58]. Responders (those with HBeAg loss and serum HBV DNA <200 international units/mL at week 48) discontinued entecavir at week 72 and all patients were followed to week 96. Although response was more common in the PegIFN add-on group compared with those who received entecavir monotherapy, the differences were not significant at week 48 (19 versus 10 percent) or at week 96 (31 versus 20 percent).

•In a third study, 200 patients who were HBeAg-positive and had received entecavir (0.5 mg daily) for 9 to 36 months, with HBeAg <100 PEIU/mL and HBV DNA <1000 copies/mL (approximately 200 international units/mL), were randomized to continue entecavir monotherapy or to switch to PegIFN alfa 2a (180 mcg weekly) for 48 weeks, after an eight-week overlap with entecavir [59]. At 48 weeks, patients switched to PegIFN had significantly higher rates of HBeAg seroconversion compared with those who continued entecavir monotherapy (14.9 versus 6.1 percent). In addition, eight patients switched to PegIFN, but none who continued entecavir monotherapy cleared HBsAg. Although the results of this study appear encouraging, the patients included were highly selected since all had low HBeAg titers and roughly 50 percent in each group had already lost HBeAg at the time of randomization.

62 patients who completed 48 weeks of PegIFN alfa-2a therapy were followed up for 48 weeks off treatment [60]. At one year post treatment, the HBeAg seroconversion rate increased from 18 percent post-treatment to 39 percent. In addition, sustained HBsAg loss was documented in six of seven patients, and sustained HBV DNA suppression was achieved in 27 of 45 (60 percent) with an end-of-treatment response. While these results were impressive, follow-up data of patients who continued entecavir were not provided; thus, it is not possible to conclude if switching to PegIFN offered any advantage.

•In a fourth study, 77 HBeAg-positive patients with compensated liver disease who were treated with entecavir or tenofovir disoproxil fumarate (TDF) for >12 months and had a serum HBV DNA <2000 international units/mL were randomized to continue monotherapy with entecavir or TDF, or to receive add-on therapy with PegIFN for 48 weeks [86]. At 96 weeks, those receiving add-on therapy achieved HBeAg seroconversion and HBV DNA suppression to <200 international units/mL more frequently (18 versus 8 percent), although this difference was not statistically significant.

●PegIFN and tenofovir – In a randomized trial of 751 patients (58 percent HBeAg-positive), individuals received one of four regimens: (A) tenofovir (300 mg daily) plus PegIFN alfa2a (180 mcg weekly) for 48 weeks, (B) tenofovir plus PegIFN for 16 weeks followed by tenofovir alone for 32 weeks, (C) tenofovir monotherapy for 120 weeks, and (D) PegIFN monotherapy for 48 weeks [61]. A significantly greater proportion of patients receiving combination therapy for 48 weeks had HBsAg loss at 72 weeks compared with those receiving monotherapy with tenofovir or PegIFN (HBsAg loss was achieved in 9.1, 2.8, 0, and 2.8 percent patients in groups A to D, respectively). HBsAg loss occurred more commonly in HBeAg-positive patients and in those with genotype A infection. These data suggest the combination of PegIFN and tenofovir may enhance rate of HBsAg loss, but the benefit is mainly observed in patients infected with HBV genotype A. In a follow-up study, there was little to no further increase in HBsAg loss at 120 weeks, with rates of HBsAg loss in groups A to D being 10, 3.5, 0, and 3.5 percent, respectively [87].

●PegIFN and adefovir – One trial evaluated 24 patients (HBeAg-positive or HBeAg-negative) treated with 48 weeks PegIFN plus adefovir followed by 96 weeks of adefovir monotherapy [88,89]. At week 144, 12 of 15 patients who were HBeAg-positive had lost HBeAg while ALT levels normalized in 23 patients, and histologic improvement was observed in 11 of 16 patients who had follow-up liver biopsies. Two patients developed adefovir resistance. Although the results appeared promising, very few patients were studied and adefovir has weak antiviral activity; thus, this combination is not recommended.

●PegIFN and telbivudine – This combination should not be used. A randomized trial designed to enroll 300 HBeAg-positive patients who would receive telbivudine alone or with PegIFN alfa-2a, and PegIFN alfa-2a alone was terminated early because of serious adverse events with peripheral neuropathy occurring in 1/54, 7/50, and 0/54 patients, respectively [90]. Although myopathy, peripheral neuropathy, and increased creatine kinase levels had been observed in patients receiving telbivudine monotherapy, the addition of PegIFN appeared to increase the risk of peripheral neuropathy.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of hepatitis B".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Hepatitis B (The Basics)")

●Beyond the Basics topic (see "Patient education: Hepatitis B (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Chronic hepatitis B virus (HBV) infection is a serious liver disorder that can result in cirrhosis, liver failure, and hepatocellular carcinoma. It remains a major global health problem affecting an estimated 316 million persons of whom roughly 550,000 die annually from HBV-related liver disease. (See 'Introduction' above.)

●Interferon (IFN)-alfa is thought to induce specific IFN-stimulated genes that inhibit HBV transcription. IFN's effect on HBV transcription appears to be partly mediated by epigenetic modifications of the HBV covalently closed circular DNA minichromosome. (See 'Mechanism of action' above.)

●A positive response to IFN is usually defined as the loss of serum HBV DNA, and hepatitis B e antigen (HBeAg) (in patients who were HBeAg-positive), followed by loss of hepatitis B surface antigen (HBsAg) in some patients. Assessment of off-treatment response is important with IFN treatment, since loss of HBeAg and HBsAg may be delayed. A successful virologic response is usually associated with decreased necroinflammatory activity, reduced liver damage, and decreased incidence of hepatocellular carcinoma. (See 'Goals of therapy' above.)

●Pegylated IFN (PegIFN) should be considered as a treatment option for adult patients with chronic HBV infection. IFN may be most suitable for patients who desire a finite duration of treatment, such as young adults, and women who are planning to conceive in the future, since IFN has been associated with more side effects compared with nucleos(t)ide analogues. (See 'Selection of patients' above.)

●IFN is most likely to benefit patients with replicative infection (HBV DNA levels >20,000 international units/mL for HBeAg-positive patients and >2000 international units/mL for HBeAg-negative patients) and active liver disease (serum alanine aminotransferase >2 times the upper limit of normal or chronic hepatitis on liver biopsy). Among such patients who are HBeAg-positive, those who are genotype A and have an HBV DNA <2 x 10⁸ international units/mL are more likely to have a favorable response. (See 'Predictors of response' above.)

●IFN is contraindicated in patients with decompensated cirrhosis, a history of suicidal tendency or active psychiatric illness, autoimmune illness, severe leukopenia or thrombocytopenia, and concurrent severe systemic disorders. In addition, IFN should not be used in women who are pregnant given concerns for pregnancy loss. (See 'Contraindications' above.)

●PegIFN-alfa 2a should be administered subcutaneously at a dose of 180 mcg once weekly for 48 weeks. The approach to treatment is described in the figure (algorithm 1). (See 'Treatment regimen' above.)

●Patients receiving IFN therapy should be assessed for evidence of toxicity, as well as for virologic, serologic, and biochemical response both during treatment and after therapy has been completed. We monitor patients at weeks 4, 12, 24, 36, and 48 during treatment, and weeks 12, 24, and 48 post treatment (table 2). (See 'Monitoring' above.)

●Patients who do not respond to IFN can be treated with nucleos(t)ide analogues. Entecavir and tenofovir are preferred. Existing studies indicate that these patients respond just as well as those who are IFN-naïve. (See 'Treatment of nonresponders' above.)